Mbx Biosciences Inc Aktie

Greetings, and welcome to the MBX Biosciences Business Update Call. [Operator Instructions]. As a reminder, this conference is being recorded.

I would now like to turn the conference over to your host, Mr. Kent Hawryluk, President, CEO and Co-Founder of MBX Biosciences. Please go ahead, sir.

Good morning, and thank you for joining us to review the once-weekly Canvuparatide 1-year data from the Phase II open-label extension study. I am Kent Hawryluk, President and CEO of MBX. I want to remind everyone that this presentation includes forward-looking statements. I encourage you to review the risk factors and other disclosures in our most recent SEC filings available on the MBX website. I'm pleased to be joined today by esteemed colleagues, including Dr. Richard DiMarchi, MBX Scientific Co-Founder and my business partner for the past 23 years. Richard and I started MBX with a sense of urgency to give back freedom to people with hypoparathyroidism through a PTH replacement therapy that's patient-friendly and once weekly just as patients have today in major diseases but not yet in HP, a product profile that frees patients from the daily burden of their disease and which patients and HCPs tell us will be their preferred choice.

MBX has expanded significantly in endocrine and metabolic diseases, while our focus remains squarely on helping transform the lives of people impacted by these diseases. We do that through novel precision peptides designed to provide consistent, steady drug exposure so important in treatment. Our 1-year data demonstrates sustained benefit of once-weekly Canvuparatide as a potential best-in-class PTH replacement therapy in chronic HP. It's in line with our expectations as we communicated and includes strong safety and tolerability.

It also demonstrates the translation of [ Canvu's ] precision endocrine peptide design to clinical outcomes and provides important reinforcement of our Phase III study design. And the HP community is very excited that we're on track to start enrolling patients in Q3. The program for today is an overview of [ Canvu ] from its inventor, Dr. DiMarchi, a clinical perspective on the HP landscape and unmet need from Dr. Michael T. Collins. A presentation of the 1-year data from our CMO, Dr. Sam Azoulay, and will be followed by concluding remarks and the Q&A session.

I will now turn it over to Richard.

This is Richard. Thank you for the invitation to participate. I'm coming to you from my office in the chemistry building at Indiana University, where I had been for the last 23 years. The next slide in this presentation, the first in my section captures a century of progress in peptide therapeutics, reaching back to that landmark discovery of animal-sourced human insulin and focuses most importantly on the last half century, something that I have personally participated having arrived at Lilly in 1980 as we were in the midst of the production of human insulin by biosynthetic methods.

That method allowed us to get control of the chemistry such that we could begin to optimize the molecule much as historical medicinal chemist had optimized antibiotics, oncolytics, anti-hypertensives. It was something that was viewed with some skepticism in the large molecule community, macro molecules, peptides, proteins and Lispro insulin as you see in 1996 was the first registered product that was purposefully optimized. It's a molecule I designed during my tenure at Lilly. And it grew to be the most popular insulin at its peak, demonstrating that chemistry can generate a better medicine.

FORTEO, the N-terminal 34 amino acid fragment of the endogenous parathyroid hormone was registered as a bolus administration, sharp up, down within 1 hour for treating osteoporosis. And then on into the transformative ability to manage type 2 diabetes and even more so obesity that we've witnessed over the last 2 decades using chemistry to achieve something that could not be achieved with the native hormone. Byetta twice a day, Victoza once a day, Trulicity the first effective once-a-week treatment for type 2 diabetes and then on into Ozempic, Zepbound and more to come.

Next slide. This slide just indicates that the chemistry that we have been using is multiple. But notably, at the very last box fatty acylatoin for extending the duration of action and the Novo Corporation deserves the lion's share of the credit for having advanced this through insulin into the incretins that we know so well. Its innovative peptide design, designing these molecules for exquisite potency, metabolic stability and this extended duration of action. And it's that middle box that really speaks to this prodrug chemistry that we have developed here in Indiana University through support from the MBX Corporation that they are now testing clinically. That provides us the ability not just to control the pharmacokinetics, but to control the pharmacology of the molecule by having extended its duration but minimizing that burst. Endocrine hormones typically have narrow therapeutic index, insulin for glucose, parathyroid for calcium, glucose -- glucagon also for glucose. And so what we wanted was a means to control the biology of the molecule. Precision as the company has emphasized and as our chemistry has brought forth over the last couple of decades.

The next slide gives you a cartoon. And it is my final slide and getting on to the biology of the -- of this opportunity and of the company. It's a cartoon that shows in the upper left-hand corner, near that, A, if you can see it Canvuparatide MBX-2109. As I remember, is a peptide that we produced here in Bloomington, it is a peptide that is fatty isolated at both ends, the end terminus and the C terminus to give it high affinity to circulating plasma proteins, notably albumin. You see that in the middle section called B where it is residing on albumin as a soluble plasma depot and the magic of this prodrug is that we have designed the end terminal fatty acid to be hanging on to a dipeptide that will cyclase to a cyclic dipeptide a diketopiperazine and leaves the prodrug to give you an active peptide that remains bound to the plasma protein by virtue of the C-terminal fatty acid.

And in the Window C, if you will, you can see the red peptide is turning to a green peptide connotating that we're going from an inactive substance to an active substance. The conversion is intermolecular. And the importance of that is that it's concentration independent. It's not going to vary, dependent upon where you are in your circulating concentration of this prodrug. That cyclization, the time action in the conversion remains constant and what controls it is temperature in PH, which is virtually in variant in a chemical sense because it's physiological temperature in PH. And you cannot vary that much and still maintain vitality.

And so that cyclization is where the magic is. It controls the burst, keeping it to a minimum amount, and it extends the duration of action, so that you end up with a profile that should look like pump infusion, but not requiring the pump. And so I'm going to conclude here and turn the program over to the physicians, Dr. Michael Collins to talk about the therapeutic opportunity that led us to apply our chemistry to parathyroid hormone, and also Dr. Sam Azoulay, to give you a measure of how close have we met the objective that we set out for, gosh, nearly a decade ago.

Thank you so much for the opportunity to participate.

Thank you, Richard. My name is Michael Collins. I'm an endocrinologist, a special volunteer and senior clinical adviser at the National Institutes of Health. And this morning, I'm going to talk to you very briefly about hypoparathyroidism the disease and a little bit about the landscape.

First, as we all know, hypoparathyroidism results from 2 little parathyroid hormones. The primary feature that follows from that is hypocalcemia. It's the hypocalcemia and its treatment that leads to many of the problems. Some of them are shown here. And these include brain fog, depression, kidney disease and even an increased major adverse event risk. Hypoparathyoidism typically onsets at around 40 to 65, in most cases are caused by [indiscernible]. About 25% of them are caused by other causes shown here. By definition, chronic hypoparathyroidism is defined as hypo -- 12 months of hypoparathyroidism following surgery, but the onset is typically sooner. This leads to impaired quality of life due to persistent mild symptoms, hypocalcemia brain fog, et cetera, and it's the treatment that can lead to impaired renal function with hypercalciuria, nephrocalcinosis and nephrolithiasis.

Hypoparathyroidism has thousands of patients worldwide. In the U.K. and U.S., over 250,000 patients with an annual incidence of about 7,000 per year. And again, the majority of those are caused by neck surgery. And most patients after neck surgery are really diagnosed within a few months. So there's a large population and this population has increased health care utilization needs for effective treatments.

This slide really gives you a snapshot of what it's like to be a patient with hypoparathyroidism. You see the symptoms in the top, including tetany. And in the middle, there's literally a snapshot of what it looks like to be a patient on hypoparathyroidism taking conventional therapy. You can see the number of patients, the number of pills that patients have to take a day and the burden that this imposes. And with this goes along with stated in these quotes here, if I go without my meds, it will be dead within days. If I skip or miss calcium, I will be in the ED in 12 hours. I no longer have the luxury of sleeping throughout the night. And it's a treatment that really leads to the hypercalciuria and the renal calcification, and a lot of this is driven by the tetany. Tetany is a terrible condition. And if the patient has ever had this, they do everything they can to prevent it. And this often includes taking extra doses of calcium, which facilitates and promotes hypercalciuria and renal calcification.

Now we know that Yorvipath, which was introduced recently, has demonstrated clearly the need and the acceptance of injectable PTH for replacement therapy. However, significant gaps remained, daily injections can lead to injection fatigue. Patients still worry about disruption leading to missed injections. And many of the patients continue to experience symptoms while on treatment with the ups and downs of the parathyroid blood levels. From the Phase II trial Avail, we know there is compelling efficacy with Canvuparatide to confirm the tolerability and to determine the starting dose. So Canvuparatide really has demonstrated positive results in Phase II and Phase III that will be coming kicked off in Q3 2026. There's a clear registrational path with endpoints that matter to physicians and payers and we hope to see normalization of blood calcium, independence of active calcium and vitamin D, normalization of urinary calcium and more patient-reported outcomes.

On the left here has shown the potential for Canvuparatide. It's a once-weekly injection, it restores normal serum and calcium and phosphate, protects the kidney from long-term damage that restores bone turnover and it frees patients from daily disease management. Once weekly Canvuparatide really does have the potential to be the new standard of care with patients for hypoparathyroidism. Market research has shown that health care professionals would switch PTH treated patients to Canvuparatide. They would start naive patients on Canvuparatide, and patients also would choose once weekly Canvuparatide. And if week-over-week consistency is borne out, it will eliminate the roller coaster of crashes and debilitating symptoms.

So in summary, we've shown that chronic hypoparathyroidism is a damaging disease. There are a lot of patients in the U.S. and EU. We've been showing -- we've seen that Yorvipath validates the need and acceptance of PTH replacement, but there are significant gaps. When once weekly Canvuparatide has the potential to set a new standard for treating chronic hypoparathyroidism, the majority of health care providers and patients would choose once weekly Canvuparatide.

And with that, I'll turn it over to Dr. Azoulay, the Chief Medical Officer.

Good morning. I'm Sam Azoulay, Chief Medical Officer at MBX, and I'm absolutely delighted to present the 1-year results of the -- 1-year open-label extension of the [ Avail ] study, which is, in fact, the first study to evaluate the safety and efficacy of the weekly Canvuparatide in patients with hypoparathyroidism.

Let me remind you about the design of the Avail study, which enrolled adults with hypoparathyroidism. We were receiving calcium supplementation, vitamin-D supplementation at a stable dose and who had albumin-adjusted calcium in the range of 8.2 to 10.6 milligrams per deciliter. Patients were randomized [ 4:1 ] to treatment with Canvuparatide, a starting dose of 400 micrograms, 600 microgram, 800 micrograms or placebo once weekly. During the first 4 weeks of the 12-week treatment period, study medication doses were maintained at the starting level. Beginning at week 5, dose adjustment was permitted at 200-microgram increments, as needed on a 2-week interval.

The maximum Canvuparatide dose range from 1,200 to 1,600 micrograms, depending on the study participants starting dose. After completion of the 8-week dose adjustment period, patients were eligible for an open -- to enter into the open-label extension study. The primary endpoint of the Avail study was a composite response rate at week 12, defined by maintenance of normal serum calcium, 8.2 to 10.6, independence from active vitamin D zero and reduced oral calcium supplement to a maximum of 600 milligrams a day. To be clear, the open-label extension study is a separate study designed to evaluate the longer-term safety as well as the durability of Canvuparatide treatment. Patients originally randomized to Canvuparatide could continue active treatment while patients originally randomized to placebo crossover to Canvuparatide with dose adjustments allowed to achieve and maintain therapeutic benefit.

In addition to responder rate at 1 year the open-label extension evaluates several measures that reflects the expected effect of PTH replacement, including changes in urinary calcium excretion, bone turnover biomarker, bone mineral density, immunogenicity and long-term safety. Importantly, the open-label expansion reflect a different treatment settings at the parent study. With patient transitioning from weekly clinic-based administration and also monitoring during the 12-week parent study to home administration and follow-up assessment every 4 to 6 weeks starting around week 14 of the open-label extension. Today, I will review the 1-year results from the ongoing open-label extension highlighting the efficacy, durability and physiological effects of the once-weekly Canvuparatide over time.

Now shown here are the baseline demographics and clinical characteristic for the Avail study participants. In this presentation, all data for Canvuparatide will reflect the pooled analysis of the 3 dose groups and comparison will be for this pool Canvuparatide versus placebo. Overall, the demographics and clinical characteristics were representative of the population of patients with HP hypoparathyroidism and similar across the 2 groups of pooled Canvuparatide and placebo. It's a very important point. As expected, the majority of patients enrolled in this study were female with long-standing post-surgical HP with a mean duration of more than 9 years for the disease. Calcium and vitamin D supplement doses and serum parameters, including calcium were within the expected range.

All along the study, the retention of patients was very, very high. Notably, the steady retention rate was high in the Avail study with 100% and 64 per patient, 64, the 64 patients included completed the study. 60 of these patients choose to continue into the open-label extension corresponding to a 94% of the patient pool. At 1 year into the extension study, 90% of these patients are still ongoing indicative of the patients and PI satisfaction with their treatment. As shown at week 12, 63% of patients in the Canvuparatide treatment group achieved a primary composite endpoint against placebo.

It is important to note that these results were achieved without the use of any PRN. At 1 year in the open-label extension study population 57% of the patients met the composite responder endpoint, demonstrating sustained efficacy over an extended treatment period and supporting the durability of the results observed in the 12-week Avail parent study. When we look at each component of the composite endpoint, a high proportion of patients maintain independence from Vitamin D, calcium supplement, while maintaining serum calcium within the normal range.

It's also worth noting that these results were achieved during an open-label extension in which a majority of patients were reconstituting, preparing and self-administering Canvuparatide at home, providing important experience with long treatment outside of the control clinical setting. Taken together, this finding supports the potential of once-weekly Canvuparatide to provide durable benefit of the 1-year treatment period.

To help to place this result in context, this slide summarizes selected primary efficacy outcome reported for [indiscernible] in this Phase II program alongside the Canvuparatide data presented today. While cross-trial comparisons should be interpreted with caution, the overall efficacy profile observed with once weekly Canvuparatide compared favorably with a currently approved PTH replacement therapy with comparable data at 1 year. The key distinction is that Canvuparatide achieved these results with a once-weekly dosing regimen compared with the daily administration required for Yorvipath. This supports our goal of providing a convenient and differentiated PTH replacement option for patients with chronic hypoparathyroidism. Before discussing additional evidence of physiologic PTH replacement, I would like to briefly highlight the pharmacokinetic and pharmacodynamic profile of once-weekly Canvuparatide we observed in the Phase II study.

On the left side of the slide, Canvuparatide continued to demonstrate the controlled and sustained exposure profile it was designed to achieve in patients. The Tmax was approximately 2 to 3 days, and we had minimal fluctuation throughout the dosing interval with a peak-to-trough ratio of approximately 1.3 over the course of the week. Importantly, this translated into stable serum calcium control over time. As you can see on the right, mean adjusted serum calcium remained in the normal range through 1 year. In the Phase II study, we also merged serum calcium as the Tmax and the trough concentration of Canvuparatide active drug showing a mean difference in serum calcium of only 0.59 milligram per DCB. Taken together, this finding continued to support the potential of once weekly Canvuparatide to provide consistent PTH replacement with stable calcium control over time.

I'm going now to look at the urine calcium. As shown on the graph, patient treated by Canvuparatide, that's the blue bar, the blue in blue, showed a reduction in urine calcium at 12 weeks of the Phase II study which is even more pronounced at while -- while very importantly, maintaining serum calcium within the normal range. On the right side of the graph, you can see that the patient initially treated by placebo also show a reduction in urine calcium, which is driven by the reduction in vitamin D and calcium supplement. But in parallel, the serum calcium decreases and fluctuate. While switching to active Canvuparatide, the urine calcium decreased further, while the serum calcium this time stays within the normal value.

Now we are looking -- going to look specifically at patients who enter the study with elevated urinary calcium excretion, which is one of the key target population for HP -- patients of HP patients, its key target for treatment. As you recall from the baseline characteristic, 45% of the patients on the study have elevated urine calcium. As shown on the left, patients randomized to Canvuparatide experienced a substantial reduction in mean 24-hour urine calcium from 426-milligram a day at baseline to 229 milligrams a day at week 12, further improving to 188-milligram a day at 1 year in the open label extension. We observed a similar pattern in patients initially randomized to placebo, while urine calcium remain near the upper limit of normal at the end of the parent study, levels declined substantially following crossover to Canvuparatide reaching 106 milligrams a day at 1 year.

The particularly striking finding is shown here, patients previously treated with placebo and moving to Canvuparatide at an even further reduction in urine calcium despite having higher serum calcium. Overall, the maintenance of serum calcium level together with a reduction in urine calcium excretion is clinically relevant because it represents an expected physiologic effect of PTH replacement on renal calcium handling. In addition to reduction in urinary calcium excretion, you observe change in several biomarkers that are consistent with the expected renal effect of PTH replacement. Through 1 year, phosphate level and the calcium phosphate product decreased. 125 remains with a normal range. And we also observed an increase in GFR over time, consistent with the favorable effect on renal function. Again, taken together, these data provide additional evidence that once weekly Canvuparatide is restoring the physiologic PTH activity in the kidneys.

Now I'm going to move to the bone biology. This slide shows the effect of once-weekly Canvuparatide on bone turnover biomarker, CTx, which is reflective of catabolism -- bone catabolism, P1NP reflective of bone anabolism over time, respectively, representative, again, of destruction of the bone and the reconstruction of the bone. As a reminder, bone turnover is typically suppressed in patients with chronic hypoparathyroidism. Therefore, increase in both bone resorption and bone formation markers expected following initiation of PTH replacement therapy.

As you can see here, both CTx and P1NP increase following treatment with Canvuparatide, consistent with reactivation of the bone remodeling. There was no change in placebo. However, once again, when placebo patients switched to active Canvuparatide both biomarkers increased similarly to what was observed in patients treated initially by Canvuparatide. After this initial increase, the markers generally stabilized or slightly decreased through 1 year of treatment. That's the profile that you want to see. The overall pattern is reassuring, because it suggests restoration of bone turnover rather than continued increase over time and is consistent with the expected skeletal effect of physiologic PTH replacement.

Correlated to bone biomarkers, we are not going to discuss the bone effect through the bone mineral density or BMD. And we're going to develop to present the Z score and we elected to present BMD through the Z score because it provides a good comparison with patient bone density that will be expected for someone of the same age, same sex and values about negative 2 are generally considered within the normal range. As I mentioned on the previous slide, restoration of bone remodeling following PTH replacement is expected to influence bone density over time. And therefore, these findings should be interpreted together with a bone turnover biomarker data.

What you can see on the 4 different locations, bone location, which was a spine, a total hip, femoral neck and the radius. Mean BMD score declined modestly following restoration of bone remodeling and remain within the normal range through 1 year of treatment. Taken together, this finding is consistent with the restoration of bone metabolism and do not suggest any new bond-related safety concern. Looking now at immunogenicity. Immunogenicity was really minimal in both parent study and the open-label extension with a single observation of anti-drug antibodies among 59 patients through year 1 and notably, the titer of this anti-drug antibodies signal was low and no detection of titer was found for the active PTH peptide. Looking now at the overall safety profile.

Most treatment emergent adverse events were mild or moderate in intensity with 5 serious adverse events, not deemed to be treatment related. Only 5% of the patients discontinued the study due to treatment-emergent adverse event. When we evaluated adverse event of special interest, hypocalcemia, hypercalcemia and injection site reaction were the most common event -- and this is absolutely consistent with the patient population with HP, hyperparathyroidism, receiving injectable PTH replacement therapy and notably began self-administration at home during the open-label extension.

In summary, we believe this data demonstrates sustained benefit of once weekly Canvuparatide as a potential PTH replacement therapy for patients with chronic hypoparathyroidism. The results are consistent with restoration of the systemic PTH activity to serum calcium normalization, reduction of urine calcium excretion, restoration of bone metabolism and increase of eGFR. Response rate of 57% at 1 year in OLE is comparable to the Phase II Avail rate at 63% at 12 weeks. We had a high retention rate with 90% of patients entering the open-label extension remaining in the study at 1 year. Canvuparatide was generally well tolerated with no new safety signals during the open-label extension. And importantly, the pharmacokinetics supports once-weekly dosing with, as shown you, low peak-to-trough ratio and stable exposure.

Phase III pivotal trials remain on track to initiate the third quarter of this year, and I'm going to give you more information about the Phase III. The Phase III trial is designed as a randomized double-blind placebo-controlled study on controlling approximately 160 patients randomized 3:1 to once weekly Canvuparatide -- placebo, sorry. Patients randomized to Canvuparatide will start at 600 micrograms once weekly and follow a titration algorithm to maintain albumin-adjusted serum calcium in the normal range while reducing conventional therapy. The primary endpoint at week 26 is a composite responder endpoint requiring patients to meet all the full criteria of normal albumin-adjusted serum calcium, independence from active vitamin D zero or calcium -- oral calcium supplementation at a maximum of 600 milligrams per day and no increase in Canvuparatide dose during the final 4 weeks of treatment.

The key secondary endpoints include normalization of urine calcium excretion in patients with elevated baseline value while maintaining normal albumin-adjusted serum calcium and we added another key secondary endpoint, an important one, which is PROs. The 1-year open-label extension data also strengthened our confidence in urine calcium normalization as a key secondary endpoint in this Phase III particularly among patients with elevated baseline urine calcium. That's where we observed in the Phase II a meaningful and sustained improvement in calcium excretion.

After the 26 double-blind -- 26-week double-blind period, patients will enter a 78-week open-label extension. Overall, the Phase III design reflects the totality of evidence observed in the Avail study and the 1-year open-label extension. We strongly believe that this data support the continued development of once-weekly Canvuparatide as a potential replacement therapy, which is designed to provide durable disease control while reducing treatment burden for patients with chronic hypoparathyroidism.

With this, I will turn back to Kent.

Thank you, Sam. Our 1-year OLE data reinforces our conviction that once weekly Canvuparatide is a best-in-class PTH replacement therapy. It demonstrates sustained benefit and hallmark PTH biology in blood, kidney and bone. The data also supports our Phase III trial design, which we view as a confirmatory study. We have an exciting year ahead for MBX with several important milestones that we're on track to achieve, including beginning enrollment in our [ Canvu ] Phase III study in Q3. We have cash to fund our operations into 2029, including fully funding our Phase III pivotal trial and pre-commercial activities that are underway. Our team has a strong sense of urgency because we know that patients are waiting.

Operator, please open the line for questions.

[Operator Instructions]. Our first question comes from the line of Seamus Fernandez with Guggenheim Partners.

Great. Just have a couple of questions. If we can first start with Dr. Collins. Dr. Collins, interested to just get your thoughts on the comparison between -- the clinical comparison that one would make between Yorvipath and Canvuparatide effectiveness here, and perhaps improvements that you could see occurring between the Phase II to Phase III results because we did see an improvement in Yorvipath effectiveness as measured at the OLE endpoint. But again, I know it's dangerous to do these cross-trial comparisons, but just interested in your thoughts on the clinical experience with Canvuparatide and how you see the opportunity here as impacting patient lives?

And then for Sam and Kent, and the team, just wanted to get a better sense again of that dynamic. As we look at the ability to dose perhaps quite flexibly all the way up to 600 -- 1,600 micrograms, just interested to know where the sort of dose range came out in the OLE and what's possible in the Phase III to perhaps even improve upon this response rate at 52 weeks.

Well, thank you, Seamus. I'll just lead off briefly and pass it to Dr. Collins and then to Sam. Again, we're just really delighted with our 1-year data. We support the sustained clinical benefit and recall, this is really the first truly long-acting PTH therapy candidate. And our 1-year responder rate really was comparable to the 12-week Avail, which achieved as primary endpoint and to the once-daily Yorvi Phase II at 1 year based on the confidence interval. And importantly, really the expected PTH effects in bone, blood, kidney for a PTH replacement therapy. So really delighted, and I'm really excited to hear Dr. Collins perspective in comparison.

Thank you, Kent, and thank you, Seamus, for the questions. If I can recall them all. So the first that you asked about is the comparison between the 2. And as you pointed out, this is a dangerous endeavor and one that I won't engage in because they haven't been compared. What we can say is that for both drugs, the results look very good, like what you'd want for a patient with hypoparathyroidism. Of course, the obvious advantage that I see is that this is once weekly dosing over daily dosing. Patients generally don't like injections. And if you can cut that down from 7 a week to 1, they'll really like that, I think.

One of the questions you asked me, which I'll probably turn over to Sam was question, something about the design of the Phase III based on what I think essentially are the learnings from Phase II. And I actually think there are quite a few and some important ones. And I think I'll leave that to Sam to talk about.

Thank you, Michael, and thank you, Seamus the question. Yes, I think we also expect to see even better results in the Phase III and because we are learning from Phase II. As a remind, Phase II is the learning phase, right? So we -- as an example, what would be the starting dose in the Phase III 600-microgram as we reported will be the starting dose, and it's a learning from the Phase II. The big, big difference with the Phase III is that we are going to go ahead with the commercial device. And the commercial device as we intending to implement will be a reliable device, it will be one injector, it will be one dose and you discard it. Very easy to use very reliable. It's very different from the Phase II. If you remember my description of the study design, patient was transitioning in the open-label extension to reconstituting themselves and self-injecting the drug. And you know that it's not -- we know that it's not perfect. And you know that it can be sourced of misdosing et cetera. So we will not have this problem in Phase III.

So all this should constitute an improvement as compared to Phase II. You also asked a question about the dose in the Phase II. So what we experienced in -- it's a broad range, and we think that we are offering to the patient the right range of doses from 400 micrograms to 1,600 micrograms, and these doses will be kept, if you want, and been confirmed to be evaluated into the Phase III program at the same, as I said, starting with 600 micrograms.

Yes, and it touches on the fact that this is personalized medicine really. There is heterogeneity in the HP patient population, and we want to serve every patient with HP, and we think that the patients and their doctors relate to the fact that they need a PTH replacement therapy. PTH is the missing hormone. And so we're advancing a dose range that we think fully satisfies their needs. And in the 6-month Phase III, we expect to get patients to their optimal dose and very excited to get on with the Phase III shortly.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

Congrats on the data, and thanks for the very thoughtful presentation. Yes, so the 57% responder rate at 1 year demonstrates a nice maintenance of response compared to the 63% at 12 weeks, of course. And with that said, can you help us put into context the increased responder rate at 6 months? And overall, the early middle and 1-year responder rates seem to line up fairly nicely with the Yorvipath Phase II data based upon one of your slides. So can you help us understand why that might be a more fair comparison relative to, say, the Yorvipath Phase III data?

Thank you, Tyler. We do look at our Phase II open-label extension 1-year responder rate as comparable to the responder rate at 12 weeks based on the confidence interval it overlays well and as well to the 1-year time point for the Phase II study responder rate for once-daily Yorvipath. But importantly, with our candidate in once-weekly administration. So we do think that Phase II to Phase II makes sense. And the Phase III trial is, of course, different. It's a placebo-controlled study with a very active engagement with the investigators. And that's where we're getting ready to start next quarter.

Anything to add, Sam?

No, I think you summarized very nicely.

Dr. Collins?

No.

Our next question comes from the line of Michael Yee with UBS.

Congrats on the data. We had a 2-part question, either for the management or for the doctor. On efficacy, I know your 57% finds very much in line with Yorvipath and at the higher end of their 1-year data as well. It came down from the initial 6 months or 6-month data and earlier time points. Can you just qualify how you think that numbers came down, whether from actual compliance factor issues or what you know about the patients who were responders at 6 months and then were nonresponders by definition at 12 months. What was going on there, if you have any insight on the patients or compliance factor given that this was not the pen or the commercial Phase III formulation?

And similarly, with the hypocalcemia, I know that the number kind of moved up in the Phase II 12-month portion, it was 8% in the middle of the year and then went up to 20%. I suspect that those increases were due to some factor that related to the compliance part of the injection. But maybe you have some insight into what happened with the people who were hypocalcemic during the open-label extension portion.

Yes. Well, thank you, Mike. We're very excited about the data, too. And when you look at these different time points, you're going to have some variability. Again, they're all very comparable overall. And in terms of the open-label extension, you're correct that during the open-label extension, you have this change from going to the PI weekly for blood draws, for getting the drug administered to kind of going in the [indiscernible] in your home and you're self-administering and you're going much less frequently for visits and assessments.

So that is playing out during the open-label extension portion of the study. And in the Phase III, we will have the pen and we will have the regular weekly assessments. The pen is one that we know from market evaluation is going to be well received. So in terms of the specific safety question, I think it's very related to what I shared, and I'll ask Sam to elaborate.

Yes. Thanks, Mike. I think that the point that Kent made about the monitoring, the frequency of monitoring, but also the patient preparing at home and in self-injected is certainly source of -- has certainly impacted the hypocalcemia level. And I can give you just one rationale is the percentage of patients with hypocalcemia during this period where they were self-injecting was 53%. 53% of the patients with hypocalcemia were self-dosing at home. So we can certainly assume that there was some mistake around the dose.

Then if you look at the other end, which is the initial 3 months period of the open-label extension, where patients were still titrating up. Well, we have 25% of patients with hypocalcemia in this period. So this period at the beginning and at the end, accounts for almost 75% of it. So if I make one additional comparison with Yorvipath. Yorvipath had in Phase II their commercial device, and we will have a commercial device in Phase III. And again, I'm very highly confident that this number will drop.

Our next question comes from the line of Roger Song with Jefferies.

Congrats for the data for the 1-year durability. Maybe I will move on to the PD markers for the serum calcium. Very helpful, you gave us the peak trough ratio and the differences. Just want to clarify, this 0.59, how are you going to put it into the context of the placebo getting during the randomized trial or the normal range you will say? And then also this 0.12, is that a standard error or it's a standard deviation?

Roger, can you clarify the 0.59 that you're referring to?

Yes, the 0.59 on the Slide 24, I believe, it is a peak trough difference.

Excellent. So really, what we have established here by design, we're seeing that flat PK almost peakless, you might say, about 1.3 over a week or infusion like without the pump. And this translated to the steady PD effects throughout the week. That's the 0.59 calcium difference, serum calcium difference, which is not only stable, but very normal physiologic fluctuation. And the second part of your question again?

1.2 is the standard error.

Very good.

Our next question comes from the line of Annabel Samimy with Stifel.

This is Jack on for Annabel. So 2 from us. So what percent of patients reached the top dose by year 1? And could they have potentially remained underdosed as in -- did you see patients up titrating consistently throughout the year and then getting capped at 1,600? Or did you see patients hitting their target dose relatively early and staying there? And then on bone health, the trended BMD looks like it's getting a bit closer to the normal limits, particularly in the radius. What are your kind of expectations for where that might end up at year 2? Would BMD kind of stabilize at this point? Or would you expect that to kind of continue trending lower without intervention?

Thank you. I'll ask Sam to address your 2-part question.

Yes. The patient can be titrated at any point if the physician thinks that it's needed. And I'm explaining. At the end of the open label -- at the end of the Avail study, if you remember, just by design, 2 groups couldn't reach 1,600 microgram. So that when they switch to the open-label extension, it was possible for this patient if they were not responder to be titrated up. Again, same thing with the placebo when they switch to the active treatment in the open-label extension, again, they can be titrated. But if for any other reason during the course of the study, patients needed to have a change in Canvuparatide, it was possible. And we -- the only thing was respecting the interval of 2 to 3 weeks between the dose increase.

In terms of -- you asked a question about the BMD and the question was related to [indiscernible]. Yes, yes. So let me explain the radius first. What the decline you see in the radius, we looked at really in detail the starting the baseline start, if you want. And what we noticed is, in fact, the patients who decrease the most are the one who start the highest. So that's exactly what you want, right, to reduce the BMD toward -- and trending towards 0. That's what you want to see.

And when you look at this population, again, the other patients, especially the one which are the lowest level didn't change. It was perfectly stable. So it's exactly what you -- it's really nice to see. In fact, even in more detail, I didn't show the slide, but we have really the effect you want to see patients starting high decreasing towards 0, patients starting low staying where they were. So that's exactly what you want to see. Now having said that, obviously, we'll continue to follow up these patients. We'll have additional data over next year, et cetera. So that will be a long-term monitoring.

Our next question comes from the line of Jessica Fye with JPMorgan.

I have one for the management team and one for Dr. Collins. For the MDX team, have you analyzed the 52-week data using the FDA's responder definition that like the one that seems stricter than what the companies use in clinical trials that I think requires the last 4 weeks to have 0 PRN, 0 active vitamin D and calcium 600 or higher or north of 600.

And then for Dr. Collins, I was curious what you make of the 15% use of active vitamin D in the 1-year data. And maybe if I could add one more in just following up on the last question on BMD. Did you just overall, Dr. Collins, see these baseline BMD measures as consistent with a typical hypoparh population?

Thank you, Jeff. I'll lead off. So this is a Phase II study open-label extension. And what we did look at is a 3-part primary endpoint that's quite comparable to the Phase III endpoint, why we look at this Phase III study as a confirmatory study. We went the extra mile beyond this 3-part Phase II endpoint and looked at PRN use during the week of evaluating the primary endpoint. We found there was none, 0 use. And again, this is really typical for a Phase II. The Phase III will be different. It will be a placebo-controlled blinded weekly visits, monitoring, and we are very confident that we have designed the study and will implement the study to have a high responder rate in the primary endpoint that's been established and aligned with the key regulatory bodies.

And in terms of Dr. Collins, can you please respond?

Yes. Thank you for the question. So the 2 questions. The first is my impression, I take it of the use of active vitamin D in the latter part of the OLE. I think this was, to some extent, probably already explained by Sam when it was noted probably because of the lack of a device and the fact that the patients were not using the drug correctly that they had more episodes of hypocalcemia and then the docs did the appropriate response of giving some active vitamin D.

I would also say parenthetically that my personal feeling as a clinician about this is I'm not that concerned, in fact, if a patient needs to take a little bit of calcitriol. And I'm more concerned about the fact that patients or the providers and the FDA are so rigorous about this because the concern with not using active vitamin D or calcium supplement has the tendency to lead to overtreatment, which could have deleterious effects on the bone, which leads to your next question was about what my thoughts were about the baseline values of bone density in these patients.

And I think that they were consistent with what's seen in other studies. I think what was seen here and is seen in other studies and to me is a bit of a surprise is there are some patients who enter this with hypoparathyroidism who we generally think of as having high bone mass that at some sites and particularly at the radius, actually have fairly low bone mineral density. This has been a bit of a surprise. And we actually did dig into this. And what Sam said is absolutely true that those with the lowest bone density really stayed quite stable. So that, I think, was very reassuring.

Yes, I can -- thank you, Mike. I can -- Jess, I can add in terms of the quantity of vitamin D, active vitamin D. It was very low. In fact, the median use was 0.3 microgram per day. So very low.

And those subjects who used it.

Yes. Yes...

And they were not responders, just to be clear, due to the 3 part 3 component endpoint.

Our next question comes from the line of Ellie Merle with Barclays.

Just to clarify on the hypo and hypercalcemia events, what proportion of these events were symptomatic? And I guess, what were the average duration of these cases? And then if you could just clarify what the severe treatment-related adverse events were in the AE side on 31. And then -- sorry, last question. I know you touched on it a bit, but just can you help us understand what you attribute to the increase in the response rate at month 6 and then the decline at week 52? And I guess, more importantly, how you think about the stability of the response beyond week 52 and sort of the confidence that it remains stable from there?

I'm going to take the first part and let Sam follow up on your multipart question. Again, you have different time points in these studies. And overall, we see comparable results. The primary endpoint for the Phase III is 6 months. I think it's a really great period to optimize the dose and show the effect. And we, of course, will have an OLE as well for the Phase III. And we just think the hallmark PTH physiology is there, including the flat PK that I mentioned, the infusion like that translated to steady PD. So we see this as a very effective PTH replacement therapy, and we believe we've designed a Phase III that's going to demonstrate that very, very clearly.

So turning it over to Sam on the other part.

Yes. I think I'm going to start with the hypercalcemia. I mean the [ hypocalcemia ] is exactly we did what was expected. In fact, we had a few patients with hypercalcemia and we had exactly 7 subjects. And no surprise there, I would say. For the hypocalcemia, I think I provided you with the rationale why we got this hypocalcemia explaining around 75% of the occurrence of hypocalcemia. So we have a good explanation for the hypocalcemia.

In terms -- I think you asked a question about the serious adverse events, right? That was the question. And so one was related to appendicitis. So obviously, not drug related, and the other one were related to the hypocalcemia for episodes. The rest of the hypocalcemia, back to your question, were mild to moderate, and there was no impact -- didn't last long. In fact, didn't last long. And in fact, very few discontinued for hypocalcemia or hypercalcemia. So in fact, 0 patients discontinued for hyper. So overall, I think that we think that this hypocalcemia will be absolutely manageable and will be manageable in the rest of the study.

our next question comes from the line of Jon Wolleben with Citizens Bank.

In the release, you guys mentioned some patient-reported outcome data, and I was hoping if you could just give some context qualitatively about what you saw there. And I might have missed this in an earlier answer, but I just wanted to check if you could confirm what percentage of patients, if any, were at the top allowed dose at year 1?

Thank you, Jon. Sam will address both of those.

Yes. I think for the top doses, I can tell you that we had patients up to 1,600 microgram. And as I told you, the median dose was 1,000 microgram. That's what we can say at this point at this juncture. In terms of PRO, yes, you're absolutely right. We had a nice trend, a positive trend in the PRO that was observed, especially for the SF36 and some of the components of the HP questionnaire. However, we did not have enough patients at baseline to be able to draw a conclusion, especially against placebo. So what we are going to do is it's a learning for Phase III. And we are so confident in these parameters and PROs that we decided to make it as a key secondary endpoint. And we worked with the FDA in order to be aligned with what we'll be exploring, and it will be an endpoint that will be part of the Phase III study.

Yes. And I'm just building on that, we really were excited with the high retention rate of 90% of the patients who entered the OLE remaining on the study at 1 year. And I think that really indicates satisfaction with once-weekly [ Canvu ]. And this is just consistent when we speak to the patients, they want to reclaim their freedom from the daily burden of their disease, taking pills day and night with a therapy they can take easily once weekly and then forget about their disease for the rest of the week. So we're really excited about the Phase III and on track for beginning enrolling next quarter. And it's very hopeful to run the Phase II to confirm the study design.

Ladies and gentlemen, our final question this morning comes from the line of Kripa Devarakonda with Truist Securities.

Congratulations on the data. You noted that there was 0 contribution from rescue therapy in the last week of the treatment period. I was wondering what -- if you can talk about CRM calcium outside of just the last week throughout the OLE. That's one question. And then you talked about your market research, which suggests that HCPs would switch a large majority of patients over time. Do you have any sense of -- if a patient is already stabilized on your path, you still have the weekly benefit. So what would be a specific clinical trigger doctor would use to justify a switch to once weekly Canvuparatide?

Thank you, Kripa. I'm going to ask Sam to address the first part, and then we are joined by Mark Soued, our Chief Commercial Officer, and he will address your market research question.

So we had -- thanks, Kripa. We had a really thorough review of the data, and we can confirm that there was no use of PRN in the last week of the evaluation. And the definition of PRN was not going above the prescribed dose of 600 milligram of calcium at any point during the week. It was not an average. It was at any time. And obviously, no use of vitamin D at all. So that was a very strong criteria. So that's why we were pleased to report that the same then for the Avail study in the open-label extension, we didn't have any use of PRN in the last week.

Yes. And Kripa, this is Mark. Just to build on the point about physician preference, Indeed, if Yorvipath is approved, really it would represent, frankly, a new standard of care with once weekly. I was going to say exactly once weekly. And when we presented this to physicians, to patients as a TPP, what we saw very clearly is for newly diagnosed patients that are PTH naive, the vast majority of physicians said that would become the preferred choice.

And same with patients. And for those patients that are already on PTH treatment, what we heard very clearly is the vast majority would also be switched over time. And I think your question is what would be those triggers? Well, I think Dr. Collins pointed to some of those. There is daily injection fatigue. We've seen this very clearly in the research, and that's something that's very real. Imagine injecting yourself every day the anxiety that still remains from potentially missing your dose during that day, some sort of a daily disruption. So again, we see a large portion of those patients switching over time, as we said. And I think as physicians and patients get experience with the therapy, if it's approved, we're going to see that dynamic play out very strongly.

Thank you. Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Mr. Hawryluk for any final comments.

I want to thank everyone for participating in this call, and stay tuned for more about our Phase III trial.

Thank you. That concludes today's conference call. You may disconnect your lines at this time. Thank you for your participation.

Welcome to everyone in the room and on webcast, and thank you for joining us for Obesity Day. Today, we are excited and honored to present our novel and transformative approach to treating this global chronic disease. We've experienced increasing interest in learning about our obesity portfolio. We thought this was a timely opportunity to highlight our remarkable progress, which we are making toward our 2026 milestones.

Standing tallest is 12-week MAD data in Q4 for MBX 4291, our GLP-1/GIP coagonist prodrug. We said that it would be important to show true once-monthly dosing and improve tolerability as a monthly drug. We also said we should expect to see competitive weight loss given these are the gold standard mechanisms.

Sam Azoulay, CMO, will present preliminary data from our ongoing blinded Phase I study, which demonstrate this target product profile. We're very encouraged by what we're seeing with MBX 4291, which reads through to our entire expanding obesity portfolio, all built on our proprietary PEP technology.

We're joined today by two leaders in the obesity field, Katherine Saunders, Co-Founder of FlyteHealth and Clinical Assistant Professor of Medicine at Weill Cornell Medicine; and Richard DiMarchi, Distinguished Professor of Chemistry at Indiana University, Scientific Co-Founder of MBX Biosciences; and my partner for more than 20 years in multiple successful companies in obesity, including Marcadia Biotech, where Richard pioneered multi-agonists in obesity, which have helped revolutionize the field. Dr. Saunders will provide an overview of the evolving treatment landscape and the remaining treatment gaps in obesity. Dr. DiMarchi will follow with the progression of pharmaceutical treatment and as the architect of the PEP platform, discuss its application to the development of long-acting therapeutics in obesity.

Sam will then present the preliminary blinded clinical data for MBX 4291, summarized in this morning's press release. Richard will introduce our newest development candidate, MBX 5765. We call it an amycretin. And it combines additional mechanisms, which are clinically validated all in a single molecule. I'll also present proof-of-concept data for imapextide in post-bariatric hypoglycemia, PBH, and provide an update on our priorities and milestones for 2026 before we open it up for questions.

Note, I will be making forward-looking statements. Please review our risk factors and other disclosures in our SEC filings, which are available on our website.

At MBX, we are completely focused on once-weekly canvuparatide in our growing obesity portfolio, where we believe we can have the greatest patient impact and long-term value creation. Multiple clinical stage programs, each designed to be best-in-class in multibillion-dollar markets are progressing well in development.

Our PEP platform combines innovative peptide design, programmable prodrug and fatty acylation to achieve unique pharmacokinetic and PD profiles. We achieved proof of concept with our PEP approach in our lead program, once-weekly canvuparatide. We presented very positive Phase II results last September, which were supportive of best-in-class. And we'll present 1-year OLE data at ENDO in June. We hope to see you in Chicago. We're on track to start enrolling our confirmatory registrational Phase III study in Q2 -- in Q3 next quarter. Mark Hope was recently appointed CCO, Chief Commercial Officer, to lead our commercial launch planning.

Turning to our obesity portfolio. Our ongoing blinded study is on track to report top line results for a 12-week MAD cohort in Q4. We believe the preliminary data demonstrate that we can design differentiated PEP therapeutics with once-monthly dosing, improved tolerability and competitive weight loss through gradually rising and steady drug exposures. MBX 5765 applies our PEP technology in multiple mechanisms in a single molecule. And preclinical data for MBX 5765 demonstrate a differentiated PK profile supportive of once-monthly dosing as well as the expected PD effects. Our triple G, GLP-1, GIP, glucagon coagonist or multi-agonist is on track for candidate selection next quarter, Q3. And we have a very focused discovery effort underway in obesity.

The obese patient population is global, heterogeneous and vast, requiring varied treatments to address it, particularly the individual needs of patients. The clinical data and new obesity candidate presented today reinforce our aspiration to become a global leader in endocrine and metabolic disease. We're well capitalized with $440 million in cash, which is expected to provide runway into 2029. It's an incredible setup and compelling program today.

So I'll now turn it over to Dr. Saunders for an overview of the obesity market landscape.

Great. Thank you so much, Kent, and thank you for having me here today. It's really a pleasure to be talking about this exciting field and the progress that we're making. Let's take a look first at the worldwide obesity prevalence. When you look at the numbers according to the World Health Organization and the World Obesity Federation, we know that 1 in 8 people worldwide are living with obesity. Breaking that down in adults, that's almost 900 million adults with obesity. And then more broadly, the overweight category is 2.5 billion adults throughout the world. In kids, the numbers are also staggering. 160 million children are living with obesity. And when it comes to overweight, there are 390 million children and adolescents with overweight. When you look at kids as young as age 5 and below, that number is even 35 million.

So just to put things in perspective in terms of the growth, obesity rates have doubled since 1990, and it's projected that by 2035, 25% of the world population is projected to have obesity. So really huge, huge, huge numbers here, which make it -- so that the obesity market, which is now $60 billion today, is projected to rise to over $90 billion through 2031. And this growth is really driven by many different factors, but you can think about it in terms of three different categories.

So the first is investment in exactly what we're talking about today, GLP-1 and next-gen treatments for obesity. We're looking at treatments with improved efficacy and safety profiles. We're looking at more oral options and more varied oral options and different routes of administration that will drive uptake and really improve adherence and persistence of medication.

Two is improved access and affordability, which we're really hoping for as clinicians to help as many of our patients as we can. This is expected to allow more patients to consider this class of medications and really be on them in meaningful ways. The Medicare expansion project, which is supposed to kick off in the next 2 months, actually, wow, hopefully, will be a big driver of improved access and affordability. And then finally, rising obesity prevalence and increased awareness of obesity medications to increase the addressable population.

Taking a look at compound annual growth rate, it's interesting to break it down in terms of BMI. When you take a look at the overweight category, Class I obesity, which is BMI 30 to 35, and Class II and III combined, which is a BMI of 35 plus. The obesity prevalence is really most stunning in the greater levels of obesity, so Class II and beyond. And estimates indicate that actually 40% of U.S. adult population will have obesity without type 2 diabetes in 2030 and nearly half of this population is in exactly that population, the patients with obesity that is at least Class II or Class III.

So let's take a look at the unmet needs. And it's really exciting to break it down in terms of exactly what we, as clinicians need to be able to help as many people worldwide as possible. So one is just the response. The percentage of patients with obesity who would benefit in terms of weight outcomes and health outcomes by losing more than 20% of their total body weight is substantial. And so looking for medications that provide greater efficacy is a big target.

Number two is prevention of weight regain. We know that obesity is a chronic disease that needs long-term treatment. We know that when people stop obesity medication, they're at high risk of regaining very rapidly and regaining very significantly. So we really need more tools and more strategies for this important phase of weight maintenance and not just the phase of weight loss.

Tolerability, the side effects that come along with many of the therapies really affect adherence and persistence. So adherence, how patients take their medication compared to how it's prescribed. And persistence, how long people stay on medication.

Convenience, what patient does not want to take something that is way more convenient than the regimens that we used to have, and it's improving very -- in a very exciting way to help people to be able to not have it be a huge burden in their life to take a medication for a chronic disease, just to make it as easy as possible would be ideal.

Weight loss quality. So we're not just talking about how much weight somebody can lose. We're talking about health outcomes, and we're talking about quality of life. And a huge part of that conversation is really taking a look at what kind of weight is lost. We know that a certain percentage of weight is lean body mass, which includes muscle. And so there's a big focus on what we can do to preserve not just muscle mass, but muscle function and other factors related to that.

And then finally, outcomes. Taking a look at different subpopulations is a big area of unmet need, pediatrics, older adults, how medications really affect these different subpopulations, and the safety, how can we make these treatments as safe as possible, not just for kids and older adults, but also for people with a wide variety of different comorbidities.

And so let's zone in a little bit on the GI side effects, which is a huge topic of conversation, both in this room and just more broadly, we see all the side effect type. What do we see clinically? So part of the mechanism of how these medications work is that they slow gastric emptying, their effect on GI motility. And so of course, we see some nausea, some vomiting, some diarrhea and the -- these side effects are really important in terms of patients' ability to stay on the medication. So the nausea, vomiting and diarrhea are typically the most frequent. And what we do now is really a lengthy titration regimen to allow people to adapt to these medications to be able to get to the optimal effective dose.

These events often happen at initiation and also during dose escalation. And why does this matter? This matters because sometimes the side effects are mild, but when they're more than just mild or when they're persistent, this is what really affects adherence and persistence. The key -- and they're a key driver of treatment discontinuation, which, as I mentioned, because this is a chronic disease, is not the outcome we're looking for. So again, the lengthy and gradual titration to improve tolerability is the current kind of standard of care. And this, again, impacts patients' ability to reach the dose they need to get to. So the goal really, optimizing exposure may improve tolerability and decrease the amount of the required titration steps. And this is something that is a very exciting prospect.

So finally, the goal really is to be able to provide obesity care with new tools in a way that helps people to achieve their weight and health goals and to keep them on medication. And so when you take a look at the status quo right now, the numbers are pretty terrible in terms of people discontinuing. And again, there are many reasons for this that we just reviewed.

But looking at the actual numbers, patients with type 2 diabetes, the numbers are a little bit lower, but 45% of people stop within a year and 64% stop within 2 years. And this is -- we're talking about a chronic disease that needs long-term treatment. When you look at obesity, those numbers are even higher. Within 1 year, it's 65% and within 2 years, it's 84%. And this is, again, not what we're looking for. When patients stop medication, they regain weight and then it's a big waste of money to have treated patients for this long, reach these outcomes and then have them back to where they were in the beginning.

So there's a huge, huge, huge need for more tolerable treatments and everything that we can be doing to get people on the medications they need and more importantly, keep them on long term.

So I'm going to hand it over to Dr. DiMarchi now. Thank you very much.

Indeed, a great pleasure to be here. I came from Bloomington, Indiana, and to be here to discuss this subject, it only took me 50 years, half century. I trained with Bruce Merrifield then to be Nobel laureate over at The Rockefeller University. And have gone on to be at the forefront of advancing this field of macro molecular medicinal chemistry, building these optimized peptides and proteins as therapeutics. Spent a little over 2 decades at Lilly and a little over 2 decades on my own at the university starting companies with the likes of Kent Hawryluk. So it really is indeed a pleasure to be here.

These last 20 years, actually, 30 years have focused, as I said, on obesity, but the history of the GLP-1s reached back to 1983, right? It's a little over 40 years when Graeme Bell cloned the gene as he was coming out of Chiron going to the University of Chicago and Svetlana Mojsov, who walked -- worked alongside me in the Merrifield laboratory up the Massachusetts General Hospital. Did the characterization, the discovery of the active ingredient in those mid-80s as Jens Holst in Copenhagen was doing the similar work.

In the 2000s, we saw this shift from a focus on diabetes, right, glycemic control to body weight, as Steve Bloom published in January of that year in Nature, the acute administration into the brain of a rat could minimize their appetite. But it was later in that year, again, still being at Lilly with Suad Efendic, who was Chief of Endocrinology at the Karolinska Hospital in Sweden that we submitted a patent that disclosed the treatment of obese type 2 diabetics for 4 weeks could lower body weight that led to Lilly having a patent that covered the whole field of GLP-1s for treatment of obesity. But it fell on deaf ears. That is -- it was 20 years before the American Medical Association declared obesity as a disease.

What's the route to treat it? Would people ever take an injection? Could you ever get a meaningful decrease in body weight? Could you get beyond the 4%, 5%, 6% to something close to what we're experiencing right now. And so in that decade that followed, exenatide, a paralog, not an analog, a paralog of GLP-1 was registered by the Amylin Corporation (sic) [ Amylin Pharmaceuticals ], Joe Cook, who had been with us at Lilly was CEO of the company.

And that was followed in 2009 when Matthias Tschop and I, he, a professor at the University of Cincinnati, I in Bloomington discovered that you could use glucagon, not as an antagonist, but as an agonist integrated in with GLP-1 to get superior outcomes. It was the beginning of what we now see being advanced as the active ingredient in retatrutide that distinguishes it from GLP-1s. Victoza was the first GLP-1 that was registered as an analog, a fatty acylated analog once-a-day medication and notice 1983 to 2010, we're at about 1/4 of a century to get that far.

And then in the decade of the 2010s, we get the emergence of what Matthias Tschop and I disclosed in a couple of landmark publications, integrating GLP-1 with GIP, which is the active mechanistic approach to Mounjaro to Zepbound, tirzepatide being the peptide and then 05 -- and in 2015, the triple agonist, right? The triple G, as Lilly refers to a GLP-1, GIP, glucagon was disclosed in a Nature Medicine publication, again, from my laboratory in collaboration with Matthias Tschop, who is now in Munich.

Saxenda becomes that first GLP that is registered for the treatment of obesity. It wasn't a terrific product, right? It was looking like the oral compounds that were giving us the 5%, 6%, 7% body weight lowering and the breakthrough, right? The breaking of the sound barrier in 2018 was Novo's disclosure in Phase III clinical studies that they could achieve 15% body weight lowering with semaglutide, the fatty diacylated peptide that has recruited folks' interest commercially into this field.

Wegovy gets approved in '21, Mounjaro, that co-agonist for diabetes in '22 and Zepbound in '23. And I think many of us are expecting that retatrutide will be approved this year or soon thereafter as the triple agonist. It's quite a journey as we move from diabetes-centric, a drug that was focused on for its glycemic effect, its incretin effect, right, on the pancreas to what is now obesity-centric.

And I will share with you early in my training, I met with Carl Djerassi. Many of you would know the name. He's the -- so professed father of pill, right, contraception. And he shared with me there are rare times in the history of the pharmaceutical industry where drugs have an impact that are bigger than the medicinal purpose for which they were registered. This is one of those cases. This is more than lowering people's glucose. This is more than lowering people's body weight. It's changing how they perceive themselves. It's changing how they perceive life.

Okay. So the whole focus now is getting from drug-centric to patient-centric. As Dr. Saunders has shared with you, we have tolerability issues, right? Compliance is not what it needs to be, and there are many patients who just cannot tolerate this medication. And we have this crazy algorithm for getting to steady state that takes as much as 6 months. That's not the typical way in which we prescribe medicines.

And so tolerability, improved compliance led me over 2 decades ago to anticipate this to be the case as we put together this chemistry, prodrug chemistry for macromolecules that is really the magic of why these substances are performing the way that they perform. Endocrine hormones have narrow therapeutic index. And we began to develop this chemistry for use in insulin, something that I know a bit about because you know what the consequences of an overdose of insulin are.

You also know in PTH, the calcium is every bit as important as glucose. And so having precise control over drug concentration so you can precisely keyword, right, precisely regulate the calcium levels was something that we put to work in canvu. And then recognizing that we could use this to address the tolerability issues that we have with the GI effects that the incretins, notably GLP-1 has.

The magic of this is that we take a dipeptide, two amino acids and we just invert the conformation. Your peptides and proteins are in the trans configuration, right? They sit like this, and that is why they're not falling apart, two amino acids at a time. By strategically inserting a methyl group, we can fix the cis conformation. And in the cis conformation, it's prone to cyclize. The more the cis conformation, the faster the cyclization, the less the cis conformation, the slower the cyclization, so we can control that cleavage anywhere from 1 hour to 1,000 hours, which gives us precise control because it's an intramolecular reaction, which means that it's concentration independent. You don't have to worry about the dose. You don't have to worry about the circulating concentration. You'll get the same cleavage rate. Very natural, amino acid-based.

And so what you see here in building upon the advances with these fatty acylated compounds that have the once-a-week time action, could we introduce another fatty acid on a dipeptide in a strategic position as we did in canvu to kill the biological activity until you get that cyclization to release an active fatty acylated product, very much like tirzepatide or semaglutide and the extended duration of action. And that entity is capable of seeing either of the two receptors, GIP, GLP bound to albumin or in the free conformation, which is only a small percent of that, which continues to circulate. That's how we extend the duration of action. That's also how we flatten the peak to trough, aiming for something that looks to have pump-like action without having to wear a pump.

And so we'll come back and talk a little bit about the clinical results, and I'll turn this over to Sam now.

Thank you, Richard. And I'm very, very excited to be here, to be before you and to present the results, the MBX 4291 preliminary results. Like -- with a nice story, I'm not going to go directly to the results, right? I'm going to keep you a little bit waiting. And I'm going to start with what are the guiding principle at MBX that really is leading to our strategy. And we do believe that there is a big, really big opportunity in obesity with a once-monthly dosing with improved tolerability.

So as Richard said, we are using our PEP platform, right, what we are going to optimize the pharmacokinetic of our molecules, our peptide in order to have something like a unique profile, very differentiated profile with the goal of a gradual, flattened and sustained exposure for a monthly dosing. And this -- when you achieve this, you should get better tolerability. And that's exactly what we want to get. So that's our strategy.

We presented the graph, the figure. We started presenting this in January, but the story started way before that. It started with modeling, with this preclinical data, and we came up with this profile, with this product profile in terms of PK here, which I can show you here in green, what you see in green here, that's our profile. And we compare this with products that all of you know very well, tirzepatide, right? No need to present a GLP-1, GIP coagonist marketed, and it's a weekly administration.

But we compare also -- we are comparing also our product profile or PK with Metsera 097i, which is in development for a monthly administration, right? So we said we want to get gradual. What does it mean? That here, smooth raise to the Tmax, really smooth look. And we compare with tirzepatide and MET-097i, look how steep this curve is, right? How it goes to the Tmax very rapidly. And we know that it's related to the GI intolerability, right?

And when you look again at tirzepatide, you see this variation around the Tmax due to the weekly administration, but it's not exactly what you want to get. You want to get something which is steady, stable with -- sorry, with no peak something like this, right? That's what you want to obtain. And again, this is also related to GI intolerability. More variation you have around the Cmax, more tolerability issue you get.

So now looking again at the MET-097i, you see that then you have a slow decline in terms of concentration, and they refer to the time to half Cmax, which is a good proxy for the half-life of 21 days. And when you want to get is a T to half Cmax as long as possible, as close as possible to the Tmax. And why? Because again, the peak-to-trough variation is limited, is small. And so you improve the tolerability on one hand, but certainly, you improve the dosing schedule with a monthly administration. And that's exactly what you want here. So they refer to 21 days, and we are aiming for and we're expecting to be beyond the 21 days, okay? So that's what we want. That's the story of how it started.

Now I'm going to speak about MBX 4291, which is our GLP-1, GIP co-agonist, right, with the goal of being administered on a monthly basis. We designed a Phase I clinical trial, which is ongoing. This study is ongoing. So the data I'm going to present you are still blinded. All the clinical data are blinded. We are mixing the data on the treatment and on placebo are together, right? So it's still blinded.

So this study -- this Phase I study, sorry, is divided in three parts: the SAD, the MAD, and again, another multi-dose administration, which is Part A for the SAD, Part B for the MAD, and the last one, which is the Part C, and you will see the differences. And each step informs the next. So the SAD will inform the MAD and the MAD will inform the last section of -- sorry, here inform. We are on the target population of subjects with BMI at or above 30. So everything we see can be extrapolated to the larger population of patients overweight -- with overweight.

So I'm going to spend some time on the SAD. The SAD will have -- we have 5 cohorts, and we evaluate -- we're evaluating 5 doses from 15 milligram to 180 milligram. We have -- each cohort has 8 subjects, 6 treated and 2 placebo. The MAD is a weekly administration, potentially followed a week administration for 4 weeks, potentially followed by a monthly administration. Again, the same target population, and we have 3 cohorts each cohort has 8 subjects, 6 treated and 2 placebo, right?

So the last, and the most important one, the Part C is, again, in the target population, and we were talking about potentially doing a second cohort. We are confirming that we'll be doing a second cohort. And so each cohort will include this time 30 subjects. So a much larger population of subjects with overweight of 20 treated, 10 placebo. One of the cohort, one of them will include a weekly administration for 4 weeks, followed by monthly administration for -- with a total exposure of 12 weeks. This study is -- has not started and is on track, however, to be delivered as promised by the fourth quarter of this year. So we're good on this.

So what are the study objectives? As any Phase I study, the first objective is to assess the safety, to assess the tolerability, but also to find the maximum tolerated dose and especially with a focus on the GI tolerability, nausea, vomiting, diarrhea. And we want to find what would be the best streamlined dose titration. Secondary objective, the pharmacokinetic. We want to get a monthly administration. So the PK is extremely important to confirm the potential for monthly. The second one, which is the secondary objective is the pharmacodynamic effect, which is a weight loss, right? And the last one, which is to identify the dose and the titration regimen we'll be pushing for Phase II, right? So that's the objective of this study. I hope I'm good in keeping you waiting for the last slide. Next one.

So now the SAD. I can show you in terms of PK, the results of the SAD. In this graph here, PK graph, you have 4 doses, which is we started with 15, 60, 90 and 180 milligram as a single dose. And the 120 milligram is still ongoing. The cohort with 120 is still ongoing. So what can we see here? We see that we have dose proportional PK, right? Dose proportionality is achieved. But very importantly, gradual increasing and sustained concentration after a single dose. You see gradual and steady, and sustained concentration. It looks very similar to our TPP, right? So I can check the box almost and say, well, we have achieved our first objective to look like our TPP.

So we like to compare and we look at tirzepatide and MET-097i again. And when you look at the Tmax, which is extremely important, it's a very important parameter. For both products, the Tmax is achieved after a maximum of 2 days, right, here, maximum of 2 days for 2.5 milligram 4x for tirzepatide and MET-097i, 1.6 milligram single dose. And we know that this burst effect here, the burst effect here is linked to GI intolerability, okay? So how does it compare? I already gave you some insight, but how does it compare with our product.

And here, you see in blue, the 60-milligram MBX 4291 and in green, the 90-milligram single dose, right? Here, that's 90 and that's the 60. And here, again, tirzepatide and the MET-097i. And you see that we have a delayed Tmax, significantly delayed by up to 13 to 14 days as compared to 2 days. So -- and we have this sustained concentration. So we can already say that MBX 4291 has a self-titrating PK profile and which is anticipated to improve tolerability. It's not us telling -- since we already know that how we create or we can improve tolerability and that through this PK, we can definitely improve tolerability.

So what is the tolerability of the SAD, that a single ascending dose. And here, you have here the 15, 60, 90, 180 milligram, 8 subjects. Again, the study is still blinded. So these 8 subjects, this adverse event profile really with a focus on nausea, vomiting and diarrhea include placebo in this report. If you look at the 15 milligram, you have only one subject with diarrhea, mild diarrhea. And in fact, there is a dose response in terms of the GI effect, GI-related effect. Dose response, we have an increase in terms of adverse event from 15 milligram to 180 milligram. And that's exactly what you want to show, right? That's what you want to go as high as possible and you push the dose in order to get to this tolerability.

So the 60 milligram, there's nothing. The 90-milligram has 3 subjects with one of each, one with nausea, one with vomiting and one with diarrhea for a total of four (sic) [ three ] events. The 180 milligram is the maximum tolerated dose with 7 subjects, which is interesting, 7 out of 8. I'm not a wizard, but I know that placebo is included because with 6 and 2. And we have the maximum tolerated dose with 7 subjects, as I said, out of 8 showing episode of nausea, vomiting or diarrhea.

So in conclusion, we can say that there is dose response, right? That the -- from 15 to 90 milligram single dose, it's well tolerated with adverse events, GI-related, which are mild. And we have reached MTD with 180. And again, as a reminder, the 120 is still ongoing, okay? So that's the SAD. And I'm going to pause because the next slide is the one you want to see.

So here it is, the MAD. The MAD is MBX 4291 was given at the dose of 30 milligram every week, followed by 4x the dose, 120-milligram single dose following these 4 weeks, right? That's here at the dose, very important. We went to 4x the dose. What you can see that you confirm that there is accumulation. Each time you give 30 milligram, there is -- the product accumulate. That's exactly again what you want to see. And here, you have a sustained concentration here of the active peptide. By the way, remember, MBX 4291 is a prodrug. Here, I'm reporting the active concentration. The same thing than the SAD. It was the active concentration of the prodrug. It's not the prodrug itself, but the active, the one really -- the one you want to see.

So in orange, here, remember, that's my MBX 4291, 180 milligram, the one that was the maximum tolerated dose, right? Remember, so we reached the same -- almost the same concentration, but a very different treatment paradigm, very, very different. Relatively fast titration, 4 weeks, right? You get to 180 and you get the same concentration that the 180-milligram single dose, which was the MTD. But here, we have a completely different tolerability profile, completely different. And I'm going to have a specific slide showing you the tolerability profile.

So we can say that MBX 4291 has a potential to self-titrate with repeated weekly starting dose, enabling better tolerability for 4x the higher dose, okay? 4x. So we compare again with MET-097i, which is -- which has a time to half the Cmax of 21 days, 20 to 21 days. It's a proxy, as I said, of half-life, okay, roughly. And what you want to get is time to half the Cmax to stay as high or as minimum as possible, as long as possible in order to improve tolerability and also to improve your chance for potential monthly administration.

The treatment paradigm was the same here, 4 weekly administration of MET-097i at 0.8 milligram, 4x followed by 1.6 milligram single dose. Same treatment paradigms at 4291, 30 milligram 4x followed by 120 milligram. And we can observe that here time to half the Cmax is 26 days as compared to 21 day. 5- to 6-day difference is highly important. It's very, very important in terms of reducing the peak-to-trough and increasing the chance for monthly administration. So that's probably the most important slide. The one really -- now we are there.

What's the weight loss? Again, the study is still blinded. So I'm reporting here 7%. 7% which is a very competitive weight loss, including both treatment and placebo in 8 subjects. And the range is 0% to 16%, the range of weight loss. In terms of tolerability, pretty remarkable. Only 1 out of 8 subjects showed a GI-related adverse event, and it was diarrhea, diarrhea following the first administration. There was no nausea, no vomiting, and there was no serious adverse event and this tolerability otherwise looks -- we are very confident in the tolerability profile otherwise, and we haven't seen anything which was unexpected. So pretty good.

And now I'm going to summarize this data. So MBX 4291 is designed for once-monthly dosing who is well-controlled sustained concentration -- with sustained concentration and improved tolerability. The data from the Phase I SAD, show a PK profile supporting a self-titrating weekly induction regimen and potential for a true once-monthly regimen, including: dose proportionality, sustained concentration of the active peptide for 28 days, and dose-dependent GI-related adverse events across the four dose cohorts ranging from 15 to 180 milligram.

The preliminary data from the MAD from -- it was the first MAD cohort, first one MAD cohort following 4 weekly induction doses of 30 milligram followed by 4x the dose of 120 milligram indicate: a gradual accumulation of the active peptide, a mean weight loss of 7%, ranging from 0 to 16% over 8 weeks in 8 subjects, again, still blinded, only one event of diarrhea, only throughout these 8 weeks.

We are also on track for the large cohort, larger cohort over the 12-week period, and we should be delivering these results by the fourth quarter 2026, so this year.

Thank you, and I'm going to pass to Richard.

Well, I'm back. And let's see where we are here. This is a discussion of an amycretin, right? Amycretin, the folks in Denmark referred to it as. And as I said, it's been a half century in getting to this level of complexity. When I first designed Humalog just inverting amino acids, people ask me, how do you know that's going to be safe? People had waited 60 years to get the native sequence. And here we are doing things that are so much more sophisticated to drive much better pharmacological performance.

The roots of this are in DACRAs, dual amylin calcitonin receptor agonist, which came after the introduction of the coagonist for GIP and GLP built on that work that I referred to that Matthias Tschop and I had been about. The Amylin Corporation (sic) [ Amylin Pharmaceuticals ] formed in 1987 was a first mover in this field of amylin, and they were formed by Ted Green and Garth Cooper to build antagonists of amylin because those amyloid-like entities that you found in the pancreas were believed to be pathological and had to be blocked that quickly was redirected to what became pramlintide, a short-acting registered amylin agonist that borrowed 3 amino acids from the rat sequence to give the human sequence a soluble biophysical property that would make it a drug. It ended up being a not terribly successful drug. It was used for treating prandial excursions in addition to insulin and had a potent effect on the gut.

And this all preceded the use of Byetta. Nordic Biosciences then advanced this concept of dual agonism, recruiting in calcitonin, which, as you would know, is an approved product for treating osteoporosis, but also with a potent ability to lower appetite and to suppress body weight to a small extent.

And it was Thomas Kruse at Novo that took this to another level in stabilizing the conformation of the peptide, putting a fatty acid on it to make it a once-a-week entity that you would know as cagrilintide. Thomas is incredibly capable chemist. He's also a co-inventor of semaglutide. And Novo has gone on to register or in the process of registering cagrilintide and the prospect of mixing it with semaglutide that you would know as CagriSema and then single molecules that bring in three activities: GLP-1, and the calcitonin, and the amylin. So a lengthy history there.

Our molecule was built off of a DACRA that we had stabilized with novel chemistry. And it is very potent in vitro at GLP-1, at GIP, less so at glucagon and quite potent and balanced at the amylin calcitonin receptors. We have profiled this molecule in rodents. The amylin activity is most notably seen in fat rats. The incretin activity is most notably seen in fat mice. And then you profile for PK purposes in lean cynomolgus monkeys and also note the pharmacology in those monkeys express appetite and any effect on the body weight in those lean animals.

And so what I'm reporting here is the prodrug of this amycretin. So this is now more than the first amycretin that Novo has spoken about, which has GLP-1 mono agonist. This has co-agonist. It also brings GIP just as Zepbound has GIP, and it's integrated in with the DACRA and formed chemically as a prodrug to extend its duration of action, improve its peak-to-trough, minimize the adverse GI effects that Sam was just referring to in the co-agonist incretin alone. And you can see that we have observed greater efficacy and tolerability in these rodent studies. And it is something that we are advancing as a single molecule as opposed to a mixture, which should facilitate the ability to develop it as a marketable product.

Here is a profile from lean cynomolgus monkeys. In green, just as Sam was showing you for the prodrug of the co-agonist, you can see this very flat pump-like exposure for the active amycretin that has activity against these -- notably these four receptors and a taste of the glucagon. And you can compare in the blues, the sema exposure, the cagrilintide exposures and the Novo amycretin, which were designed to be once-a-week drugs, right? And so it's the same story that you just heard about in the ability to treat this in a chronic mode in a way that sustains a precise level of drug, but never getting to these excessively high levels. And for those of you who are not chemically oriented, I would suspect you have a surge suppressor on your computer and your TV and your precious electronic devices to protect it from highs and lows.

What we're doing here molecularly is protecting your kidney, your pancreas, your liver and your brain from excessive highs and lows. And what's more precious than those organs relative to your personal computer.

In the course of developing this, doing the toxicology assessments of this compound, we make measurements in these nonhuman primates. And what you see here at a competitive dose to where we typically dose incretins and amycretins. In fact, this is slightly higher than where you could dose a cagrilintide molecule, because cagrilintide molecule has such adverse effects. driven by the GI discomfort, as I was sharing with you in pramlintide.

What we see over the course of 3 weeks after a single dose in a monkey, and remember, monkeys clear these drugs 3x faster than a human. It's because their half-life of albumin is cleared 3x faster, a profound decrease in the body weight despite the fact that these are not obese monkeys, right? But this is industrial strength pharmacology aiming for toxicology, right, 50 nanomoles per kilogram, where in an obese rat, we're using 2 to 10 nanomoles per kilogram.

But it gives us a sense of have we improved the therapeutic index? And the answer is, yes. We don't see the projectile vomiting. We do see the malaise at these very high concentrations that are typical of these incretin DACRA activities, but much less profound than what we see in the comparative single species. So 1 plus 1 equals more than 2 in terms of the efficacy and the safety, and we will publish all of the story in a respectable peer-reviewed journal.

And I'd be glad to answer questions as we come to close here just to reflect the fact that MBX has built this very nice portfolio of compounds that have built upon the ability to use synthetic chemistry in a way we were still building 50 years ago across on the east side of Manhattan in the Merrifield laboratory to generate molecules that are focused on pharmacology, not just physiological replacement that have used these fatty acids to extend the duration of action, atom efficiency, bioclearance. A fatty acid doesn't bring with it the toxicities that you see in a large molecular peg and also using this design to integrate in 2 and 3 activities and now 4 and a bit of the fifth.

And so today, we just shared with you, we have selected that prodrug amycretin as a once a month could be used more frequently for those who want even more precise exposure. And later this year, we hope to bring back to you a triple agonist that builds upon the work that we have done with the co-agonist. So let me stop there. And again, thank Kent and Pete for inviting me to join with you. Thank you.

Well, thank you, Dr. Saunders, DiMarchi, and Azoulay for that master class. For those of you on the webcast, you can just feel the energy in the room here, so I want to bring it forward to another program.

STEADI Phase IIa proof-of-concept study in post-bariatric hypoglycemia or PBH, consisted of 3 mixed meal tolerance tests administered to patients at 2 different dose levels of imapextide and initially to establish baseline values.

As a reminder, imapextide is a fatty isolated GLP-1 antagonist with a 90-hour half-life. As we observe on this slide, looking at the left, imapextide led to changes from baseline of approximately 20% to 35% increase in glucose nadir.

And there on the right, 10% to 45% decrease in insulin peak. Additionally, glucose nadir increased in 90% of patients at 100 milligrams and 100% of patients at 200 milligrams dose of imapextide.

With normalization of insulin that is greater than or equal to 70 milligrams per deciliter achieved in 8 out of 10 patients with 100 milligrams and/or 200 milligrams of imapextide. Based on these changes observed in these key biomarkers, imapextide achieved proof of concept in PBH. I would like to thank the patients and the investigators who participated in STEADI and our dedicated MBX team.

Given our growing number of peptide-based therapeutics candidates and our strategic focus, we are not committing additional resources to conducting a Phase IIb study. We believe the preliminary data for MBX 4291 demonstrate that we can design differentiated PEP, novel PEP candidates with potential best-in-class profiles.

Notably, we demonstrated true once-monthly exposure with time to half Cmax of approximately 26 days compared to the MET-097i, let's remember, mono agonist, which has reported 20 to 21 days time to half Cmax. 7% mean weight reduction at 8 weeks, and that's following a 4-week induction period and single once-monthly dose of 4291.

And the self-titrating PK profile, Tmax about 2 weeks, which helps tolerize the patients to the drug. Again, only 1 GI-related AE during the 8 weeks. So we're on track to present top line results in Q4 for a 12-week MAD cohort.

MBX 5765 applies our PEP technology and combines multiple validated anti-obesity mechanisms in a single molecule, which we call our amycretin. So the preclinical data, as you saw, demonstrates a differentiated PK profile, support of, we believe, a once-monthly dosing, superior efficacy and improved tolerability.

So at MBX, we are entirely focused on 2 areas: canvuparatide, which is on track to begin enrolling a confirmatory Phase III registrational study next quarter and our growing obesity portfolio.

In these 2 areas, we see the greatest opportunity to help transform the lives of people living with endocrine and metabolic diseases and to deliver long-term value. Recapping some of our key 2026 milestones. We have initiation of our registrational and confirmatory Phase III study in Q3. We have top line results coming in Q4. And as I mentioned, we have cash of $440 million, which we believe will support our operations into 2029. So it's a tremendous setup. I'm really proud of our team's effort and excited about our future.

And with that, I will open it up for questions. I'll start here in the front with Mike Yee at UBS.

Good afternoon. Michael Yee from UBS. Thanks for the great presentations, and it's great to see Richard here as well. Maybe just 2 questions. First, on the MAD dosing, great initial blinded data.

Can you talk about what your design of the study and design of the PK was expected to deliver? Is it expected to deliver more drug than tirzepatide such that you could get great tolerability? But as you keep going up either in this dose or the following cohorts, which are still coming, there's more drug available, so there's possibly better efficacy.

Just maybe characterize the goal of what you could see between the first, second and third cohorts. And then one second question is just on the disclosure of the amycretin or amycretin program. I noticed that it's a GGG actually with amylin. But maybe do you have a view on whether or not balanced calcitonin amylin receptor delivery is a good thing or a bad thing given that eloralintide is particularly not hitting calcitonin is, very differentiated and whether that's the right way to go?

Thank you, Mike. I'll start with Sam for the first part of the question regarding the MAD dosing regimen, and then Richard will take the second part.

Yes. Thanks, Mike. I think what we have already observed with the 4291, 30/120 is something, as you've seen that which probably in the range of concentration of the 5-milligram tirzepatide, but it's not something that we will be how can I say, only looking at because the pharmacodynamic effect might be different. Remember that it's not a -- it's also a GLP-1, GIP coagonist, but might have a more potent effect on the pharmacodynamic on the weight loss. So that's something we'll be exploring later.

And Richard, regarding our amycretin. Tomato, tomato. We're going to say amycretin, okay?

Let me just add to what Sam was saying. I'm a great believer that performance is the most important criteria, right? I had often said at a time when Lilly was struggling with parenteral products that if you have a life-saving therapy, people will stand on their heads and inject in their eyes, okay?

And maybe Regeneron actually went off and proved that people will inject in their eyes if they have a retinal disease. And so when I built this chemistry, it was all about performance, greater efficacy, greater safety, greater tolerability.

And we'll manage through the other elements that pertain to commercialization. I'm very encouraged by what I see in MBX and what they have done with PTH and now what I see emerging with the prodrugs.

Again, I go back to 1996 when Suad Efendic and I patented the ability to lower body weight in obese humans subjects, 4 subjects for 4 weeks, okay? But it was predictive of where we have gone.

So in vitro, in vivo and veritas, put it into patients, let me see what's occurring, then we can decide how to further optimize this. As to the amycretins, this is a less than clear story right now. Elora, you remember, is a DACRA that is maybe less than a DACRA because it has been diminished in one of the subtypes of the amylin receptor.

I'm not as certain about calcitonin. Lilly would have to speak to that. We can only be guided by our own data. And we've yet to detect that you can maintain the full efficacy we strive for when we are removing one of the subtype activities, when we are removing calcitonin or amylin activities.

The best-performing molecules have the full cascade of R1, R2, R3, amylin receptors, and have calcitonin receptors. And remember, we've been using calcitonin as a therapeutic. And so for people who have fears, there's reason to think about it, but I haven't seen any safety aspects that hold me back.

Again, I've been a big proponent of glucagon and people trying to tell me that I was going to get hit by lightning or something. And over the last 20 years, we've shown how you can use that in concert with other agonism.

So the prodrug is something that extends the duration of action. And elora has a delayed clearance. It has a flatter peak to trough, nothing like what you get with a prodrug. And until I'm shown otherwise, one person's opinion, I think that a good deal of the improvement that they're reporting, if it continues to hold up in subsequent studies comparing appropriate compounds may be contributed or partially contributed by the improved PK. And if that's true, then I think our prodrug should be doubly attractive.

Thank you, Richard. And giving you some insight into Richard's mastery of translation to marketed drugs is part of his resume, he didn't mention earlier that he was Group Vice President at both Lilly and Novo Nordisk, which I'm told is similar to a baseball player playing for both the Yankees and the Red Sox. But it's a really unique perspective. So I'm sure you appreciate his participation today. I see one on the -- Tyler Van Buren. Can we have a microphone or just project maybe, Tyler. There you go.

Tyler Van Buren, TD Cowen. I appreciate the presentation. Just a follow-up on the MAD. When you see that last monthly dose, the exposure looks better than the Metsera candidate. And clearly, you could potentially lead to greater weight loss.

So I'm excited to see the future cohorts. But -- can you maybe compare the program or position it against what you've seen with Amgen's MariTide data and what your view is of that candidate? And then also with respect to just in the maintenance peak-to-trough variability, clearly, 4291 is going to have lower peak-to-trough variability in the maintenance based upon what we're seeing. So is there a clinical benefit to that maybe?

Why don't we lead off with Sam again? And Richard, you're welcome to add to it. We'll go back to the slide as a reference.

Yes. I think in terms of variability and just the fact that the time to have the Cmax is much longer that and reach 26 days is really aligned with the peak to trough variability -- a small peak to trough variability.

That's the goal is really to minimize the peak to trough. And I think Richard was referring to infusion like. That's the best example, in fact, in terms of being stable, but over time and as long as possible.

So that's what we are, again, aiming for, and we're starting demonstrating already here. And when you can see -- and again, here, we're comparing concentration, not necessarily the pharmacodynamic effect, right, because it might be a different PD effect on the weight loss and also on the tolerability. And just what we observed with the really great results we already observed with 30/120 show really a remarkable tolerability profile compared to Metsera or any other drug.

And recall, MariTide is fundamentally an antibody as it relates to its PK profile. So you're really going to have this burst effect reflected here, getting to Tmax rapidly. Richard, any additional thoughts?

MariTide is an interesting substance, in many circles, a controversial substance because as you would know, it is a GIP antagonist. It's an antibody that blocks GIP action to which they have semisynthetically added a very high potency GLP-1 agonist, and it's used at pretty high doses, right, hundreds of milligrams.

I think in Phase II studies, they were up almost to 750 milligrams or more. I think so much of the success of that compound should be rooted in whether GIP antagonism can add something above and beyond what you can do with GLP alone and is there a unique contribution relative to GIP agonism.

And then that's where the controversy comes as to how can you have a GIP agonist and antagonist seemingly doing the same thing. I'm reminded of Fitzgerald saying that a form of higher intellect is the ability to hold two opposing forces in your mind and not lose your sanity, right?

And so maybe this is one of those cases. Let the data talk. I'm a great proponent of do the experiment, let's see the data and try and sort this out. The published results of a year ago just suggested that it was mechanistically different that the GIP antagonism was actually promoting GLP agonism. It was making the GLP a super agonist as opposed to blocking GIP action. But I'm not the most informed here. It's not just Amgen. There's a company in Copenhagen. Jens Holst has been a part of it called the Antag. Bring the data. Let's -- and then we'll sort this out.

Jon Wolleben here at Citizens. Can you get a microphone, please?

Jon Wolleben with Citizens. Just wondering if you could talk about the relative potencies for the GLP and GIP receptor in 4291. And then seeing 16% weight loss from a patient here at 8 weeks, can you talk a little bit how the different PK profile might change time to peak weight loss in these patients?

Richard? Thank you, Jon.

So the compound was designed to make as few changes as possible. I've been a part of drug development programs where in trying to reach for the ultimate, we changed several things simultaneously.

And you end up failing because you didn't understand the interactions that occur. So this molecule was designed to have tirzepatide-like performance, structurally unique, structurally proprietary, balance at those 2 receptors that look very much like tirzepatide in human subjects and then make a prodrug of that substance. So what we were aiming to do was to change the pharmacokinetics, right, as opposed to changing the molecular mechanism of action.

I see a question from Seamus Fernandez at Guggenheim.

Thanks for the question, Kent. So a couple of quick questions. First off, can you just help us understand a little bit better the sort of full tolerability profile? We talked about GI AEs, but I think we also see other potential AEs in other charts.

So it would be helpful to just have the context of things like injection site reactions, dynamics like that. But I know these are the GI AEs specifically. And then separately, maybe, for the doctor, if you could just give us your sense of the impact of injection frequency on patient drop-off in particular, how much would a monthly potentially impact your practice? And is it more important to have lower -- a better tolerability profile more so than a less frequent injection profile?

The first part of the question, very simply, this is an ongoing blinded Phase I trial. What we're sharing here in this table is the tolerability for the single ascending dose. And we've just highlighted the 3 GI-related AEs that, as Dr. Saunders mentioned, are just the most focused or most commonly associated with these amycretins and of interest and no serious adverse events.

And as Sam said, nothing unexpected overall. And in the MAD, recall, this is just really remarkable with this very brief 1-month induction period and in a single monthly dose, only one event of diarrhea and nausea or vomiting. So Dr. Saunders, can you elaborate on just the dosing frequency and patient preference?

Yes, absolutely. Great questions. So when you take a look at what actually leads to better weight outcomes and better health outcomes, the 2 metrics that we talk about regularly are adherence, which means how patients are taking the medication compared to how it's prescribed.

So if they're missing doses, if they're taking half the dose, whatever that is, and persistence, how long people stay on. And since obesity, again, is a chronic disease, people need to stay on the medication long term to achieve the optimal results and then to sustain those results long term.

Any of my patients on weekly would love to be on a monthly injection instead of having to do it every week. People often miss doses if they're traveling, if they forget. So having the ability to just do once a month would be very, very advantageous in terms of getting those outcomes. And then if you talk about what actually leads to these outcomes, is it more tolerability? Is it more ease of use? It's both. It's absolutely both. So the more we can do to improve tolerability, to improve ease of use, the better the outcomes we're going to see.

And I guess I would also say it provides optionality. It's not just a once-a-month drug. If you want to use this every week, you can do that, you'll get an even flatter profile than what you will get once, once a month. Remember, oral semaglutide is a once-a-week drug. It's used every day, right? So in a marketplace where there may be as many as 1 billion subjects, we shall see. There's going to be preferences for many different presentations. And the more optionality that we can provide, the better.

I see a question from Annabel Samimy.

Annabel from Stifel. So clearly, you've reached your target PK profile there, you're looking for a smooth slow release, extended duration. And you're managing through the titration -- simplified titration just with the weekly dosing. I guess I'm wondering in a very heterogeneous population, obviously, many people are going to need many different types of doses to reach their target profile.

So how do you envision having those doses available for a broad population? And I noticed in the A, Part B, Part C, the number of cohorts was actually declining. So what kind of optionality with will physicians have in the real world to find that right dose for that right patient? That's the first question.

Let me kind of break that in two, and thank you, Annabel. Let's go back to Sam, just talking about this progression from SAD to MAD to the 12-week MAD and what we're going to learn from that in terms of informing our Phase II trial, which we are already conducting the Phase II enabling studies and planning our Phase II for 4291. And just in terms of the treatment optionality, that was a really interesting point Richard made. And maybe I'll ask Dr. Saunders to elaborate?

Yes. I think we from -- as I said, these 3 parts and each part informs the next, right? And we have not been so bad, that bad in terms of expecting this cohort with a really great results. And it's a good testimony of learning from the other. We may not have started as we did here with 30 followed by 120, but we did because we learned from the SAD and we progressed as we went. And the same thing that we'll be doing for the next cohort. So that's why, at this time, we cannot commit on the second cohort because we are learning as we go. I think Kent said it very nicely. We are -- this study is still ongoing. So we are learning from this Phase I. And I think from my side, at least it's a little bit premature on how we are going to perform our Phase II study and our Phase III program. But really the good learning here is we get exactly the PK we wanted with a really great tolerability profile with quite good weight loss.

Let's recall that MET-097i began with 12 once weekly doses and then extrapolated to show monthly. And what we've shown here today on this ongoing blinded Phase I study is true monthly dosing, right? After a single once-monthly dose, we were able to show this impressive weight loss in this time to have Cmax of 26 days. So Dr. Saunders, monthly, you mentioned you think your patients would be interested in that. Can you talk more about that, please?

Sure. Yes. No, I think going back to the idea that obesity is such a heterogeneous disease and everybody responds differently to different doses. People have different side effect profiles. But again, the goal is improving tolerability, keeping people on medication. I think the more levers that we have as clinicians to be able to really fine-tune and listen to our patients in terms of the timing of side effects or the timing of when they're having hunger, cravings, food noise and really be able to choose to do weekly or monthly, that is a huge benefit.

And it's currently how we practice now when we're able to, given sort of limitations with different medications, like some patients, we do every other week, and that works better for them or we do a half a dose twice a week, and that works better. So the more flexibility that we have to really listen to what's going on with our patients in terms of side effects and symptoms, the better that we can treat everyone. And again, the monthly is a big asset.

Okay. So just to follow up really quickly on that. So your, I guess, way of addressing a heterogeneous population more in the frequency of administration as opposed to necessarily the dose, like perhaps a patient reaching max their Tmax, some might reach a Tmax maybe at 5 weeks and then you start monthly or I mean, I guess I'm trying to figure out how you deal with that heterogeneous population.

Taking a step back. Really, the way we focused on addressing this is through our obesity portfolio, where we have 3 programs, right, that we're advancing. Our most advanced one here, 4291 now an amycretin. And soon, next quarter, right, a GLP-1, GIP glucagon triple agonist. All of them are built with this PEP approach for the gradually increasing and steady drug exposures. We talked about self-titrating. These drug candidates self-titrate to help the tolerization for the patients. And we think that we can make that with monthly be a really successful treatment option. And then we have these others that are coming as well.

And can you show the MAD results for a minute? I want to make sure that everybody has connected on those. You gave -- as I understand it, Sam, you gave 30 each week for 4 weeks.

Yes.

And then in the next 4 weeks, you did not increase the monthly dose. you gave the same amount of drug in the next 4 weeks, which means that the dose that they got in week 5 was 4x larger than what they got in weeks 1, 2, 3 and 4 without causing adverse event.

Exactly. Yes. Exactly.

I find that pretty spectacular relative to how we so slowly titrate people 4 weeks, 4 weeks, 4 weeks, 4 weeks, It's that regimentation and the way we're doing this that is a problem. So I'm optimistic about what this may foretell and how quickly can we get to that therapeutic dose that will be meaningful for most. Can we get back to conventional medicine where you go to see your doc, they give you a dose, if it's safe, you can increase the dose if you need to increase the dose. We don't have to live on this regimented schedule of 4, 4, 4. And if you fall off that schedule, then what do I do? How do I get back on the ligand? So I'm encouraged. But let's be clear. These are limited numbers. We're talking about 2 months of data here. The amount of weight loss that's being cited is about 1% per week, which is about 2 pounds per week. No need to go any faster than that through the first 8 weeks. Where do we go from here, right?

I talked about a patient being able to take a dose of MBX 4291 once a month when they pay their rent or mortgage and not have to think about their disease for the rest of the time. That is really quite a transformation in the lifestyle of patients living with obesity.

Leland Gershell with Oppenheimer. Thank you for the presentation. Really, really encouraging data. We look forward to seeing what you'll have for us later in the year with the extended results. Two questions. First on sort of the data itself and kind of what they could mean. I mean, obviously, if you go to the previous slide from this one, you have the comparison with the Metsera compound, which is now part of the Pfizer portfolio. It seems like -- first of all, I'm wondering if you're able to characterize what the weight loss may be in that second month versus just the 7% over the 8 weeks. But if you're not prepared to do that, then I'll just move on to my next question.

Yes, ongoing study, blinded. So Q4, you'll get the top line results.

It seems like you have a lot of room here given the AUC between 4291 and then what is a very much smaller AUC with the Metsera compound. And also I think that's only a GLP-1, whereas you guys have the dual mechanism. So looking forward to those data. And I'm wondering, given the tolerability comes down, given the titration that patients kind of accustomed to this medication, how much room you may have to go up further?

And again, based on this kind of PK profiling and clinical data we've seen, I think this dose, I'm not sure how much Metsera shown, but at a much higher dose, I think they got to 12.3% weight loss in the VESPER- 3 study. Just curious if you have any take there? And then I have a second question for the physician.

I think you're referring to a longer time point. And again, this is a Phase I ongoing study, and we'll have data in Q4. But Sam, maybe you lead off.

No, I think it's -- first of all, we don't have the individual data. I mean I cannot see who is placebo or treated. Even we have some ideas, but it's not sure, right? And we have been conservative in our evaluation of 7% because we mixed everybody. So that's what I can say in addition to.

12-week data in Q4, very exciting.

Okay. I'll stay patient.

We continue to explore this Phase I is ongoing. And again, in terms of AUC, et cetera, we will have more data as we go.

Great. And you brought up the topic of muscle loss with weight loss, which is, I think, more and more of a problem that people are aware of here societally. Just wondering what you may be able to share with us in terms of the outlook on mitigating the muscle mass loss with dosing regimens that are less frequent and/or maybe operating on multiple receptors.

I mean, I think I'm not sure if tirzepatide is any better than semaglutide in that regard, but it's a once weekly, wondering if once monthly would be better. And perhaps it just comes down to compliance. If patients who cycle on and off therapy, how much of a problem is that when it comes to muscle preservation versus being able to stay on the drug a long time without going on and off?

Let's start with Richard on 4291 design and then Dr. Saunders on clinical experience.

4291 in what respect?

4291 and the amycretin?

Yes, the amycretin, the 5000 series.

Yes, 5765.

Again, this is -- it's different from the co-agonist and triagonist incretins where we make a molecule that is the same size as the native hormone and we just make a chimerized sequence. But at the end of the day, it's like a master key that can see all 3 receptors, but it looks physically like a glucagon, a GLP or GIP. In this instance, the 2 hormones are sufficiently different, and the receptors are sufficiently different that you have to use both peptides and tie them together.

And you would know that Novo has spoken about the fact that they make a linear fusion of these 2 molecules. And I might remind you that the first in this series was davalintide, which was an amylin molecule where they had taken pramlintide and tied it in with ASCEND or ASCEND-4, right, by Takeda and quickly divorced themselves from the area because they saw such severe GI effect in that compound, the projectile vomiting that they said we can't go.

Both of these mechanisms have a GI adverse effect. And so there was real question as to why anybody would want to make a DACRA. But to the credit of the folks at Nordic Bioscience, and I said to the folks at Novo, they really did a terrific job in advancing the DACRAs, and now Novo leading in putting this into a single molecule. Ours is also a single molecule. I'm not prepared to tell you exactly the chemistry that we use. But as I promised, it will be in a peer-reviewed report.

And maybe you both can comment. My understanding is that preclinically, we've seen some signs that amylin DACRA can preserve lean mass, but we're still looking for that signal in the clinic. But as...

Again, when we're in monkeys, we don't go above 30 nanomoles per kilogram when we're studying these molecules, right? When you're doing aggressive dosing. With this prodrug, we get to 15 nanomoles per kilogram without seeing those side effects that we had seen at 30 in a lean monkey. And it's, again, a nature of the fact that it is a fully potent DACRA, but has a prodrug.

So the story is unfolding. Dr. Saunders, please share some clinical insights.

Sure. So just briefly in terms of -- there's so much hype right now about muscle loss. And I think in many ways, there's almost too much hype and fearmongering. And what we actually see is no matter how people lose weight, regardless of the mechanism, literally from diet to a range of medications to surgery, about 25% to 33% of what people lose is lean body mass, which includes muscle. And so it has nothing to do with the mechanism. It's more to do with how much people lose and what that looks like. We're learning much more with so many trials underway about different mechanisms that can affect this.

But basically, what we do right now is make sure that people don't lose weight so quickly that they're not able to keep up with protein requirements and physical activity, including strength training.

So that's what we do right now. And the ability to sort of use precision to make sure that people aren't losing weight too quickly or too slowly is a huge asset. And also the ability to have everything be just much more streamlined because as you said, if people stop medication, then they gain weight, and then it's the cycling that's also a problem because you don't necessarily rebuild all of that lean mass each time, and it can get worse. So having the characteristics that we're talking about here, we'll have to see with the data but are promising in terms of the effect on lean body mass.

I share that perspective. Very much. And what goes around comes around and takes us back to the late '90s when we were all focused on sarcopenia. And I think what we're seeing is we reduce body weight that elderly subjects suffer from sarcopenia to certain degrees. And unquestionably, if you can find a substance that is safe and the emphasis on safe, right, testosterone builds muscle like no other substance.

But again, it's not something that is viewed as being suitable for long-term treatment. If we can find something that is capable of building muscle and elderly subjects safe, safely, would be great just as a stand-alone and additive or integrated as part of the amycretin, wouldn't that be lovely.

I love the reference to Precision. It reminds me of our PEP platform, right, Precision, endocrine, peptide. Well, Pete's giving me the sign.

It's not quite the sign. Just given questions online, maybe you or Sam can address. Just confirm that we're not seeing anything notable or concerning with regard to injection site reactions in the SAD/MAD data for 4291.

Yes, I can definitely confirm this. I would say it's no concern with regard to the ISR. I mean it's a peptide. So we observed some reaction, but nothing that will be worrisome of a concern.

Okay. I see a question in the back second to last row. Arm raised. Yes, there. Thank you.

Jess Fye, JPMorgan. First wanted to ask about the MAD. So based on Cohort B, I guess, the B portion of the MAD, is 30 milligrams weekly followed by 120 monthly the favorite regimen at this point? And can you confirm if that's one of the regimens in Part C? And what's the other dose combination regimen for Part C? Will the disclosure in the fourth quarter be for one of those Part C MAD cohorts or for both? And then second one is just commercially for Dr. Saunders, just a bit kind of high level. Can you talk about where you see the injectables living in this large market and where you think the orals are going to live in the market?

I'll take the first part. This is an ongoing Phase I trial where Sam said, the SAD or week MAD informs the Part C. I think Sam was a bit understated, we really did well choosing this first MAD Cohort, right, Cohort B1. And we'll see what we end up deciding for the Part C. But I want to be clear, that has not started yet or the final decision on dosing regimen has been decided either. But Dr. Saunders, you're popular with the questions today, please, on the oral alternative question.

Honestly, I think the more options we have, the better because different people want different things, different people respond to different things, where orals have a big role right now is initiation of treatments. And then just given the efficacy of the available orals versus the efficacy of injectables, if people are on an oral and they max out and need to step up, then we would switch them over to injectable. Most of our patients, when they know their oral options come in saying, "Oh my gosh, can I switch over from an injectable to an oral?"

But when we explain kind of the differences and especially if someone is on a higher dose of an injectable, an oral may not cut it for them. And so most of them choose to stay on an injectable. I think that people don't -- it's not such a crazy idea anymore to be on an injectable for obesity. When we were convincing people to take a daily injectable, that was a little bit harder. But if something is working and tolerable, then people will take it.

So I think short answer, there's a role for both. I think oral more for initiation and injectable just right now is they're the more effective medications and to be able to do a month -- a weekly or a monthly instead of taking something every day is absolutely very attractive for many people.

I see a question also a second row from the back. Can you -- I can't see too well from here, but please, can you pass the mic down? Srikripa, please announce yourself.

This is Srikripa from Truist. So for -- between tirzepatide and 4291, you reached Tmax, obviously, at a different time frame. Could there be a difference in appetite suppression for the first 2 weeks of -- for patients who are on 4291? And how does that -- how will that evolve? And also for Dr. DiMarchi, going back to the PEP platform, how tunable is the cyclization rate? And maybe from a life cycle management perspective, would there be a potential quarterly in the future?

We'll start with Sam and go to Richard again.

I don't think it will have any impact on the appetite suppression, and we saw it even from our first B1 cohort as we get the 7% weight loss average after 8 weeks. So I don't think that will have a significant impact or any impact.

The PEP platform, this chemistry is incredibly versatile. As I said, you can go from 1 hour to 1,000 hours, no enzymes, no co-factors, intramolecular, all dependent upon time, temperature. That's not the challenge. We just dial in what do we want the speed to be. The bigger challenge in doing what you just asked, can you make it once a year or once every 6 months is how big is the dose going to be because now you got to give 365 days of drug as opposed to 1 day of drug. And what are you going to use as the protractor?

Because what we have here is built on albumin or plasma proteins, predominantly albumin as the reservoir, circulating reservoir. It's turning over with a half-life of 21 days, right? So whether you convert into an active entity or not, the albumin that it's bound to is going to disappear, right? So you have nonproductive clearance. So you have to introduce a second mechanism for extending the duration of action. And we have published on some of that, and this is not the forum to discuss it, but it is something that is possible and something that I would be interested in continuing to work on.

Yes, we are. We're down to the last question. Pete, you can direct it. Please ask a question. The microphone is coming.

Ellie Merle, Barclays. Congratulations on the data. Just a quick follow-up for me. So on the second dose or dosing regimen that you're adding to the phase -- or the Part C portion, can you elaborate on sort of how you're thinking about that, particularly the phrasing that you had on another potential dosing regimen, sort of what you might be thinking about there in terms of exploration? And just -- I think it was asked already, but I just want to confirm, will we get that second cohort from Part C at the data update later this year?

I'll lead off. Thank you, Ellie. We are committing to the first 12-week MAD cohort in Q4 as previously guided. We have also today announced that we intend to have a second cohort. The timing of that, we've not yet committed to. But in terms of how we're thinking about it, I'll let Sam give some more thoughts.

Yes. We are clear about first cohort will be a weekly administration for 4 weeks, followed by a monthly administration over the 12-week period, and that's what we are thinking right now. So the things that we'll have to determine it will be what dose we will be exploring in this cohort C.

And based on the MAD B1 cohort data, which Sam shared, I think you can understand why we're pretty excited about advancing potentially that dosing regimen in Cohort C1. With that, I think we can declare Obesity Day a success. Thank you for participating in it, and we wish you a great rest of the day.

Great. Good afternoon, everyone. Welcome. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing our 44th Annual Healthcare Conference today with MBX. First, you're going to hear a presentation from the company, and then we're going to go into some Q&A. So if you're in the room here and you have a question, just raise your hand, someone will come over with a microphone or alternatively, you can also submit questions online, and I can read them off the iPad up here. But with that, let me turn it over to MBX's CEO, Kent Hawryluk.

I'd like to thank Jess and the JPMorgan team for the invitation to present at the JPMorgan Healthcare Conference now for our fourth year. MBX is an Indiana-based company. So we're very thrilled right now with the success of our IU football team, brought my hat. But maybe no one more thrilled than a VIP guest. We have Richard DiMarchi, distinguished Professor of Biochemistry at IU. And frankly, a legend, as one investor in our last meeting pointed out. Inventor of Humalog, the first GLP-1/GIP co-agonist and first GLP/GIP glucagon triple agonist, the precursors to Mounjaro, Zepbound, retatrutide. And I would just say that as exciting as football is hearing in a national championship, more important is the impact that Richard's discoveries have had on millions of patients with metabolic diseases. And it's really an honor that he's here because he and I have been partners for the last 20 years and more.

He's a co-founder of MBX. He's a key architect of our precision endocrine peptide or PEP platform technology that's clinically validated and producing some potential best-in-class therapeutics. Today, I'm going to be presenting for the first time preclinical data on our newest next-generation PEP candidates in obesity, underscoring our commitment to addressing the full spectrum of the disease. I'll be making forward-looking statements. I encourage everyone to review our risk factors and other disclosures in our SEC filings. MBX is pioneering PEP therapeutics with a passion to give patients their freedom through convenient and tailored treatments for endocrine and metabolic diseases. We have a pipeline of potential best-in-class therapeutics addressing proven markets and significant unmet need. We have our most catalyst-rich year in our company's history.

In terms of our lead program, Canvuparatide, we have a number of major milestones this year. Most importantly, in the initiation of our confirmatory Phase III trial in Q3. Building on the Phase II successful data release, which clinically validated our PEP platform technology and also the encouraging preclinical data on our first obesity candidate, a 4291, a GLP-1/GIP co-agonist with potential once-monthly dosing and better tolerability. And we're now tripling our obesity portfolio this year with the finalization and selection of an amycretin and a GGG agonist in the second quarter and third quarter of this year. In the fourth quarter, we will be releasing the MAD 12-week data from our Phase I study that's underway. And that study is designed to demonstrate once-monthly dosing and better tolerability. We have for Imapextide a Phase IIa proof-of-concept study readout in Q2.

MBX is in a strong financial position, especially following the successful $200 million public offering on the heels of our positive Phase II data last September, which left us with around $375 million in cash at year close. This supports all of the clinical studies that I've described and more, completion of the Phase III -- 2 Phase I proof-of-concept studies in our 2 newest obesity candidates as well. So we believe that we have a tremendous opportunity to demonstrate benefit for patients in 2026 and beyond. Now I'm going to take you briefly through our precision endocrine peptide PEP technology, starting on the left with innovative peptides that are designed to optimize for potency, including multiple mechanisms of action in a single peptide, dose volume, shelf life, other properties to enhance the patient experience. Next is our programmable prodrug technology, which provides slow release of the active peptide in the bloodstream without needing any enzymes. It's through a natural chemical process.

The purpose of this is to improve tolerability through a slow rise and steady exposure. We often talk about infusion-like exposure without the inconvenience of a mechanical pump. Then fatty acylation to extend the time in the bloodstream. And this is to provide extended exposure and more convenient, less frequent dosing. So we synergistically combine these technologies to provide potential best-in-class therapeutics with convenience and personalization. There's a lot of enthusiasm building in the hypoparathyroidism, HP community for Canvuparatide. Patients point out that they really are excited to regain their freedom from the daily burden of their disease, and they specifically say that once weekly will make a big difference in their quality of life. And this is a pretty sizable population. We estimate a U.S. and EU prevalence of over 250,000. The standard of care is antiquated. It does not address the root cause of disease, PTH deficiency, and it's a steep burden.

Think of taking large doses of active vitamin D and calcium throughout the day and night. And for some, it's setting your alarm clock for the middle of the night to wake up and take a handful of pills. The symptoms are devastating from cramps to brain fog to seizures and the long-term complications are even more serious, kidney stones, chronic kidney disease and cardiovascular issues. But there's reason for hope. New treatment guidelines stress the importance of PTH replacement therapies, and our competitor is establishing the market through once-daily YORVIPATH. And with our recent positive Phase II data, we believe it supports best-in-class and a new standard of care and an opportunity to get more patients on a PTH therapy. Our Avail Phase II study, very successful. It -- we saw a 63% responder rate at 12 weeks. That was highly clinically significant -- clinically meaningful and statistically significant. That rate improved to 79% at 6 months.

Importantly, 94% of the patients who completed the 12-week study chose to enter a 2-year open-label extension study. One KOL remarked that, that was one of the strongest indications he saw of our drug's efficacy. We had excellent safety and tolerability. There were no discontinuations. We had no treatment-related SAEs. 96% of responders at 12 weeks remained responders at 6 months, pointing to the excellent durability of effect. And well, I think you can see why we're very excited to advance to Phase III. It's been great to see the translation from the original PEP design from Richard through the preclinical and Phase I results and then last September, the Phase II. Once weekly drives preference in HCPs and HP patients. These are new primary market research data that I'm presenting. And you can see that over on the right, 100% of patients said they would choose a weekly over a daily and the vast majority of health care professionals.

Importantly, looking down below, 80% of the docs said they would intend to switch their patients from a once daily to a once weekly. This isn't surprising. It's been consistent with what we've been saying in our conviction that we would become the category leader. And it's what we see in other indications when you switch from a once daily to a once weekly. You see rapid adoption of the once-weekly and an expansion of the number of patients on therapy. It's a big year ahead for the program. We are, again, really excited to start enrollment, we expect in the third quarter of this year and to continue updating with data from our open-label extension with 1-year data expected in the second quarter at a major medical meeting. Based on our confidence in having a successful Phase III study, we don't want to lose any time on commercialization. So we've already begun the pre-commercial activities and intend to recruit a Chief Commercial Officer this year.

Well, in the 20-plus years that I've been in obesity, I would say I witnessed nothing short of a revolution. Just think back 2005, we were talking about obesity being a result of lifestyle choices and that it was virtually impossible to treat the disease safely and effectively and how far we've come. And yet there's still more work to do. And I think there's now a recognition that we're entering a phase of looking at the individual needs of patients and bringing to them sophisticated next-generation therapies. And it's really our goal to become a leader in the obesity field and address the full spectrum of the disease. So how are we addressing the unmet need? Let's start from the pharmacokinetic or PK perspective. We know that some major needs for patients when we talk to KOLs, when we talk to industry partners is tolerability. And think about it, what good is a drug even if it's effective in lowering weight, if the patients feel lousy, they're not going to stay on it.

Also, dosing frequency. This is a chronic disease. We realize it takes lifetime treatment. And so patients want less frequent dosing. This graph is a concentration curve designed to kind of show you how we differentiate, starting with the red curves, which is representing Zepbound or tirzepatide. So if you look at that on the left, you see the steep rise in exposure and then it's kind of trailing off and then that repeats every week. It is a once-weekly therapy. And the KOLs tell us is that steep rise to Cmax exposure and the fluctuations that's causing the GI distress. So when -- and nausea, vomiting, leading to discontinuations, poor adherence. Now let's look at the green curve. This represents our target product profile based on translational modeling. Instead, you see this slow rise and then steady exposure. One endocrinologist who looked at our data described it as almost peakless or without peak. And we think that's a great way to look at it.

Again, infusion-like exposure without the pump. And we believe we'll have a long exposure to support once-monthly dosing, but with tolerability. I mentioned the full spectrum of needs, and I'll start with 4291, our obesity candidate in the clinic. This uses the gold standard of GLP-1 and GIP mechanisms proven in Zepbound. But like I shared, with better tolerability and once-monthly dosing. Next, one of our newest next-gen PEP candidates Amycretin. Significant weight loss through a synergy of the incretins and also this complementary mechanism, amylin, which is thought to not only suppress appetite and lower weight, but potentially preserve muscle. It's a recurring theme, but once monthly and better tolerability as well is our expectation for our Amycretin. And then our GGG. Introducing glucagon to turbocharge weight lowering as we saw with retatrutide with nearly 30% weight loss last December in their Phase III, but with tolerability issues where we think we can improve. So MBX is developing a robust obesity portfolio with the potential to give patients choices.

Now we'll kind of look behind the scenes at how we got -- how we get to that green curve of the target product profile. This is 4291 invented by Richard. In the illustration in the lower left, we depict our 4291 in red because it's a prodrug. It's designed to be biologically inactive. However, in circulation, note the red zig-zag at the left, that slowly releases the active peptide. So on the right side of the left panel, you see it's now a neon purple, indicating it's active. And note the yellow tail as well, that is the fatty acylation, which associates with the heart-shaped molecule albumin. So over on the right, this shows the mechanism of action at work. The active peptide is able to release from albumin and bind to either GLP-1 or the GIP receptors, which are known mechanisms to drive weight loss. I'm going to present some proof-of-concept data supporting the tolerability hypothesis that I gave.

Let's look at the left in this concentration curve. After a single administration in nonhuman primates, we see that slow rise in exposure, and it's dose proportional. After the fourth once-weekly dose, we see flat as a board exposure and some accumulation as expected. So this is very representative of that infusion-like exposure. As well, we did see good tolerability here in this 4-week study. The NHPs did not show nausea or vomiting while losing almost 20% of their weight. Note in NHPs, they turn over albumin 3x faster than in humans. So you -- we tend to see a shift for longer activity in humans, in fact. This is where we are today. We have a Phase I study underway, and we are on track to present top line results for our 12-week MAD study in the target population, BMI 30 and above. And it's designed to show once monthly dosing and better tolerability. We have the potential for multiple cohorts to try different dosing regimens as well.

If there's one slide to remember from the presentation, I would say this is it. This is our big reveal for JPMorgan this year, and we're showing how we're, like I said, tripling our obesity portfolio. On the left, this is our Amycretin, where we're finalizing our development candidate selection. I'm comparing -- now you're used to concentration curves. I'm comparing the novo Amycretin in blue where you see that steep rise and then the exposure is falling off, to our Amycretin prodrug active peptide following release from prodrug. There in green, you see the slower rise and steady exposure out supporting, we believe, monthly dosing. Now over on the right, we see a very similar profile for our triple agonist program. In green, in this case, it's not retatrutide, but our proprietary triple agonist, but has very similar PK characteristics.

And again, the steep rise and the falling off and yet the triple agonist prodrug active peptide has the slower rise and steady exposure. We can't wait to see this translate and look forward to sharing updates on our development candidate selections and clinical plans later in the year. In our effort to treat the full obesity spectrum, we recognize that patients experience post-bariatric hypoglycemia or PBH after undergoing bariatric surgery, itself a mainstay obesity treatment. Pretty sizable population as well, frankly, similar in size to hypoparathyroidism by our primary market research, over 125,000 patients in the U.S. are affected. And the impact on quality of life is devastating, particularly due to the unpredictable timing of the severe hypoglycemia, which can lead to loss of consciousness, even death. So there's a fear factor. Imapextide is designed to be a potential best-in-class treatment for PBH as a GLP-1 antagonist with intended once-weekly dosing. It's fatty isolated GLP-1 antagonist.

And the idea here is to give patients their life back through given peace of mind, days and nights without crashes or interventions. And we have Phase IIa proof-of-concept data expected in Q2. Similar to the response we saw from our market research in HP, again, once-weekly dosing really drives preference. We saw that almost all of the patients would choose based on our profile, looking at our data, our once weekly versus a once daily and a majority of the HCPs as well. So very encouraging. And with that, I would say we have a great setup for this year. We are unique, I believe, in having 3 clinical stage programs, 2 new obesity programs that will be on their way to the clinic, a track record in innovation in obesity, I would say, perhaps second to none in biotech companies of our size and cash to give us a lot of optionality in how we advance these programs to patients. So I -- very excited to share throughout the year updates on our progress and data. Thank you. I think we now have questions.

Great. So as a reminder, if you do have a question in the room, just raise your hand so someone can bring you a microphone. One here?

I have a -- firstly, I have a question about your amylin analog program. Have you disclosed, is this high selective on amylin receptor over calcitonin receptor or not?

We have not disclosed that. Stay tuned.

And the next question is, can you adjust the speed of the prodrug's cyclization? I mean, are you using the same internal design for each molecule or you are trying different combos?

We call it a programmable prodrug because we can tune it for different release times.

Yes. I mean, if you are using different ones, why don't you choose one -- the slowest one for all the molecule?

One aspect is our molecules are fatty acylated and albumin has a 21-day turnover in humans. So we pay attention to that as well. You don't want sort of wasted a drug onboard due to the albumin turnover.

The last question about your long-acting design, expected prodrug design, is there any special design of the active drug?

The active drug is the starting point, and that's where I referred on -- if you recall the slide on the left, the innovative peptides. And there's a lot of protein engineering that goes into that to increase the potency, dial in multiple mechanisms and pay attention to stability, solubility, et cetera. And that's where I go back to just having an exceptional expertise in MBX.

So maybe just at a high level, while we're talking about the platform, can you talk about your framework for selecting targets and potential drug candidates?

Staged, evidence-based. We look at our protein engineering strengths, where we can apply that, the unmet need and certainly market size.

All right. Maybe starting with Canvuparatide, can you talk a little bit more about how the design and mechanism of Canvu compares to YORVIPATH or AstraZeneca paratide?

Yes. It's very different. Remember, we have this slow release through our prodrug which cyclizes in -- under physiologic pH and temperature at a controlled rate. Importantly, the active peptide is fatty acylated. So it has a long half-life, or semaglutide, tirzepatide, which are fatty isolated. It's the combination of these 2 technologies, I want to stress that creates this infusion-like profile, PK profile, and that's very differentiated. In terms of similarities, it's replacing the missing hormone PTH. And our active peptide is a full agonist at the PTH-1 receptor as is Ascendis' YORVIPATH's active peptide. So one of the features is we had a peak to trough over a week. We showed in our Phase I data in healthy volunteers, that was the same as YORVIPATH's over a day, which we believe is more infusion-like.

And I guess if we look to the Phase II Avail data, what are the specific kind of metrics or endpoints that you think best support the differentiation of your drug?

Sam?

Yes. So we had very positive results at 12 weeks after the double-blind placebo-controlled period with 63% statistically significant and certainly clinically meaningful. And we got the 79% at 6 months during the open-label extension. I think that's a really good number in terms of responder rate. And also the number of -- the percentage of patients moving from the double-blind placebo controlled to the open-label extension, we had 94% of the patients moving to the open-label extension. All these characteristics, I think, are extremely valuable results and can also good sign for our Phase III program.

How should we think about the higher-than-expected placebo response in Phase II?

So I'm going to start again by saying that we got statistically significant results versus placebo, which was not only significant but also meaningful. And our placebo response rate is not surprising, and it's very similar, in fact, to what YORVIPATH observed at the end of their double-blind placebo-controlled at 4 weeks in their Phase II, which was in the ITT population was 27%. We got 31%. So not that very much difference there. However, what is the most important thing is that what will be the placebo response at 6 months. And we do believe that in -- aligned with what YORVIPATH observed with 5% placebo rate response at 6 months, we would expect to see the same thing. It's very simple to explain. It's very unlikely that the patient with Hypoparathyroidism who need treatment can stay 6 months with a placebo. So we are expecting to see also in our Phase III program, a low placebo rate at 6 months.

When we look ahead to the 1-year open-label extension data coming up, what would you orient folks to watch for in terms of efficacy and safety? And should we expect to see any new metrics with that update? And can you remind us of the competitive benchmark at the 1-year mark?

So at 1 year, what you would expect to see is, first, the retention rate. Again, we got 94%. So it will be important also to see how many patients are still in the study. We'll be looking at the durability of effect, right, the response rate at 1 year. But if you remember, we looked at the bone biomarkers, they were moving to the right direction and even some experts, especially Will Dere who is the one who developed FORTEO was very enthusiastic about the bone biomarker. So it's great. But most importantly is that the biomarker is the BMD so that will be a new data that we'll be releasing. And what we want to see is in this population, the BMD is pretty high. They have a dense bone. There's no turnover. So we showed that the turnover is back through the bone biomarkers, but the BMD will be an important measure. We'll be also looking at urine calcium and we'll be looking at safety and tolerability.

You mentioned the dense bone. So do you want to see it kind of start to normalize?

Yes, exactly. So what you would expect to see on the bone biomarker increase is normal when you reestablish a PTH condition. So that's what you would expect. But after a certain period, you would expect to see a plateau. BMD should go down. But within the normal value, the same thing that YORVIPATH observed within the normal value when matched in terms of gender, age and ethnicity.

Okay. How many patients are still ongoing in the Phase II OLE?

So you will have to wait a little bit when you will be releasing the data.

All right. And what about -- I think you mentioned you've got an end of Phase II meeting coming up here. What do you intend to discuss as it relates to trial design? And is there any possibility of an outcome that would enable you to get urinary calcium data in the U.S. label?

So the end of Phase II is a normal process with the FDA. So we meet with the FDA at the end of the Phase II before initiating a Phase III program, which is a normal path. And so we'll be discussing with the FDA the design, the study design. And again, we are not going to recreate the wheel. We are going to follow the path for this type of product for PTH replacement therapy, which we'd expect to be a double-blind, placebo-controlled study for 6 months, followed by an open-label extension. The endpoint, the good thing is the endpoint that we chose in the Phase II. We are going to use something very similar in Phase III. In fact, the same composite endpoint with -- in addition, the FDA is likely to require -- I'm not speaking on behalf of them, we'll see, but it's likely to require a stable dose during the last weeks. And we will be discussing also with the FDA the condition for urine calcium and other parameters that would help us being, how can I say, highlighted in the label or elsewhere. But really, that will be a condition to be discussed with the FDA.

From an enrollment perspective, would you still expect to enroll kind of patients who had normal urine calcium even if it wasn't elevated?

So we are going to select a population of hypoparathyroidism, but we are going to stratify and to make sure that we have enough patients with elevated urine calcium that will help us also to show and demonstrate the reduction in this population.

Okay. How do you think about Phase III enrollment time lines in light of YORVIPATH's commercial availability?

It's a global study. We had really strong enrollment. Remember, in our Phase II when YORVI was on the market, we exceeded our original enrollment target. We have a lot of enthusiasm from patients and PIs. And Sam, do you want to elaborate?

Sure, sure. So I have a number of anecdotal stories. I'm not going to tell you all of them. But just -- we were in the hypopara association, which was, I believe, in October last year. And we got a lot of enthusiasm, not only from the physician, but also from the patient. You know that this population know very, very well their disease. They were enthusiastic about the potential for weekly administration. So we are not concerned by the recruitment even in the U.S., to be honest. In fact, our Phase II was also concomitant. The recruitment was concomitant with YORVIPATH. And the population is large, so we are not concerned. But all the anecdotal stories I said, one of them being that the physician wanted to be a site -- physician wanted to be a site for Phase III and put their patient in the study, include their patient in the study.

We view the launch of the daily YORVIPATH is going well. There's still a vast majority of patients who are not on a PTH replacement therapy. Let's be clear. And then in our market research, we had CenterVue provide our blinded profile to ES treating HP patients. And they came back to us that this would be their drug of choice and drive switching. So we -- combined with the enthusiasm we're hearing from the PIs, we think we'll be in a real strong position to enroll the trial. We -- by the way, are currently looking at approximately 4 quarters for enrollment kind of in line with other studies, other type of Phase III studies. As we understand the enrollment rate, we'll provide updates.

So maybe this will get you to share some more anecdotes. But what are you hearing from KOLs on the back of your Phase II data about their reaction to the clinical profile? And where do they see Canvu fitting into the market?

Yes. I already gave you the feedback from Will Dere, Will has developed FORTEO. So he knows very well the field. And when he saw our bone biomarker increase and the drug effect, he was really enthusiastic about the potential that this drug has. And again, when we meet with our investigators, but also with other experts and at the hypopara association as an example, we find this similar enthusiasm. And it's aligned with the market research that Kent just discussed, completely aligned that the weekly administration is a driver.

So what market share do you think Canvu could ultimately capture?

We aim to be the #1 prescribed PTH replacement therapy. And we believe we can back that up with our clinical profile, which continues to improve and with the market research that we've conducted.

Any PTH questions in the room? And we will shift to obesity. So you're heading into a Phase I readout in the fourth quarter. What do you want to see both in terms of weight loss and tolerability? And what's the right competitive benchmark that we should hold this data up against?

Yes. So the Phase I which is in the target population. So we even could speak about -- talk about Phase IIa almost, target population of patients with BMI above 30. So this study is divided in 3 parts, and each part informs the next. So the first one is the SAD when we'll be evaluating different doses. And we'll have already a good idea about the tolerability, GI effect like nausea, vomiting, diarrhea, et cetera, but also a good idea about the PK. Then we'll be moving to the MAD. The drug will be given weekly for 4 weeks. And again, good idea about tolerability and PK. But the most important part will be the last one, the 12-week portion of the study, where, again, we will be evaluating potentially different treatment algorithm in order to optimize the tolerability.

One of them being, as an example, to administer MBX 4291 on a weekly basis for 4 weeks, then monthly. So at the end, we will have a tolerability profile, right? If we are right in terms of what the PK we discussed, we will have the confirmation about the monthly PK because it will be a real monthly administration. And the last one will be an idea about weight loss. So -- and if everything is combined, then it opens the path to the Phase II, the next step of development.

And I would just emphasize the tolerability. I think they're fair to say there are a number of parties out there that are pursuing longer-acting incretins, for example, but they're focused on the tail. In other words, the exposure duration, but they're less focused on the burst effect that we continue to hear from KOLs is actually driving the intolerability. So we believe that our prodrug approach is a novelty that can give us some confidence that we'll see that better tolerability show up in our 12-week study.

So what's the benchmark that you want to beat on nausea, vomiting, whatever tolerability metric you want to look at?

Well, we want to compare it to other once monthly. That's important. assuming that we can indeed dose once monthly in our 12-week study as we intend to. And there, we've seen some challenges with other monthlies that employ different technologies such as antibodies or antibody derivatives, think of Fc fusions, where you get that steep rise to Cmax and then you're having to lower the dose, titrate, et cetera. We just have a very different approach. So really can't wait to see the data. I think it's going to be -- 12-week data is really currency in the field.

Okay. So 291, let's say you're going to start to see what you want to see. Where does this fit in the market, which seems to be evolving, right, among not just injectables, but also orals?

The beauty of the monthly incretin injectable subcu that we're developing is that it can be better tolerated and also drive better adherence with a convenient once-monthly dosing and a durable effect. And with orals, there are some questions. If you lack adherence and you get back on, you can get some spikes in exposure and the GI issues, similar that I talked about earlier. So I think we're in a sweet spot. If you pull patients whether they would prefer to remember to take a pill every day versus once a month, I don't know, maybe when they're paying their mortgage or rent, take it a subcu injection, easy and you don't have to think about it. I like our positioning. But I go back to -- this is now in the field of -- or in the time of individual needs, addressing individual needs. There's no question how large the obesity market is, the unmet need is. And I think there's a role for different treatment approaches.

All right. Well, with that, we're out of time. So we'll stop there. Thank you.

Thank you.

Thank you.

Ladies and gentlemen, greetings, and welcome to MBX Biosciences Conference Call. Today's call is being recorded. [Operator Instructions] As a reminder, this conference is being recorded.

It is now my pleasure to turn the call over to MBX Biosciences Senior Director of Investor Relations and Communications, Jim DeNike.

Thanks, Rob. Good morning, and thank you for joining us this morning to review the exciting top line results from our Avail Phase II clinical trial. I'm very pleased to report that earlier this morning, we issued a press release announcing positive results from our Phase II trial of once-weekly canvuparatide in patients with hypoparathyroidism as well as six months results from the ongoing open-label extension study. The press release and presentation slides are available on our website.

So, before I turn the call over to our speakers, I want to remind everyone that this presentation includes forward-looking statements. These statements are based on current expectations and projections and are subject to risks, uncertainties and assumptions. I encourage you to review the risk factors and other disclosures outlined in our most recent SEC filings, all of which are available on our website.

Joining me on the call today from MBX are Kent Hawryluk, CEO and Co-Founder; Dr. Sam Azoulay, CMO; and Rick Bartram, CFO, who will be joining for Q&A.

I'll now turn the call over to Kent.

Thank you, Jim. Good morning, and welcome. Today, we are thrilled to share positive top line results from our Avail Phase II trial. The results exceeded our expectations and reinforce the potential of once-weekly canvuparatide as a best-in-class treatment for hypoparathyroidism. We took a peptide PTH with a natural half-life of an hour and engineered it into a therapy that can be given once weekly. This is a powerful demonstration of our Precision Endocrine Peptide or PEP platform technology. Today marks a seminal moment for the company and the patients we serve.

We committed to provide 12-week results this quarter. Due to the rapid enrollment of the trial and the high rate of patients choosing to continue into the extension study. In today's update, we are able to include six-month results alongside the 12-week double-blind portion. These data offer a comprehensive picture of once-weekly canvuparatide's clinical profile and provide a strong foundation as we plan for Phase III and ultimately registration.

I know you're eager for the data, so let's begin with the top line results shown on Slide 4. These results are exceptional, and they redefine what's possible for patients in our PEP platform. At week 12, 63% of patients receiving once-weekly canvuparatide achieved the primary composite endpoint compared with 31% who responded on placebo, representing a statistically significant difference. Importantly, every patient completed the 12-week study and 94% chose to continue into the open-label extension. We view this exceptionally high rollover as a clear testament to patients' enthusiasm for continuing their once-weekly treatment.

In the ongoing open-label extension, overall responder rates increased to 79% at six months, highlighting the consistency and potential durability of response with once-weekly canvuparatide as doses are optimized over time. At week 12, urine calcium excretion was reduced in canvuparatide-treated patients with elevated baseline values, highlighting the therapy's ability to help restore calcium balance. We also saw increases in bone biomarkers in canvuparatide-treated patients at week 12 with continued improvement at six months, which is consistent with reestablishing normal bone physiology. Once weekly canvuparatide was well tolerated in the 12-week trial with no treatment-related serious adverse events or discontinuations. Together, we believe these results underscore the potential of once-weekly canvuparatide to establish a new standard of care for adults with hypoparathyroidism and strongly support advancement into Phase III development.

Before diving deeper into the results, let's review the disease background. As shown on Slide 5, HP is a chronic condition with significant unmet need that affects over 250,000 people in the U.S. and Europe combined. The disease is caused by a deficiency of parathyroid hormone or PTH, most often due to inadvertent removal of the parathyroid glands during neck surgery. Because PTH is responsible for maintaining calcium homeostasis in the blood and in tissues such as nerves and muscle, its absence disrupts multiple systems. It is important to note that acute symptoms and long-term complications, which include kidney stones and chronic kidney disease arise both from PTH deficiency itself and from the standard of care.

Turning to Slide 6. Due to the limitations of existing treatment options, patients on standard of care do not have restoration of the body's natural physiology and may experience large swings in serum calcium. Conventional therapy is burdensome, requiring patients to take pill supplements frequently throughout the day and night. A PTH replacement therapy was approved in 2024, but requires an injection every day. In contrast, canvuparatide is designed as a potential once-weekly best-in-class, long-acting PTH replacement therapy with continuous infusion-like PTH exposure. Increasingly, we're seeing in multiple therapeutic areas such as type 2 diabetes and obesity that patients and prescribers rapidly adopt the weekly treatment option for both its convenience and its improved real-world outcomes. We believe once-weekly canvuparatide can offer these same advantages.

I will now turn it over to Sam to go over the results from our Phase II Avail trial and ongoing open-label extension study.

Thank you, Kent. But let me start first by telling you how excited I am to share these results with you.

I will begin with an overview of the Avail Phase II trial design and open-label extension study. The Avail trial was a randomized 12-week double-blind, placebo-controlled Phase II study designed to establish the optimal dosing range and titration strategy for Phase III while also assessing the efficacy and safety of once-weekly canvuparatide.

Eligible patients were adults with a confirmed diagnosis of HP for at least six months who required conventional therapy consisting of active vitamin D plus calcium above prespecified minimum threshold levels. After an optimization period, a total of 64 patients were randomized and equally distributed into one or four treatment arms, once weekly canvuparatide starting at 400, 600 or 800 microgram or placebo. The 12-week blinded treatment period consisted of a four-week fixed-dose period, followed by an eight-week dose adjustment period where patients could adjust their dose every two weeks in a 200-microgram increment up to a maximum of 1,600 micrograms depending on their starting dose. Throughout the 12 weeks, patients could also receive conventional therapy as needed to maintain normal serum calcium by following a prespecified titration algorithm.

The primary composite endpoint was a proportion of responder at week 12, which is defined on the slide. Select secondary and exploratory endpoints are also listed and will be discussed in more detail today. All 64 patients completed week 12 and 60 elected to continue into a two-year open-label extension study. We view this as a strong indication of both patient interest in remaining on the once-weekly canvuparatide and the favorable profile observed in the study. The objective of the open-label extension is to evaluate the long-term safety, potential durability of effect and optimize dosing of once-weekly canvuparatide as patients continue treatment beyond the initial 12-week study.

Turning now to Slide 9. We will review the patient demographics and baseline characteristics. Overall, the group were well balanced across the four treatment arms. The median age was 49 years and female made up 80% of the study population, which is typical for this indication. Race and ethnicity were well balanced across group.

Similarly, on Slide 10, we have the baseline disease characteristics. The mean duration of HP for the total patient population was approximately 10 years. About 90% of patients had chronic HP in the postsurgical setting, which was one of the two stratification factors, while the remainder had HP from other causes, including idiopathic, genetic or autoimmune. At study entry, the median daily calcium dose was 2,000 milligrams with a wide range from 800 to 13,500 milligrams per day, while the median active vitamin dose was 0.75 microgram per day ranging from 0.5 to 2.5 microgram. These numbers illustrate the high treatment burden patients were carrying at baseline. The mean baseline serum albumin adjusted calcium was 9.2 milligram per deciliter in all patients and mean serum PTH level range from 9.2 to 12.1 nanogram per liter across treatment arms with slightly higher level noted in the placebo group. This low PTH level were consistent with the disease.

The other stratification factor was patients with 24-hour urine calcium or below -- above or below 250 milligram per day and fewer than half of patients in the trial had baseline urine calcium expression above 250 milligram per day. Overall, we believe our trial enrolled a very representative HP population, also similar to patients studied in other recent clinical programs.

Let's now review the clinical results, which we believe highlight the exciting potential of the once-weekly canvuparatide. Here, on Slide 12 are the results of the prespecified primary composite endpoint. At week 12, 63% of patients across all starting dose of once-weekly canvuparatide achieved the primary composite endpoint compared with 31% of patients on placebo. This one -- this was a statistically significant difference. Patients met this endpoint in the full canvuparatide-treated group with zero contribution from PRN, demonstrated that responses were achieved with a once-weekly administration without the need for rescue therapy. When looking at the proportion of patients meeting each individual component of the composite criteria at week 12, all three showed a statistically significant difference between canvuparatide-treated patients and placebo. These results provide strong evidence of once-weekly canvuparatide's potential efficacy across these key measures of disease control.

On Slide 13, we look at responder status at week 12 by starting dose group, which was a prespecified secondary endpoint designed to explore the dose response. As shown in the table, 50% of patients in the 400-microgram arm achieved responder status at week 12 compared with 69% of patients in the 600 and 800 microgram arms. With the 800-microgram arm achieving statistical significance. In addition, the 800-microgram dose was a median dose of responder at week 12. Overall, this data demonstrate that responder rates were generally higher at the 600 and 800 microgram starting dose compared with the lowest 400-microgram starting dose. This data not only demonstrates once-weekly canvuparatide dose response and wide therapeutic range across multiple dose levels, but also help inform dose selection for Phase III and increase our confidence in identifying the optimal dosing strategy moving forward.

On Slide 14, we are showing the albumin-adjusted serum calcium level over 12 weeks. It's a key measure in HP patients since maintaining calcium within the normal range is a central goal of therapy. Over time, patients treated with canvuparatide consistently maintain serum calcium within the normal range at every visit. Placebo patients trended downward initially, but then leveled out through continued use of conventional drug. We'll take a closer look at supplement use later in the presentation. We believe these results support the profile of a once-weekly therapy providing stable control.

Now let's turn to Slide 15, which shows the effect of once-weekly canvuparatide on the 24-hour urine calcium excretion, which is an important endpoint as elevated urine calcium is a well-recognized complication of conventional therapy and a major contributor to long-term renal risk. As expected with PTH replacement therapy, 24-hour urine calcium decreased in patients treated with canvuparatide with a more pronounced reduction in patients who entered the trial with elevated baseline levels. In this subgroup at week 12, urine calcium decreased by 203 milligram in the canvuparatide group versus 117 milligram in placebo. This reduction in the canvuparatide group occurred while maintaining serum calcium in the normal range with less reliance on conventional therapy compared to placebo. In summary, the 12-week results shows that once-weekly canvuparatide achieved the primary endpoint and helped restore the key features of PTH physiology.

Now we are going to turn to the results from the ongoing open-label extension study. At six months in the open-label extension, 79% achieved responder status, an increase from 63% observed at week 12 in the blinded portion of the study, which is a terrific result. Patients who had already been receiving canvuparatide continued at their last assigned dose with the option for further titration if needed, while those previously on placebo started at 400 micrograms once weekly and follow the same titration algorithm to reach their optimized dose.

Now I'm going to break it down by components. 90% of patients gained independence from active vitamin D, 81% gained independence from therapeutic dose of oral calcium and 95% maintained adjusted serum calcium within the normal range. The results of the individual components were comparable or higher that what we observed at week 12, providing highly encouraging evidence of the potential durability of once-weekly canvuparatide over time.

On Slide 18, you can see changes in serum calcium level from the start of the Avail study through month six in the open-label extension. Calcium levels were in the normal range in both the canvuparatide and placebo groups before treatment. As we have already shown, canvuparatide-treated patients maintained normal serum calcium through 12 weeks. In the extension, those patients continued to maintain stable calcium at six months, supporting the durability of once-weekly canvuparatide beyond the initial treatment period. In the placebo group, calcium level declined early and remained low through week 12 despite ongoing use of active vitamin D and calcium supplement. However, after switching to canvuparatide in the open-label extension shown in light blue, serum calcium level in these patients increased to well within the normal range, demonstrating a direct effect of once-weekly canvuparatide in restoring physiological calcium control. This occurred while active vitamin D and calcium supplements were gradually decreased or discontinued, which we review on the next slide.

On this slide, Slide 19, you can see the changes in the active vitamin D dose and total daily calcium dose from the start of the Phase II study through six months in the open-label extension. On the left, in the canvuparatide-treated group, active vitamin D dose decreased rapidly within the first two weeks and nearly all patients discontinued use altogether. In contrast, a substantial proportion of placebo patients were still taking active vitamin D during the 12-week period. Upon crossing over in the open-label extension at a starting dose of 400 micrograms of canvuparatide, those patients were able to decrease active vitamin D and ultimately discontinue. On the right, you see a similar pattern for calcium supplement with patients on canvuparatide reducing their daily intake, while placebo patients required higher dose until they transition into the expansion. Overall, these results demonstrate durability of effect of canvuparatide in both patients who started on therapy and those who switched from placebo, maintaining normal serum calcium while greatly reducing the heavy pill burden of conventional therapy.

One final result I would like to highlight here on Slide 20 is the effect of once-weekly canvuparatide on bone health in patients with HP. As a reminder, in the absence of PTH, the skeleton cannot properly release calcium and phosphate. This leads to abnormally low bone turnover. Here, we are showing three markers of bone turnover and formation over the 12-week double-blind period and through six months into the open-label extension. CTx is a marker of bone resorption and overall turnover, while BSAP and P1NP are bone formation markers. The blue line represent patients treated with once-weekly canvuparatide and include patients who crossed over from placebo after 12 weeks.

What we observed is a substantial increase in all three bone markers during the first 12 weeks in canvuparatide-treated patients in comparison to placebo. This upward trend continued through the six months. We are very encouraged by this finding. They show that once-weekly canvuparatide is restoring normal bone remodeling activity, both formation and resorption, which is a hallmark of reestablished PTH physiology and contributing factor to long-term bone health.

Now let's turn to the safety. On Slide 22, we demonstrate that once-weekly canvuparatide was generally well tolerated. As you can see in the top row, 73% of canvuparatide-treated patients and 63% of placebo patients experienced treatment-emergent adverse events with rates that were fairly similar between all treatment cohorts. Importantly, the vast majority of events were reported as mild or moderate in severity and recovered without dose interruption. Approximately half of patients in the pooled canvuparatide group and approximately 40% of placebo patients experienced adverse events that investigators considered related to drug, and I will go into those details on the next slide. There was one serious adverse event in the 600-microgram cohort, a case of Bell’s palsy that was not considered treatment related and resolved without sequela. Finally, there was no study drug-related discontinuation, no study discontinuation and no deaths during the 12-week treatment period.

On Slide 23, we provide additional detail on the most commonly reported adverse events. This table lists any treatment emergent adverse events that occurred in more than 5% of patients in any treatment group and at least 2% more frequently than in the placebo group. The most commonly reported events among canvuparatide-treated patients were headache, hypercalcemia, arthralgia and nausea.

On Slide 24, we will take a closer look at adverse events of special interest. Starting with hypercalcemia. This was reported in approximately 13% of patients in the 400 and 600-microgram group and 31% of patients in the 800-microgram group compared with 6% or one patient in the placebo arm. Hypercalcemia is an expected outcome from PTH replacement therapy, and it was also observed more frequently in the highest dose cohort during the four-week titration phase, while patients were still titrating down from conventional therapy. Importantly, none of the cases required hospitalization. Hypocalcemia was reported in four treated patients, one patient in each of the 400 and 600-microgram group and two patients in the 800-microgram group compared with three patients on placebo.

As expected, nearly all hypocalcemic events occurred within the first weeks of the titration period, again, while patients were still titrating down from conventional drug. None of the patients with reported hypocalcemia required hospitalization. We are also very pleased to see that injection site reactions were infrequent overall, occurring in 18.8% of treated patients versus 12.5% on placebo.

Finally, I would like to close by highlighting safety data from the ongoing open-label extension, and that is so far to date, we are seeing similar trends as to what we observed in the double-blind study and we are highly encouraged by the favorable safety profile. Taken together with the efficacy results, we believe this data strongly supports the potential of once-weekly canvuparatide to become a new standard of care for patients with HP.

And with that, I will hand it back to Kent.

Since our IPO one year ago, we set out to deliver on the promise of once-weekly canvuparatide. So it is particularly gratifying to share data that bring that vision to life. These results are very encouraging and reinforce our conviction that canvuparatide is poised to be best-in-class. The strong Phase II Avail data unequivocally demonstrate that once-weekly canvuparatide can generate high responder rates in treated patients. Data from our open-label extension study showed the potential of even higher responses on canvuparatide as patients are titrated to their appropriate doses. Our results are already competitive to historical studies of an FDA-approved once-daily injection.

HP is a chronic disease and is a significant unmet medical need. We estimate the U.S. and the EU represent a multibillion-dollar market opportunity and once-weekly canvuparatide is well poised with a best-in-class profile. The reason we believe that once-weekly canvuparatide may grow to be preferred by both health care providers and patients is simple. highly competitive results to date, infusion-like PTH exposure with far fewer injections. Patients don't want to have to think about their disease every day, let alone inject themselves daily. Once weekly canvuparatide can provide freedom by relieving patients from the significant burden of current standard of care and daily injections.

Going all in on this program, I wanted to share some of the upcoming milestones. First, we plan to debut our data at the International HypoPARAthyroidism Conference being held October 3 to 5 in Texas. We'll be scheduling our end of Phase II meeting with the FDA. Additionally, we will be presenting full Phase II data at a major medical conference and in publication. In 2026, we plan to report 52-week results from our open-label extension trial as well as begin dosing patients in our global registrational Phase III trial.

Finally, I'd like to thank the patients and their caregivers, the investigators, partners and the passionate team at MBX who made all this possible.

Now I'll turn the call back to the operator to open up the line for questions.

[Operator Instructions] And our first question today comes from the line of Seamus Fernandez with Guggenheim Partners.

Congratulations on the data. So a couple of things to just clarify. We got a lot of questions on the placebo response here. And there's also a lot of questions on relative comparisons around that.

Just hoping you could help us understand the 31% placebo response. Admittedly, I think the dose response that you see with the 600 and 800 microgram clearly suggests a very wide margin between placebo on your endpoint. But maybe you can just help us understand how you're looking at the data from a comparison perspective versus the Yorvipath Phase II data that we have. Really appreciate those data. And again, congratulations.

I appreciate the OLE data as well. I think it's important to look at the characterization of the response when you kind of convert from the OLE. But last question is just what other opportunities might you have to improve upon the response rate in the Phase III? I think 79% in the OLE would suggest that, that's going to be a little bit challenging to improve upon. But how do you think about Phase III design? Is it identical to this Phase II? Or are there other nuances that you could bring to the table to perhaps improve the response or even improve upon what's already a great safety profile?

Thank you, Seamus. We are very happy with our statistically significant results at week 12 despite the placebo response. And as you point out, the fact that the response rate in the treatment group increased further at six months, we believe, confirms the potency of canvu in this patient population. And the placebo group was higher than originally planned, but it's not unusual, noting the small sample size. And also, there's a precedent in HP. The daily injectable showed a placebo response of 27% in Phase II, which reduced to 5% in Phase III, and we would expect that trend in our Phase III study.

That said, it's an important question, and our team has looked very closely into it. So I'll ask Sam to provide some more color.

Yes. Thank you, Kent. We also checked our results with four experts and author of the hypoparathyroidism guidelines. After looking at the baseline characteristic and the responder rate across the different arms, we decided to perform a sensitivity analysis, including patients with PTH less than 20 picogram per ml before treatment. Patients with low PTH are usually considered as more severe than patients with inappropriately normal PTH. A PTH above 20 picogram per ml indicates some residual PTH secretion, also not sufficient to maintain serum calcium level in the normal range for a long time. So when you apply this criterion, we identified a total of eight patients, three in the placebo group, five in the treatment group that were excluded from this sensitivity analysis.

Excluding these patients from both groups, the placebo response declined to 15%. And the canvuparatide pooled responder maintained a robust response at 60% at the 12-week time point, which is highly statistically significant with a p-value of less than 0.01. And the active to placebo difference was 45%. We also carried over this rule into the open-label extension study and excluded those eight patients, and our responder rate was still very strong with 76%.

So we believe -- I mean, really this sensitivity analysis strengthens our primary analysis and confirm our conviction in our results. It's also a learning for Phase III in which where the patients will be stratified between treatment and placebo to ensure equal distribution. That was one of the learnings already from the Phase II.

And then just on the Phase III. The Phase III, the possibility, is it -- do you see any changes in Phase III that would be necessary other than just sort of the stratification you talked about? Is there a possibility of perhaps even titrating weekly? Or does that put too much of a burden on the clinical trial or the population? Certainly, I could see a faster response rate being achieved if you were to titrate or allow for a titration after four weeks that was a little bit faster.

We really don't see the need to change to a more rapid titration. At this time, we're evaluating the data, and we'll be finalizing our study Phase III study design following the anticipated end of Phase II meeting with the agency.

I'd also like to point out the very high responder rate we got from the placebo after they, if you will, crossed over following the 12-week Avail study with 14 and 15 becoming responders by the end of the -- by the analysis we did at six months. So, we again, are really encouraged by these results.

Seamus, it's a dose-finding study. Seamus, it's a dose-finding study at this Phase II. So we'll be looking in every detail and apply the learning to the Phase III program just to make sure that here, we are delivering the top line results, but we'll be looking at all in order to optimize the Phase III program.

Congratulations. The sensitivity on the placebo was also super helpful. Appreciate that.

The next question comes from the line of Jessica Fye with JPMorgan.

I had a few here. First, can you please clarify the definition of PRN calcium used in the trial? I guess my specific question is, if a patient had reached a daily calcium dose of zero and then they took 300 milligrams of calcium, would that be a PRN event even though the daily dose was still under 600? And does the same definition apply to the six-month open-label extension data? And what, if any, was the contribution of oral calcium to the six-month open-label responder rate? And I have a follow-up.

So, the PRN was initially defined as that more than one day of use of any vitamin D or calcium supplement for a total dose of more than 600 milligram a day. However, we went one step further and we look at any use of anything during the week of the evaluation and patients didn't take any additional calcium, any vitamin D during that period.

So we went -- it's really going -- being very, very conservative and going very strict in terms of use. So we are very pleased to report that none of the patients took any PRN or any calcium supplement of vitamin D during the last week.

And then is it the same definition for the six-month data? And was it also zero contribution to the six-month responder rate?

So, it's a similar thing in the open-label extension. And we are looking in more detail in the results because the patients are seen a little bit less frequently, right? And -- but I can guarantee that what we observed in the Phase II 12-week is will be reproducible and reproduced into the open-label extension.

Right. PRN is not driving our response in this trial.

That's the key message.

Okay. And then just a couple of follow-ups were what does the PD data look like over the dosing interval? I think you took measurements at Cmax as well as trough. And then how does the hypercalcemia rate look over the six-month OLE? Are you seeing less of that as the trial goes on, so sort of like less in the second three months than in the first three months?

Well, it's an ongoing trial, Jess. And as Sam said, we're seeing similar safety in the OLE. And as you would expect, as more patients are normalized, and we provided the calcium -- the serum calcium measures in the slides.

And Sam, you're welcome to add.

Yes. No. And the retention rate is pretty good. So also something to confirm that the patients feel good about canvuparatide. So, that's a good sign.

Great. And then just the PD at max trough?

So we didn't see anything that will be a concern. We saw -- in fact, we saw that serum calcium stayed within the normal fluctuation and didn't create any episode of hypercalcemia, et cetera. When we looked at hypocalcemia, there is no pattern in terms of when the hypercalcemia happened during the week. And so it was not particularly a certain day during the week. It was at any point could happen.

And overall, had a low occurrence of hypercalcemia in the trial.

The next question is from the line of Roger Song with Jefferies.

Congrats for the impressive data. Maybe my question relates to the dose response. I think you showed us the 12-week period. So, just curious about the open-label OLE portion, how the dose response look like?

And then another question leading to that is the -- what's your current thinking about the dose selection for the Phase III considering this seems higher efficacy at the 800, but also a little bit higher hypercalcemia.

I mean I'm going to start with the dose selection for the Phase III. We are analyzing the results, and it's a dose-finding study. So, the main objective is to find the right dose to start this patient into the Phase III program. We'll be looking not only at efficacy, but also the best tolerability profile and especially when we are decreasing the vitamin D and calcium supplement. So, that's more to come in terms of dose selection and finalizing the dose for Phase III.

Got it. And then how about the dose response for the OLE portion?

So, I'm not sure I understand the question. Because the 79% I referred to the open-label extension dose response.

Yes, that's the pooled patients. So, how about each individual different doses, starting dose?

The patient dose in the open label, it's a wide range of response. I mean, confirming one thing that it's some sort of personalized medicine and every patient will need a different dose level to satisfy their needs. And that's what we will be releasing the data later when we will have the full set of information. But for now, it's top line results.

Our next question is from the line of Jonathan Wolleben with Citizens.

Congrats on the data. Just another one on the Phase III trial design and dose optimization. Wondering if you expect to see kind of an improvement in the hypocalcemia as you perhaps dose slower or start at a lower dose, given the mention that most of these events happen during dose titration? And then I have a follow-up as well.

Well, I think that fundamentally, with our PEP design, we have an excellent PK curve with a peak to trough over a week that's comparable to the competition over a day and a bit of a self-titration built into our molecule. And I think that's reflected in the stable control we've demonstrated and the really strong safety.

Yes. I think -- and the initial PK data that we got from the patient also confirmed that the PK we observed in healthy volunteers is similar to the one we observed in patients with for now a peak-to-trough ratio, which is also in the same order. So which is a really good news in terms of comparing healthy volunteers PK and patients. So very happy with that.

And then with the six-month data today that we were quite expecting, how do you think about additional disclosures from the open-label study? Is it going to be on a set time period of follow-up or when you think there's a fulsome update or an opportunity to present? How should we think about additional disclosures? And how do you think canvu's profile to evolve over time?

We expect to present 52-week follow-up data on the OLE, and we think that our profile is excellent.

Our next question is from the line of Tyler Van Buren with TD Cowen.

Congratulations on the tremendous data update. Can you -- just the zero PRN utilization at week 12, that's clearly very impressive. Can you discuss if that was maintained through the end of the six months in the OLE? And was the dose for canvu set in the last four weeks of the OLE or were patients continue to be titrated?

And then second question, just on quality-of-life data, what quality-of-life data are you collecting in the trial, if any, or maybe any anecdotes you've heard from investigators or patients in the trial following treatment with canvu.

Well, the PRN available, data are not available yet. We'll review those when they arrive and plan to present those at an upcoming meeting. The -- so in terms of anecdotes, we've heard very strong interest in our once-weekly drug. I think that's a drug candidate that's reflected in the strong 94% entry into the OLE and the retention as well through the OLE.

Yes. Can I -- in terms of quality of life, I see a good testimony of patients being confident in the product is the rate -- the percentage of patients moving from the double-blind to the open label. 94 patients moved -- 94% of patients moved from the double-blind to the open-label extension. I think it's a good and the retention rate that we observed so far is pretty good.

In terms of -- I can tell you that the PRN in the open-label extension is not driving the results, just to be clear.

I think you had another question about changing the dose during the -- when moving to the open-label extension. Just I'm going to get back a little bit to the study design. And the study design, by design we had four different groups, 400, 600 and 800 microgram and only the 800 microgram could get to the 1,600 during the eight-week period, you can increase by 200 microgram every other week. So, it's 4x. So, four opportunity to increase the dose.

So when the patients switch to the open-label extension and if by any chance, they are not responder at the time of the switch, they can definitely see their dose increased if needed once again. So that's why we -- in the open-label extension, we will see patients taking up to 1,600 microgram. Does it answer your question?

Yes.

Our next question is from the line of Annabel Samimy with Stifel.

Congratulations on the data. Just on the prior question regarding the titration during the OLE, you mentioned that patients who had -- were at the 800 milligram were the only ones to reach the 1,600 milligram. To what extent did the other patients have to titrate up? Like do you have the various percentages of patients who had to continue titrating up? In other words, do you feel that patients had, for the most part, reached a steady state at 12 weeks, and it was just a little bit of tinkering in the doses going forward.

And then I guess, secondly, during the OLE period, the secondary biomarker data were great. I was just wondering if you had any additional biomarker data, the urinary calcium biomarker data and the bone biomarker data all the way through the six-month period? And if you don't, do you have any sense of whether it remains going in the right direction?

So, just a good -- back to the design and the results. Well, in terms of responder, 63% at the end of the double-blind period were responder, right? And this number increased up to 79% at the end of the open-label extension. I think it's done also to continuing to titrate up the patients who needed to be titrated up. And I hope that this answers your question.

About bone biomarkers. Bone biomarkers on the slide, in fact, you see the results that at 12 weeks, but also at six months. including the patients who were initially on placebo and switched to treatment. And you see that still continue to improve in terms of all the bone markers, CTx, P1NP and on the very good right direction and maintenance of the positive effect that we saw at 12 weeks.

Okay. Did you have the same for urinary calcium as well at six month?

At this stage, we don't have the results. As I said, we have to make some choices in terms of top line results. We got that quite a week ago, and we had to really analyze the data as much as possible.

Okay. Got it. And just one other question. you mentioned that -- I mean, you had the sensitivity analysis regarding the stratification of patients with baseline PTH level. And are you planning on doing that stratification in Phase III? And did Yorvipath do that stratification to get the placebo responses lower, I guess. Just trying to understand if it's going to be similar design as to what Yorvipath in Phase III.

So, what we are going to do is really to analyze in depth our Phase II data and look at what could influence furthermore even from the sensitivity could influence the placebo response and adapt it include this modification -- potential modification into the Phase III.

As I said, the PTH is a good marker, and it would make sense to stratify. So, it's likely that we will be doing it.

And in general, we'll be looking to the precedent of Phase III studies in this disease, not really full thought reinventing the wheel.

Our next question is from the line of Trevor Allred with Oppenheimer.

My congrats on the data as well. I got a few questions. First, is there anything you can share about the active dose levels where we saw AEs? Since we're titrating here, were these presentations seen above 800 micrograms?

And then also, can you give us any detail on what the placebo response rate might be if there was no PRN use there? And can you also clarify PRN criteria was only for the last week?

So, PRN criteria was for the last week of the evaluation because patients could be titrated up to the week 10. And so we did -- we thought that it was appropriate to look at PRN in the last week of -- at the period -- at the time of the evaluation, if you want.

The placebo, they were not -- I mean, they were not responders for most of them, 70% of them. So, the PRN use was not interesting as an information. We looked also at the five patients with placebo, but I don't remember if I had the PRN news or not. We looked mainly into our active treatment.

Got it. And can you also -- is there anything you can share about the active dose levels where we saw some of those AEs? Were they seen above 800 micrograms?

Yes. So the AEs happened mostly during the titration period, mostly because -- and that's why you see it at 800 microgram because when you start decreasing the supplement, calcium supplement and vitamin D, it may not be fast enough when you start a higher dose. And that's the reason why we observed this hypocalcemia at the time of the titration and with the 800 microgram. That's the rationale behind.

Our next question is from the line of Uy Ear with Mizuho Securities.

Congrats on the data. I guess one question that we've gotten is maybe could you sort of help us clarify the proportions of patients that may be titrated up and those that titrated down in the study?

And the second question that we have is, I guess you expect to meet with the FDA. Maybe just sort of help us understand the time line to that meeting.

I don't have the proportion of responder exactly -- the exact proportion of responder, but I can tell you already that most of them were titrated up. But you can see during -- in the table, you can see that the extent of the dose in the 600 and 800 micrograms, if I remember correctly, the dose could go down to 400 microgram. That's an option the patient -- the investigator has to not only go one direction, but if needed, go the other direction. But clearly, the goal and what we observed is, in most cases, was titrating up.

So, we're really thrilled with our positive top line results and our clear clinical proof of concept for best-in-class. So we are eager to request an end of Phase II meeting, and the team is just very energized to go pursue our global Phase III registration studies with a sense of urgency.

At this time, we've reached the end of our question-and-answer session. I'll hand the call back to Ken for closing remarks.

I'd like to thank everyone again for joining us today to discuss the compelling top line results from our Avail Phase II trial. We cannot be more thrilled with the results and look forward to sharing further progress as we continue to advance canvuparatide's development with the goal of bringing a best-in-class once-weekly treatment option to patients in need.

Thank you. This concludes today's conference. You may disconnect your lines at this time. We thank you for your participation. Have a wonderful day.