Larimar Therapeutics Inc Aktie

Welcome to the Larimar Therapeutics Investor Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be available on the Larimar website following the conclusion of the event. I will now turn the call over to Alexandra Folias of LifeSci Advisors. Please go ahead, Alex.

Thank you, Wilson, and thank you all for participating in today's conference call.

Before we start, I would like to point out that there is a slide deck that accompanies today's presentation. It can be viewed using the webcast link provided on the Investors page of the Larimar Therapeutics website. Also posted on this web page as a news release issued earlier today.

Before passing it off to company management for prepared remarks, I would like to remind everyone that some of the information disclosed on this conference call contains forward-looking statements that are based on the company's beliefs and assumptions and on information currently available to management. These statements include, but are not limited to, statements regarding the company's plans and ability to develop and commercialize Nomlabofusp, the timing of its clinical trials and BLA submission interactions and filings with the FDA and the potential for accelerated approval in time to launch in other matters regarding the company's business strategies, use of capital and financial position, and other risks described in the filings made by the company with the Securities and Exchange Commission available at www.sec.gov. These statements are based on facts and factors currently known by the company about which cannot be certain, and as a result, may not prove to be accurate. The company assumes no obligation to update any forward-looking statements, except as required by law.

Speaking on today's call will be Dr. Carole Ben-Maimon, President and CEO of Larimar Therapeutics. In addition, Larimar's CMO, Dr. Russell Clayton; CDO, Dr. [ Gobi Shankar ], CFO, Mr. Mike Celano, and key opinion leader, Dr. [ Marshall Summer ], CEO of [ Uncommon cures ] will be available during the question-and-answer session following the prepared remarks. With that, I will now turn the call over to Carole.

Thanks, Alex, and good morning, everyone. Today is a pivotal day for Larimar and most importantly, for the Friedreich’s Ataxia community. I'm very excited to share that with the submission of the first module, we have officially initiated our rolling BLA seeking accelerated approval of Nomlabofusp for the treatment of Friedreich’s Ataxia, and that we are doing so alongside positive longer-term data from our ongoing open-label study.

As we proceed with this presentation, I think you will find some of the data novel and incredibly interesting.

Before I begin the formal presentation, I would like to welcome Dr. [ Marshall Summer ]. Dr. Summer is the CEO of [ Uncommon cures ], one of our largest sites and the largest site to enroll pediatric patients.

Dr. Summer has 40 years of clinical experience treating rare disease. He built the world's first rare disease center of excellence in partnership with the National Organization for Rare Disease, or NORD, Children's National in Washington, D.C. He has been involved in over 220 clinical trials studying rare diseases and was Chairman of the Board of NORD for several years. Thank you, Dr. Summer for being here today, and thank you for all your contributions to those suffering from rare diseases.

With that, I would like to begin today's presentation. First, as the data from the Nomlabofusp clinical program expands and matures, the results continue to reaffirm the disease-modifying potential of Nomlabofusp. We must always keep in mind that Nomlabofusp is the first potential therapeutic to target the root cause of Friedreich’s Ataxia, frataxin deficiency. Skin frataxin levels increase following Nomlabofusp treatment and elevated levels at 1 year that are comparable to those in asymptomatic carriers.

Importantly, these increases are associated with disease improvement across key clinical outcome measures. 13 participants in the open-label study have now completed a year of dosing and assessments. As we further characterize the safety profile of Nomlabofusp, it continues to be generally well tolerated with long-term dosing and anaphylaxis rates consistent with those we saw in September 2025. We will review this data in more depth shortly.

Second, following the receipt of minutes from a multidisciplinary Type B pre-BLA meeting, the FDA confirmed that our existing data package is sufficient to support a BLA submission seeking accelerated approval. The FDA also reaffirmed their willingness to consider frataxin as a novel surrogate endpoint. Approval will be a matter of review.

The FDA also agreed to receive the submission and rolling format, which allows us to submit each module as it is completed.

Importantly, it is because of our fast track and breakthrough designations that we are eligible to request a rolling submission. We are pleased to share that we have submitted the first module with the remaining modules expected in the second half of this year.

This is a tremendous milestone for us as a company. and we believe for the FA community. We plan to provide the next update on our BLA submission once the submission is complete.

Third, we are on the cusp of starting our confirmatory global Phase III study with dosing of the first patient in the U.S. expected in the third quarter. Note that the patient population of this study differs from our open-label study as only ambulatory patients will be eligible to enroll.

On the financial side, we ended the first quarter with $200 million in cash as of March 31, which we expect provides runway into the second quarter of 2027. We also expect to be eligible for a priority review voucher at the time of approval. With that backdrop, let me provide more detail on the program.

The comprehensive data package was submitted to the FDA as part of our briefing package prior to our multidisciplinary type pre-BLA meeting. Importantly, the FDA confirmed that the existing data package appears sufficient for BLA submission seeking accelerated approval and that approval will be a matter of review.

In addition to reaffirming its willingness to consider skin frataxin as a novel surrogate endpoint FDA agreed that our exposure response analysis, linking Nomlabofusp exposure to clinical outcomes is the type of data that could support the planned BLA and that prospectively collected exploratory gene expression and lipid biomarkers may provide additional support for the novel surrogate endpoint and mechanism of action of Nomlabofusp beyond tissue for tax and concentrations.

Lastly, the FDA agreed to a rolling submission. And as I mentioned earlier, we have submitted the first module with the remaining modules expected in the second half of this year.

Across our development program, 76 participants have been enrolled, and 66 have received at least 1 dose of Nomlabofusp. To date, more than 10,000 doses of Nomlabofusp have been administered in the open-label study alone. Given that FA is a rare disease, these numbers collectively represent a robust data set.

In the open-label study, specifically, 43 participants had been dosed as of this month, 32 had prior exposure to Nomlabofusp in an earlier study and 11 had no prior exposure, a distinction that I will discuss later.

Of the 43 participants dosed, 22 remain active and 21 have discontinued. This will also be discussed later in the presentation. Our longest treated patient participants are now beyond 800 days of daily dosing, which is over 2 years. We also have approximately 11 additional adults and adolescents in screening with dosing planned over the next couple of months.

For our open-label study update, we are pleased to share that we now have 13 participants who have completed 1 year of dosing, seven who have completed 18 months of dosing and three who have completed 2 years.

First, Nomlabofusp administration is indeed increasing skin frataxin levels. and those levels are sustained over time. Importantly, they are achieving levels comparable to asymptomatic carriers with 82% reaching these levels at 6 months 100% at 1 year and 100% maintained in 18 months.

As you may remember, the data to support the use of skin frataxin is a novel surrogate endpoint and the correlation to affected tissues has been published in peer-reviewed journals and has been submitted to the FDA.

Second, the increases in skin frataxin are resulting in improvement in key clinical outcomes. Nomlabofusp treatment led to a 2.6-point mFARS advantage over the FACOMS reference group at 1 year. That widened to a 4.6 point advantage at 18 months.

And third, the safety profile of Nomlabofusp is well characterized. Long-term daily dosing of Nomlabofusp remains generally well tolerated in participants taking it for up to 800 days or 2 years. The most common adverse events continue to be mild to moderate injection site reactions that decrease over time and do not lead to study discontinuation.

We have had 10 cases of anaphylaxis nine of them with exposure to Nomlabofusp in a prior study. It is becoming more and more clear that exposure to Nomlabofusp followed by discontinuation for long periods of time greater than 3 to 4 months, then restarting therapy increases the risk of anaphylaxis.

Collectively, these findings deepen our understanding of the clinical profile of Nomlabofusp. And as you will hear more today support the potential of Nomlabofusp to be the first disease-modifying therapy for a broad spectrum of patients, including adults and children with FA.

FA affects approximately 20,000 patients globally, including roughly 5,000 in the United States with a meaningful concentration of patients in Europe. About 70% of patients present before the age of 14.

It is caused by a genetic defect on both [indiscernible] that prevent production of the critical mitochondrial protein frataxin, resulting in lower tissue frataxin levels.

On average, most patients with FA only produce about 20% to 40% of the frataxin levels seen in homozygous healthy people. Not having enough frataxin leads to a myriad of debilitating symptoms, including unsteady posture and frequent falling, symptoms are [ progressive], typically causing patients to be wheelchair-bound 7 to 10 years after the initial diagnosis.

The symptoms of FA include loss of musculoskeletal function, blindness, deafness and inability to speak clearly and diabetes. Unfortunately, patients with FA have a life expectancy of only 30 to 50 years, with the most common cause of death being heart disease.

Nomlabofusp is a recombinant fusion protein designed to directly address the root cause of the disease frataxin deficiency. We do this by attaching a cell-penetrating peptide to the frataxin molecule, allowing the delivery of the protein across the cell membrane and into the mitochondria.

With the exception of the cell-penetrating peptide, the sequence of Nomlabofusp is identical to the sequence of endogenous frataxin.

Throughout the world, Nomlabofusp has earned a strong set of designations intended to expedite development, in the United States, these include breakthrough therapy designation, participation in the start pilot program, orphan drug designation, fast track in rare pediatric disease designations.

Recall that Breakthrough Therapy designation was granted in February of this year for the treatment of adults and children with FA based on preliminary clinical evidence of substantial improvement over available treatment on a clinically significant endpoint.

Importantly, outside the U.S., we also have secured a substantial set of designations, including orphan drug and prime designations in the EU and the Innovative Licensing and Access Pathway or ILAP in the U.K., reflecting the same level of interest in Nomlabofusp from regulators around the world as we have seen in the United States.

With that overview, now let's get into the data. Our ongoing open-label study is currently evaluating the long-term safety and tolerability, the pharmacokinetics and key clinical outcome measures in the ability of Nomlabofusp to increase tissue frataxin levels over longer periods of time following daily administration of 50 milligrams Nomlabofusp. The clinical outcome measures are compared to a matched reference population from the FACOMS database, a longitudinal natural history study that includes patients with confirmed FA diagnosis.

The comparison of clinical outcomes to an external control is intended to support the accelerated approval and a finding that frataxin is reasonably likely to predict a clinical benefit.

The study has been expanded to include adults, adolescents and children 2 to 11 years of age who have not participated in a prior Nomlabofusp study.

To give you context on the patient population, you can see from the participant baseline characteristics and demographics that this is a substantially more severe population compared to many other FA trials. The mean baseline mFARS total score is approximately 55, representing participants with severe disease. Approximately half of the participants are non-ambulatory.

As of the March data block, we have 41 subjects in this data set with two additional patients dosed after the data lock. Of note, you may remember that in last September data set, there were eight participants at 1 year. As of March, we have team participants at 1 year. These five additional participants have a lower age of onset and a higher mean mFARS score of 60 compared to 51 in the eight participants from September, indicating more severe neurologic impairment in this participant group.

Daily Nomlabofusp increase skin frataxin levels, which reached steady state by about 3 months and were sustained over time. On the left, you can see the absolute levels of skin frataxin, and on the right is the change from baseline. The dotted line marks frataxin levels that are 50% of the levels found in healthy volunteers which is similar to the levels found in asymptomatic carriers.

It is worth noting that we measured frataxin levels from both skin and buckle cells, but are focusing on skin following FDA recommendations since it is less variable than buckle cells and also correlates well with the tissues that matter most in this disease.

This slide shows the absolute levels of frataxin in the lower table. The top table shows that 82% of participants at 6 months and 100% at 1 year achieved frataxin levels above 50%, the level in asymptomatic carriers. This was maintained in the three participants assessed at 18 months. In other words, frataxin and levels go up and they stay up over time.

Now to safety. With additional participants in longer-term follow-up, we have a well-characterized safety profile. More than 10,000 doses have been administered in the open-label study. And long-term dosing with Nomlabofusp continues to be generally well tolerated up to 800 days or 2 years. 13 adults have been on treatment for 1 year, 7 for 18 months and 3 for over 2 years.

The most common adverse events continue to be local injection site reactions that are mild to moderate tend to decrease in frequency over time and have not led to any withdrawals from the study.

In total, 21 participants have discontinued from the open-label study, 10 for anaphylaxis three for generalized urticaria, which, by the way, has not occurred since the implementation of an antihistamine regimen and eight who withdrew from the study, including three due to other adverse events.

Of the 10 who experienced anaphylaxis, nine had exposure to Nomlabofusp a prior study and one did not have prior exposure. Anaphylaxis has typically occurred during the first 3 months of dosing. These participants return to their usual state of health after standard treatment with no further sequela. It is important to note that in the open-label study to date, 11 participants had no exposure to Nomlabofusp and only one of these 11 experienced anaphylaxis, suggesting that there is a much lower incidence of anaphylaxis in participants without prior exposure to the drug.

Now let's turn to the clinical outcome measures. Since the open-label study is a single arm, we compared our participants against a matched natural history reference group as well as use the participants as their own controls. From the FACOMS data, set we can identify 362 patients whose baseline characteristics, age, agent symptom onset, baseline mFARS, FARS ADL and 9-hole PEG test fall within the range of our open-label study participants.

Importantly, our methodology for constructing this reference group incorporated the FDA's review and recommendations.

Encouragingly, with more participants in long-term follow-up, we are consistently observing improvements across key clinical outcome measures, which are associated with increased frataxin levels.

As I mentioned earlier, for mFARS, which is a commonly used 93-point scale that assesses progression in patients with FA and has been used as the primary outcome measure in other clinical trials. We observed a 1-point improvement at 1 year and a 2.3 point improvement at 18 months for treated participants in the open-label study relative to a 1.6 point worsening in the FACOMS reference population. The 2.3 point worsening at 18 months is a calculated data point based on the rate of change in mFARS over a 3-year period.

When you look at the difference between the FACOMS and the Nomlabofusp-treated group, you get a 2.6 point advantage of 1 year and a 4.6 point advantage over the FACOMS reference group at 18 months.

Similarly, directional improvements were observed in the other three clinical outcomes measured against the FACOMS reference population at 1 year.

The 9-hole PEG test measuring fine motor coordination, specifically appropriate in this population, had a 15.6 second improvement versus a 6.1 second worsening in the FACOMS population. This is a particularly important measure in a population of patients who do not have the use of their lower limbs.

Strikingly, among the participants who have reached 1 year, one of six non-ambulatory participants at baseline became ambulatory after 1 year of dosing, and none of the seven ambulatory participants progressed to a non-ambulatory status of 1 year. In a population this advanced, we are very encouraged to see these benefits and clinical outcomes.

Given the advanced state of disease for the majority of participants in the open-label study, we are very excited to see consistent directional improvements across key clinical outcome measures. We believe this is the first time any intervention has been both -- has shown both increased frataxin levels in patients with Friedreich’s Ataxia to this extent and demonstrated improvement in multiple clinical outcome measures over time.

Here, we are comparing the mean change from baseline for mFARS following mFARS treatment to the FACOMS reference group. The FACOMS reference group is the gray curve and shows disease worsening that progresses over time. In comparison, the Nomlabofusp-treated participants show an improvement that appears to continue over time.

Importantly, we are seeing a 2.6 point difference in mean mFARS score for the Nomlabofusp-treated participants compared to a FACOMS reference group at 1 year and I calculated 4.6-point difference at 18 months. Although there are only seven participants at 18 months, we are very encouraged to see this kind of disease modification and look forward to seeing the 2-year data.

This is the data I was referring to in my introduction. Remember, all 13 of these participants were in a prior study that occurred on average 2.5 years ago. Hence, we have the baseline from that study, and the baseline in the same patient from the open-label study. On these graphs, the dotted lines are the changes over time when these patients were not in trial.

The graph at the top left graph presents the frataxin levels. The frataxin levels, as you can see, do not change when the patient is not receiving Nomlabofusp. Once they begin participation in the open-label study, the frataxin levels rise. The other three graphs present outcomes over time for mFARS, FARS ADL and 9-hole PEG test, you can see that the patients worsen between studies with no treatment and then improve once they start Nomlabofusp. This is very important data as it allows for the patients to act as their own controls. We think this is very exciting, but the story gets even more interesting.

This slide shows the same data. The frataxin in the top left and the three clinical outcomes in the other graphs. Now we break the patient population into three categories based on disease duration. The red line is patients with less than -- sorry, less than 12.5 years since disease onset. The green are those with 12.5 up to 25 years since disease onset and the purple are those who had disease onset over 25 years or more before entry into the open-label study.

Again, you see the patients worsen between studies on no drug, and improve once they initiate Nomlabofusp. These findings reinforce the importance of considering multiple clinical outcome measures when assessing the impact of an intervention on disease progression, particularly in the Nomlabofusp program, which includes patients of all ages and at all stages of disease.

This slide shows the four clinical outcome measures -- each graph shows the overall participation -- participant population at 1 year on the left. The three other sets of bars represent the breakdown by duration of disease. The blue bars represent those who have improved with 1 year of Nomlabofusp treatment. And the gray bars represent those who have worsened.

As you can see on the left-hand side of each graph a majority of participants improve for all durations and for all outcomes. Of note, the majority of participants improved with treatment in a disease that you would only expect to see worsening. This is an incredibly important result.

Looking ahead, our global confirmatory Phase III is a double-blind placebo-controlled study with 1:1 randomization between 50-milligram Nomlabofusp and placebo, evaluating 18 months of treatment. We are studying ambulatory patients a less severe population than the open-label study and will focus on patients who are 2 to 40 years of age with about 2/3 of the participants under the age of 21. We are targeting roughly 100 to 150 patients and plan to have sites in the U.S., EU, U.K. and Canada and Australia.

The primary outcome measures or upright stability in the United States and [ MLRs ] in the EU, reflecting feedback from both the FDA and EMA, both of which have reviewed the protocol.

We have an exciting 12 months ahead of us. We have initiated our rolling BLA and submitted the first module. We expect to dose the first patient in the global Phase III trial in the third quarter of this year. We expect to complete the rolling BLA submission with submission of the remaining modules in the second half of this year. And if approved, we are targeting a U.S. launch in mid-2027.

Beyond the U.S., we intend to pursue development in the EU, U.K., Canada and Australia throughout 2027 and 2028 and including initiation of our Phase II activities in Europe.

As you heard today, Nomlabofusp has the encouraging potential to be the first disease-modifying therapy that addresses the root cause of FA. Nomlabofusp is poised to help shape the treatment landscape across children, adolescents and adults with FA, and we plan to pursue a broad label.

Given that Nomlabofusp is designed to address the underlying frataxin inefficiency driving FA we believe it has the potential to be a first-line therapy. Our clinical data continues to reinforce that all patients can benefit from Nomlabofusp treatment, with potential for the greatest responses in patients with earlier intervention.

Before I conclude, I want to thank our clinical to participants and their families, addressing the unmet needs of people living with FA remains our central source of inspiration, and I really commend their bravery and dedication.

I also want to thank the FDA for its engagement throughout this process and our employees, partners, investigators and the patient advocates at the Friedreich’s Ataxia research alliance all of whom have helped bring Nomlabofusp to this exciting point.

With that, I would like to move on to today's Q&A session. Again, we are also pleased to welcome Dr. [ Marshall Summer ] CEO of [ Uncommon cures ], past Founding Director of the Rare Disease Institute and [ Marget Maly ] Chair of Genetic Medicine at Children's National Hospital. We will now open the line for questions. Wilson?

[Operator Instructions] So our first question comes from [ Delma Kaiti ] with Guggenheim.

I have a question for Dr. Summer, if I may. So how do you frame based on your clinical experience, how do you frame the overall benefit risk profile of the drug in the context of a disease like FA? And specifically on the anaphylaxis signal, do you view this risk as manageable in routine clinical practice with the current mitigation strategy?

That's a great question actually. And I'm not surprised by from the risk benefit strategy, given the lethal nature of this disease, it certainly falls within my experience that would be a very favorable risk benefit from that standpoint.

The other thing too, of course, everyone uses the word anaphylaxis, and they always think of it as the extreme, but there are mild forms of anaphylaxis. So require bus to the ER, some do not.

Having participated in a number of recombinant enzyme studies over the years and actually in the lysosomal field, I certainly wouldn't be this is excessive or anything along those lines. I also was part of the [ Palynziq ], which is [indiscernible] PKU therapy trial. And there, we saw more common anaphylaxis from those patients, and these are manageable issues that you can use moving forward.

When you look at the number of doses administered to these patients, and to me, it really does fall within those acceptable parameters from risk standpoint. We always just make sure we train the patients well. Of note, actually, though, we get called by the families who have anaphylaxis, which unfortunately that they had to leave the study. And for those patients we really want to get back on the drug. There were some of our patients that were showing really nice improvement.

So I think it's a tangible issue, I think -- like I said, given the nature of this disease, it's one that the patients are accepting on as well, too.

Our next question comes from Myles Minter with William Blair.

Maybe just start with Dr. Summer and then one for the company. some. I was wondering whether you can just comment on like sort of patient interest in enrolling in the open-label study and as we prep up for a Phase III for the company, just family and care give us wanting to put patients into the trial. I ask because there is a 50% dropout rate here from the data for various reasons. And if I look back at what the updates were I think September through to March, they added two patients from March through to this quarter, they've added another two, there's 11 patients in the pipe to start therapy. How do you kind of conceptualize real-world interest in Nomlabofusp just given the safety profile. That's the first one.

And then for the company, at the Type B meeting, did the FDA ask about the number of patients that they'd like to see on the revised treatment protocol. That's the one where you do the test dose, the 25 and then the 50 and the antihistamine pretreatment, did they specify a number of patients they'd want to see on that protocol to get more comfortable with that potential anaphylaxis risk?

I'll let Dr. Summer start first, and then we'll follow up.

Yes. So that's another good question. So just kind of as a benchmark for this, when we started doing the more intense study last year, we have an enrollment portal, where I think we had 30 patients to come in on that. That portal filled within 45 minutes, patients who want to be part of the study.

I actually think the slowing of the recruitment has to do more with technical issues, getting new sites open. The company has been very good about wanting to try to have patients go closer to home. And of course, as you know, opening up academic sites always takes longer from that standpoint.

I don't really think that the anaphylaxis has put off a lot of patients not from talking the community realized to the [ Hillie ] with [ Rimbartac ] and [ Sara ]. So I also kind of hear what they're thinking, what's going on there. And once again, like I said, the risk it seems to be very positive from that standpoint. And it's certainly of the things being developed around Friedreich’s Ataxia, definitely the most advanced program and one that really cuts to the baseline issues.

So from our standpoint, we've had good success with patients coming in I think the numbers being small probably is really just kind of one of those kind of things, you see getting things open, stuff like that. I haven't seen reluctance on the patient part.

Yes, Myles, I'll give you some color on that as well and then answer your second question. We have had no problem recruiting patients. Unfortunately, the patients who have had anaphylaxis can come in and even some of those patients, and Dr. Summer can speak to that because he's told me this, want to come back in the trial. They just can't. The issue for timing really relates to the fact that we had to amend the protocol for the new regimen. And as Dr. Summer alluded to, when you're working with academic sites, it's not just amending the protocol, it means it has to go to the academic RRBs, which can take months to get through, sometimes up to 6 months. And we did not want to enroll new patients on the old regimen. We wanted to make sure everybody was starting on the new regimen. So there was a delay for more than a couple of months. where we just could not enroll patients.

And so we've been up and running in the last couple of months. I'll just let people remember that we had 39 patients in the data set in September. We now have and we had 41, and we have two who are -- have started dosing but are not actually in the data set because of the data cutoff. So patients are starting to come in the trial, we have the 11 now that are in the queue, and they will dose over the next several months, and we'll continue to be enrolling at some point, we'll probably stop. But right now, the goal is to get patients in who have not been exposed to the drug as we really believe that, that's the key. The drug is not intended to be stopped for long periods of time.

We know that you can stop for a day, a week, a month very safely, but it is not intended to be stopped for a long period of time. And so that's the goal here.

To answer your second question, the FDA has not asked for additional information on the -- or a minimum -- it didn't even come up the revised regimen. They believe when we've asked them specifically, do they need more implementation on anaphylaxis they've very clearly said, no, they have enough to characterize the drug.

And I'll just add one quick thing to that. Having spent 4 years in academics. Carole is being a little bit generous to those of us who used to do that. It can take a year or more depending on what's going on with protocols and things like that. Also, the number of calls my staff get for patients who want to restart or join the study has been robust.

Our next question comes from Tessa Romero with JPMorgan.

Great. So just to double-click a little bit here. What was the tenor of the Type B meeting that you had with the FDA and the minutes that you received? And any other kind of further granularity you'd give us on the topics that you covered?

And for Dr. Summer, thanks so much for being here as well. Where do you think the discontinuation rate may ultimately come out for a profile like this in the real world?

The tenor was very -- look, I'm going to be perfectly frank, I'll give you the details. We actually got the preliminary comments from the FDA, and they were so clear and so noncontroversial, they basically said that we should -- and obviously, in legally words, they said that it was -- that we had enough data to submit the BLA.

It was a very long set of preliminary comments, mostly focused on what we need to make sure we have in the BLA, in particular, with the [ CMC ], even as detailed as to give us the tables, what the table should look like.

And so being very frank, we actually did not meet with them because the preliminary comments were so clear. And what happens when you don't meet with them is the comments actually become your minutes.

So based on those comments, we have a clear direction from the FDA of what the BLA needs to look like and how -- what needs to be contained in it. We have communicated with them since. We got the rolling submission communication from them. We've had other communications with them. They are totally supportive of submitting the application they make it very clear that approval will be a matter of review. And we will have to show a benefit risk assessment that makes sense for an approval.

And I'll tackle that question that was directed to me it's [ Marshall Summer ]. I actually don't think the dropout rate will be significant or frankly, it will be very minimal given the nature of the disease. Some of the gaps that I think how to result in sort of an immune priming for these patients did not occur because patients didn't want to be in the study, things like that.

So I think once you were actually available to the patient community -- and I really want to applaud the company for going ahead and doing a pediatric group because otherwise, I think if you had -- just an adult-only approval, then you get a lot of off-label use, I would not anticipate drop out for really any compliance issues given that this is the old game in town renew and nature of the improvement.

Our next question comes from Joseph Schwartz.

I was wondering, first, if you could just walk us through how many patients anaphylaxis or had anaphylactoid reactions to test dose versus the 25- and the 50-milligram doses, so we can understand how successful the modified dosing regimen is.

And then do you expect the label to recommend that patients begin dosing in the clinic? And when do you envision that they might be able to at all transition to at-home dosing.

And then do you think that REMS will be included on the label? What kind of recommendations will you be making to the FDA when it comes to those issues?

We do not have enough data to really know anything about the modified dosing. My personal opinion is that it's not going to have much of an impact at all. But that's an opinion. I don't have the data yet. And the reason for that is that I think this is very much related to taking the drug stopping for 6, 8, 10 months and then restarting it.

The patients who were in the older studies, as you saw from the data we presented, where we showed the baselines, we're off the drug for 2.5 years. some as long as 3 to 4 years, and then it was reintroduced. And I think this is all -- that's what this is all about. And I think what will be in the label is that you shouldn't stop your drug for long periods of time and then restart because you have an increased risk.

Now that doesn't mean you can't restart if you stop because we have many patients who had -- did receive drug in the early studies had the same length of time hiatus are in the study in the open-label study and have not had anaphylaxis. So the risk increases, it doesn't mean that you can't restart your drug. And I think that's an important differentiation. People can restart drug.

But we know from our own data that people who take a month or 2 break they don't have the same increased risk that if you're out over 3 or 4 years.

So I'm much more optimistic that as we get more naive patients in who have not participated in or who have not been exposed that, that will be the best way not to have an increased incidence abdominal of anaphylaxis.

Your second question is I do believe that we will require people to take their first dose in a doctor's office and be observed for several hours. I think that's the right thing to do. I think it's a mild inconvenience to patients, but I think it's important just to make sure there isn't whether we anticipate an allergic reaction or not, there's just nothing else that goes on.

I think it's important also so that we can ensure that they know how to inject themselves and they know how to draw up the drug, and that they can be observed as they do that. I think those are important learnings, not people don't inherently know how to give themselves an injection or a caregiver to give them an injection. So I think that will be in the label, but I think it will be the first dose and then subsequent doses will be at home.

I think if you do, there will be something in the label that says that if you do stop for greater than a certain period of time, your first dose when you restart should also be in the doctor's office. And then with regard to [ REMS ], we have not had those conversations with the agency yet. They need to see the data. They need to look at the risk benefit. There are a lot of drugs out there that have -- when you're going to have anaphylaxis or have black box warnings for those things, but don't have [ REMS ] or had [ REMS ] and then they don't have a [ REMS ] after people get it comfortable using the drug.

So my first inclination is that we will have our first dose in the doctor's office. We will not have subsequent doses in the doctor's office. And I don't know about [ REMS ] yet. Dr. Summer, you had a...

Yes, I wanted to add something to that, which is there are also some opportunities to look at desensitization that's been used some of the other enzymatic therapies where patients have had reaction. So even those patients who have had a bad anaphylaxis or at least an anaphylaxis are not for one to be clinically significant. They are actually going to be methods and opportunities to try to work them back into the program as well.

Yes. Thank you for that. And we -- Dr. Summer and I have and the company as a whole and Dr. Clayton as well have talked about as we move forward and get more resources are starting to initiate some of those protocols.

Our next question comes from Samantha Semenkow with Citi.

I had two for Dr. Summer, if I may. If Nomlabofusp to receive FDA accelerated approval, I'm wondering how you would approach using it in your center? Specifically, what percentage of your patients would you consider potential candidates for the drug? And then this has been a discussion, but just to put a finer point on it, given the rates of anaphylaxis appears to be meaningfully lower for naive patients versus those that take a treatment holiday. I'm just wondering how that impacts your thoughts on prescribing and managing patients particularly given some might require treatment holiday at some point during their time on therapy.

First off, what I should clarify is I do not practice clinical anymore. I run a clinical research program at this point in time for rare diseases. So I would not have new patients coming in to seeing on a regular clinical basis.

Having said that, however, we're still in practice, I would see no problem with actually prescribing this. And like this thing, since we will have pediatric data.

There is a concept known as point of maximal impact when you're treating rare disease and frankly, in the pediatric population, you want to actually be treating the disease before the symptomatology has progressed. Some of the damage in Friedreich’s Ataxia is going to be permanent. You would really like to treat those patients before there is evidence for that. So our molecular testing can certainly be helpful, subsequent siblings, things like that. Because as you know, many of the patients aren't diagnosed until they're somewhat symptomatic. So I wouldn't want to treat as early as possible for this patient population.

In general, and then I'll go back to my experience in lysosomal which goes back to the 199scoliosis, very rarely do patients take big drug holidays with this type of therapy, not only because the ramifications are pretty serious for them, particularly in these families where they've seen the progression of the disease and stuff, they're not going to do that. I do think though it's pretty easy to bring the patients in observe them. If we do have a good duty sensitization protocol, use that if a patient has been on for a while, and he's going to restart. But nothing that's, I think, extraordinary or out of the ordinary for this sort of thing.

Our next question comes from Laura Chico with Wedbush.

I guess one clarifying question on the final modules for the rolling BLA submission. I apologize if I missed this earlier. I know the completion time is timing is expected in the second half of '26. Is there any additional clarity you can provide just with the status on those? I guess, kind of what would kind of drive that either closer towards the beginning part of second half versus the latter part? Any clarity on that front?

And then, I guess, just with respect to the mid-27 launch timing, is there still the assumption that priority review would be granted?

Yes. So we -- the modules will be going in throughout the second half. I don't want to give more clarity right now, Laura, until we get a better feel for how they're being going to be completed.

Obviously, we want to complete them as early as we can and as soon as we can. But as we collect data -- and I'm not talking about clinical data, this is the data that will go into the BLA. We're not -- obviously, we're continuing to collect safety and we're continuing to enroll patients. But the data cut that you're seeing now is the data that's going to go into the BLA. But we are going to be -- we are finishing up, as we've talked about publicly the [ CMC ] section. I want to make sure it's perfect. We have seen -- we see people all the time get [ CRLs ] and I want to do the work now so that we don't get a [ CRL ]. We'll save a lot of time taking a month or 2 now and taking our time. rather than waiting and then ending up with the [ CRL ].

So we'll be able to give more clarity as the year progresses and we will. But I don't want to give ever by a blow by blow because it's just going to be confusing for everybody and not helpful. So once the final -- the remaining modules are in, we will make an announcement.

With regard -- what was your second question? Oh, about launch? Yes, we do expect to get priority review. I think it would be -- I'd be very, very surprised given the process we've gone through with the FDA if we did not, we are eligible for sure. And with the breakthrough and rare pediatric, I can't imagine that we would get priority with you.

Our next question comes from Jonathan Wolleben with Citizens.

Just wondering, Dr. Summer, if you've had experience with Skyclarys as well? And if so, could you kind of talk us through the different responses you're seeing with these drugs?

And then, Carole, you guys noted an association between frataxin and the clinical outcomes, wondering if you're able to flesh that out a little bit more with some details.

I'll let Dr. Summer go first.

All right. The experience I have and just from talking to the community is the drug Skyclarys, it's really more of a try to prevent deterioration trying to hold steady, which it is not tremendously affected that lift.

And if you think about it, you're not addressing a problem you're really kind of addressing mitochondria stability or dysfunction, which is more of a generic thing from that standpoint.

So really, it's kind of apples and oranges you're comparing different things. I think from the standpoint of actually going straight at the protein makes a lot more sense. And frankly, would replace it pretty quickly. I'm not really sure there'd be much of a need for the other exits as moves forward. Does that answer your question, Jonathan.

Yes. thank you.

And your second question was, I meant to write it down, Jonathan, but I didn't.

The association between frataxin and the clinical data.

Yes. So we do see correlations. Obviously, these are small numbers, but we sort of showed you some of what we're seeing when we gave you the four graphs with the frataxin levels on the left. And then you can see how the patients respond over time. But there are correlations.

There are also some really -- I don't -- people may not have picked up on it because I know there was a lot of information provided. But the agency has multiple times highlighted gene expression and lipid profiles.

And in particular, in the pre-BLA minutes, they again brought up that those to outcomes if correlated frataxin and which they are. We already have most of that data can add value to supporting frataxin as a novel surrogate end point clinically likely to produce a clinical benefit. So they have picked up on some of these other I don't want to call them biomarkers to other chemical outcomes that we can look at or such as gene expression and lipids.

So there seems to be a correlation between frataxin and clinical outcomes, but in particular, some of these other less than -- some of these other outcomes and chemical outcomes that we can look at and look at orations. You don't have to be out a year to see those kinds of changes.

Our next question comes from François Brisebois with LifeSci Capital.

Okay. I was just wondering on that chart, maybe for Dr. Summer here. When you look at the FARS ADL, the mFARS, the whole peg test data, is there a hierarchy here in terms of those readouts of what is more interesting from a physician's perspective?

Sure, we do mind bringing that slide back up, please?

I don't think we can -- yes, we can. We have, we can. We'll keep this one.

This thing you're talking about? Another...

Yes. It's a mix of this one and the next one, just like what is mostly -- yes, correct.

There's a couple of things that really stand out to me. 9-hole PEG which most people kind of dose count, particularly as these patients have more aggressive disease and they start to lose their ability to walk in mobility. I hope PEG is one of those things that you see kind of towards the end and would actually still have room for improvement. So that one, oddly enough, I right, fairly high.

The other one interesting enough is Activities Daily Living, therefore is ADL. And one of the things people forget about that is everybody thinks it's just a survey. So what does it matter? But the elements that are in there actually require a lot of complex underlying skill sets. So it's almost, in some ways, a good composite for what's going on with those patients.

The mFARS obviously, that's become such a good standard and obviously been around for a while and it's been well developed. Of course, it's the follow-on to the FARS and refinement of that from that standpoint.

So if I had to look at it, I'd say particularly for these more severe patients, 9-hole PEG, and then the mFARS and the ADL would kind of be the ones I'd look at next. I think if you're looking at a presymptomatic group or group early in symptomatology, I would say ADL and mFARS would then start to climb up in my hierarchy but with the more severe patients, 9-hole PEG is a good one.

Absolutely. And then maybe, Carole, if I can ask it. You talked about the difference from the September update last time to end of 8 and end of 13. I was just wondering, I think you mentioned that there are more severe impairments here with these patients. And just wondering how to read into that impact on the delta scene between [ NOLA ] and the FACOMS on the mFARS.

Yes, I think that's an important question, Frank, and that's why we sort of did the next slide, which was break it out by disease duration. But what I wanted to -- the patients who came in the additional five into the 1-year time point had a mFARS score of 60 versus 51, which is a real difference, especially because as you get further up in the scale the change is -- it's harder to necessarily measure.

I think the take-home message here is really need to look at multiple different outcomes, mFARS is a very good tool but it has its limitations, as Dr. Summer just said. And in different populations, some of these outcome measures may be more sensitive or less sensitive. And so I think looking at overall data set and not focusing on any one particular data point, but looking at the overall data set and the trends is really important.

In the earlier stage, and Dr. Summer, correct me if I'm wrong, but in an earlier population that has less disease, they're not -- they may not improve all that much because they don't have as much disease or I don't have to wait much of a way to go.

On the other hand, they may actually improve more on certain outcome measures where they're still struggling because they are symptomatic. Do you want if you want to comment that would be.

Yes, let me comment on that real quick. I think let's take a look at the mFARS graph up there like this -- while this is the number of years of disease duration, it probably has a little bit of a correlation to age as well to notice the purple line for those who have disease longer than 25 years, probably the disease has burned its course, so to speak. So there's not going to be a lot of room for improvement in those patients.

Interestingly enough in both less than 25 and the outer 12.5, you can see those patients are just starting to deteriorate because the scores have been going up over that 2.5 gap here. and they're stabilizing and actually showing improvement from that standpoint.

I think the one thing to keep in mind, too, once you do get approval here, we're starting to use this in patients who are either presymptomatic or early symptomatic you may not see a lot of move. That's actually a great thing because if they're starting off with minimal disease, that's where you want to keep them and then they're starting up with almost no symptomatology wine. So you really wouldn't see much change in these different measures here because they really wouldn't have had a chance to become more symptomatic from that standpoint. So just kind of keep that in mind.

I still wish that fair when they had done this, it reversed the scale so that low was not as good and high was bad, but there you go because it makes it -- it's counterintuitive when you look at it graphically, but that ship sailed.

Yes. The other thing I would comment on is if you look at the 9-hole PEG on the slide, you do see improvement in that population. And that's -- and you also see it with ADLs. And so -- that's why I was trying to drive home that mFARS is useful, but you may need to look at different measures in different populations or at least look at all measures in the different populations.

Also to Dr. Summer's point, you expect these patients to get worse. You don't expect them to get better. So the fact that they're flat is even an improvement. So no change in this population is still a good thing quite honestly. I don't know if Dr. Summer if you want to comment on that?

Yes. I mean, honestly, I would have considered when if it was flat. The fact that we are seeing improvement in these was rather surprising to me. I think probably what it means is there are sales left that are not functioning properly, but are still alive. And if you actually restore frataxin and then actually those cells become healthier, you may actually show improvements in some of these functional areas. We used to think that with this sort of condition, once you've lost stability, it was gone. But I think there's a reserve of cells that actually you're seeing had performed better. So that's why I think we're seeing the improvements here.

It's certainly not a placebo effect, not with over those time periods. So that's found that very encouraging. But like I said, I would have considered when, if we've seen that purple line on the top where it was just flat and the patients didn't get worse.

Excellent. No, that was super helpful. And you can also see in that chart, the 9-hole PEG is those error bars are only getting tighter as well on the red line. All right. That's very helpful.

Our next question comes from Catherine Novack with Jones Trading.

Just wondering if we can get a little bit more detail on the -- you've mentioned the ambulation status for some of the patients -- so for the patient who did become ambulatory, how long have they been non-ambulatory buyer to starting Nomlabofusp? Is it common for ambulation sets to reverse during this time frame? And is -- do you have any frataxin expression analysis to suggest that any of these changes or preservation of ambulation status might be drug related? .

Yes. So it's a pretty interesting question. I want to make it clear. This person didn't get up and run a marathon, okay? They went from being completely wheelchair-bound to being able to walk with significant assistance.

So the way the scale works because this is just a change in a scale. The patient was what is called [ 5 ]. They were bedridden or completely wheelchair bound. And they went to 1 level less which is still severely affected with severe ataxia.

So I don't want to imply that the person got up in just around away. That's not the case. But that said, nobody who was ambulatory deteriorated also. And so that's an important point as well.

And so I don't want to make more out of this than it is. It's an interesting data point that we obviously have, and it's an important data point because if you can get somebody who's bed written, up and a little bit mobile, it allows them to at least potentially sit at the dinner table with their family. And so again, I don't want to make more of it than a data point. but I do think it is an interesting and important observation.

All of the patients, 100% of the patients at 1 year are above the level of asymptomatic carriers. So it doesn't really seem to matter whether you're at 60% or 75% you should be okay. So I can't really say that there'll be a correlation, but that patient obviously had significant increases in frataxin, and I don't know how long they wheelchair-bound. We don't collect that information.

With a lot of these different replacement type therapies, we do, there's sort of a threshold effect. So once you've sort of stabilized mitochondrial function, once you have resulted so that the cells either stable or doing regular housekeeping things as opposed to always fighting deterioration. You seem to reach that.

And those are always hard points to take out. It can be individual based on genetics and other things that are going on. So I suspect that might be the case here, there's probably a threshold effect.

There. Our final question comes from Chris Chen with Baird.

Just one for the team first. Just regarding the 11 patients in the queue for the open-label study. I apologize if you might have mentioned this, but can you provide just some more color on how close they are to enrolling and/or where they are in that process?

And then just one for Dr. Summer you touched on Skyclarys a little bit already. But just regarding [ Nomlabofusp ] potential approval and usage, do you see any contraindications regarding its use in patients switching from Skyclarys?

Yes wouldn't see any contraindication to switching on that. In fact, a patient, for instance, decided to say on Skyclarys, I really wouldn't see it interfering with the therapy, anything like that. I mean happy mitochondria or happy mitochondria that this actually has any potentiation. That's fine, but I really wouldn't see an issue of switching from one to the other.

And Chris, I can tell you, we have patients, as you know, who are in the study who are on [ OMV ]. And the safety profile doesn't -- it seems fine. The big issue, obviously, is going to be third-party payers and convincing them to pay for two expensive drugs. But I don't see -- there doesn't seem to be any issue from the standpoint of safety.

Okay. With regard to the Q, there are these 11 people that means by saying that they are in screening. They have all signed informed consent. Obviously, not all of them will necessarily pass screening. So we do have screen failures intermittently. But if they do pass screening and qualify for the study. They should be dosing over the next couple of months or so. screening period is about 4 months -- sorry, 4 weeks of a month. So I think it's a little longer. The rest is in like maybe 6 weeks we -- yes, sorry, it's 6 weeks. So depending upon where they are in the screening process, they'll -- assuming, again, they pass screening, they'll be dosing in the next couple of months.

I'll now turn it back to Carole to close up the call.

Thank you, everybody, for participating in the call. We really appreciate it. We're very, very excited about this data, and we look forward to the next 12 months. And hopefully, over the next period of time, we'll be talking more and more about the commercialization process. So thank you for your time, and thank you for your questions.

Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.

My name is [ Henry Chang ]. I'm with the banking team here at JPMorgan, and it's my pleasure to introduce Larimar Therapeutics today. Presenting today will be Dr. Carole Ben-Maimon, President and CEO of Larimar. Just a quick note, we'll have time for Q&A after the presentation. So please wait until then for any questions, and we'll get you a microphone.

But without further ado, I'll turn it over to you, Carole.

Thank you. Thank you, everybody, and welcome, and thanks for coming to learn more about Larimar. We're excited to be here today. These are our forward-looking statements. I'm not going to go through them, obviously. So let me tell you a little bit about Friedreich's ataxia.

Sorry about that.

It's okay. So Friedreich's ataxia is a neurodegenerative disease that is really devastating. It's a rare disorder. It is an orphan disorder. There are about 5,000 patients in the United States, about 20,000 throughout the world. Patients are usually diagnosed about 70% of them before the age of 14. So it is a disease that occurs in pediatric patients and really continues to progress throughout life with an early death.

It is caused by a deficiency in frataxin, a protein that's active in the mitochondria of the cell. And so therefore, the goal here is to restore frataxin. Patients with FA walk around with about 20% to 40% of frataxin, but the severely affected actually have much less, around 5% to 10%. The heterozygous carriers, so the parents of these children are essentially phenotypically normal. They have no signs of the disease, but they do walk around with about 50% to 75% of normal healthy people.

So the goal here is you don't have to get to 100%. If you can just get over the 50% mark, you can actually hopefully slow or stop the progression of the disease, which is the target. The patients are actually born looking healthy. It's actually a really tragic disease. And as they start to get towards puberty 5, 7, 10, 11 years old, they start to become clumsy. They can't ride their bikes as well as they used to. They can't run as well as they used to. By the age of 20, most of them are in wheelchairs. And by the age of 30 to 50, they die. It is a systemic disease. Any cell in the body that has mitochondria, which is essentially every cell in the body with one exception, erythrocytes, has frataxin.

And so they have the neurodegenerative part of the disease, but they also suffer from a Hypertrophic Cardiomyopathy. Many of them develop diabetes. They have skeletal muscle issues. They develop scoliosis and often need surgery for the scoliosis. They have problems swallowing. And so treating the entire body is really critical. Most of them die from a Hypertrophic Cardiomyopathy. So it is the heart disease that ultimately they succumb to.

Many of these families actually have more than 1 child with the disease, which is really devastating. We actually had a family in our office a couple of months, maybe 6 months ago, 4 children and 3 of them are in wheelchairs. And that happens because most of these families have had all their kids by the time the first one is diagnosed. So it really is an incredibly devastating and tragic disease. There remains an unmet medical need. It's very important to note there is one approved therapy, but it works downstream. It does not attack the root cause of the disease, frataxin deficiency. So we believe that we will be potentially the first disease-modifying therapy for FA.

Let me tell you how we do what we need to do. The challenge here is getting the protein into the cell, but then also getting it into the mitochondria. So what you see on the left is Endogenous frataxin. It's the normal frataxin that 95% or more of these patients have. Frataxin is actually coded in the nucleus. It's produced in the cytoplasm, and it's produced is what I like to call a pro protein. So it has the frataxin moiety, which you see in blue here, but the green is the mitochondrial targeting sequence. And that's the part of the cell -- of the protein that takes it into the mitochondria. And once in the mitochondria, a specialized enzyme cleaves off the mitochondrial targeting sequence, leaving the active human frataxin.

On the right, you see nomlabofusp, the molecule that we're developing. And you can see that the cell-penetrating peptide that's going to get it into the cell is not attached to the frataxin moiety, it's attached to the cell -- to the mitochondrial targeting sequence. That's important because that maintains the cleavage site between the MTS and the frataxin moiety. And so when the cell crosses -- when the protein crosses the cell membrane, the mitochondrial targeting sequence is there to get it into the mitochondria where the cleavage site is still in existence so that MPP, the mitochondrial processing peptidase can actually cleave off the cell penetrating peptide and the MTS, leaving the identical sequence to the normal endogenous frataxin. So both the MTS and the frataxin moiety are identical to endogenous frataxin.

We've done some market research, and it's important to note that clinicians actually really do understand that there still is an unmet need for something that targets the root cause of the disease. And so they understand that the root cause is a deficiency in frataxin and that getting at the deficiency in frataxin could very well be disease modifying. And so we're very excited about that. We actually launched a disease awareness campaign back in the fall. And we do know that people really do realize that there is a need for further therapies.

A little bit about the levels of frataxin in patients. It's important to know that if you have lower frataxin levels, so the lower your frataxin level, the earlier the onset, but as importantly, the faster the progression. So what you see in the table on the left is if you have 11% of frataxin, your disease -- your age of onset is about 7 years old, with about a 3-point progression every year in the FARS score, which is just a tool that's used to measure progression. If you increase to 22%, so you don't have to go all the way up to 50%, you increase to 22%, you delay the onset of the disease by 4 years. But as importantly, you actually slow the progression of the disease by a full point. So what we're looking to do is provide enough frataxin to these patients that they will either halt the disease progression or slow significantly and delay the loss of speech and delay the loss of ambulation.

So again, we have the potential to be the first disease-modifying therapy in a terrible neurodegenerative disease. We have completed 4 studies, a SAD, a MAD, a dose-exploration study and a PK run-in study -- PK study in adolescents. We have one ongoing trial right now, which is our open-label study, where we're collecting frataxin at various time points to demonstrate the increase in frataxin. We're also collecting obviously, safety and clinical outcomes as well. We are pursuing an accelerated approval with a filing in the second quarter of this year, and it will be based on using frataxin levels as a novel surrogate endpoint. We -- and the BLA will go in and launch is planned for early '27.

From the standpoint of regulatory, we have Orphan Drug designation in the U.S. and the EU. We have Rare Pediatric Disease and should the voucher system be extended, we will be eligible for a Pediatric voucher at the time of approval. We have Fast Track. In Europe, we have PRIME and in the U.K., we have ILAP. And we were very excited to receive start designation back in 2024, which has allowed us to have incredible conversations with FDA. They have just been really, really engaging and really, really constructive in all of our meetings.

The time line for announcements is we do plan to have a regulatory update. There will not be data, but a regulatory update after conversations with the FDA that will occur this quarter. And the BLA will be submitted seeking accelerated approval in the second quarter. There will also be a data release once we have the final data for the BLA and then launch is targeted for early '27.

From an IP perspective, we have Composition of Matter patents in the United States to take us out to 2020. We also have a Formulation patent, and we have some Platform patents that provide that people can't just tweak the molecule by changing a couple of amino acids. But most importantly, we got our first European patent issued for -- which is a Composition of Matter patent. And so we're very excited now to also have patent protection in Europe.

A little bit about the ongoing open-label study. So this study started as a study, an extension study. So the initial population was only patients who had participated in prior studies. And those patients were in a study, they stopped dosing until we opened this study in the first quarter of '24, and then they restarted the drug. And that's important because some of these patients have shown an allergic reaction. And I'm going to talk more about that as we get forward. But that's why the regimen that you're seeing up here is now the new regimen.

We have recently expanded the population to include the adolescents who participated in the PK run-in study, so children 12 to 17 years old. And we've also now expanded it to include patients who have not participated in other studies. And that's important because we are expanding our population. We do plan to enroll children 2 to 11. That amendment is in progress, and we're working to get that started as early as we can. We -- the dose regimen is antihistamines. They start them 5 days prior to initiating their first dose. They get -- in the doctor's office, they get a 5-milligram test dose. If they do well after an hour, they get a 25-milligram dose, which they take then at home, self-administered or administered by a caregiver for 25 days, and then they increase the dose to 50, which is our target dose and what we think our final dose will be.

This is the frataxin data in skin. I'll talk a little bit about skin. We have submitted to FDA a whole package that included all of that data to support the novel surrogate endpoint, and they accepted it, and they said it would be an issue for review only. And so we know that skin -- changes in skin frataxin actually correlate very nicely with dorsal root ganglion, skeletal muscle and heart, all target tissues for the disease. And you can see on this slide, the dot is the median. The horizontal bars are the 25th and 75th percentiles. The dotted line on the left is where heterozygotes gets lived, that 50% mark, which is where we really would like to get above.

And you can see that by day 180, all of the patients who have been treated are above the 50% mark. The number, the 50% mark, we did a normal healthy volunteer study where we genetically tested 60 people to make sure they had 2 normal alleles. And we know that normal skin frataxin levels are around 16 picograms per microgram protein. And as you see here, the 50% would be 8 picograms per microgram protein. And you can see we're well above that mark with the treated patients by day 180.

This is the same data just shown in a table form. On the right, though, are the absolute numbers. We have this in here for [ pay pilled ]. It's on our website, obviously, but we're excited to see the response we've gotten.

This is another way of animating this, and I'll focus on the right. As we had our normal healthy volunteer study, we were able to divide the frataxin levels into quartiles. And what we see here is the patients at baseline, and those are the patients represented in black, are very low. Actually, in this population by day 180, there was like less than -- sorry, at baseline, they were less than 17%. By day 180, you can see that the treated patients, which is all of them, have increased to over the 50% mark. And those are the patients that are represented in green. You can also see that at day 90, some of the patients have increased by 1 quartile, which is the blue and -- but many of them have also gotten to greater than 50%. So we're very comfortable that the 50-milligram dose is the best dose for most patients.

I'll talk a little bit about safety now. We've had 65 people who have been exposed to at least 1 dose of drug. 39 of those patients have enrolled in the open-label study. The most common adverse events are injection site reactions, local injection site reactions. They are mild to moderate. They resolve pretty much on their own. They seem to decrease over time, and nobody has dropped out due to an injection site reaction.

I think that's really important because we have patients now as of March, who will be out 2 years, and these people are staying on the drug, and I'm going to show you that in a little bit. But 7 patients have actually had anaphylaxis. They respond to standard therapy, EpiPen. We do provide epinephrine auto-injectors to all of the patients so that they have them if they need them. All of the patients have returned to their normal state of health. All of these events have occurred within the first couple of months of dosing, most of them on the first day of dosing. And once they get past the first couple of weeks, we have not seen any allergic events, quite honestly. They return to their normal state of health, and they have no further sequela.

6 of the 7 patients had been exposed to nomlabofusp in the prior study. There was one who had not -- who had received placebo. There are also 10 participants in the study that had only received placebo. They never received nomlabofusp. And only that one patient has seen anaphylaxis. So we think the incidence is much, much lower in patients who have not been -- had prior exposure with a long break. Some of these patients had a break of over 3 years. So it's important to note that we think -- important to get into the trial, some of these naive patients so we can actually follow them for longer.

Long-term safety, it's generally well tolerated. Other than this, we don't really see anything novel except for the injection site reactions, which I said decrease over time and don't cause withdrawal. We have 14 patients at 6 months as of the data cut in August, so those patients are now further along and 8 patients at a year. So that data continues to progress, and we continue to enroll.

What are we doing to try and mitigate the risk? So first thing is education. Getting people, patients and doctors to know how to recognize anaphylaxis, how to treat it and make sure that they understand and they have all the tools at their bed sides to make sure that they can take care of it. We started the histamine blockers. We modified the dosing regimen to allow for that test dose, which we think is important, not only because it's a lower dose. So hopefully, the reactions will be less severe, but more importantly, because it could very well prevent by desensitizing the mast cells and basophils, the release of histamine actually prevent the anaphylaxis. And then finally, we give everybody an epinephrine auto-injector to make sure that they have something that they can treat themselves and it works very well.

This is the -- a chart of dropouts. And what I want to focus you on is here. This is the first 90 days of treatment. And this is really where most of these events occur. Once you get out past 90 days, there is an occasional discontinuation, but they really are few and far between. And as I said earlier, we now have patients who are going on 2 years' worth of dosing. One thing I learned a couple of days ago from our statistician that I hadn't realized, we've given almost 8,000 doses of drug across our trials. So that's like a really a lot of -- in a rare disease to be able to say that you've given 8,000 doses is tremendous. And that's partially because the patients who are going on 2 years, they would have over 7,000 doses each. And so it's really quite a remarkable, in my mind, data package for a rare disease.

In addition to looking at frataxin, we've also looked at clinical outcomes, and that's really important. And we've -- most of our patients are in wheelchairs. They are more progressed than some of the Phase III studies. And what we've done here is we've basically looked at the baseline characteristics of our patient population, then looked into the natural history study, the FACOMS database, which is the natural history study that was conducted by the Friedreich's Ataxia Research Alliance, the patient advocacy group. And we pulled out a subset of patients as a reference population that matched our patients. And what we see here, the blue is the clinical -- the nomlabofusp group. The tan is the FACOMS data. And so if we focus on mFARS, which is the outcome measure used in most clinical trials, you see that the improvement and down is better, higher scores are worse.

So if you go -- if you look at the first look here, right here, we have an improvement of 2.25 in our population, while the same population, the reference population in the FACOMS database worsens by 1 point. That's important to put into context. So the only approved therapy, omaveloxolone, had an improvement at 1 year of 1.56 points. We have an improvement now of 2.25. So we at least know that from a regulatory perspective, that is considered clinically meaningful.

In addition to mFARS, we looked at activities of daily living, which is here. And we looked at 9-hole PEG test, which is an upper arm dexterity measure, which is very important in our population since so many of them are wheelchair bound. And we looked at a fatigue score, which is the bar one on the right. And you can see that all of the measures improved in our patient population and in the FACOMS database, all of them worsened. So we are making a difference. And I have to tell you, I was incredibly surprised when I looked at this data. I really thought this drug would halt the progression of the disease. I never ever thought that it would improve patients and patients are continuing it looks like to actually improve. And that probably due to creating a more efficient system in the cells so that they can make more ATP and they can actually normalize the healthy cells that they still have.

So we basically believe that we could be the first disease-modifying therapy. We are attacking the root cause of the disease. The data suggests that increasing frataxin levels may halt the disease progression and potentially even improve it. We do have to deal with the anaphylaxis, but it's totally treatable with an EpiPen and patients do well once they are treated, and they have all known how to handle it. And overall, the drug is generally well tolerated with the most common adverse events, injection site reactions, which don't -- which seem to decrease over time and do not lead to withdrawal.

This is a very busy slide, and I'm not going to go through it. I would focus you first on the very top. We have agreement with the FDA that we can use frataxin as a novel surrogate endpoint, and it would be a review issue. We also have a recommendation from the FDA that we should use and focus on skin frataxin levels and not buccal cells, which we also collect, although they show pretty much the same thing, but the skin is just less variable and clearly, changes in skin frataxin correlate very, very nicely with dorsal root ganglion, skeletal muscle and heart, all target tissues.

I'll focus also, we are pursuing an accelerated approval, which means that we are required to do a Phase III confirmatory study. And I'll spend a little time on that in the next couple of minutes. But finally, we're working very aggressively on our CMC to make sure that we have all of the things completed that need to be done for the filing. And we've been interacting very closely with FDA and routinely with FDA to make sure that we don't have any hiccups in our CMC.

With regard to the Phase III trial, we're looking at ambulatory patients, so a different population than we're currently in. Patients 2 to 40 years of age with 2/3 of them being under 21 because that's a population that progresses more quickly. So we'll make the placebo group more -- progress more quickly so we can differentiate our drug. And we are looking at about 100 to 150 patients, probably close to 130 or so. It will be 50-milligram dose for 18 months with mFARS in Europe and upright stability in the U.S. Both EMA and FDA have reviewed this protocol. They have both given us comments. Those comments have all been incorporated. We did propose upright stability for Europe. The EMA wants very much to have a broader score. And so we'll be -- we are using upright stability in the U.S. and mFARS in Europe. Otherwise, they are identical protocols.

The trial is being initiated. We had to amend the protocol for the new regimen, but it's now complete and amended. Our sites are all selected. There'll be U.S. sites followed by European sites, U.K. sites and then a little bit later, Australia and Canada. Regulatory submissions are going in and have gone in, and we're interacting now with the EMA through the [ CEDAS ] system and we'll be announcing the first dose when we achieve that.

So all in all, we're very excited about where we are. We think that this could be -- very well be the first disease-modifying therapy. We believe it will really change the lives of some of these patients, and we really are very hopeful. We believe this is the beginning of the journey, not the end of the journey. We're planning for a second quarter submission to the FDA with an early 2027 launch.

So with that, I'll turn it over to you, and you can ask whatever questions you need to.

Yes. Thanks, Carole. Really appreciate having you with us here today. So I'll open it up. If anyone has any questions, please raise your hand, and we can get you a microphone. Otherwise, I can also kick us off.

You mentioned there's a regulatory update in Q1 of this year. Could you just provide a little bit more color on what that update will entail?

So it won't be data because we're not going to do another data cut, but we will be having conversations with the FDA. We've been very actively talking to them, and we've had periodic conversations with them for some time. But we do want to make sure we pull all of the package together and they see exactly what they're going to get in the BLA. And so we're making those submissions. We'll be scheduling a meeting to talk to them about those submissions, and we'll be providing an update once we have better clarity on what their thoughts are.

Great. And also just given the severity of FA and the lack of disease-modifying options, you mentioned the benefit risk profile to regulators, but how would you frame that towards families and families of patients as well as physicians?

Yes. One of the things I can just say to you is we have never had a problem with enrollment. There are patients who want to get into these trials. And quite honestly, the limitation is not the number of patients. It's the capacity of the sites to actually conduct the trials. They can only handle so many patients at a time. And so it's really important, I think, to recognize that people understand that this is a devastating disease. They lose their children day in and day out. Any of us who have kids, we all know what that must look like when every day you wake up and you think your kids going to be worse off than they were the day before.

And from a patient perspective, I think it's really important to think about what happens. At 20 years old, these kids are starting to lose their speech. They're cognitively completely healthy, but they start to lose their ability to communicate. That must be so isolating in a population of kids who are so social -- we're all so social at 20 years old. And so it's really important to put this in context. These kids have trouble swallowing. These patients have trouble swallowing. They can't eat, they can't drink. And what happens, they become dehydrated and they lose weight.

And so as we -- if we can even treat some of those things that are really part of the ADL score, the activities of daily living, it's really important. We have -- we talk to a patient -- parent actually a while ago at the beginning of the summer and they have a 20-something year old with FA. She's in a wheelchair. And she happened to be starting an internship, and she was -- the father was very upset about and very concerned about how she was going to get to the internship, it was in the city. How should we get the elevators. And what was the child interested in. She was afraid that they were going to think she was stupid because she couldn't -- she slurred her speech.

So these people really, really suffer. And so I think the FDA is very aware of this disease. They understand it. This division, DN1 that we're in has already reviewed 2 applications and approved 1. So they're very familiar with the disease. They understand the unmet medical need. And I think that shows in their interactions with us and the fact that they gave us a start designation. We do have to deal with the anaphylaxis. There's no question. But let's remember that once that's treated and if they don't go back on the drug, they don't suffer from any other sequelae. It's not like liver function tests where if you damage your liver, you now have to live with a damaged liver. They go right back to the usual state of health, which isn't great, but it's the usual state of health. So I think the benefit risk here is very clear, and I think the agency sees that.

Maybe one more for me is what are your plans for the confirmatory Phase III trials?

Yes. So we're starting that study. Obviously, we all know that it needs to be enrolling at the time we make our submission. We are in discussions with FDA as to what our -- what the plan will be and what our commitments will be. But as I said, the regulatory authorities have all reviewed it. It's in the process of being initiated -- very far into the process of being initiated. And we fully anticipate that we'll be dosing our first subject definitely this year and probably early in the year.

Great. Well, I think that's all our questions. So once again, Carole, thank you very much being here.

Thanks for having us.

Thank you all for joining.

Have a good morning.