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.

Good morning, and welcome to the Larimar Therapeutics Conference Call. [Operator Instructions] Please be advised this call is being recorded at the company's request, and a replay will be available on the company's website. I would now like to turn the call over to Alexandra Folias of LifeSci Advisors. Please go ahead.

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

Before we start, I'd 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 is 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 expectations and assumptions regarding the future of the company's business, the company's plans and ability to develop and commercialize nomlabofusp, formerly referred to as CTI-1601, and other matters regarding the company's planned clinical trials, business strategies, use of capital, results of operation and financial position.

These forward-looking statements involve risks, uncertainties and other factors that may cause actual results, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include, among others, the success, cost and timing of the company's product development activities, nonclinical studies and clinical trials, including nomlabofusp clinical milestones and continued interactions with the FDA, that earlier nonclinical and clinical data and testing of nomlabofusp may not be predictive of the results or success of later clinical trials and assessments and that clinical trial data are subject to differing interpretations and assessments.

The company's ability to raise the necessary capital to conduct its product development activities and other risks described in the filings made by the company with the Securities and Exchange Commission and available at www.sec.gov. These forward-looking statements are based on a combination of facts and factors currently known by the company and its projections of the future about which it 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 Chief Financial Officer, Mike Celano, will be available during the question-and-answer session following the prepared remarks.

With that, I will now turn the call over to Carole.

Thank you, Alex, and good morning, everyone. We are excited to share some new data that highlights the strong therapeutic potential for nomlabofusp for patients living with Friedreich's ataxia and also serves as a pivotal milestone to support our planned BLA submission.

Importantly, we are pleased to report today positive 25-milligram and 50-milligram data from the ongoing long-term open-label study evaluating daily subcutaneous injections of nomlabofusp, self-administered or administered by a caregiver and participants with Friedreich's ataxia or FA. We will also be providing updates to our nomlabofusp development program.

Recall in December, we shared open-label study data from the 25-milligram dose, which showed increased tissue frataxin and early trends in clinical outcome measures after 90 days of dosing in 8 participants. Today, I am pleased to report that we continue to see consistent directional improvements in all key clinical outcome measures, including the modified Friedreich's ataxia rating scale, or mFARS.

We also see consistent directional improvement in FARS Activities of Daily Living or ADL, which measures activities of daily living, the 9-hole PEG test, which measures upper extremity fine motor coordination and the Modified Fatigue Impact Scale, or MFIS, which measures levels of fatigue.

We collected these data every 3 months in participants enrolled in the open-label study and now have data after 1 year of dosing in 8 participants.

We also constructed a reference population from the FACOMS natural history study database, which will be -- we will describe later on in the presentation. In that reference population, we observed a worsening in these outcomes, focusing for a moment on mFARS, the modified Friedreich’'s Ataxia Rating Scale, which is a commonly used measure that assesses progression of disease in patients with FA and has been used as a primary outcome measure in other clinical trials.

We observed a median 2.25 improvement in the open-label study participants treated for 1 year with nomlabofusp daily relative to a worsening of a median of 1 point observed in the participants in a FACOMS reference population.

We believe that these observations are incredibly exciting. The increases in skin frataxin levels and the improvement in clinical outcomes, combined with the improvement in abnormal lipid profiles observed in prior completed studies further support that our frataxin replacement approach is successfully increasing skin frataxin levels in patients with FA with the resulting potential for clinical benefit.

100% of participants at 6 months achieved skin frataxin levels of more than 50% of those found in healthy volunteers, which means participants are at levels found in asymptomatic carriers who do not develop disease. With regard to safety, anaphylaxis has been reported in 7 participants in the open-label study, with most of these events occurring on the initial day of administration and all occurring within the first 6 weeks of dosing. All participants return to their usual state of health after receiving standard treatment.

Importantly, there have been 65 participants who received at least 1 dose of nomlabofusp across the clinical development program and 39 have been exposed to at least 1 dose in the open-label study with 14 patients at 6 months and 8 at 1 year.

Long-term treatment with nomlabofusp was generally well tolerated. The most common adverse events were local injection site reactions that were mild to moderate and did not lead to any participant withdrawing from the study.

Following the 2 most recent cases of anaphylaxis, Larimar consulted with its internal and external experts and decided to modify the nomlabofusp dosing regimen in an effort to decrease the number and potential severity of these events. Larimar has provided to the FDA a full update on the clinical development program, including the safety, skin frataxin levels and clinical outcome measures and the FDA agreed with our new dosing regimen.

The compelling long-term increases in skin frataxin levels, along with the clinical data, heighten our conviction in the potential of nomlabofusp to be -- to address the root cause of FA and thus be the first disease-modifying therapy.

Given these encouraging results, we continue to target our BLA submission in the second quarter of 2026, seeking accelerated approval.

With that discussion of today's exciting news, I'd now like to take a step back to provide an overview of Larimar and the nomlabofusp program. For those less familiar with the Larimar story, Larimar is a clinical stage biotechnology company with a novel protein replacement therapy platform with first-in-class potential. Our lead program is being developed for the treatment of Friedreich's ataxia, a rare, progressive and systemic disease with neurologic deterioration. It is caused by a genetic defect in both alleles that prevents 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, frequent falling. Patients will often present before the age of 14 and 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. In 2023, omaveloxolone was approved by the FDA as the first therapy indicated for FA in what was a critically important breakthrough for patients. Omaveloxolone has no impact on frataxin levels. And currently, there are no approved therapies designed to increase frataxin and address the deficiency underlying FA's horrible symptoms.

Because of this, key opinion leaders, patients with FA and advocates have made it clear that there is still a pressing unmet need for novel therapies to treat the underlying cause of FA. To address the needs of patients with FA, Larimar is developing nomlabofusp, the first potential disease-modifying therapy designed to systemically address the underlying frataxin deficiency in FA.

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.

Low frataxin levels are known to be associated with disease progression in patients with FA. Data from published literature indicate that the lower person's frataxin levels, the earlier the onset of -- the earlier the age of onset of disease, the faster the rate of progression and the shorter the time to loss of ambulation.

The table on the left shows the relationship between frataxin levels as a percentage of healthy volunteers, the median age of onset and the rate of disease progression as measured by the Friedreich's Ataxia Rating Score or FARS. From this table, you can see that if your frataxin level is 11% relative to healthy volunteers, your age of onset is typically very young, a median of 7 years old. As frataxin increase -- levels increase, so do the age of onset and the rate of deterioration as measured by FARS decreases as frataxin levels increase.

This table also highlights that this is not a threshold effect. Rather, it is a continuum. It is also important to note that the age of onset correlates with progression in clinically meaningful outcomes as demonstrated by the data in the table on the right. The earlier the onset of symptoms, the faster a patient will lose the ability to ambulate.

So connecting the dots, if you can increase frataxin levels, you may be able to delay loss of ambulation as well as other clinically meaningful outcomes.

Now let's turn to the exciting findings from our ongoing open-label study. The goal of our open-label study is to evaluate the long-term safety and tolerability, the pharmacokinetics and the ability of nomlabofusp to increase tissue frataxin levels following long-term daily subcutaneous administration, along with exploratory pharmacodynamic markers like lipid profiles and clinical outcomes as compared to a reference population from the natural history database.

As stated earlier, we are pursuing accelerated approval with the potential to use frataxin as a novel surrogate endpoint. The frataxin data and safety data from this open-label study are intended to be used to support the potential accelerated approval submission. In the open-label study, participants initially received the 25-milligram dose. In the fourth quarter of 2024, we began transitioning participants to the 50-milligram dose, with all newly enrolled patients starting on 50-milligrams.

Participants who completed treatment in the Phase I study and the Phase II dose exploration study evaluating nomlabofusp were the first group of eligible patients to screen for the open-label study. We have now amended the open-label study protocol to include adolescent and adult patients who have not participated in a prior nomlabofusp study.

As of August 27, 2025, 39 participants had received at least 1 dose of nomlabofusp and 25 participants, which includes 19 adults and 6 adolescents were receiving daily dosing of nomlabofusp for up to 527 days with a mean of 154 days. This includes the time from the initial dose of 25 or 50 milligrams to the last dose of nomlabofusp prior to data cutoff.

We are now modifying the starting dose regimen to include a 5-milligram test dose followed by a 25-milligram dose 1 hour later, both under observation and then daily for 30 days at home. After 30 days, the 25-milligram dose will be increased to 50 milligrams once daily. Antihistamines will be administered 5 days prior to the first dose and for 90 days after the first dose. An epinephrine auto injector such as EpiPen will be dispensed to all participants to take home in case it is needed.

Recall in December of 2024, we presented initial positive data for the 25-milligram dose showing increases in both skin and buccal cell frataxin levels. We also demonstrated that skin frataxin levels as a percentage of healthy volunteers are higher at 90 days compared to baseline. These data support the potential of nomlabofusp to increase frataxin levels in tissues and address the protein deficiency leading to the FA's devastating clinical course.

In this data set, we will be showing only skin frataxin levels as a result of an agreement with FDA that increases in skin frataxin levels were less variable and correlate with frataxin levels in target tissues. Today, I will show that exposure to the 50-milligram dose further increases skin frataxin levels across all participants and that these increases are sustained over time.

The graph on the left shows median skin frataxin levels from baseline to day 180. The graph on the right shows the median change in frataxin levels from baseline at day 30 to day 180. Based on the preclinical studies we conducted to understand the relationship between skin frataxin levels and frataxin levels in target tissues, our extrapolations from the skin results of the participants in the open-label study indicate that increases in frataxin levels from baseline should also be expected in the heart, dorsal root ganglion and skeletal muscle of these participants.

Once again, as regards to skin, both graphs demonstrate an increase in skin frataxin levels over the course of 6 months in the open-label study participants.

To get a sense of whether these increases in frataxin are clinically meaningful, we compared these levels to 50% of the skin frataxin levels found in healthy volunteers. As mentioned earlier, this is the level of frataxin that is found in heterozygous carriers of FA that do not display any symptoms. This table shows participants with quantifiable levels of skin frataxin at baseline, day 30, day 90 and day 180, who received 25 milligrams, 50 milligrams or had increased from 25 to 50 milligrams.

The percentage of participants who achieved 50% of healthy volunteer levels increased over time. And on day 180, 10 out of 10 participants achieved this threshold.

Now let's look at the data in a different way. In these graphs, we depict how many participants had a shift in their frataxin levels in skin cells as a percentage of average healthy volunteers at day 90 and day 180 of treatment. As in prior slides, these data include participants that initially started on 25 milligrams and were transitioned to 50 milligrams as well as those who start dosing at the 25-milligram dose.

On the far left of the figure, you can see categories of percent of healthy volunteers' frataxin levels. Skin frataxin levels from our healthy volunteer study were divided into quartiles. Open-label study participants would then fit into those quartiles based on their baseline skin frataxin levels. The people in black on the left-hand side of each graph represent participants at baseline. So the right of the black vertical line are where each participant ends on day 90 and on day 180. In blue are participants that increased their frataxin levels from baseline to between 25% and 50% of the average frataxin levels in healthy volunteers.

Similarly, in green are the participants who increased their frataxin levels from baseline to over 50% of the average frataxin levels in healthy volunteers. By day 90, all participants had increased their frataxin levels. And by day 180, all 10 participants had increased their frataxin levels to above 50% of healthy volunteers, which is similar to levels of heterozygous carriers of FA who do not develop this disease.

Here, we have the absolute values for median skin frataxin levels from baseline to day 30, day 90 and day 180 at each time point. In all the participant groups, the levels of skin frataxin increase over time. And from our simulation and our data, we believe we are at steady state.

Here, we have the disease characteristics of participants in the open-label study. To get a better sense of the clinical benefit of increases in skin frataxin levels following nomlabofusp, we compared the clinical outcomes from our open-label study to participants to those of patients with the FACOMS natural history study. The Friedreich's ataxia clinical outcome measure study, or FACOMS, is a longitudinal natural history study that includes 955 patients with a confirmed FA diagnosis.

Based on key baseline characteristics of participants in the open-label study, Larimar identified patients from the FACOMS data set with similar characteristics using data recorded over the last 4 years of each patient. A group of patients from the FACOMS database was identified as a reference population. This subset was constructed using the range of each baseline characteristic of the population in the open-label study.

Encouragingly, we are consistently observing improvements across a number of clinical outcomes following long-term daily nomlabofusp. 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 other clinical trials, we observed a 2.25 point improvement in open-label study participants treated for 1 year relative to a worsening of 1 point observed in patients in the FACOMS reference population.

Similarly, directional improvements were observed in the other 3 clinical outcome measures against the FACOMS reference population. This includes a 1-point improvement versus a 1-point worsening in the FARS ADL, which measures activities of daily living and for which the minimal important change in 1 year is thought to be 1.1 points. The 9-hole PEG test measuring fine motor coordination had a 7.4 second improvement versus a 3.4 second worsening in the FACOMS population. The open-label study change represented an approximate improvement in time to completion of the base -- from baseline of 10% change relative to a worsening of 3% in the FACOMS reference population.

From the literature, a change of 15% to 20% is believed to be clinically meaningful. The MFIS, Modified Fatigue Impact Scale is used to assess fatigue and had a 6.5-point improvement versus a 1.5 point worsening in the FACOMS reference population. Based on the literature, a score of 35 points in MFIS indicates severe fatigue and a change of 4 or more points on the MFIS indicates a real difference in the severity of fatigue.

Given the advanced state of disease for the majority of patients in the open-label study, we are very excited to see consistent directional improvements across all outcome measures. We believe this is the first time any intervention has been -- has shown increased frataxin levels in patients with Friedreich's ataxia to this extent and demonstrated improvement in multiple clinical outcome measures. Based on all this information, we continue to believe that nomlabofusp has the potential to be the first disease-modifying therapeutic and could very well change the treatment paradigm in FA.

Now let's talk -- turn to safety. There have been 65 participants in nomlabofusp studies who have received at least 1 dose. The 39 in the open-label study had participated in at least 1 prior study, 7 of these participants experienced anaphylaxis. Most events occurred in the -- on the initial day of administration and all participants returned to their usual state of health after standard treatment.

Nomlabofusp was generally well tolerated with long-term daily dosing, including 14 participants on treatment for at least 6 months and 8 for over 1 year. Most common adverse events were mild to moderate local injection site reactions that did not lead to any withdrawals.

Following the 2 most recent cases of anaphylaxis, Larimar consulted with its internal and external experts and decided to modify its dosing regimen in an effort to decrease the number and severity of reactions. Larimar provided the FDA with a full update on the clinical development program, including the safety, frataxin and clinical data, and the FDA has agreed with our approach.

All participants who experienced anaphylaxic reactions have been discontinued from the study as have 3 participants who experienced generalized urticaria. Other discontinuations include 1 seizure, which is the same event as was reported in December 2024, 1 vasovagal event and 2 nontreatment-related discontinuations.

In conclusion, outside of anaphylaxis, nomlabofusp is generally well tolerated with injection site reactions being the most common adverse events. These reactions have been mild to moderate and have not resulted in any discontinuation. We are also pleased to see that the long-term pharmacokinetic profile of nomlabofusp is consistent with our Phase I and Phase II studies. Nomlabofusp demonstrated rapid absorption after subcutaneous administration with exposure appearing to reach steady state in plasma by day 30 at both the 25- and 50-milligram doses with no further accumulation.

In our adolescent PK run-in study, which included 14 adolescents, 12 to 17 years of age, 9 of whom received a weight-based equivalent dose of 50 milligrams of nomlabofusp for 7 days and 5 of whom received placebo for 7 days. Participants demonstrated a PK profile similar to adults on 50 milligrams of nomlabofusp.

Following completion of the PK run-in study, these adolescents were eligible to screen for the open-label study. Based on these exposures, we will not be conducting a second cohort in children 2 to 11 years of age, but we do plan to include these patients in the open-label extension. We continue to expand our nomlabofusp clinical program to ex U.S. geographies with our global Phase III study. We have received feedback from FDA and EMA on the study protocol for our global Phase III study and are currently qualifying sites in the U.S. Europe, U.K., Canada and Australia.

The global study will be a double-blind placebo-controlled study with 1:1 randomization of 100 to 150 ambulatory patients that are more heavily weighted to younger patients. The study will include patients 2 to 40 years of age, of which approximately 2/3 will be under 21 years of age. Nomlabofusp will be evaluated following 18 months of dosing in the Phase III study. Primary outcome measures will include upgrade stability and mFARS.

As you heard today, FA is a devastating and progressive neurodegenerative disease with high unmet needs, and we are focused on bringing nomlabofusp to a broad range of patients globally. We previously gained clarity on our potential path towards BLA submission, seeking accelerated approval using skin frataxin concentrations as a novel surrogate endpoint.

Based on the compelling data, we continue to target submission of our BLA seeking accelerated approval in the second quarter of 2026. For our open-label study, we plan to continue enrolling participants on the new starting dose regimen with a long-term 50-milligram dose, including adolescents and those new to nomlabofusp study.

We are also excited to begin enrolling children 2 to 11 years of age directly into the study as there are no approved therapies for these patients with FA under 16 years old.

Taking an overall view of the program, nomlabofusp is strongly positioned to be the first disease-modifying therapy for patients with FA. These data demonstrate that the potential clinical benefits of nomlabofusp include 100% of participants increasing frataxin levels to greater than 50% of healthy volunteers by 6 months and an improvement of 2.25 points in 1 year in the mFARS score, the primary outcome measure in other clinical trials.

Patients in the FACOMS reference population worsened over 1 year. In addition to improvements in mFARS, there were also improvements in FARS ADL, 9-hole PEG test and the fatigue scale compared to worsening in the FACOMS reference population.

Importantly, nomlabofusp is designed to systemically address the root cause of this disease. We, along with what we have heard from the FA community, believe it is of utmost importance to consider these compelling benefits as well as the severity of this disease when thinking about the risks of the treatment. It is important to remember that Friedreich’'s ataxia is a life-shortening disease with patients losing their ability to walk and their ability to communicate.

Although there is a risk of developing an allergic reaction to nomlabofusp, this risk needs to be considered in the context of the disease we are trying to treat. Nomlabofusp could very well be the first disease-modifying therapy available to the FA community. I have spoken to many of you over the years. And many of you have heard me say when asked what would be a home run that a home run would be stopping or slowing the progression of this disease.

Personally, I never believe that in patients who had been sick for so long, we would be able to see meaningful improvement. Well, I may very well have been proved wrong. This data suggests that nomlabofusp may have the ability to actually improve patients, even patients with late -- in their late-stage course of disease. I don't believe any study that I am aware of has demonstrated this kind of potential outcome.

With that in mind, the Larimar team is even more committed to bring this potential therapeutic to market and make it available to as many people with FA as possible. We continue to work with FDA and are targeting our BLA submission for the second quarter of 2026, seeking accelerated approval. Following our recent capital raise, we are well capitalized with pro forma cash of $203.6 million as of June 30, 2025, and projected runway into Q4 2026.

Before I conclude, I would like to sincerely thank our clinical trial participants and their families. Addressing the unmet needs of individuals with FA remains our key source of inspiration. I commend their bravery and their dedication. I would also like to thank the FDA for their engagement throughout the regulatory process thus far as well as our talented and dedicated Larimar employees, our partners, clinical trial investigators and patient advocates at the Friedreich's Ataxia Research Alliance, all of whom helped nomlabofusp get to this exciting point in its development.

With that, I'd like to now move on to today's Q&A session, where I'll be joined by our Chief Financial Officer, Mike Celano. We will now open the line for questions. Operator?

[Operator Instructions]. Our first question today comes from the line of Yatin Suneja with Guggenheim Partners.

A couple for me. I'll start on the efficacy first and then move to safety. So the initial clinical efficacy really looks very positive, especially when you compare to the synthetic control that you have created here at one arm. Could you comment on how does the data look for 14 patients at 6 months versus the historical control? And then how many patients do you estimate you will need to achieve static there? Do we know what FDA expecting there? So that's one on the efficacy, then I'll come back on safety.

Yes. Thanks, Yatin. Nice to talk to you. It's not really possible to compare at 6 months, and that's why we looked at 1 year because the FACOMS data set only collects data annually. So that would mean you would have to extrapolate and whether or not things are linear or not, I think, it's still unknown. So we did not really look at 6 months. I mean we see improvement. We saw improvements, if you remember, at 90 days even at the 25-milligram. But the best comparison really is at the 1-year time point because of the fact that FACOMS is only collects data annually.

With regard to the number of patients for FDA, obviously, they've seen all these data sets. We are pursuing accelerated approval based on skin frataxin levels. So there is actually no requirement for clinical outcome data. Obviously, this kind of data is incredibly impressive And the value will be taken into account. Obviously, we wanted to see some trends. We wanted to see some meaningful changes. But the fact that we're seeing improvements of 2.25 points, I don't think anybody else has seen that kind of improvement over 1 year in mFARS. And as I said in closing, I never really anticipated that we were going to be able to improve these patients by any clinically meaningful amount. And so the fact that we actually have been able to see improvements wherein the FACOMS database patients worsen is really, really an important outcome, and I think quite compelling.

All right. Helpful. Then on the safety, could you provide maybe a little bit more color on the severity of these anaphylaxis? Like what treatments do they require? And is this hypersensitivity triggered by the protection or by other components of the formulation?

So let me start with end. I don't know what's triggering it, and it may be different what's triggering in different patients. The formulation itself is all grass excipients. There's nothing unusual in there. But people can be allergic to anything. But really, as you well know, it's not uncommon to have allergic reactions with proteins.

Every protein I know of that's out there has seen some sort of hypersensitivity reaction. And there are some with quite severe hypersensitivity reactions that they do all kinds of things, including treatment with methotrexate and other stuff to try and minimize. The treatment that we give is totally standard of care. It consists of epinephrine, antihistamines and steroids. And all of the patients have responded to it to date, and they respond very quickly. And within several hours, they tend to be back in their normal state of health.

Got it. Maybe final question, if I may. So we talked to some regulators in the past, specifically one FDA Director. And then he basically said anaphylaxis would not be an absolute problem as long as you can manage it. So the question is you're changing this dosing a little bit. So how confident you are in this titration dosing strategy on the impact of [indiscernible]?

I actually feel pretty good about it, quite honestly. We have an internal expert in our Chief Development Officer, Gopi Shankar, who is an immunologist. And we have some really good external consultants that we've been working with, including one of them that is on our DMC. And the idea here is to give the 5-milligram test dose to see whether or not we can mitigate some of these reactions when they get a larger dose. And I'm not going to go into the basic science that supports that. But this has been done with other drugs and slower titrations can also be done. But we don't think that, that's necessary at this time.

We have to remember that the patients who [ are ] currently starting in the open-label extension, and that is now starting to change, but the adolescents and the initial patients were all patients who had been exposed to the drug previously in prior studies. There were a few that had been on placebo, but the vast, vast majority of the patients had, had an exposure and then have had a drug a period of time, which could be quite long where they were off drug and then were being reexposed. We believe that actually increases their risk.

That's not to say that a patient won't develop an allergic reaction over time, but we do think that the majority of these cases have occurred on the first day in the clinic. And so we think that a lot of this is related to the prior exposure and the long-term holiday that they had from the drug. But we are very confident and feel very good about this dosing regimen. And I have to tell you, even with these reactions, as your expert concluded, you have to look at that in the context of this disease.

And I think what speaks really towards that is we have had -- even with the informed consent, including all of these events, we have had no problem enrolling patients. We have opened now to the naive patients, and we have a long list of patients who know this. This is out there in the public domain, and they still want to take advantage of this -- at least try with this drug.

And that's, I think, because if you look at the efficacy data, I mean, we had heard anecdotes before this and anecdotes are anecdotes. It's an open-label study. You don't know how to interpret that. But we don't have anecdotes anymore. We now have data at 1 year, granted only in 8 patients that clearly suggests that these patients may very well be improving, not only not getting worse, but may actually be showing signs of improvement.

And so I think the data is incredibly compelling. And I hope that we continue to move as quickly as we can to bring this product to market for as many patients as we can. And we continue, obviously, to work with FDA. They have been incredibly supportive. As I've said before, the start program has been just incredible. I know a lot of people are still talking about having issue -- or talking about having other slowdowns and things like that with the agency. We have not seen that to date. So we believe we're in a good position.

Our next question is from the line of Joori Park with Leerink.

Two from me. Can you help us better understand the 7 anaphylaxis events? I'm not sure if you have this data, but did you see a difference in patients who had a drug holiday who started with a weight-based equivalent dose of 50 mg versus those who started with a 25 and then increased to 50 mg?

And then I believe that you said that the FDA agreed with your proposal for the new dosing regimen. Can you provide more color on the nature of this agreement? Is the FDA requiring any new additional specific safety follow-up data from the amended protocol? Is there any way that the timing can get reset as a result of the amended protocol?

So almost all of the patients -- as I said, almost all the patients who are enrolling in the open-label extension are patients who received at least 1 dose of nomlabofusp prior and had a drug holiday. We do not necessarily see a difference between how long the patients are. And the adolescents are not going to be any different, and we don't see any difference, whether it was a weight base or 25-milligram or 50.

This is an exposure issue. Whether it is related to the fact that there was a drug holiday or not, we'll see as we start to get patients who were never exposed before into the trial, but it doesn't appear to be anything related to dose.

With regard to the agreement, I don't know how much more I can say. We submitted all of the safety data, the frataxin data, the clinical outcome data. They have reviewed all of that. We have proposed the new regimen, and they have said, go ahead, do what you need to do. And that's been the extent of our conversations with them. There has been nothing modified, nothing changed in the plan, except that we will now be dosing patients with a test dose prior to the initial dose.

Our next question is from the line of Samantha Semenkow with Citigroup.

Congratulations on the data today. A couple for me, Carole. I just wanted to confirm that all 7 anaphylaxis events have been in patients that were previously dosed. And do any of those include adolescent patients?

And then secondly, I'm wondering if you saw any benefit from the prophylactic use of antihistamines that you had previously installed? And then just lastly, how do you expect this new dosing regimen that you're deploying to help mitigate the risk of anaphylaxis? If you see a patient develop hypersensitivity or anaphylaxis on 5 milligrams, what are the next steps? Do they move on to 25 for 30 days? Or do you halt treatment completely? Or how do you handle that?

Okay. So almost all of the patients have been exposed. I think there may have been one that had not had prior exposure. We have seen both in adults and adolescents. So it is not an age issue or -- I mean, they're being -- the adolescents are being exposed to essentially the same level of drug even though the dose may be different. So it does -- it appears to be an exposure issue.

With regard to the test dose administration, it really provides 2 things. One, it gives us a low dose that if they react to it, we can deal with and not give the 25-milligram dose if the reaction is severe enough. The other thing it does, and this is sort of what I've learned through talking to these experts -- sorry [indiscernible] is it may help with preventing the anaphylaxis as it ties up some of the receptors on the mast cells. Now that's somewhat hypothetical. But as we move forward, we'll be able to see whether or not it does help to preclude the development of the anaphylaxis. Does that help, Sam?

It does. One additional question. The trend you saw on mFARS is quite encouraging. Wondering if you saw similar trend, similar magnitude for upright stability?

Actually, we didn't -- I'm sure our statisticians looked at upright stability because they looked at all the subscores, but I have not looked at that data, no.

The next question is from the line of Joon Lee with Truist.

The data you presented today, 10 for skin frataxin at day 180 and 8 for mFARS and ADL. Just safe to assume that they were all from the 50-milligram dose? If not, let me know. Basically, I want to understand how comfortable you are about fulfilling the FDA requirement of at least 10 patients on 50 milligrams for 12 months.

And then how many patients were already on stable background Skyclarys in your open-label extension? And I have a quick follow-up after that.

Okay. So everybody at this point is on 50 milligrams, except the adolescents who are obviously on a weight-based adjusted dose that is equivalent to 50 milligrams. But it does include patients who started on 25 milligrams and were switched to 50. So they did spend some of the time at that 1 year on 25 milligrams. I think if I recall the data, it's 9 months or so, they've all had at least 9 months or so of 50-milligram dosing, but they did spend some of the 1 year on 25.

We are very comfortable that we can hit the 10 for 1 year. I think that's much less of a problem than even the 30 months -- the 36 months. But I do believe, given the benefit risk assessment here and the fact that these events are occurring very early in the course of the disease, the agency will be comfortable with the data that we are targeting for the BLA submission in 2026.

I mean this -- the clinical -- I mean, FDA does this all the time, right? They do look at clinical benefit risk assessment and they do consider the population of patients that you're treating. And so here, we have, I think, a very well-defined safety profile. There is a risk of allergic reactions that's obvious. But we also have incredibly convincing long-term data that, as I said earlier, I would have never expected to see in patients who are this far along in their disease. Remember, more than half of these patients are in wheelchairs and have been for a while, yet there's still signs of the fact that they may be improving.

With regard to omav, there's about 53% of the patients who've been on omav. You may recall that once -- if you're -- you could not get into the trial until you were on omav for at least 6 months initially. So all these patients were stable on omav dose when they entered the trial. One of the patients actually did discontinue their omav and decided they didn't need it. And we did have one patient start omav after 6 months on nomlabofusp, and they were not allowed -- because they were not allowed to start omav until they have been in the trial for 6 months.

Yes. Great. And then just a quick follow-up. How would you characterize the rate and severity of anaphylaxis vis-a-vis other ERTs such as Palynziq and Aldurazyme, both of which have black box warning and that need to carry EpiPen? And were there any differences in the baseline characteristics between the patients who experienced anaphylaxis versus who didn't?

So let me start with the last one. We do believe that -- sorry, the majority of patients who developed anaphylaxis, the vast majority had been exposed to nomlabofusp prior trials. So that is a little bit different. One of the differences, the patients who had not been exposed or who had been on placebo did not necessarily -- did not develop anaphylaxis. There are a handful that had only received placebo in prior trials. We'll see whether or not that changes as we start to enroll naive patients, patients who had never been exposed. We don't have that population. So we don't know the data, and we don't know those incidence rates yet. We'll have to uncover that as we move forward.

From the standpoint of other proteins, especially Palynziq, we actually have a quite benign safety profile, except for the anaphylaxis. And I know that may sound somewhat silly, but when you look at Palynziq, they have a whole host of other very serious, let's say, adverse events that need to be dealt with [ granuloma, ] skin reactions and other things. Yet it's clear that in PKU, when you look at the benefit risk, it's very important for them to continue on the drug. And so we'll deal with the anaphylactic reactions. As I said earlier, right now, we are discontinuing those patients.

I do want to say that if you take some of these other proteins like Palynziq, they actually do continue to dose or redose and restart patients who've had anaphylactic reactions. And we are looking at other ways to do protocols that look at desensitization or -- building tolerance in these patients. And so that's for the future. It's not for now. Right now, these patients are being discontinued. But the hope is that as we move through the development process even after approval, we would be able to get some of these patients back on drug through either dose type or slower dose titrations or some concomitant medication or predosing with some more aggressive therapy. So that's still out there.

Right now, compared to many of those drugs we have really allergic reactions and then injection site reactions, which are quite manageable. And other than that, we're not really seeing things that jump out of this. Not to say that there aren't people who have some nausea and vomiting and some headache and all of those things that you see with diseases like this and with new treatments. But the 2 key safety issues we are dealing with are the allergic reactions and the injection site reactions.

The next question is from the line of Myles Minter with William Blair.

Congrats. My first one is just on the patient number of data reported here. I think previously, you've said 30 to 40 patients worth of data I think I see 18 at baseline in the skin frataxin biopsies. Is there -- if I add back in the 14 discontinuations, is that kind of where that 30 to 40 patient number came from? Or were there some that had biopsy that didn't have any detectable levels maybe later on down the track and you remove that data? I'm just trying to triangulate the patient number. That's the first one.

The second one is just on the 3 additional patients that had the urticaria that required discontinuation. I mean, do you view that as similar to sort of going down the path of anaphylaxis here? Did they resolve in the first 6 weeks of therapy? Or did they occur in the first 6 weeks of therapy? Any more on that would be helpful.

And then finally, I think the FACOMS that you're comparing to came in at 1 point worsening over the first year. That seems a little bit under what I'd expect some of their prior publications that were about 1.8 points. Just wondering how the ambulatory versus non-ambulatory patients factored into that.

Okay. Myles, nice to talk to you. So what we have said in the past is that there would be 30 to 40 patients who had received at least 1 dose. So that's where that number comes from. Obviously, we did have some discontinuations. There are 25 patients in the study still, and there are 14 patients who have reached 6 months and 8 who have reached the 1-year time point.

There obviously were the 7 patients with anaphylaxis, and we, in our remarks, talked about the other discontinuations, if you recall, the 3 allergic reactions, which you picked up on as well as the seizure that we reported last December. A vasovagal event and 2 that were completely unrelated to anything.

And so for the frataxin levels, there are a bunch of issues that occur. First, we pool the samples, and we only ship at certain frequencies. So some of the patients may have samples that just didn't ship by that time. And so we don't have samples. And the other is that they have to have 2 measurable samples, right, to be able to get a change. They have to have a baseline and a second sample. And sometimes we don't have enough tissue to measure frataxin at a given time point. But a lot of them are related just to shipping timing and when we do the data cut.

With regard to the 3 allergic reactions, I don't know what would have happened had we continued those patients. We don't know that they would have gone on to develop something more severe. But at this time in the development program, we felt that it was the best thing to discontinue them and not take a chance. They do occur early usually, but they can occur later. But most of them do occur early.

With regard to the 1.8 for FACOMS, this is a function of our population. And that's why the reference population that we're using is actually a subset based on using our inclusion -- I'm sorry, not our inclusion -- our demographics of each of the different outcomes. So using the ranges for each of the baseline characteristics of our population and narrowing that we have in our trial. It's easier to measure changes in mFARS in ambulatory patients simply because they have -- some of the scales on the mFARS in patients who are non-ambulatory are basically topped out. They can't change anymore. They're at the top -- they have the maximum measure. And so you don't see changes as easily. And so this is a reflection of the population. The one point is a reflection of the population that we have and I think reflects the sensitivity of the mFARS assessment in this patient population. I hope that answers your questions.

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

One on safety and then one on the mFARS data. You guys didn't break out any other adverse events in like a mild, moderate serious manner. You mentioned injection site reactions. But assuming the urticaria and anaphylaxis are considered serious, but anything else to flag maybe in the moderate bucket that aren't detailed in the presentation?

There is not really, Jonathan. We really -- that's why I said the safety profile for this drug is actually very clean except for the anaphylaxis and the allergic reactions. I mean we have looked and there are some -- like I said, there are the intermittent reports of headache or nausea, vomiting or feeling lightheaded in a population that has lightheadedness anyway. But there's really nothing that jumps out as something that we need to identify other than these -- the things that we've outlined here.

Lab tests are quite benign. We do see some eosinophilia, but that's usually associated with the patients who may have these adverse events. And that seems to go away over time and decrease. So we're really not seeing anything that really is obvious to us that in the moderate category.

Got it. Okay. And on the mFARS was wondering if the baseline values for these 8 patients that you give the 1-year update from is consistent with the larger group you provide. And then can you remind us how often you're going to be measuring the trajectory of change here? Are we going to get another update prior to submission or potential approval? Or how frequently you're going to see clinical benefit updates?

Yes. So the -- sorry, you asked about the FACOMS? What was that about?

Well, so you gave the change for 8 patients, but the baseline values for 38. Just wondering if that's consistent for the change.

Yes. I think in the deck, there is -- there are both. The comparisons are very close. The baselines are very similar. And that's how we constructed that reference data set, right? We took our baselines and their baselines and tried to come up with people who were relatively similar. This is not a propensity matching where we matched patient to patient. But at least we wanted to make sure we had a reference group that was similar in its disease characteristics as well as gender and things like that and age. And so they are very similar.

From the standpoint of an update, we haven't even gotten there yet. I think as we get closer to the BLA and we do a data cut, I would anticipate that we would provide that information to investors as well as we put it in the BLA. Obviously, we're going to be very highly focused on filing and getting that BLA that data into the BLA. But of course, if there's anything material or anything that changes, we'll be hypersensitive to making sure that it gets out to the investor community.

Our next question is from the line of Cory Jubinville with LifeSci Capital.

Correct me if I'm wrong, you mentioned that 6 out of the 7 patients who experienced anaphylaxis had prior drug exposure. Thinking about this from a commercial perspective, if patients take a drug holiday, do you have a sense of what might be the minimum holiday that could drive an increased risk of anaphylaxis? And kind of building off of that point, you say most occurred at treatment initiation. Specifically, how many of these cases occurred beyond the first day? And did any of these patients miss a sequence of doses that potentially could have led to the delayed cases of anaphylaxis?

So I can't give you an exact number of how many days are off. I don't believe that weeks necessarily matter very much, but I do believe that months do. But right now, the way we're addressing this is all patients who are starting the drug will be treated with that 5-milligram test dose. And all patients who are starting the drug, no matter what, will be receiving the 5 days of antihistamines prior to initiating their dose, and we'll continue those antihistamines.

There's no way right now with the number of patients we have to basically tease out exactly what's happening. I don't think we're disclosing right now the number that happened on the first day simply because the data is still being collected on a couple of the patients. but they all occur very early. And then some -- there are patients who had to, for various reasons, take a long-term drug holiday, 6 months or more. who also were considered restarts. And there was one patient at that point who did have an -- but again, it was on the first day of the restart.

So patients will have to be careful. I mean, should they have to stop their drug for a period of time. They have a surgical event that they have to be off of the drug for 6, 8, 10 weeks. I'm making this up, I don't know the exact number. They may very well have to undergo the start protocol again with the 5-milligram test dose under observation. But we'll see as we go forward and start to get the data, we'll get a better sense of what this all means.

Got it. That's helpful. Yes. And on today's mFARS data, I mean, these are really impressive improvements given that this is generally a more severe patient population. With the caveat that this is a small sample size, have these data helped inform at all any of your powering assumptions going into the confirmatory study? And either way, can you walk us through what the current powering assumptions are based on either mFARS or uprate stability?

And I guess, particularly, how should we be thinking about translating some of these efficacy assumptions driven by today's data in a more severe primarily non-ambulatory population into the younger entirely ambulatory population that we'll be seeing in the confirmatory study, considering these mFARS, the improvements that they might be seeing are going to be in -- most likely going to be in completely separate domains.

Yes. So they are a different population. I mean, ambulatory patients the measurements are just much easier to do and there's more room for change. And so I don't think you can use these data necessarily to change the powering statements in your Phase III. Does it mean that we could possibly need less patients or see a greater magnitude of effect for sure. But I don't think that we want to make those assumptions now, I think we'd rather be more conservative and make sure we have an adequate patient population in numbers in the Phase III to make sure we don't shoot ourselves in the foot and end up with a negative result because we just didn't have enough patients.

I can't speak to the powering statement, quite honestly. I can get you that information from our statisticians. But it's -- we're using, obviously, the data in the public domain from other trials and other drugs. And most of these studies have all had somewhere around 130 patients or so in them. And I don't think our study will be any different. And that's because the assumptions are essentially the same. But you're right, it could be different. It could mean that we would have a greater magnitude of the effect and therefore, need less patients. But I think it's a bit risky to make that assumption.

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

Thanks again to all who joined our call, and thanks to everybody who asked questions. We really appreciate the time. I must also extend a big thanks to FDA for their engagement throughout the regulatory process, as well as to our clinical trial participants, their families and to all our employees, partners, investigators and those of the Friedreich's Ataxia Research Alliance for the important contributions made to the nomlabofusp program. We really do thank all of you. We are very excited about this data, and I wish you all a good day.

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

Good morning, and welcome to the Larimar Therapeutics Conference Call. [Operator Instructions] Please be advised this call is being recorded at the company's request and a replay will be available on the company's website.

I'll now turn the call over to Alexandra Folias of LifeSci Advisors. Please go ahead.

Thank you, operator, 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 is 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 expectations and assumptions regarding the future of the company's business, the company's plans and ability to develop and commercialize nomlabofusp, formerly referred to as CTI-1601 and other matters regarding the company's planned clinical trials, business strategies, use of capital, results of operations and financial position.

These forward-looking statements involve risks, uncertainties and other factors that may cause actual results, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include, among others, the success, cost and timing of the company's product development activities, nonclinical studies and clinical trials, including nomlabofusp clinical milestones and continued interactions with the FDA, that earlier nonclinical and clinical data and testing of nomlabofusp may not be predictive of the results or success of later clinical trials and assessments and that clinical trial data are subject to differing interpretations and assessments.

The company's ability to raise the necessary capital to conduct its product development activities and other risks described in the filings made by the company with the Securities and Exchange Commission and available at www.sec.gov. These forward-looking statements are based on a combination of facts and factors currently known by the company and its projections of the future about which it 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 Chief Financial Officer, Mike l Celano, will be available during the question-and-answer session following the prepared remarks.

With that, I will now turn the call over to Carole.

Thank you, Alex, and good morning, everyone. We are excited to share some critical regulatory updates for our nomlabofusp program, which we believe represent truly exciting development for both Larimar and the Friedreich's Ataxia community. Nomlabofusp is the generic name for CTI-1601, and I will be using the generic name in this presentation. We are thrilled to announce that we have received recommendations from the FDA, reflecting their thoughts about the size of the safety database. We now have clarity on what is recommended to support a BLA submission pursuing accelerated approval. Specifically, the FDA recommended that Larimar evaluate safety data from a total of at least 30 participants who had continuous study drug exposure for 6 months and a subset of at least 10 participants who had continuous study drug exposure for 1 year.

The large majority of the safety data should be from participants receiving the 50-milligram dose. These recommendations were provided to us after the FDA's complete review of a briefing package containing all the safety data and exposure data collected in the nomlabofusp study trial. Based on the safety database, recommendations by FDA to submit with 10 patients with continuous exposure for 1 year with a large majority of the data in patients on the 50-milligram dose and our plan to request approval for a broad patient population, including adults, adolescents and children. We will be moving our guidance on the timing of the BLA submission, seeking accelerated approval to the second quarter of 2026.

Recall, in our December update, we announced that patients had begun transitioning from the initial 25-milligram dose to the 50-milligram dose. That transition was completed in the first quarter of this year, and those patients are expected to complete 1 year of dosing in the first quarter of 2026. Therefore, to analyze and incorporate the data into the BLA, we plan to submit the BLA in the second quarter of 2026. With this update, we believe we now have written recommendations from the FDA on the critical elements of the BLA submission seeking accelerated approval, including the use of skin frataxin concentrations as a reasonably likely surrogate endpoint.

Here, we have outlined critical elements of the BLA seeking accelerated approval, and we are very excited to say we have clarity from FDA on expectations across these key elements. We appreciate the collaborative nature of the interactions with the FDA and look forward to continuing to collect the data to support the submission. As we reported in March, the FDA has provided written correspondence that the agency is open to the use of skin frataxin concentrations as a reasonably likely surrogate endpoint and acknowledge that the submitted data appear to support a relationship between increased skin frataxin concentrations and relevant tissues such as the heart, dorsal root ganglion and skeletal muscle.

Acceptability of increases in skin frataxin concentrations for accelerated approval will be decided during future BLA review. As we discussed in the previous slide, we now have FDA recommendations on the safety database to achieve our near-term submission goals. For our clinical data package, we plan to include clinical data from our successfully completed and ongoing clinical trials, including our completed single ascending dose and multiple ascending dose Phase I studies, which support the safety and tolerability of nomlabofusp. This package will also include our Phase II dose exploration study. Lastly, data from the ongoing open-label extension study will also be included and will provide the data supporting long-term increases in skin frataxin concentrations and long-term safety in adults, adolescents and children.

Our global Phase III study is ongoing with the identification and qualification of sites in the U.S. as well as sites in the EU, U.K., Canada and Australia. The Phase III study is expected to be underway at the time of BLA submission and is currently intended as the confirmatory study to verify clinical benefit as required by FDA's accelerated approval pathway. The trial will evaluate clinical outcomes measures, including upright stability and mFARS. Across our studies, we continue to see consistent findings, including that nomlabofusp has been generally well tolerated and dose-dependent increases in tissue frataxin levels in skin have been seen following treatment.

For our pharmacology and toxicology elements, we plan to submit all of our nonclinical studies that support the use of frataxin as a novel surrogate endpoint, a complete toxicology package, including a juvenile toxicology study and data from clinical studies supporting improvements in patient lipid profiles and gene expression. And lastly, for our chemistry manufacturing and controls, or CMC elements, we will include the required data supporting the lyophilized drug product, which is stable at room temperature, data on batches manufactured at a commercial scale and analytical methods and proposed specifications.

Overall, we are very pleased with our progress. We are now confident that with these written recommendations in hand, we are well positioned to submit our planned BLA seeking accelerated approval in the second quarter of 2026. With that discussion of today's exciting news, I'd now like to take a step back to provide an overview of Larimar in the nomlabofusp program. For those less familiar with the Larimar story, Larimar is a clinical stage biotechnology company with a novel protein replacement therapy platform with first-in-class potential.

Our lead program is being developed for the treatment of Friedreich's ataxia, or FA, a rare, progressive and systemic disease with neurologic deterioration. It is caused by a genetic defect on both alleles that prevents production of the critical mitochondrial protein frataxin, resulting in low 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.

Patients will often present before the age of 14 and 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. In 2023, omaveloxolone was approved by the FDA as the first therapy indicated for FA in what was a critically important breakthrough for patients. Omaveloxolone has no impact on frataxin levels. And currently, there are no approved therapies designed to increase frataxin and address the deficiency underlying FA's horrible symptoms.

Because of this, key opinion leaders, patients with FA and advocates have made it clear that there is still a pressing unmet need for novel therapies to treat the underlying cause of FA. To address the needs of patients with FA, Larimar is developing nomlabofusp, the first potential disease-modifying therapy designed to systemically address the underlying frataxin deficiency in FA. 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.

Now let's turn to our clinical program. Our open-label extension study is currently evaluating the long-term safety and tolerability, the pharmacokinetics and the ability of nomlabofusp to increase tissue frataxin levels over longer periods of time following daily administration of nomlabofusp. Participants initially received the 25-milligram dose. In November of 2024, we began transitioning participants to the 50-milligram dose with the transition being completed in the first quarter of 2025. Currently, all patients are receiving 50 milligrams daily. Enrollment of the remaining adult patients who participated in prior studies as well as enrollment of the 14 adolescent patients who participated in the PK run-in study is ongoing.

In December of 2024, we presented initial positive data for the 25-milligram dose, and I would now like to briefly review some of that data. Recall, following 25-milligram daily administration of nomlabofusp, we showed increases in both skin and buccal cell frataxin levels with skin frataxin levels shown here on the left. We also demonstrated that skin frataxin levels as a percentage of healthy volunteers are higher at day 90 compared to baseline. These data support the potential of nomlabofusp to increase frataxin levels in tissues and address the protein deficiency leading to FA's devastating clinical course.

Encouragingly, we observed early trends towards improvement across a number of clinical outcomes following long-term 25-milligram daily nomlabofusp. Decreased values indicating early trends towards improvement were observed in Modified Friedreich's Ataxia Rating Scale, or mFARS, FARS activities of daily living, Modified Fatigue Impact Scale and the 9-Hole Peg test at day 90 relative to baseline. These data support the potential that nomlabofusp administration and resultant increases in tissue frataxin concentrations may lead to clinical benefit across a broad spectrum of patients with FA.

To date, we have reported data showing increases in frataxin in 3 independent clinical studies, trends towards normalization in gene expression and lipid profiles and early trends in clinical outcomes. Thus, the totality of the data continues to support the therapeutic potential of nomlabofusp. Looking at safety, nomlabofusp continues to be generally well tolerated in our open-label extension study, which includes some participants on treatment for up to 15 months. The most common adverse events were local injection site reactions with most being mild, brief in duration and self-limited.

No participant has withdrawn from the study due to a local injection site reaction. Anaphylaxis has been deemed an adverse drug reaction likely related to nomlabofusp by the Larimar safety team. This is common to proteins and biologics. Participants with prior exposure who have been off treatment for some time seem to be more likely to develop an allergic reaction. Premedication with antihistamine starting 5 days prior to the first dose and continuing for the first month is being administered to patients who have participated in a prior nomlabofusp study. Although data is not available at this time, we are hopeful that these medications will mitigate some of these reactions.

As we further advance our open-label extension study, we have made several recent updates to the study design, including introducing the lyophilized drug product formulation intended to be used for commercialization. This formulation is stable at room temperature, making use much more convenient for patients. As mentioned, we also amended the protocol to include antihistamine premedication for patients who participated in a prior nomlabofusp study. And to further broaden the program, we will be enrolling eligible adolescents from the PK run-in study as well as patients with FA who have not participated in a prior nomlabofusp trial. Note that due to the inclusion of patients who have not participated in the prior nomlabofusp clinical trial, we will now refer to the open-label extension study as the open-label study.

The significant clinical and regulatory progress we have achieved for our nomlabofusp development program has been expedited through our participation in the START pilot program, which has been incredibly valuable and continues to help us further advance efficiently. The START pilot program, support for clinical trials advancing rare disease therapeutics is a new pilot milestone-driven program launched by the FDA in September of 2023. It is designed to accelerate the development of novel therapies for rare diseases. We are very proud to have been 1 of 7 programs selected for participation by the FDA.

FA is a devastating and progressive neurodegenerative disease with high unmet needs, and we are focused on bringing nomlabofusp to a broad range of patients around the world. As outlined earlier, following FDA's recommendations on key BLA elements, we are excited now to have clarity on our potential path towards BLA submission, seeking accelerated approval using skin frataxin concentrations as a novel surrogate endpoint. We expect to submit our BLA seeking accelerated approval in the second quarter of 2026 and are planning a U.S. launch of nomlabofusp in early 2027.

For our open-label study, we continue to enroll patients with FA on 50 milligrams of nomlabofusp daily. We are also beginning to introduce the lyophilized dosage form, making it easier for patients. We are expanding the study to include patients who have not participated in a prior nomlabofusp trial, and we are considering enrolling children 2 to 11 years of age directly into the open-label study. This decision will be made after discussions with the FDA and our DMC. We continue to monitor safety data regularly in this ongoing open-label study and plan to provide data from the next formal data cut in September.

This will include data from 30 to 40 participants who received at least 1 dose of nomlabofusp. We expect to share skin frataxin concentrations and clinical outcomes data, provide a full safety update as well as an enrollment update for the study. For our adolescent PK run-in study, dosing of 14 adolescents 12 to 17 years of age for 7 days at a weight-based dose expected to match the PK of adults receiving a 50-milligram dose is complete. And in September, we expect to report data from 14 participants, some of whom were on placebo, including safety and pharmacokinetic data. Eligible participants are currently transitioning into the open-label study. Lastly, we have started to expand the nomlabofusp clinical trial to ex-U.S. geographies with our global Phase III study following feedback from both the FDA and EMA on the study protocol.

Activities are ongoing, including identification and qualification of sites in the U.S., Europe, U.K., Canada and Australia. The global study will be a double-blind, placebo-controlled study with 1:1 randomization of 100 to 150 ambulatory patients that are more heavily weighted to younger patients. The study will include patients 2 to 40 years of age. We are particularly excited by the prospect of generating data in pediatric patients as the only approved treatment for FA is not indicated for use in those under 16 years old. Nomlabofusp will be evaluated following 18 months of dosing in the Phase III study. Primary outcome measures will include upright stability and mFARS.

As you heard today, we believe we have clear recommendations from FDA on key elements for our BLA submission, seeking accelerated approval for a broad population, including adults, adolescents and children and are advancing nomlabofusp towards BLA submission in the second quarter of 2026 for the treatment of FA. This progress has reinforced our confidence in the differentiated potential of nomlabofusp to deliver meaningful benefits to a broad population of patients with FA. Current treatments for FA do not address the root cause of the disease and high unmet needs remain. Nomlabofusp is designed to directly increase tissue frataxin concentrations to address the root cause of FA.

Supported by the clinical and nonclinical data generated to date, nomlabofusp is poised to potentially change the treatment paradigm as the first potential disease-modifying therapy for FA. Our clinical program continues to advance as we further collect long-term data, broaden our program to younger patients, new geographies and those new to our studies. Importantly, we have several near-term catalysts, including long-term data from the open-label study and PK and safety data from our PK run-in study expected in September of 2025. On the regulatory front, we have clear FDA recommendations on the path towards submission. And now with FDA alignment on key elements in hand, including the potential use of skin frataxin concentrations as a surrogate endpoint and the recommendations for the safety database, we plan to submit our BLA seeking accelerated approval in the second quarter of 2026 and are targeting a U.S. launch of nomlabofusp in early 2027.

With this clear path for nomlabofusp and our strong maturing clinical data set demonstrating a differentiated mechanism of action, we believe we are well positioned as we seek to address the urgent unmet needs of the FA community. Before I conclude, I would like to thank our clinical trial participants and their families. Addressing the unmet needs of individuals with FA remains our key source of inspiration, and I commend their bravery and dedication. I would also like to thank the FDA for their engagement throughout the regulatory process thus far as well as our talented and dedicated Larimar employees and our partners, clinical trial investigators and patient advocates at the Friedreich's Ataxia Research Alliance, all of whom helped nomlabofusp get to this exciting point in its development.

With that, I'd like to now move on to today's Q&A session, where I'll be joined by our Chief Financial Officer, Mike Celano. We will now open the line for questions, operator.

[Operator Instructions] Our first question today is coming from Yatin Suneja from Guggenheim.

I have a couple. So first one is on this -- on the BLA submission. I mean could you do a rolling BLA submission where you can submit the other module first? -- if -- I mean, in the past, you had given a guidance of BLA submission by year-end. So the question is, how does this safety requirement lines up with your initial expectation, keeping in mind that earlier you were expecting it to be submitted this year. And I do have a question on OLE. I'll ask after you answer these questions.

Sure. Yatin, thanks for the question. We have not yet started conversations with the agency about a rolling submission. It is clearly a possibility. But right now, we're planning for the second quarter because of the safety data that we need to collect, specifically the 1-year data, 10 patients at a year on 50 is really the challenge. And I want to make sure we highlight the fact that I think the agency has shown real flexibility and has been really, I think, acknowledge that this is a rare disease and there is a significant unmet medical need by only asking for 10 patients.

That said, we had thought with the 1-year data could include the 25 milligram. But clearly, they actually made it very clear that they would like to have the large majority on the 50-milligram dose. And since we didn't complete switching patients until the first quarter of this year, it's going to take us a little more time. But rolling submission is something that we're thinking about and considering.

Okay. Helpful. Then could you also give us a sense of the average duration we should expect for these 30 to 40 patients that you'll be announcing data on in September? And for clarification, that 30 to 40, does that include the 14 adolescent patient and then maybe finally, would you be -- or are you willing to present the lipid profile and gene expression data for the 25- and 50-milligram OLE in September or sometime this year?

Yes. So I can't really give you the average duration because the data is still being collected. Remember, this is an ongoing study. So until we do a formal data cut, we really don't have totally clean data. Obviously, we look at safety on an ongoing basis. But other than that, we really need a formal data cut before we can provide that. But what I can tell you is we dosed our first patient in that study last March, March of 2024. So some of these patients are out 15 months. They just remember, had started on 25 milligrams and then were switched. So it will be a combination of -- duration will be a combination of 25 and 50 for some people. But clearly, people are coming up on 6 to 9 months' worth of data on the 50 milligram.

With regard to the lipid and gene expression data, that probably will not be part of the September update, mostly because we have to run all those samples and we're dependent on an academic center to do that. And so that data will probably be provided in a later update, potentially prior to BLA submission, but in a later update.

Next question is coming from Joe Schwartz from Leerink Partners.

Congrats on all the progress. I guess my first question is, given that there have been a lot of changes at the FDA as recently as last week with the departure of [ Nick Holver ] done. Can you discuss how much buy-in you feel you have behind or beyond these former leaders? And how much -- how high up within the new CBER regime has this plan been discussed?

First of all, Joe, nice to talk to you, but we are not in CBER. We are actually in CDER. And so we actually have not had very much change, quite honestly. I was actually down at the meeting in D.C., actually at FDA with [ Dr. Makary, ] the first meeting with the industry that they had. He's very engaged. He's very focused on rare disease. He's very focused on expediting rare disease. We have been getting all of our responses in a timely fashion. The comments and the recommendations we got from them were in writing. They were on time to their commitment. I think START has been a huge help, the START program, but they seem to be meeting their time lines. They seem very focused on rare diseases. I think when you look at this data set, they showed the flexibility and the acknowledgment that this is a rare disease. So we're actually feeling very good and very optimistic about that.

Excellent. Great. And we noticed the statement you made that acceptability of increases in skin frataxin for accelerated approval will be decided during future BLA review or NDA review. Can you help us understand what would be more likely be viewed as adequate data on that front by the FDA?

Yes. So how this all works is we submit data packages, which are our interpretation of the data. It's -- we provide data, obviously, but we don't actually submit the raw data when you're submitting a briefing package. Whenever the FDA agrees to something, they always leave their out that it's a review issue. But as of now, we know that they have put in writing for us that they do believe that they are open to the data that we have already submitted and they have reviewed the briefing package, and they are open to considering skin frataxin concentrations as a novel surrogate endpoint.

When they talk about that it's an issue for review, they reserve the right, obviously, that when we actually submit the raw data that they could come to a different conclusion than us. But I can tell you that we feel very comfortable the conversations have been incredibly candid. We have provided them everything that they've asked for, don't usually like to disclose conversations with the agency, but they've even made the comment that you've pretty much done all the work. So we are very confident that the use of skin frataxin levels will be acceptable. And now with the data set where it's at, we're actually very confident that we know what they want from the standpoint of the safety data.

Next question is coming from Joon Lee from Truist Securities.

For the September update from 30 to 40 patients, is it fair to assume that all will be on 50 milligrams for at least 90 days? And if so, why do you need to expand the study?

So yes, it is fair to assume that they will all be on 50 for 90 days, unless, of course, somebody dropped out. The -- like I said, it's an ongoing study. So anything can happen. But yes, you can assume that they would all be on 50 for 90 days. The reason for expanding the study is a couple of reasons. First, we want to make sure we have a broad population. So we need data on our adolescents as well as on our -- on children in order to be able to get an indication that is in all populations. So that's one reason.

The second reason is to allow patients who may not be eligible for other trials. So remember, our Phase III study is going to be all ambulatory patients, right? And we have certain ages in that trial, 2 to 40, I think we said. And so by expanding to patients who are not -- who may not be eligible for the Phase III trial and have not participated in prior trials, it gives options to patients who may not be able to participate in other clinical trials. Remember, all the Phase III trials to date have been in ambulatory patients, and that leaves out a huge population of patients, those who can't walk or who may be more debilitated.

Carole, I may have misunderstood Joon's question, but his question, I think, was in September, will all 30 to 40 patients be on 90 days.

No, they will not. They will all be on 50, but they may not be at 90 days.

All right. I have a quick follow-up. Will the start of Phase III now, I mean, still on track for sometime midyear? Or is the timing change given the shift in timing for the BLA as well?

No, it's still on track. And it's actually still on track, and it's actually a good thing because remember, the agency requires that the Phase III be enrolling before they will give an accelerated approval. So the further along we are with that study, the better. So we are going to continue at the same pace. And hopefully, we'll just have more patients by the second quarter than we have in the first quarter.

Our next question is coming from Samantha Semenkow from Citi.

A couple for me. Just first off, do you view the regulatory update as a delay for the program as it relates to the timing of a potential launch? Is that also expected to be pushed out? And then secondly, can you remind us just on your cash balance, I think it's to 2Q. Is that going to be sufficient to support operations through BLA filing? And are there any opportunities to further extend that runway? And I have a follow-up.

So I'll respond to the launch question, and I'll let Mike talk to the cash balance. We had always intended to launch in the first quarter of 2027. So the launch has actually not been delayed at all. And that's because we have to make enough product to be able to supply the market. So the launch has not changed.

Yes. And so Sam, as of March 31, we have $158 million of cash, which is runway into the second quarter of '26. So from a financing perspective, we'll continue to be opportunistic, ensuring that what we do is in the best interest of the shareholders. We are actively considering and evaluating nondilutive financing alternatives, including royalty financing, which we believe is very possible given our proximity to the BLA submission.

Got it. And then just on the, I guess, the open-label study now, as you call it, has FDA reviewed any of the efficacy data, specifically the skin frataxin data from patients that have been on 50 milligrams for a reasonable amount of time? Or is the alignment on skin frataxin driven almost primarily by the 25-milligram data?

Thanks. So we have not done a data cut, a formal data cut for the 50-milligram dose yet. So they have relied mostly on the 25-milligram -- but they -- a lot of what they reviewed was the data actually -- first of all, the lipid data was very impressive to them, and they were very interested in that because it's obviously not effective -- there wouldn't be any placebo effect. It's a biochemical marker. But they also had a lot of animal data. And all of the animal data that we submitted, they were able to look at the exposures of the 50-milligram dose that were generated out of the dose exploration study.

And so I think what made them comfortable, and it's hard for me, I don't really want to speak for them, but we did provide them with blood levels, both in animals and in people and in patients at 50 milligrams, and they overlap dramatically. And they acknowledged in their written responses and in the minutes that they actually were happy to see that the concentrations that were achieved in the animals that showed adequate distribution were at the same exposures as in the patients. So that's the data that they've seen.

By the way, we will be publishing the animal data, hopefully, over the next couple of weeks, if not a couple -- over the summer for sure. The publication has been accepted in a peer-reviewed journal. So it's just a matter of when it comes out.

Next question is coming from Myles Minter from William Blair.

First one is just on if the FDA is going to require any sort of functional data in this BLA filing for accelerated approval. Obviously, we have alignment on safety. We've got the questions on frataxin expression in skin, but is a functional outcome important there given your peer gene therapy company that appears to be going both on frataxin expression and a cardiac functional improvement measure there? That's the first one.

The second one is, was there any sort of breakdown between the number of adolescent and adult patients from the safety database that you need out to 6 months or potentially even a year to secure an accelerated approval in both adolescent and adult populations? Or is it just 30 patients as you get them at 6 months and 10 patients as you get them at a year?

Yes. So we obviously will be submitting functional data. Thanks, Myles, by the way. We will be submitting functional data as we're collecting it every 3 months. But there has not been any discussion as it -- we don't need to be p-values, right? This is an open-label study. We would like to see some trends. But I do want to remind people, I think it's important to remember, more than half of our patients in this trial currently. Now that may change as we get more patients in. But even so, I think most of our patients coming in are going to be further progressed than a lot of other studies -- when half of these patients are in wheelchairs. I think it's not realistic to expect that these patients are going to get up and walk or that they're going to improve by all that much.

What we're hoping is we halt the deterioration and we stop them from getting worse. And if you talk to patients, that's a huge thing. If they can continue to swallow better, if their speech is maintained and they don't lose the ability to speak, those are really things that have a significant effect on their quality of life. And so I think we will be providing functional data. Obviously, we're also following the data in the FACOMS database and looking at how best to present that. And we will be doing matches, creating a synthetic arm when we're finally -- we'll be submitting to the FDA. But I think what we're trying to do is maintain function. But yes, I think they will want to look at it, whether there's any requirements or not.

And they specifically called out phospholipids. So they have specifically in correspondence called out the fact that if we can show correlations with changes in lipid levels, that would be of interest to them. And that's data we pretty much have already. So we're actually presenting at a conference in Bordeaux, France this week, I think, where we're presenting some data with the key opinion leader who works -- who is at Montreal Heart Institute and is working on all of this with us. And so she had asked that one of our employees go with her and talk about the industry side of the whole thing, but she's actually presenting some of the data.

And then you asked about adolescent safety data. There was no breakout. They do know the studies. Obviously, we've submitted all of our studies. We have conversations with them all the time. I think the advantage of submitting, quite honestly, in the second quarter is that we'll have quite a bit of data on the adolescents. The adolescents are actually transitioning as we speak. So they should be coming into the study or most of them should be coming into the study over the summer. And so we should have quite a bit of data on the adolescents.

Next question today is coming from Andreas Argyrides from Oppenheimer.

This is Eka on behalf of Andreas. Congratulations on today's update. One quick one. So Biogen is initiating a pediatric study in 255 children. I want to ask, do you have an idea of what this overlap is going to be for the sites? And how this is going to impact the enrollment in your studies concurrently?

No worries. So Andreas, it is a very good question, and it is a lot of patients. The sites do have overlap. But as we've been activating and looking at sites for the 301 study for our Phase III study, we've also started looking at different sites for that study. So we have a lot of interest from investigators. They clearly believe that getting at the root cause of the disease is a critical thing to do. And I think they are very interested in participating. I can tell you, we haven't had a lack of interest from patients at all.

We even have identified some children 2 to 11 who want to be in the study. And they all know that they can't be in 2 studies at one time. It's a pretty sophisticated population. So I don't think there's going to be a huge effect. I do think where the effect that we've already seen is these sites are really busy, and they have limited capacity. And it's not only because of omaveloxolone or even studies in FA. They may be doing studies on other ataxias and that takes not -- it creates resource issues, study coordinators, et cetera. So that's why we're looking to open more sites aggressively and looking at sites that are also not in the United States, but are in Europe and other parts of the world.

That's helpful. And if I may ask one more question. For the Phase III primary endpoint, have you decided on mFARS or upright stability? Or is it possible to use both?

It may be both, and it may be different in different parts of the world. We're actually watching the PTC story. As you know, PTC submitted their NDA even though they did not meet their primary endpoint for mFARS, but they did meet upright stability. But they've been very public about the fact that the EU has not been as open to that. And so there is a good possibility that it will be upright stability in the United States and mFARS in the EU. And then we'll see what happens in other parts of the world. But our preference is to do upright stability wherever we can.

Next question today is coming from Cory Jubinville from LifeSci Capital.

Congrats. It's really great to get this level of clarity. As it relates to the adolescent PK run-in patients who are enrolling into the open-label extension, can you comment on the duration of drug holiday between completion of the PK study and restarting [indiscernible] OLE? You mentioned that the adolescent patients are screening and enrolling, but have any of these patients been dosed in the OLE yet? And have you observed any additional cases of allergic reactions either in the adolescent population or any newly enrolling OLE patients?

So we announced, if you recall, that we started the PK run-in study early this year and that we finished in the first -- at the end of March essentially. And we are now enrolling them. So you can do the math of what the hiatus has been. We -- obviously, these studies are still ongoing. What I can say is we have not seen anaphylaxis in the PK run-in study. I can't say more than that because the studies are still ongoing. I would like to take the opportunity to make one other comment.

One thing that made us so pleased about what the agency agreed to for the safety database was the fact that they clearly aren't concerned about the safety data. They've seen everything. They clearly have bought into the potential for a benefit here that we are getting at the root cause. And they seem actually very comfortable with the safety profile. I can't speak for them, obviously. But based on their agreement to what is a relatively limited database, granted is a rare disease, but it is a relatively limited database. They've shown quite a bit of flexibility. So they seem to be as comfortable as we are.

That's really helpful. And earlier, when you say the large majority of patients or exposure should be at the 50 mg dose, what does that mean qualitatively? Is there a certain percentage they're looking for or duration, et cetera?

I don't -- honestly, that's their wording. I think it's going to be somewhat of a judgment call and a discussion with them as we move on. But it obviously a large majority is more than half. And that's why we think we really need to look at those patients who were switched earlier and make sure that we have the numbers that we need in the long term. I don't -- I mean, what really seems to happen here is as the patients continue on the drug, we have more and more compliant -- they are more and more compliant. We have less and less issues with, number one, safety and less and less issues with dropouts. And that's a very encouraging sign because patients who don't perceive any benefit may very well not want to take an injection every day.

And so again, it's an open-label extension. So we have to make sure we put all those caveats in, but we're very optimistic about the way things are going.

Next question today is coming from Jon Wolleben from Citizens.

A couple for me. Can you remind us when you reached steady state for drug and frataxin at the 25-milligram dose? And if that was a similar time frame for the 50 milligram? And then any sense of how many naive patients you expect to enroll in the open-label study?

We reached steady state around within -- let's put it this way, within 2 weeks. It may be sooner than that, but surely within 2 weeks, sorry, and it appears to be the same both for the 50 and the 25. They appear to behave well. We haven't really decided how many naive patients we're going to accept at this point. I think it will depend on how much interest we have. But we'll try and accommodate as many patients as we possibly can. This population is really needy and has -- it's important that they have access to clinical trials.

And one more. Is it fair to assume that you won't be pursuing approval of the 25-milligram dose as well, just the 50 milligram based on FDA feedback?

Yes.

Next question is coming from Laura Chico from Wedbush Securities.

Just a couple of clarifications, Carole. For the regulatory submission in 2Q '26, I just wanted to clarify, this is simply due to the need to reach the proper duration on exposures in that longer term, that 1-year 10-patient bucket. I guess, are there any other gating factors that could impact the timing of the submission? The reason I'm asking, I'm trying to clarify the enrollment of the participants not previously in a trial, is that also impacting timing? And what was the rationale here by the agency for the request for the naive, I guess, patients? Sorry if I missed that earlier.

I'll start with the last one. It was not the agency that requested. We decided to open it. It had nothing to do with the FDA. We just think it's -- the more patient data we can get in more people, the better it will be for a review. And it also, like I said, gives patients access to clinical trials and to drugs that they wouldn't have access to. So it was not a request by the agency. With regard to exposure at 1 year, I don't think there's any kind of issue with PK or anything like that. It's just -- you remember, the ICH guidelines are 100 patients for a year. So they're asking us to give them 10. And so it's just a matter, I think, of having patients that are on drug for a long enough period of time that they feel that they have adequate information to be able to draft a label and that there's not something that's happening later in the course of their disease or later in the course of therapy that they're missing.

So it's not a matter of PK or frataxin levels or anything like that. It's a matter, I think, of just having appropriate exposure.

And just to follow up to that. So in terms of the submission then, are there any other items or gating factors that could impact timing at this point? It doesn't sound like it, but I just wanted to clarify.

Not that I can anticipate right now. I mean there's always something that can happen that you don't anticipate. But based on everything I know, we are very confident with those dates. You and I have talked about it at other times that we needed to -- the one thing that could really have an impact was the safety database. And now that's out of the way. We know that they're willing to accept skin frataxin levels, at least to review the data, the detailed data, but they've seen a lot of it. So we feel very good now that we've checked most of the boxes.

Okay. And then last question here is just what would be the timing for understanding the dosing in the 2- to 11-year-old population. I think that would be started later in the Phase III study, but just trying to understand what additional information do you need to migrate to that population?

Yes. They will be in the Phase III study, but we will also -- we're now thinking about whether -- remember, the original PK run-in study, the original design was to do the adolescents and then to do the kids 2 to 11 as a cohort to confirm exposures and then put them in the open-label extension. We're actually reconsidering that now because we think it's better for them to go into the -- 2 to 11-year-olds, putting them through a PK study that they may not need to be in doesn't seem to be very smart.

So we're actually working with FDA now and the DMC to amend the protocol to allow the 2- to 11-year-olds to come directly into the open-label extension because we do PK in the open-label extension. And we saw the data from the PK run-in study in the adolescents, which looked really good. So we're -- like I said, we still need confirmation from FDA and the DMC that they'll be comfortable with that, but that is sort of the plan that we're transitioning. But that won't happen until much later this year.

Our next question today is coming from Catherine Novack from Jones.

I just want to get a sense of from you how firm is the FDA guidance on safety database. Is there any risk that later they say they want all patients on 50 milligrams or that they want more patients at 1 year? Just trying to assess what level of risk there still is in the BLA time lines.

Yes. I think the risk is limited, Catherine. There's always a risk. I mean we could have some unexpected unanticipated adverse event or something that gets their attention. But they're hesitant to put in writing things that they don't follow through on. And so unless there's something unexpected that happens -- and remember, like I said, we do have patients out for quite a bit of time. So unless something unexpected happens, I don't think that their request will change. But it's a regulatory agency. They always have the right to change their minds until they don't, right? So -- and even after an approval, they have a right to change their minds if something pops up.

So like I said, we have now written correspondence and all the key elements. That obviously is not written in stone, but it is much more firm than not having that. I feel very comfortable. And I think it also, like I said earlier, shows their comfort level with what they're seeing.

And then just wondering, can you speak to turnover on the review team since you've started working on the BLA with the FDA? Is the original team still in place? Have new people been appointed or removed without being replaced? What does that look like from your perspective?

I can tell you that the head of the office, the head of the division and our lead reviewer are all people that were at our pre-BLA meeting like 6 years ago. So they are -- and now they've been promoted. They weren't the head of the office and head of the division at the time. But they've been with us from the beginning and they're very interested in the program, and we have not seen any effective turnover at all.

I can tell you at the FDA meeting, [ Dr. Makary ] basically said they are hiring reviewers and they are even hiring back some of the people that were let go. We haven't seen that because we just haven't -- we haven't experienced any people leaving the team.

Next question is coming from Joel Beatty from Baird.

This is [ Chris ] on for Joel. I just had a couple of questions. First on dosing. In terms of the adolescent study, you mentioned it's weight-based. Is there a chance based on weight that some of these adolescents will get more than the 50 mg dose? And then just a follow-up on that last question on FDA. Can you clarify if you had discussions with Dr. Makary regarding this in the new regime and kind of maybe some clarity on that.

So the weight-based dose is capped at 50, Chris. So nice to talk to you. Nobody can get over 50. I don't really want to say what I talk to Dr. Makary about, but what I can tell you is that during the meeting, what I spoke about was the value of the START program. They gave everybody an opportunity, all 75 of us or 76 of us to speak, believe it or not, I really can't believe they're actually going to do 5 of these because we hear the same thing over and over again. But I wanted to impress -- there was a lot of discussion on communication and being able to get quicker feedback than the Type A, B, C, D meetings allow for. And what I tried to make the point was that the START program really has been spectacular and really has helped to solve a lot of those problems, and he was very receptive to that.

So real quick, you were part of that after the roundtable a couple of weeks ago, you were part of those 75 people who were able to talk to them right after that roundtable.

Yes. They did the roundtable in the morning. And then in the afternoon, they did these listening sessions, which they're doing in other parts, right? They're doing one in Boston, one in New York, one in San Diego, one in San Francisco. This was the first one.

Next question is coming from Rev Saru from -- I'm sorry, Ram Selvaraju from H.C. Wainwright.

Firstly, I was wondering if you could provide some clarification on the extent of long-term stability that you currently have on existing produced batches of nomlabofusp?

We have a lot. I honestly don't know off the top of my head, but it's well over 2 years. And it is on the lyophilized drug product as well and the drug substance.

And then with respect to the Phase III study as planned, can you comment on whether it might be reasonable to expect final top line results from this study before the end of 2028, obviously, depending upon the pace of enrollment?

I do not think that you will get final results before 2028. It's 18 months of dosing, as I said. So if you figure -- it might be close to figure a year to 18 months to enroll and then 18 months of dosing, you're talking about 3 to 4 years, I would think. That's not guidance. That's just a calculation off the top of my head.

Thank you. We have reached the end of our question-and-answer session. I'd like to turn the floor back over for any further or closing comments.

I just want to thank everybody for participating and the questions were great, and we're very excited and look forward to moving this program forward.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.