Larimar Therapeutics, Inc. (LRMR) Earnings Call Transcript & Summary

Good morning, and welcome to the Larimar Therapeutics conference call. [Operator Instructions]. Please be advised that 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 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 all listening 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, 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 activity, 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 in 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 important progress on the nomlabofusp registrational program, which we believe represents key advances in both Larimar and the Friedreich's ataxia community. Importantly, we are pleased to report today positive initial data from our ongoing long-term open-label extension study evaluating daily subcutaneous injections of 25 milligrams of nomlabofusp in participants with Friedreich's ataxia or FA. We will also provide updates on our efforts to expand the nomlabofusp development program and next steps for our regulatory pathway. Specifically, we will be presenting data on long-term safety, Frataxin levels in peripheral tissue, long-term pharmacokinetic data and early clinical outcomes data from the open-label extension study. In addition, we will be providing an update on increasing the dose to 50 milligrams in the open-label extension study and initiating the pediatric PK run-in study. As a preview of the data, long-term administration of 25 milligrams daily nomlabofusp in 14 participants was generally well tolerated for up to 260 days. Importantly, tissue frataxin levels showed a mean change from baseline of 1.32 picograms per microgram in buccal cells and 9.28 picograms from microgram in skin cells at day 90. Tissue frataxin levels increased and were maintained over time with mean levels increasing from 15% of healthy volunteers at baseline to 30% in buccal cells and from 16% of healthy volunteers to 72% in skin cells at day 90. These data further support the daily dosing can sustain increased peripheral tissue frataxin levels, further reinforcing the therapeutic potential of nomlabofusp to address frataxin deficiency, the known root cause of the disease in patients with Friedreich's ataxia. From a pharmacokinetic perspective, we are seeing nomlabofusp demonstrate a predictable pharmacokinetic profile similar to what we saw in our Phase II dose exploration study and our Phase I multiple ascending dose study. Nomlabofusp reaches steady state by day 30 with no accumulation after long-term dosing. Encouragingly, we are also seeing early trends towards improvement across multiple clinical outcomes designed to assess the rate of disease progression over time. That said, we do need to keep in mind that this is an open-label study without a control arm. Still, this is the first evidence of potential clinical benefit for nomlabofusp. To date, we have reported data showing increases in frataxin in 3 independent clinical studies. We have also shown data suggesting positive trends for normalization on gene expression and lipid profiles, and we are now showing early trends in clinical outcomes. Together, this suggests that nomlabofusp has the potential to alter the natural history of this disease. With this continued clinical success, we are further advancing multiple aspects of our nomlabofusp program to support a registrational pathway. For our open-label extension study, we currently have 6 participants receiving 50 milligrams of nomlabofusp daily. We plan to increase all other participants in the trial to 50-milligram -- to the 50-milligram dose and initiate all newly enrolling participants on 50 milligrams daily. We expect to report open-label extension data for participants who have been receiving 50 milligrams in mid-2025. We have also initiated our pediatric PK run-in study with the adolescent cohort currently screening. We plan to start dosing at a weight-based dose equivalent of the adult 50-milligram daily dose in early 2025. For our global confirmatory study, we are actively identifying sites in the U.S., EU, U.K., Australia and Canada and are finalizing the protocol based on advice from the U.S. FDA, the EU EMA and other regulatory authorities. We remain on track to initiate the trial mid-2025. We also continue to target our planned BLA submission for the second half of 2025 to support a potential accelerated approval. We are further advancing discussions with the FDA on the advice needed -- on the evidence needed for that filing, including the data needed to support the use of frataxin as a novel surrogate endpoint and the size of the acquired safety database. With that brief 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 or FA. FA is a rare neurodegenerative disease caused by a genetic defect that results in patients having insufficient amounts of the critical mitochondrial protein frataxin. To address the needs of patients with FA, we are developing nomlabofusp, 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. Currently, we are the only treatment in clinical development designed to increase frataxin level systemically. Our nomlabofusp program in patients with FA has been awarded orphan drug designation in the U.S. and EU, rare pediatric disease designation in the U.S., making us eligible for a priority review voucher, as well as Fast Track in the U.S., PRIME in the EU and ILAP in the U.K. We were also accepted into the FDA's START pilot program. These designations suggest that regulatory authorities around the world are aware of the unmet need in FA and understand the need for a therapeutic that addresses the root cause of the disease. We have seen consistent findings across our clinical studies. In our completed multiple ascending Phase I study and Phase II dose exploration study, nomlabofusp was generally well tolerated and demonstrated dose-dependent increases in frataxin levels from baseline in skin and buccal cells. As mentioned earlier, we are intending to pursue accelerated approval with the FDA using frataxin as a novel surrogate endpoint. Based on our discussions with the FDA, they have acknowledged that frataxin deficiency appears to be critical to the pathogenic mechanism of FA, and that there continues to be an unmet need for FA treatment that addresses the unmet medical need and the pathophysiology. We are currently having ongoing discussions with the FDA regarding the evidence needed to support an application for accelerated approval, including data to support frataxin as a novel surrogate endpoint and the content of the safety database. Included in the data package will also be supportive pharmacodynamic data and clinical outcomes from the open-label extension study and nonpharmacology data from animal studies. Our confirmatory study is on track to initiate in mid-2025 prior to our BLA submission, which we are targeting for the second half of 2025. For our open-label extension study, we are increasing the dose to 50 milligrams with 6 participants already on 50 milligrams daily, and we expect our next clinical catalyst to be long-term data from the 50-milligram dose in mid-2025. We also have initiated our pediatric PK run-in study. The first cohort is the adolescent cohort, and we expect dosing to begin early next year at a weight-based dose equivalent of the adult 50-milligram dose. We will follow this cohort with a cohort of children 2 to 11 years of age and expect to transition both the adolescents and children into the open-label extension study after assessing safety and exposure data from each group. As of September 30, 2024, we had approximately $204 million in cash and investments, which provides projected cash runway now into the second quarter of 2026. We expect our 2025 operating cash burn to average approximately $30 million per quarter as we pursue our strategy of accelerated approval. With this next slide, I'd like to briefly provide some background on Friedreich's ataxia and the current treatment landscape. Friedreich's ataxia is a rare, progressive and systemic disease with neurological 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. Most patients with FA only produce on average about 20% to 40% of the frataxin levels seen in homozygous healthy people. We also see from our data that many patients actually have lower levels than even the 20%. Later in the presentation, we will show important data that demonstrate the frataxin levels correlate with disease progression. FA affects about 20,000 patients globally with about 5,000 patients in the United States and most of the remaining patients in Europe. About 70% of patients present with FA before age 14. FA is a progressive disease with initial symptoms that include unsteady posture and frequent falling. Patients are eventually confined to a wheelchair. Patients with FA have a life expectancy of only 30 to 50 years with an early death most commonly caused by heart disease. Last year, 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 agents designed to increase frataxin and address the deficiency underlying FA's horrible symptoms. Because of this, key opinion leaders, FA patients and advocates have made it clear that there is still a pressing need, unmet need for novel therapies to treat the underlying cause of FA. Low frataxin levels are known to be associated with disease progression in patients with FA. Data from published literature indicates that the lower a person's frataxin levels, the earlier the age of onset of the disease, the faster the rate of progression of disease and the shorter the time to loss of ambulation. The table on the left shows the relationship between frataxin levels as a percent 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 levels increase, so does 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 theft, 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 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 improve other clinically meaningful outcomes. With that overview, now let's turn to the design of our ongoing open-label extension study. Patients who previously completed a nomlabofusp clinical trial are eligible to screen for our multicenter open-label extension study. The study is designed to evaluate long-term administration following daily subcutaneous injections of either 25 milligrams or 50 milligrams of nomlabofusp. Initial participants who enrolled in the trial received 25 milligrams of nomlabofusp daily. Based on the positive data with 25 milligrams, we have completed dosing with 25 milligrams and currently have 6 patients on 50 milligrams daily of nomlabofusp. Participants still receiving 25 milligrams daily will transition to the 50-milligram dose and new patients enrolling in the study will start on the 50-milligram dose. Daily dosing will continue throughout the study, and there will be no switch to every other day dosing due to the findings in our Phase I and Phase II studies. Importantly, nomlabofusp injections are self-administered by participants or are administered by a caregiver. The goal of the open-label extension study is to evaluate the safety, tolerability and long-term pharmacokinetics of nomlabofusp, as well as tissue frataxin concentration and clinical outcomes as compared to 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 extension study are intended to be used to support the potential accelerated approval submission. In this study, other objectives include the evaluation of the long-term subcutaneous administration of nomlabofusp on measures of clinical efficacy, which as stated earlier, will be compared to a matched set of untreated patients from the Friedreich's Ataxia Clinical Outcome Measure Study, also known as FACOMS. The methodology for selecting these patients has been prospectively defined. With that overview, now let's get into the data. At the time of the data cut off, 14 adults with FA were included in the analysis with up to 260 days of exposure with the mean exposure of 99 days. The participants in the open-label extension study are diverse and representative of the broad population of adults with FA. Among these adult patients, 57% are non-ambulatory. As you may recall, throughout the program, we have been collecting frataxin levels in 2 tissue types, buccal cells and skin cells. Although skin cells appear to be more stable and have less variability, buccal cells have been used by others to assess the relationship between frataxin levels and clinical outcomes. The lower the frataxin level in buckle cells, the earlier the onset of symptoms and the faster the rate of progression. This clinical relationship has not been studied for skinny frataxin levels. Because of this, we are continuing to collect both buccal cells and skin cell frataxin levels, though we do believe that skin is a more representative tissue due to the slower cell turnover and the more reproducible data. With that in mind, we will first review the frataxin data from skin cells. On the left, you can see the absolute levels of frataxin over time, normalized total protein with the 25-milligram cohort. Within the graph, the dots represent medians and the horizontal lines to the 25th and 75th percentile. The dotted line in green represents 50% of the mean frataxin levels measured in skin in a cohort of 60 healthy volunteers. Looking at the absolute values, nomlabofusp increased skin frataxin levels at day 30 and day 90. On the right-hand side is the change in frataxin levels from baseline, which show a similar finding. As you can see, samples were only taken at 3 time points for skin, baseline, day 30 and day 90. There were no skin biopsies required by the protocol at day 60. Therefore, we cannot determine at this time whether skin frataxin levels are at steady state by day 90. Looking at the buccal cell data. In the graph on the left, you can see a similar trend as seen in skin cells with increases in frataxin across time points, but with a lower magnitude as you have less frataxin in buccal cells as we have described in the past. For buccal cell frataxin, we do achieve steady state as early as day 30 and remain at similar levels at day 60 and 90. Now let's look further into how these data compared to frataxin levels that are seen in healthy volunteers. Looking at buccal cells on the left, we can see that participants in the open-label extension study had a mean baseline frataxin level that was about 15% of the mean levels found in healthy volunteers. After 90 days of 25 milligrams daily of nomlabofusp, these levels reached a mean of 30% of the mean levels found in healthy volunteers. When we look at skin cells, you can see a similar trend, but with a larger magnitude. At baseline, the mean frataxin levels in skin cells were about 16% of healthy volunteers. After 90 days, these levels increased to a mean of 72%. To put this into context, people who are carriers of FA have no symptoms at all, and have frataxin levels that are approximately 50% of the mean values observed in healthy volunteers. We look forward to building on this long-term data with data from the 50-milligram dose. In past studies, we have seen significant dose response and our simulations in skin suggests that more than half of the patients should be above 50% of healthy volunteers when receiving 50 milligrams. These data show the absolute numbers for skin and buccal cells and include the medians and means for baseline. Day 30, day 60 and day 90 and the change from baseline. As stated earlier, it is important to note that for skin, samples were not collected at day 60 as per the protocol. This was designed to limit the frequency of skin biopsies, which are more invasive than buccal cell swaps. Similar to the figures, nomlabofusp is increasing tissue frataxin in both skin and buccal cells and maintaining these increases over time and achieving median tissue frataxin levels of 1.89 picograms per microgram in buccal cells and 7.65 picograms per microgram in skin cells at day 90. It is important to remember that based on our study of 60 healthy volunteers, 50% of the frataxin level in healthy volunteers is approximately 4 picograms per microgram for buccal cells and 8 picograms per microgram for skin cells. We have also included the data from our dose exploration study, which was completed earlier this year. It is interesting to note that the change in tissue frataxin levels for both tissues is similar to what was seen for the 25-milligram dose in that study where participants were dosed daily for 14 days. It is also interesting to note that the participants currently enrolled in the open-label extension are starting at a slightly lower baseline than the participants who participated in the 25-milligram cohort of the dose exploration study. Based on this data and the data from the 50-milligram cohort in our dose exploration study, we should see important increases in frataxin levels as we increase the dose to 50 milligrams in the open-label extension. Now let's turn to the clinical outcomes to get a better understanding of whether frataxin delivery by nomlabofusp could be having an effect on clinical outcomes. I have to say that given the sample size, the low dose and the length of exposure, we truly did not expect to see any consistent changes in these clinical measures. So we are very encouraged by this data. This table depicts several assessments designed to capture various clinical outcomes assessing the rate of progression over time in patients with FA. We are not presenting data on the time 25-foot walk test due to limited participant ambulatory status. The other 4 measures include the Modified Friedreich's Ataxia Rating Scale, or mFARS, which is a 93-point scale. This assessment is performed by the investigator and includes assessments of both upper extremity and lower extremity function. We also measured FARS activities of daily living or FARS ADL, which is performed by the patient or a caregiver and is a 36-point scale designed to measure the participant's ability to conduct activities of daily living. The Modified Fatigue Impact Scale is also an assessment performed by a patient or caregiver and is an 84-point scale that assesses the level of fatigue a participant is experiencing at a given time. Fatigue is a very common and highly impactful component of FA. Finally, we've looked at the Nine-Hole Peg test. This is a tool used to assess upper limb dexterity and fine motor skills. Given that more than half of the participants in the study are wheelchair bound, this is a very important assessment for our patient population. At the time of the data cut, 8 of 14 participants had baseline end data at 90 days. For those 8 participants, we see trends that may suggest some improvement across all 4 tested clinical assessments. Again, it is important to note that this is an open-label study, and there is no control arm. That said, these are interesting findings. And when taken together with the increases in frataxin levels and the findings we reported from our dose exploration study on gene expression and lipid profiles, we believe these findings may suggest that nomlabofusp could be having a positive impact on clinical outcomes. The data being presented in the middle of 2025 after longer-term participation in the open label extension and with dosing at the 50-milligram dose should allow us to better assess the clinical effects of nomlabofusp. Before we leave this slide, I want to provide some additional context to these data. As noted earlier, more than half of these patients are in wheelchairs, so the upper limb measurements are particularly important. Of note, when we were reviewing the details of the subscores of the mFARS, the 2 subscores that drove the improvement in the total mFARS with upper limb assessment and the upright stability score, not the bulbar score or the lower limb assessment. This is consistent with the changes that we see in the Nine-Hole Peg test, which is also a measure of upper limb dexterity. So it does appear that there is consistency in the data and that the improvements that are being reported may be due to improvements in upper limb function. Also important to note is that the Nine-Hole peg test is reportedly less subject to a placebo effect. And as you can see, improves by quite a lot in this limited data set. Finally, to put some context around the fatigue scale, as stated earlier, this is an important and highly impactful symptom for FA patients. There was a publication that looked at this scale in multiple sclerosis, and determined that a change of 4 points or more is clinically meaningful. So although not FA, MS similar to FA is a slowly progressive neurodegenerative disease with fatigue as an important component. Now let's discuss the pharmacokinetics of nomlabofusp. We were pleased to see that the pharmacokinetic profile for nomlabofusp seen in this study is similar to the pharmacokinetic profile we have seen in earlier studies. Nomlabofusp demonstrated rapid absorption after subcutaneous administration and reached steady state in plasma by day-30, the first visit day after initiation of dosing. There also was no further accumulation after study state was reached. For safety, we continue to see nomlabofusp is generally well tolerated. As stated earlier, there were 14 adults with FA that were included in the data readout with up to 260 days of long-term daily treatment of 25 milligrams of nomlabofusp. As I have discussed with some of you, although we initiated the study in the beginning of this year, enrollment slowed as we got to the summer. Challenges with vacations, et cetera, really limited enrollment rates. This has shifted, and we have seen enrollment increase with 1 additional patient since the data readout and a second patient scheduled to dose before the end of the year. We fully expect enrollment to be robust as we enter 2025 with numbers of patients participating increasing significantly through the early part of next year. Back to safety and participant disposition. From the 14 participants, 2 participants withdrew from the study for nontreatment-related reasons. Two participants experienced serious adverse events, but return to their usual state of health within 24 hours. These 2 participants also withdrew from the study. The serious adverse events were reviewed by the Data Monitoring Committee and submitted to the FDA as required by regulation, and the study is continuing as planned. Similar to our earlier clinical trials, nomlabofusp continues to be generally well tolerated. The most common adverse events in the open-label extension continue to be injection site reactions that were mostly mild, brief in duration and self-limited. There were no study discontinuations due to injection site reactions and all resolved. Based on the tissue frataxin level and the safety data we have increased -- have increased or are increasing the dose to 50 milligrams in participants already enrolled in the study and are starting all new patients on 50 milligrams daily. We have also initiated our pediatric PK run-in study with weight-based dose equivalent to the adult 50-milligram dose. As you have heard today, we have made some exciting progress across our program. Taking a step back, we believe the totality of evidence supports an encouraging potential for nomlabofusp to slow disease progression in patients with FA. First, nomlabofusp is addressing the underlying root cause of FA frataxin deficiency. Importantly, we have gained FDA alignment that frataxin deficiency appears to be critical to the pathogenesis of FA. In multiple clinical studies, we have demonstrated the treatment with nomlabofusp leads to a dose-dependent increase in frataxin levels. And now this data shows that these levels are maintained over time. Secondly, the potential for nomlabofusp to display functional activity is supported by the observed trends in gene expression and lipid profiles we presented at ICAR that suggests nomlabofusp may affect downstream metabolic pathways disrupted in FA. And most importantly, we reported the first evidence that nomlabofusp may lead to a clinical benefit, which was supported by trends towards improvement across multiple measures of disease suggesting the potential to benefit both ambulatory and nonambulatory patients. Collectively, we believe these data support the potential for nomlabofusp to alter the natural history of FA. With this in mind, we are focused on bringing nomlabofusp to a broad range of patients around the world. We are continuing our ongoing open-label extension study and have initiated the 50-milligram dose in 6 participants to date and plan to transition all other enrolled participants as well as to start newly enrolled participants on the 50-milligram dose. We have also initiated our pediatric PK run-in study and are currently screening adolescents 12 to 17 years of age. This cohort will be followed by a cohort of children 2 to 11 years of age. Participants completing the PK run-in study are eligible to screen for the open-label extension study after an assessment of safety and exposure data in each cohort. 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. As stated earlier, we are targeting a potential BLA submission for the second half of 2025. Prior to BLA submission, we are planning to initiate a global double-blind placebo-controlled confirmatory study, which is on track to initiate by mid-2025. This is a pivotal time for Larimar. Today, we reported positive long-term data reinforcing nomlabofusp could be the first therapeutic to potentially slow disease progression by increasing frataxin levels systemically and addressing the protein deficiency leading to FA's devastating clinical force. These long-term data demonstrate that nomlabofusp was generally well tolerated at doses tested over 8 months. Nomlabofusp also increase skin and buccal cell frataxin levels and maintain these increases over time, with mean levels increasing from 15% of that observed in healthy volunteers at baseline to 30% of healthy volunteers at day 90 in buccal cells, and from mean levels of 16% to 72% of healthy volunteers in skin cells. Importantly, early trends towards improvement observed across multiple clinical outcomes at day 90 support nomlabofusp treatment could lead to functional benefit across different patient types. Along with these promising clinical findings, we are advancing our program towards registration. We increased the dose to 50 milligrams in the open-label extension study with 6 participants currently on the 50-milligram dose. We continue to increase dose in all other participants, and we are starting new patients on 50 milligrams. We have also initiated our pediatric PK run-in study with the initial cohort being adolescents 12 to 17 years of age and following assessment of safety and exposure, these adolescents will be eligible to screen for the open-label extension. We are actively pursuing clinical sites in the U.S., EU, U.K., Australia and Canada for our planned confirmatory study and are finalizing the protocol based on feedback from the U.S. FDA, EU EMA and other regulatory authorities. Earlier this year, we were selected by the FDA to participate in its start pilot program, which is a new milestone-driven program designed to accelerate development of novel therapies intended to address an unmet medical need for rare diseases, and we are excited to be part of this new program, which is helping to move the nomlabofusp program forward in a more efficient manner. Lastly, we are in ongoing discussions with the FDA regarding use of frataxin as a surrogate endpoint to support accelerated approval. As we look ahead for our nomlabofusp program, we expect to initiate dosing in the pediatric PK run-in study in adolescents in the first quarter of 2025 and in children in the first half of 2025. We are on track to initiate our global confirmatory study in mid-2025. Also in mid-2025, we expect data from the 50-milligram dose in our ongoing long-term open-label extension study. Importantly, we remain on track to submit our BLA in the second half of 2025 with plans to pursue accelerated approval. With these near-term registrational catalysts ahead of us, a robust clinical data set demonstrating therapeutic potential with a differentiated mechanism of action as well as current cash balance in excess of $204 million, we believe we are well positioned to continue our mission 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 with 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] And our first question today will be from the line of Yatin Suneja with Guggenheim Partners.

Carole excellent presentation, a nice data today. A few questions, some that came from investor and some that I have. So the first one is on these 2 assays. Are you able to articulate what exactly was the -- what were the 2 AEs? And then have you received FDA comments on these SAEs. And then what about the other 2 discontinuation? It seems like there are 4 discontinuation total. So if you can articulate like exactly what was the reason?

Sure. So thanks, Yatin, nice to talk to you. The 2 SAEs were, 1 was a severe allergic reaction, which we expect will happen with proteins intermittently and the woman was fine, she was treated and she's fine. And obviously, she was discontinued because she's allergic to either one of the excipients of the drug. The second was a seizure in a patient who was very severely debilitated with significant comorbidities, in particular had pretty severe heart disease, ran a pretty low blood pressure and was quite sick. Obviously, both were submitted to our data monitoring committee as well as to the FDA, and there was no further follow-up from either of them.

Got it.

Regarding 2 discontinuations, this is a really rigorous study, requires multiple trips to the doctor, requires them to have -- a lot of these people have a caregiver because they simply don't have the dexterity to self-inject. And so those 2 patients wanted to be in the study, but just couldn't -- they couldn't comply with the protocol.

Got it. With regard to the BLA filing, could you maybe articulate for us that what would be needed, like how -- I mean, given that you have RMAT and probably have more interaction with the FDA, what is your understanding of the data package that might be needed? And then in terms of the confirmatory study, do you have a sense of the endpoint that you might be using there? Is it going to be the mFARS or the Nine-Hole or some sort of a composite endpoint?

Yes. Sure. So we are in discussions with the FDA on what will be needed. I think it will be frataxin levels. And I think we've pretty much put that to bed. I mean we have patients well over 180 days that frataxin levels are maintained. We didn't present that data because there aren't -- there just aren't that many people, there's only a couple. But it does look for sure by the 90-day data that frataxin levels are maintained. And so we're trying to pursue it as a novel surrogate endpoint. They do want to see -- or will want to see, I think, some nonclinical data in addition to the clinical data, and we are developing that and pursuing that. The other thing I think that's still a bit outstanding is the size of the safety database. And now that we have what are, I think enough data to start discussions with them on the safety, what the safety looks like. We'll be initiating those sometime early next year.

The next question is from the line of Joori Park with Leerink. Moving on. Our next question is from the line of Myles Minter with William Blair.

Congrats on the data. Just the first one on the serious adverse events here. I gather the allergic reaction was immediately after early dosing in the open-label extension. But can you comment on the time line, at which the seizure did happen in that 1 patient and whether they had a history of seizures prior. That's the first one. And then the second one is actually on the FXN expression. It does seem in skin that at 90 days, it is accumulating here. I think you hit a median of 7.65 picogram per microgram. I recall from modeling data presented at ICA that the median levels of the 50-milligram dose was projected at 8.17 picogram per microgram. So just wondering, given today's data in this expected accumulation in skin, in particular, whether that modeling has changed and whether you expect to hit higher frataxin expression levels than what's quoted in that modeling data?

Thanks, Myles. Good to talk to you. You're right about the allergic reaction. Obviously, that occurred early. The patient who had a seizure, it was also quite early in the study and he had no other problems. And he also did not have high levels of drug or frataxin. And so we don't have a lot of detail as to why that occurred. It may -- we don't have another cause that we can actually blame it on, but it may or may not be related to the drug. There was a family history. He did not have a history, but there was a family history of seizures. But that's really all the information I can provide. We really want to be careful that we're not -- because we're going to have [SEs], these patients are very sick patients, and they have a terrible disease. So we fully expect that there will be more adverse events, it just is bound to happen. With regard to the frataxin levels, we can't really tell whether we're at steady state and skin because we only have 2 time points. And as you're suggesting or as you noticed, the frataxin still increased between day 30 and day 90, which is pretty much what we would have expected. But given that there's really no safety signals, and there doesn't appear to be any problems with frataxin levels, we're very comfortable that we can increase it to 50 and be in the range that we anticipated with our modeling and simulation. This data doesn't really change that much at all.

The next question is from the line of Samantha Semenkow with Citi.

Two for me. Just the first one is can you just put the positive trends that you're seeing on the outcomes data in a bit more context, how do these early data, particularly in the upper limb scores compared with, say, omaveloxolone?

Yes, Sam, I can't really compare it with the omaveloxolone simply because we only have 90 days of data, and they had either 48 weeks or 3 years. So it's really hard to compare it. I think this is early in the going and we're very excited because honestly with this number of patients and this length of time and at a 25-milligram dose, I honestly did not, as I said in my prepared remarks, honestly, did not expect to see very much. And I think it's very encouraging that we're seeing this movement. I think also -- the fact is it's upper limbs in a population that we knew wouldn't be able to do a lot walking is also really useful and helpful. And so I don't want to read too much into it because it is only 90 days of dosing, and it is a relatively low dose. But I think it really starts to show and you put the data all together and you say, we're increasing frataxin levels. We've seen effects on some biochemical markers, the gene expression and the lipids, all trending towards normalization. And now we're seeing consistent data between the different measures that suggests that these patients may actually be having some improvement, not only slowing the deterioration, but they may actually be having some improvement I think, is just really encouraging. But I think we have to be careful. It will be really important to see the 50-milligram data in the middle of 2025 when we'll have more patients longer term and a higher dose, but very encouraged by this data.

Got it. That's very helpful. And then I guess, just looking forward to that data in the middle of next year, is that any follow-up for the some of the scales that you can take it to FDA to start really solidifying the trend between -- or the connection rather between frataxin increases and improvement. Is it necessary to show that? And is that sufficient follow-up for the BLA?

I don't know if it's necessary. It obviously would be very, very helpful if we can show that. But for a novel surrogate endpoint, I think you just really have to show that it's reasonably likely to predict. And so if we do have persistent trends, I think that would be -- quite honestly, I think that would be that will close -- just close the book, we would have a novel surrogate endpoint. But I also think the agency is willing to accept nonclinical data, looking at relationships between various tissues as well as exposures in humans as compared to animals, and we've collected all that data and are in the process of pulling it all together. So we're cautiously optimistic. I've been telling everyone for a while now, I really do believe that this is a logical program for an accelerated approval. There are just very few neurologic diseases -- neurodegenerative diseases where you know the cause and you're fixing the cause. And we see in our animal models, we see an effect. We're now seeing a biochemical effect as well as potentially a clinical effect in patients. And so I'm very optimistic that we'll be able to pursue an accelerated approval. That said, we still have to have our conversations with the agencies.

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

I apologize for getting disconnected earlier. And apologies if these questions have been asked. But the first one is on safety. I was just wondering when -- of the 2 patients who had the serious adverse events, do you know when the safety signal arose? And then how long have you dosed the 6 patients on the 50 mg dose cohort? Just trying to see relative to when the safety signals arose in the 20 mg versus how long you've been dosing the 50 mg. And I have a follow-up.

I think, I stated the 2 SAEs occurred early in the course. One was immediate, obviously, it's an allergic reaction. So it occurred right after dosing. The other one was a little bit later, but early in the course. And the 50 milligram, I can't answer that question because I don't know off the top of my head how long, but it hasn't been that long. I would say probably the longest maybe a couple of weeks to a month, but I don't know exactly, Joori, how long we've been dosing the longest person.

Okay. Got it. That's helpful. And then I was just wondering if you've done any modeling work or looked at the correlation, like the direct correlation between the frataxin biomarker improvement and the trends in functional improvement that you're seeing?

We don't have enough patients yet and enough data to do that. We will, but we don't have enough. We have looked at the differences in lipid profiles and they do seem to have a relationship. So the higher the frataxin level, the more likely they are to shift. But it's not -- there's just not a lot of data yet.

Okay. Understood. And then finally, when could we expect to get an update on how the progress is going with the regulatory agency and pursuing an accelerated approval pathway?

I'm hesitant to give you a timing simply because dependent on them. I mean -- it depends on their schedules and their availability. But we are -- the start program, I have to say, has really been helpful. We do get feedback relatively quickly. And it's really been very useful in getting feedback on the protocol, like the confirmatory study, CMC work. So we are in an active dialogue with them. And as soon as we have something definitive, we will be happy to put it out.

Next question is from the line of John Wolleben with JMP Securities.

Thank you for all the updates today. Just a simple question. How many patients were enrolled in the open-label extension and dosed? And then how many you said you expect to see an acceleration in 2025? How many do you hope to ultimately get enrolled?

Yes. We -- 14 have been enrolled. Actually, there's a couple more that were enrolled after and started dosing after the data cut. So we're continuing to actively enroll. I don't know off the top of my head exactly how many, but we should have a significant number. As I've said in the past, there have been 61 patients, unique patients who've been in our trials. Not all of them are eligible like people who have an allergic reaction aren't going to be eligible. And some of them had other reasons why they're not eligible. As I said, it's a pretty cumbersome study. These patients have to travel back and forth and really make an effort to be in this study. They're getting biopsies every month and then every 3 months. It's a very cumbersome study. So there will be those patients who just aren't interested in being in the study -- or there may be patients [indiscernible] and they omaveloxolone and they're satisfied. So it will be some subset of that. But whether it's going to be 30 or 40, I can't tell you exactly.

Okay. And then maybe as a follow-up to that, you mentioned the size of the safety database is outstanding. What is your current understanding of what that could look like or what are you proposing to the FDA? And then can you talk a little bit more about the nonclinical data that FDA is going to want to see? Is that related to nomlabofusp? Or is it related to frataxin increases and how that may link to a benefit or both? Just hoping for a little bit more color on those developments with FDA?

Yes. What was your first question? I'm sorry.

Your expectation for safety database necessary?

Okay. Sorry, sorry. I think it's premature to predict that. They tend to be very flexible with rare diseases. And so we really have to have those discussions with them. But as you can imagine, we have people who are on more than 8 months at this point. By second half of next year, those patients will have been on for well over a year, assuming they don't drop that. And then the patients who are already at 90 days will have been on for a year. So we're starting to collect enough data that I think we can start those conversations with the agency. But as we get more color and more clarity, we'll be happy to provide that. With regard to the animals, it's a combination of things. I think it's a whole -- we have a lot of data, data that we -- I have to tell you there were studies I didn't remember we had done. And we've gone through all that and really pulled that all together and we'll be submitting that to the FDA and having conversations with them. I think it's mostly related to relationships between tissues, relationships between the exposure in humans versus the exposure in animals and just really being able to pull the whole story together in a cohesive, I think it's less -- we have -- you've seen our cardiac data, we have neuro data. We have a lot of data on effect in animals. So I think that we don't have to generate anything for that. But we do have to pull it all together. So we have a cohesive, coherent story to tell. I hope that answers your question.

Our next question is from the line of Laura Chico with Wedbush Securities.

Just two for me. Were there any skin sample biopsy that exceeded 100% of normal or healthy volunteer in the analysis?

Yes, there were, and we fully anticipate, based on our simulation, Laura, at 50 milligrams, we figured they'll be about 13% that are above 100%, but they're not double or triple. They're just above. So -- and we don't see a signal with those. The data that was -- the animal data that was presented years ago by the gene therapy folks, it suggested toxicity wasn't until you hit like 20x normal. So we're nowhere near that level.

Got it. Okay. And then just another clarification. You're providing the 50 mg OLE data in the middle of next year. Just wanted to clarify, would that also include additional longer-term 25 mg OLE data at that point as well?