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

Good morning, and welcome to 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'd like to point out that there is a slide deck that accompanies today's presentation. It could be viewed using the webcast link provided on the Investors page of the Larimar Therapeutics website. Also posted on this web page is a news release issued earlier today. Before passing it off to company management for our prepared remarks, I would like to remind all of you that some of the information disclosed on the conference call contains forward-looking statements that are based on the company's beliefs and assumptions and on information currently available to management. These statements include, but are not limited to, statements regarding expectations and assumptions regarding the future of the company's business, the company's plans and ability to develop and commercialize Nomlabofusp, formerly referred to as CTI-1601 and other matters regarding the company's planned clinical trials, business strategies, ease of capital, results of operations and financial position. These forward-looking statements involve risks, uncertainties and other factors that may cause actual results, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include, among others, the success, cost and timing of the company's product development activities, nonclinical studies and clinical trials including nomlabofusp clinical milestones and [ continued ] interactions with the FDA. The earlier nonclinical and clinical data in testing of nomlabofusp may not be predictive of the results or success of later clinical trials in assessment and that clinical trial data are subject to different 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 due to projections of the future about which they 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 Therapeutic's Chief Financial Officer; Mike Celano; Chief Medical Officer, Dr. Rusty Clayton; and Chief Development Officer, Dr. Gopi Shankar will be available during the question-and-answer session following the prepared remarks. With that, I'll now turn the call over to Carole.

Thank you, Alex, and good morning, everyone. We are excited to share some key updates on nomlabofusp development program, which we believe represents truly exciting developments for both Larimar and the Friedreich's ataxia community. Nomlabofusp is the generic name for CTI-1601. Importantly, we are pleased to report today the positive top line data and successful completion of our 4-week placebo-controlled Phase II dose exploration study of nomlabofusp in participants with Friedreich's ataxia. Nomlabofusp was generally well tolerated in both cohorts and demonstrated dose-dependent increases in frataxin levels in skin and buccal cells. The clear dose response and the magnitude of the increases in frataxin levels seen in peripheral tissues further reinforces the therapeutic potential of nomlabofusp to address frataxin deficiency, the known root cause of the disease in patients with Friedreich's ataxia. Participants treated with 50 milligrams had individual frataxin levels in skin increase from less than 17% relative to healthy volunteers at baseline to 33% to 59% of healthy volunteers after 14 days of treatment. Patients treated with placebo did not increase during this period. In addition, we are seeing the majority of treated patients in both cohorts with quantifiable levels of frataxin at baseline and day 14 achieved at least a 10% increase in tissue frataxin in skin cells and at least a 30% increase in tissue frataxin levels in buccal cells. When dosing is switched every other day, the magnitude of the increase declines. This was seen in prior studies as well and suggest that daily dosing needs to be maintained to sustain increases in frataxin. These promising Phase II results build upon our prior clinical proof-of-concept data and demonstrate consistent findings between our Phase II and Phase I studies. Moreover, these clinical data further expand our nomlabofusp safety database and strength in clinical support for the generally well-tolerated safety profile and low discontinuation rates seen across studies. This study reinforces the clinical evidence supporting the fact that nomlabofusp can substantially increase frataxin levels and that these increases may have a clinically meaningful effect on disease progression in patients with Friedreich's ataxia. When comparing frataxin levels between skin and buccal cells, we are seeing a consistent pattern across our clinical studies, which include our Phase I and Phase II studies as well as our study in healthy volunteers. We observed higher variability in frataxin levels in buccal cells and we also see a consistent relationship between skin and buccal cells, where skin cells have about twice as much frataxin as buccal cells. We also see a strong correlation in the changes in frataxin between skin and buccal cells, even though there is more variability in buccal cells. We believe the variability of frataxin levels in buccal cells is due to the fact that buccal cells turn over much more quickly than skin cells and that the sampling technique for buccal cells leads to more variability in the amount of protein collected. The variability associated with the sampling of buccal cells is not unique to us and has been described by others in the field. Skin on the other hand is a more stable tissue with a lower sell turnover rate and has a well-established and standardized collection method. Following the success of this Phase II study, we remain focused on advancing the nomlabofusp clinical program. And in January, initiated the first clinical site in the Open Label Extension trial or OLE. Dosing in this study will be at 25 milligrams daily. Based on the data to date, we plan to continue daily dosing and will not be switching to every other day dosing in order to maintain frataxin levels. This study will inform on our long-term safety profile and frataxin levels collected over longer periods of time. We have had high patient interest in the study and remain on track to have initial data in the fourth quarter of 2024. We have also initiated discussions with the FDA on the use of frataxin as a novel surrogate endpoint. The FDA has acknowledged that frataxin deficiency appears to be critical to the pathogenic mechanism of Friedreich's ataxia and that there continues to be an unmet need for treatments for Friedreich's ataxia's patients that address the underlying disease pathophysiology. Therefore, we intend to pursue accelerated approval using frataxin levels support of PD and clinical outcomes information and safety data from the Open Label Extension study, along with additional nonclinical information, we are also beginning to plan for a confirmatory study to be initiated prior to the BLA submission, which we are targeting for the second half of 2025. With that brief discussion of today's exciting news, I'd like to now 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. Based on the data we will discuss today, we are pleased to see consistent findings across our multiple ascending dose Phase I study and Phase II study, including a generally well-tolerated safety profile and dose-dependent increases in frataxin levels in skin and buccal cells following treatment. As mentioned earlier, we are intending to pursue accelerated approval with the FDA. 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 treatments that address the underlying pathophysiology. We are currently having ongoing discussions on the evidence needed to support an application for accelerated approval. At this time, we intend to pursue an accelerated approval using frataxin levels as a novel surrogate endpoint as well as long-term safety from our Open Label Extension study. We will also have supportive pharmacodynamic data and clinical outcomes from the Open Label Extension study and nonclinical pharmacology data from animal studies. We are beginning to plan for a confirmatory study that would start prior to a BLA submission and are targeting a BLA submission in the second half of 2025. Our next clinical catalyst will be from our Open Label Extension study that we initiated in January with a dose of 25 milligrams daily. Patients are currently being screened and dosing will begin shortly. The Open Label Extension study will inform on the long-term safety frataxin levels and self-administration of nomlabofusp following daily subcutaneous administration. We expect to provide interim data from this study in the fourth quarter of 2024. To potentially escalate dose in the Open Label Extension study, the data from the 50-milligram cohort from the dose exploration study as well as available data from the 25-milligram dose in the Open Label Extension study will be submitted to FDA for review as we are currently subject to the continued partial clinical hold. As of December 31, 2023, we have cash and cash equivalents totaling $86.8 million, which provides runway into the first quarter of 2025. We expect our 2025 operating expenses to be higher year-over-year at a level similar to the 2024 increase 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 neurologic deterioration. It is caused by a genetic defect on both alleles that prevents production of the critical mitochondrial protein, frataxin, resulting in lower tissue frataxin levels. Most patients with FA only produce about 20% to 40% of the frataxin levels seen in homozygous healthy people. Later in the presentation, we will show important data that demonstrate that frataxin levels correlate with the disease progression. Not having enough frataxin leads to a myriad of debilitating symptoms, some of which are summarized on the slide. Patients will often present before the age of 14, and symptoms are progressive typically causing patients to be wheelchair-bound 7 to 10 years after the initial diagnosis. The symptoms of FA include loss of musculoskeletal function, blindness, deafness, and inability to speak clearly and diabetes. Unfortunately, patients with FA have a life expectancy of only 30 to 50 years with the most common cause of death being heart disease. 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 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 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 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 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. With that overview, let's turn to our Phase II dose exploration study. The trial evaluated 2 doses of nomlabofusp, Cohort 1 evaluated 25 milligrams and Cohort 2 evaluated 50 milligrams. Participants in either the 25-milligram or 50-milligram cohorts were randomized 2 to 1 to receive daily subcutaneous injections of either nomlabofusp or placebo for 14 days than every other day for an additional 14 days for a total 28-day dosing period. The goal of this study was to assess safety, better understand the pharmacokinetics of nomlabofusp and evaluate frataxin levels at lower doses over longer periods of time. On the next 2 slides, you can see the demographics and disease characteristics of participants who enrolled in the 25-milligram and 50-milligram cohort of the Phase II trial. It is important to note that only 1 out of the 15 participants in the 50-milligram cohort previously participated in the Phase I program. We believe this demonstrates the continued interest and access to nomlabofusp through clinical trial participation. I won't go through this in detail now but we'll note that the demographics in this trial are similar in both cohorts and similar to those in our Phase I program. First, we will review the frataxin data from skin cells. On the left, you can see changes from baseline in frataxin concentrations normalized to total protein for the 25-milligram cohort in aqua and for the 50-milligram cohort in blue. Within the graph, the dots represent medians and the horizontal lines, the 25th and 75th percentile. After 14 days of daily dosing, we observed a clear dose-dependent increase in frataxin levels from baseline and skin cells. Looking at the 28-day time point, which is after participants were switched to every other day dosing for 14 days, we still observe a dose-dependent increase in frataxin levels, but the magnitude has decreased. The decrease in the frataxin levels seen when the dose regimen is switched from daily to every other day, was also seen in our MAD study and is what led us to initiate the Open Label Extension at 25 milligrams daily with no switch to every other day dosing. On the right is a waterfall plot depicting the individual changes in frataxin levels from baseline and skin cells on day 14. Each bar represents an individual patient with placebo-treated participants in gray, the 25-milligram cohort in aqua and the 50-milligram cohort in blue. You can see that the majority of patients treated with nomlabofusp had substantial increases in frataxin levels, while placebo patients were basically unchanged. Importantly, there also appears to be a dose response as frataxin levels are notably increased in most of the 50-milligram cohort over the 25-milligram cohort. Looking at the buccal cells data in the graph on the left, you can see that the buccal cells display a similar dose response as the skin cells, but with a lower magnitude as you have less frataxin in buccal cells as pointed out earlier. The buccal cells also do not maintain the increased frataxin levels following the switch to every other day dosing between Day 15 and Day 28. This may very well be due to the relatively quick turnover of these cells. Similarly, the waterfall plot on the right demonstrates that most treated patients have increases in frataxin levels, while all placebo patients remain unchanged. Now let's look at the absolute numbers. What you see here is data from skin for both cohorts at Day 14 and 28. The table show the medians and the means for baseline Day 14 and Day 28 and the change from baseline. We are just presenting the 2 active groups since you can see from the prior slides as well as the table in the press release that the placebo group did not change. With the 25-milligram cohort, the median change from baseline is 2.81 at Day 14. And for the 50-milligram cohort, it is 5.57. As you can see from the table, the median and mean values are similar. It is also apparent from the table that although the changes decreased at Day 28 after 14 days of every other day dosing, they do not return to baseline for either cohort. For buccal cells, we see a similar picture with increases of 0.56 and 0.72 for the 25- and 50-milligram cohorts, respectively. Again, although these increases in frataxin decrease at Day 28, they do not completely return to baseline. Now let's look at the data a different way. In these graphs, we are depicting how many people had a shift in their frataxin levels in skin cells as a percentage of average healthy volunteers after 14 days of treatment. On the left is the 25-milligram cohort and on the right is the 50-milligram cohort. On the far left of each figure, you can see categories of percent of healthy volunteers. They start with patients who have less than 12.5% of average healthy volunteers and are categorized by increases similar to what was presented in the published literature. The people in black to the left of the black vertical line represent patients at baseline. To the right of the black vertical line are where each patient ends up on Day 14. In blue are those that increased by 25% to 50%. And in green are those that also increased, but additionally exceeded 50%. To put this into context, people who are carriers of FA have no symptoms and have frataxin levels that are approximately 50% of average values observed in healthy volunteers. You can see on the left that in the 25-milligram cohort, all participants, except one, had increases in frataxin levels and one exceeded 50% of healthy volunteers. On the right, in the 50-milligram cohort, patients actually started out slightly lower. All participants increased moving up from below 25% to greater than 25% with 3 participants exceeding 50%. For buccal cells, there is a similar pattern occurring with patients increasing frataxin levels above baseline. In the 25-milligram cohort, 2 participants increased and in the 50-milligram cohort 5 participants increased. To put this in perspective, based on the published literature, patients at 11% of values observed in healthy volunteers had a median age of onset of 7 years old. When patients had frataxin levels above 30% of the median age of onset was approximately a decade later than the rate of progression was slower. Nomlabofusp, when dosed at 25 milligrams for 14 days daily moved all but one participant into the 25% of values observed in healthy volunteers or greater category and when dosed at 50 milligrams for 14 days daily, moved all participants from a baseline of below 25% to between 33% and 59%, with 3 participants moving to greater than 50%. We are very excited by these results. We believe this is the first time any intervention has increased frataxin in patients with Friedreich's ataxia to this extent. We have now seen dose-dependent increases in frataxin levels with nomlabofusp at multiple doses in several studies. The next step is to collect long-term safety and pharmacodynamic data from our Open Label Extension. It is yet to be seen whether changing a patient's frataxin level translates into the disease modification. But based on the fact that frataxin deficiency is the root cause of the disease, the fact that there are lower levels of frataxin correlate with disease burden and that animal model showed that increasing frataxin mitigates clinical outcomes, this appears to be a logical assumption that we can further explore in our long-term dosing studies and warrants the continued development of nomlabofusp. We were also pleased to see the predictable pharmacokinetic profile for nomlabofusp in our Phase II study. Consistent with findings in our earlier Phase I studies, nomlabofusp demonstrated quick absorption after subcutaneous administration and had dose-dependent increases in exposure with increasing dose. For safety, a combined summary of the Phase I and Phase II safety data from our clinical program is represented here, which supports that nomlabofusp is generally well tolerated. In total, 61 individuals with FA have participated in our trials and 46 have received at least 1 dose of nomlabofusp. Across our Phase I and Phase II trials, there have been no serious adverse events reported to date. There was one allergic reaction, which was considered to be a severe adverse event in the Phase II study that resolved with standard treatment. 44 of the 46 clinical trial participants dosed with nomlabofusp completed their respective study. One Phase II participant in the 25-milligram cohort withdrew due to the aforementioned allergic reaction that resolved with standard treatment and one Phase I participant in the 50-milligram cohort withdrew due to mild to moderate nausea and vomiting after a single dose. The most common adverse events reported in our clinical program have been mild and moderate injection site reactions. All of the reactions resolved without intervention, there were no study discontinuations due to injection site reactions. We are further evaluating the long-term safety and tolerability, the pharmacokinetics and the ability of nomlabofusp to increase tissue frataxin levels over longer periods of time following daily administration of 25-milligrams in our Open Label Extension study outlined here. Patients who previously completed a nomlabofusp clinical trial are eligible to screen for our multicenter OLE study. There has been a lot of interest from patients so far, and we are excited to begin this important study. After screening, participants who enroll in the trial will receive daily subcutaneous injections of 25 milligrams of nomlabofusp. 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 will be self-administered by patients or administered by a caregiver, providing a first look at real life experience. As stated earlier, we also plan to pursue frataxin as a novel surrogate endpoint to support accelerated approval. The frataxin data and safety data from this study will be used to support the accelerated approval. Additional data to support accelerated approval will include data from nonclinical pharmacology studies as well as other pharmacodynamic and clinical outcomes from this Open Label Extension. In this study, other objectives include the evaluation of the long-term subcutaneous administration of nomlabofusp on measures of clinical efficacy, which will be compared to a match 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. We were pleased to have initiated the Open Label Extension in January, and we expect to report preliminary data from the trial in the fourth quarter of 2024. As noted earlier, to potentially escalate dose in the Open Label Extension, 25-milligram treatment data from the Open Label Extension as well as the data from the 50-milligram cohort of the Phase II study will be submitted to FDA due to the continued partial clinical hold. We are focused on bringing nomlabofusp to a broad age range of patients around the world. Our nomlabofusp clinical program includes an ongoing Open Label Extension study as described previously. We also anticipate including a pediatric placebo-controlled multiple ascending dose trial in individuals with FA who are between the ages of 2 and 17. Participants in this planned trial will be eligible to roll into our Open Label Extension. 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. Prior to initiating the pediatric study, we will need to submit additional data from adult patients for FDA review. 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. In summary, the data reported today represents a major step forward in the clinical development of nomlabofusp as the first therapeutic intended to increase frataxin levels systemically and address the protein deficiency leading to FA's devastating clinical course. Nomlabofusp was generally well tolerated up to 4 weeks, had a predictable pharmacokinetic profile and led to dose-dependent increases in frataxin in skin and buccal cells. Importantly, skin frataxin levels as a percentage of healthy volunteers more than doubled in all patients after 14 days of daily dosing with 50 milligrams. On the regulatory front, we have initiated discussions with FDA regarding use of frataxin as a novel surrogate endpoint to support accelerated approval with a potential BLA submission targeted for the second half of 2025. We are beginning preparations to expand the nomlabofusp clinical program to ex U.S. geographies. As we look ahead for our nomlabofusp program, we remain on track to report initial clinical data from our Open Label Extension study in the fourth quarter of 2024. With these milestones ahead of us, and a robust clinical data set demonstrating a differentiated mechanism of action with nomlabofusp as well as cash balance in excess of $86 million, we believe we are well positioned as we seek to address the urgent unmet needs of the FA community. Before I conclude, I would like to thank our clinical trial participants and their families, addressing the unmet needs of individuals with FA remains our key source of inspiration, and I commend their bravery and dedication. I would also like to thank the FDA for their engagement throughout the regulatory process thus far as well as our talented and dedicated Larimar employees, our partners, clinical trial investigators and patient advocates at the Friedreich's Ataxia Research Alliance, all of whom helped nomlabofusp's 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; our Chief Medical Officer, Dr. Rusty Clayton; and our Chief Development Officer, Dr. Gopi Shankar. We will now open the line for questions. Operator?

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

Carole, thank you for that presentation, really put data in context very appropriately. So 3 questions for me. So the first question is, based on our interaction with KOLs, they had noted that if you show just a 10% absolute increase in frataxin level that should be enough. I know some of others have said 30%. So you clearly hit that bar. In fact, you are significantly above that threshold on the 50-milligram dose. So the question is, what is your confidence around the increase in frataxin level and the corresponding functional benefit? I have 2 more after this, I'll ask.

So in animals, obviously, if you increase frataxin levels, you'll improve clinical outcomes. We'll obviously have to look at that in the clinic as well. As I said, we're starting to have conversations with the FDA, and we have started to have conversations with the FDA about using frataxin as a novel surrogate endpoint. And also, we will be looking at clinical outcomes in the Open Label Extension. And as we said -- I said in my prepared remarks, we said that those data will be compared to the FACOMS database as well. And that population has been prospectively -- and the mechanism to do that have been prospectively defined. So the fact that we know the decreases in frataxin are correlated with disease progression and that we know that in animals when you increase frataxin levels, you mitigate the disease progression. But again, it has to be proven in people, which is obviously our next step.

Got it. Then we're getting a lot of questions from investors regarding different tissues. So is skin a good surrogate for other tissues like cardiac or skeletal muscles? And are you looking at muscle biopsy in the OLE?

So we believe that skin -- we know that buccal cells correlate with disease progression. That data has been generated by others. And we see that there is a very strong correlation in our data between skin and buccal cells. So we do believe that if you can increase skin -- skin frataxin levels, you can impact the disease. But again, that has to be proven. We can only suggest that. We are not planning to do muscle biopsies at this time. We are evaluating whether that would be appropriate or not. The concern we have about muscle biopsies is their reproducibility and the reliability. And if we're going to do something that's that invasive. We want to make sure that we're going to get data that's very useful and that we can interpret. But skin doesn't turn over as quickly as buccal cells, which is more like target tissues. I mean, cardiac tissue and neurons don't turn over very quickly at all. And so the skin may actually be a good surrogate, but we'll have to see how that works as we move through the clinic.

Got it. Final question for me. This is on the regulatory part. So what lies under your confidence around accelerated approval in the BLA in second half of 2025 beyond frataxin level, what are other evidences that you might need to generate and when we might be able to see that?

Yes. So obviously, frataxin levels over time. I think the more important piece or the thing that will take more time is the safety. I mean, obviously, we're going to have long-term safety data, which we're collecting through the Open Label Extension. We also are likely to need some additional pharmacology studies in animals to look at other pharmacodynamic measures and potentially assess changes in the clinical outcomes of those animals. We obviously have a good bit, but we are looking at whether we need to have some additional supportive data. And then, of course, we also are going to have started or at least initiated a global placebo-controlled trial border confirmatory evidence. Obviously, it's important to start those studies prior to the BLA submission. So that's what we're looking at. And when will you have it, the first cut of the data from the Open Label Extension will be available in the fourth quarter of 2024.

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

Congrats on the data. Follow-on from Yatin's question on the 10% increase over frataxin baseline. We've got some feedback from KOL suggesting that if you hit that, there'd be no reason to dose escalate from here. I just wanted your latest take on thinking of going to that 100-milligram dose from here. And if that's something on the cards that you'd want to discuss with the FDA. And I have a follow-up question.

Yes. I don't think we need to go to 100 milligrams given the data that we're seeing here. Obviously, these patients in the 50-milligram cohort, I want to just draw your attention to the fact these patients actually started very low. They started at less than 17% of healthy volunteers and we were able to increase them to 33% to 59%, which is quite a nice increase and very important and very rewarding when we saw that. And so I don't think that we need to dose escalate in this study, in particular. We are obviously going to be collecting long-term data at -- in the Open Label Extension. And if we see that we don't think we're getting where we need to go with 25-milligrams, we obviously will talk to the FDA and submit data to be able to propose increasing to 50-milligrams. And then if we still see that some people are not getting high enough, we may very well want to go to 75-milligrams, but we think we can do that all in the Open Label Extension, and we are not sure Myles, that will be necessary. Quite honestly, we know we're at steady state by Day 14 for the [indiscernible] nomlabofusp, but we don't know whether we're at steady state for frataxin. So it is possible that we could start seeing even higher levels with the 25-milligram and/or the 50-milligram as we go for longer periods of time.

Okay. Makes sense. And then just on the skeletal muscle biopsies or the cardiac biopsies, which is said that you're not planning to do at this stage. When you have your discussions with the FDA and they seem amenable to using frataxin levels, there's a potential surrogate endpoint for accelerated approval here. Did they mention specifically what tissue types they'd like to see that in? And did they specifically rule out the need for cardiac or skeletal muscle biopsy?

So I'll be careful about what we say with FDA. Obviously, our discussions are preliminary. But they have seen the buccal cells and the skin data, and they have not requested additional tissues. Now that's not -- I want to make sure you understood that. It's not to say that they won't or that's not to say that we won't consider it. But like I said, if you're going to do something as invasive as what we're talking about, you need to make -- we need to make sure that we're going to get useful data. And so far, I haven't seen any real evidence that you can get reproducible data out of -- necessarily out of skeletal muscle. Again, we are looking at it, though. So I don't want to dismiss it completely.

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

And congrats on the data. I just wanted to follow up on the dosing questions. You seem to say that 50-milligrams seems to be hitting those targets as discussed by the KOLs. I wonder would you consider longer dosing interval since you're reaching a bit higher than what these KOLs have suggested?

I don't think so at this time, Samantha, simply because we know that when we switch to every other day dosing, the levels decreased and granted at the 50-milligram, they were still high. But there doesn't seem to be any harm in being above 50%. I mean you and I are walking around with 100%. And so I think we feel that we're more likely to have a clinical effect or potentially even a rest of the disease progression if we can get to levels that are higher rather than lower. I think what still needs to be evaluated as we go through the Open Label Extension, and we collect more data and have more people, we'll be able to see whether different people with lower levels need more to get to the same place because we just don't have enough data to look at that yet. And like I said, we still aren't 100% sure that we're at steady state for frataxin. So I think we'll look at -- we'll continue to evaluate the regimen and if we do start to see that we are continuing to accumulate frataxin going to a lesser -- going to a less frequent dosing regimen would be considered. But I think at this point, given our Phase I and Phase II data, and the fact that it goes down when you go to every other day, I think we're going to pursue every day dosing at this time.

Got it. Understood. And then caveat for small numbers in the 2 cohorts that you've presented, but I did notice that the 50-milligram cohort, I think you mentioned this in prior answer as well as the lower [indiscernible] baseline frataxin versus the 25-milligram cohort. I guess when you look at these on an individual patient level, do you see any correlation between the degree of baseline frataxin, what the magnitude of the change is after dosing with nomla? I'm just trying to get a sense of how the baseline frataxin concentration influences the degree frataxin increase?