Good morning and welcome to the Larimar Therapeutics conference call. All participants are now in listen-only mode. There will be a question-and-answer session at the end of this call. If you'd like to ask a question at that time, you may press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Please be advised this call is being recorded at the company's request, and replay will be available on the company's website. I would now like to turn the call over to Alexandra Fol ias 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 webpage 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 the 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, non-clinical studies, and clinical trials, including nomlabofusp clinical milestones and continued interactions with the FDA.
That earlier non-clinical 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 Solano, 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 + 25 mg and +50 mg data from the ongoing long-term open-label study evaluating daily subcutaneous injections of nomlabofusp, self-administered or administered by a caregiver, in 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 mg dose, which showed increased frataxin and early trends in clinical outcome measures after 90 days of dosing in eight 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 Nine-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 three months in participants enrolled in the open-label study and now have data after one year of dosing in eight participants. We also constructed a reference population from the FACOMS Natural History Study database, which 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 one year with nomlabofusp daily relative to a worsening of a median of one point observed in the participants in the FACOMS reference population. We believe that these observations are incredibly exciting. The increases in 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 frataxin levels in patients with FA with a resultant potential for clinical benefit.
100% of participants at six months achieved 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 seven participants in the open-label study, with most of these events occurring on the initial day of administration and all occurring within the first six weeks of dosing. All participants returned to their usual state of health after receiving standard treatment. Importantly, there have been 65 participants who received at least one dose of nomlabofusp across the clinical development program, and 39 have been exposed to at least one dose in the open-label study, with 14 patients at six months and eight at one 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 two 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, frataxin levels, and clinical outcome measures, and the FDA agreed with our new dosing regimen. The compelling long-term increases in frataxin levels, along with the clinical data, heighten our conviction in the potential of nomlabofusp 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%-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 years- 10 years after the initial diagnosis. The symptoms of FA include loss of musculoskeletal function, blindness, deafness, an inability to speak clearly, and diabetes. Unfortunately, patients with FA have a life expectancy of only 30 years- 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 a person's frataxin levels, 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 seven years old. As frataxin 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 mg dose. In the fourth quarter of 2024, we began transitioning participants to the 50 mg dose, with all newly enrolled patients starting on 50 mg. 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 one dose of nomlabofusp, and 25 participants, which includes 19 adults and six 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 mg to the last dose of nomlabofusp prior to data cutoff. We are now modifying the starting dose regimen to include a five- mg test dose followed by a 25 mg dose one hour later, both under observation, and then daily for 30 days at home. After 30 days, the 25 mg dose will be increased to 50 mg once daily. Antihistamines will be administered five days prior to the first dose and for 90 days after the first dose.
An epinephrine autoinjector 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 mg 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 mg 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- 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 the skin, both graphs demonstrate an increase in skin frataxin levels over the course of six 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 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 frataxin at baseline, day 30, day 90, and day 180 who received 25 mg, 50 mg, or had increased from 25 mg- 50 mg. 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 mg and were transitioned to 50 mg, as well as those who start dosing at the 25 mg dose. On the far left of the figure, you can see categories of percent of healthy volunteers for frataxin levels. Skin frataxin levels from our healthy volunteer study were divided into quartiles. Open-label study participants were 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. To 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 increased 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 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. Friedreich's Ataxia Clinical Outcomes Measures 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 dataset with similar characteristics using data recorded over the last four 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 in other clinical trials, we observed a 2.25-point improvement in open-label study participants treated for one year relative to a worsening of one point observed in patients in the FACOMS reference population. Similarly, directional improvements were observed in the other three clinical outcome measures against the FACOMS reference population. This includes a one-point improvement versus a one-point worsening in the FARS ADL, which measures activities of daily living and for which the minimal important change in one year is thought to be 1.1 points. The Nine-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 from baseline of 10% change relative to a worsening of 3% in the FACOMS reference population. From the literature, a change of 15%-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 the MFIS indicates severe fatigue, and a change of four 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 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 turn to safety. There have been 65 participants in nomlabofusp studies who have received at least one dose. The 39 in the Open-label study had participated in at least one prior study. Seven of these participants experienced anaphylaxis. Most events occurred 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 six months and eight for over one year.
Most common adverse events were mild to moderate local injection site reactions that did not lead to any withdrawals. Following the two 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 anaphylactic reactions have been discontinued from the study, as have three participants who experienced generalized urticaria. Other discontinuations include one seizure, which is the same event as was reported in December 2024, one vasovagal event, and two non-treatment-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 mg and 50 mg doses with no further accumulation. In our adolescent PK run-in study, which included 14 adolescents, 12 years- 17 years of age, nine of whom received a weight-based equivalent dose of 50 mg of nomlabofusp for seven days, and five of whom received placebo for seven days, participants demonstrated a PK profile similar to adults on 50 mg 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 two 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 one-to-one randomization of 100- 150 ambulatory patients that are more heavily weighted to younger patients. The study will include patients two to 40 years of age, of which approximately two-thirds 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 upright 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 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 the long-term 50 mg dose, including adolescents and those new to nomlabofusp study. We are also excited to begin enrolling children 2 years- 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 six months and an improvement of 2.25 points in one year in the mFARS score, the primary outcome measure in other clinical trials. Patients in the FACOMS reference population worsen over one year. In addition to improvements in mFARS, there were also improvements in FARS-ADL, Nine-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 believed 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 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 a 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 Solano. We will now open the line for questions. Operator.
Thank you.
If you'd like to ask a question at this time, you may press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to withdraw your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we call for questions. Thank you. Our first question today comes from the line of Yatin Suneja with Guggenheim Partners. Please proceed with your question.
Good morning, everyone. Carole Ben-Maimon, thank you for that presentation. A couple from 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 it 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 six months versus the historical control? And how many patients do you estimate using need to achieve statistical significance? Do we know what FDA is expecting there? So that's one on the efficacy. Then I'll come back on safety.
Yeah, thanks, Yatin. Nice to talk to you. It's not really possible to compare at six months, and that's why we looked at one 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, is still unknown. So we did not really look at six months. I mean, we see improvements. We saw improvements, if you remember, at 90 days, even at the 25 mg.
But the best comparison really is at the one-year time point because of the fact that FACOMS 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 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 one 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.
The fact that we actually have been able to see improvements where in the FACOMS database patients worsen is really, really an important outcome and I think quite compelling.
Got it. Thank you. On the safety, could you provide maybe a little bit more color on the severity of these anaphylaxis? What treatments do they require? And is this hypersensitivity triggered by the frataxin or by other components of the formulation?
Let me start with nomlabofusp. I don't know what's triggering it, and it may be different what's triggering different patients. The formulation itself is all GRAS 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.
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. Got it. Maybe final question, if I may. 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. But the question is, you're changing this dosing a little bit. To how confident you are in this titration dosing strategy on the second two? Thanks.
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 five-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, 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 had had a drug, a period of time, which could be quite long, where they were off drug and then are being re-exposed. 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 one year, granted only in eight 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 this 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 issues 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.
Thank you.
Our next question is in the line of Joori Park with Leerink. Please proceed with your question.
Hi. Thank you for taking our questions. Two from me. Can you help us better understand the seven 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 mg 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? Thank you.
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 one 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-based or 25 mg or 50 mg. 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 their initial dose.
Okay. Got it. Thank you.
Our next question is from the line of Samantha Semenkow with Citi.
Please proceed with your questions.
Hi. Good morning. Thanks very much for taking the question, and congratulations on the data today. A couple from me, Carole. I just wanted to confirm that all seven 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 a hypersensitivity or anaphylaxis on five mg, what are the next steps? Do they move on to 25 mg for 30 days, or do you halt treatment completely? Or how do you handle that? Thanks very much.
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 a—I mean, the adolescents are being exposed to essentially the same level of drug, even though the dose may be different, so it appears to be an exposure issue. With regard to the test dose administration, it really provides two things. One, it gives us a low dose that if they react to it, we can deal with and not give the 25 mg 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, one second, 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. Thank you very much. One additional question. The trend you saw on mFARS is quite encouraging. I'm wondering if you saw a similar trend, similar magnitude for upright stability? Thank you.
Actually, I'm sure our statisticians looked at upright stability because they looked at all the subscores, but I have not looked at that data now.
Got it. Thanks very much.
The next question is from the line of Joon Lee with Truist. Please proceed with your questions.
Hey, guys. Thanks for the updates and for taking our questions. The data you presented today, 10 for skin frataxin at day 180 and 8 for mFARS and ADL.
it safe to assume that they were all from the 50 mg dose. If not, let me know. Basically, we want to understand how comfortable you are about fulfilling the FDA requirement of at least 10 patients on 50 mg for 12 months. And then how many patients were already on stable background Skyclarys in your open-label extension? Thank you. And I have a quick follow-up after that.
Okay. So everybody at this point is on 50 mg, except the adolescents who are obviously on a weight-based adjusted dose that is equivalent to 50 mg. But it does include patients who started on 25 mg and were switched to 50 mg. So they did spend some of that time, that one year, on 25 mg. I think if I recall the data, it's nine months or so. They've all had at least nine months or so of 50 mg dosing.
But they did spend some of the one year on 25 mg. We are very comfortable that we can hit the 10 for one year. I think that's much less of a problem than even the 30 at six 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, 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 they'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 you could not get into the trial until you were on Omav for at least six months initially. So all these patients were stable on their 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 six months on nomlabofusp, and they were not allowed because they were not allowed to start Omav until they had been in the trial for six months.
But that's okay. Sorry, go ahead.
No, that's all. I was finished.
Yeah, great. And then just a quick follow-up. How would you characterize the rate and severity of anaphylaxis vis-à-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? Thank you.
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 in prior trials. So that is a little bit different.
One of the differences, patients who had not been exposed or who had been on placebo did not necessarily 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, I'd say, adverse events that need to be dealt with: granulomatous 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 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 at us. And 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 two key safety issues we are dealing with are the allergic reactions and the injection site reactions.
Thank you.
The next question is from the line of Myles Minter with William Blair. Please proceed with your questions.
Hi. Congrats, and t hanks for taking the questions. My first one's just on the patient number of data reported here. I think previously you've said 30- 40 patients' worth of data. I think I see 18 at baseline in the skin frataxin biopsies there. If I add back in the 14 discontinuations, is that kind of where that 30- 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 removed that data and just kind of triangulate the patient number? That's the first one. The second one is just on the three 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 six weeks of therapy, or did they occur in the first six 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 one point worsening over the first year. That seems a little bit under what I'd expect. Some of the prior publications that were about 1.8 points. Just wondering how the ambulatory versus non-ambulatory patients factored into that. Thanks very much.
Okay. Hi, Myles. Nice to talk to you. So what we have said in the past is that there would be 30-40 patients who had received at least one 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 six months and eight who have reached the one-year time point. There obviously were the seven patients with anaphylaxis, and we in our remarks talked about the other discontinuations, if you recall, the three allergic reactions that you have picked up on, as well as the seizure that we reported last December, a vasovagal event, and two 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 two 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 three 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 do 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.
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. Using the ranges for each of the baseline characteristics of our population and narrowing the dataset to reflect the type of patients 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. You don't see changes as easily. 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.
No, it does. Thanks very much, Carole.
Our next question is from the line of Jon Wolleben with JMP Securities. Please just use your questions.
Hey, thanks for taking the question. One on safety and then one on the mFARS data. You guys didn't break out any other adverse events in 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 in detail in the presentation?
There is not really, Jonathan. 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 and 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 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 in the moderate category.
Got it. Okay. And on the mFARS, wondering if the baseline value for these eight patients that you give the one-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 are you going to see clinical benefit updates?
Yeah.
Sorry, you asked about the FACOMS. What was that about?
Well, so you gave the change for eight patients, but the baseline value is for 38. Just wondering if that's consistent for the change.
Yes. Yeah. I think in the deck, there are both. The comparisons are very close. The baselines are very similar. And that's how we constructed that reference dataset, 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 in 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 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 data into the BLA. But of course, if there's anything material or anything that changes, we'll be hyper-sensitive to making sure that it gets out to the investor community.
Got it. Thanks, Carole.
Our next question is from the line of Cory Jubinville with LifeSci Capital. Please proceed with your question.
Good morning. Thanks for taking our questions and congrats on the update. Correct me if I'm wrong. You mentioned that six out of the seven patients who experienced anaphylaxis had prior drug exposure.
Thinking about this from a commercial perspective, if patients take a drug holiday, give 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 mg test dose.
And all patients who are starting the drug, no matter what, will be receiving the five days of antihistamines prior to initiating their dose and will 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 there are patients who had to, for various reasons, take a long-term drug holiday, six months or more, who also were considered restarts. And there was one patient at that point who did have an anaphylaxis. 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 surgical events that they have to be off of the drug for six, eight, 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 mg 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.
I hope that answers your question, Cory.
Yeah. 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?
Either way, can you walk us through what the current powering assumptions are based on either mFARS or upright 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 most likely going to be in completely separate domains.
Yeah. So they are a different population. I mean, ambulatory patients, the measurements are just much easier to do when 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 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 effect and therefore need less patients. But I think it's a bit risky to make that assumption.
Very helpful. Thank you.
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 all our clinical trial participants, their families, and to all our employees, partners, investigators, and those at 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. 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.