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. At that time, if you'd like to ask a question, you may press star one on 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 who are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. 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 webpage is 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 plan, and ability to develop and commercialize nomlabofusp, formerly referred to as CTI-1601, and other matters regarding the company's plan, clinical trials, business strategies, use of capital, results of operations, and financial position. These forward-looking statements involve risks, uncertainties, and other factors that may cause actual results, performance, or achievements to be materially different from the information expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others, the success, cost, and timing of the company's product development activities, nonclinical studies, and clinical trials, including nomlabofusp's clinical milestones and continued interactions with the FDA.
That earlier nonclinical and clinical data and testing of nomlabofusp may not be predictive of the results or success of later clinical trials and assessments, and that clinical trial data are subject to differing interpretations and assessments. The company's ability to raise the necessary capital to conduct its product development activities and other risks described in the filings made by the company with the Securities and Exchange Commission and available at www.sec.gov. These forward-looking statements are based on a combination of facts and factors currently known by the company and its projections of the future, about which it cannot be certain and, as a result, may not prove to be accurate. The company assumes no obligation to update any forward-looking statements except as required by law. Speaking on today's call will be Dr. Carol 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 Carol.
Thank you, Alex. And good morning, everyone. We are excited to share some important progress on the nomlabofusp's registration 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 tissues, 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 pg/μg in buccal cells and 9.28 pg/μg 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 that 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 two dose exploration study and our phase one multiple ascending dose study. Nomlabofusp reached a 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 three independent clinical studies. We have also shown data suggesting positive trends towards 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 our registration pathway. For our open-label extension study, we currently have six participants receiving 50 milligrams of nomlabofusp daily. We plan to increase all other participants in the trial 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., E.U., U.K., Australia, and Canada, and are finalizing the protocol based on advice from the U.S. FDA, the E.U. 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 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 required 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 levels 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 one study and phase two 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 treatments 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 nonclinical 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 six 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%-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 that 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 indicate 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 % of healthy volunteers, the median age of onset, and the rate of disease progression, as well as measured by the Friedreich's Ataxia Rating Scale, 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 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 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 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 six 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 one and phase two 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 concentrations 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 Outcomes 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 a 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 two 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 buccal cells, the earlier the onset of symptoms and the faster the rate of progression. This clinical relationship has not been studied for skin frataxin levels. Because of this, we are continuing to collect both buccal cells and skin cells 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 to total protein for the 25 milligram cohort.
Within the graph, the dots represent medians, and the horizontal lines, the 25th and 75th percentiles. 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 shows a similar finding. As you can see, samples were only taken at three 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 day 90. Now let's look further into how these data compare 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 a significant dose response, and our simulations in skin suggest 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 swabs. 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 pg/μg in buccal cells and 7.65 pg/μg 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 pg/μg for buccal cells and 8 pg/μg 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 timed 25-foot walk test due to limited participant ambulatory status.
The other four 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 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, eight of 14 participants had baseline and data at 90 days. For those eight participants, we see trends that may suggest some improvement across all four 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 sub-scores of the MFARS, the two sub-scores that drove the improvement in the total MFARS were the upper limb assessments 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 four 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 steady 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, etc., really limited enrollment rates.
This has shifted, and we have seen enrollment increase with one 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, two participants withdrew from the study for non-treatment-related reasons. Two participants experienced serious adverse events but returned to their usual state of health within 24 hours. These two 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-limiting. There were no study discontinuations due to injection site reactions and all resolved. Based on the tissue frataxin levels and the safety data, we 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 that 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 suggest 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 non-ambulatory 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 six 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 two 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 course. These long-term data demonstrate that nomlabofusp was generally well tolerated at doses tested over eight months.
nomlabofusp also increased skin and buccal cell frataxin levels and maintained 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 six 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., E.U., U.K., Australia, and Canada for our planned confirmatory study and are finalizing the protocol based on feedback from the U.S. FDA, E.U. 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 the 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 a 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 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. At this time, if you'd like to ask a question, you may press Star 1 from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press Star 2 if you'd like to withdraw 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. One moment, please, while we poll for questions. Thank you. And our first question today will be from the line of Yatin Suneja with Guggenheim Partners. Please proceed with your questions.
Hey, good morning. Thank you for taking my question. Carol, excellent presentation, nice data today.
A few questions, some that came from investors and some that I have. So the first one is on these two SAEs. Are you able to articulate what exactly were the two AEs? And then have you received FDA comments on these SAEs? And then what about the other two discontinuation? It seems like there are four discontinuation totals, so if you can articulate exactly what was the reason.
Sure. So thanks. Nice to talk to you. The two SAEs were one 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 or the drug. The second was a seizure in a patient who was very severely debilitated with significant comorbidities.
In particular, he 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. Thank you.
And then with regards to the two discontinuations, this is a really rigorous study. It requires multiple trips to the doctor, requires them to have a lot of these people to have a caregiver because they simply don't have the dexterity to self-inject. And so those two patients wanted to be in the study, but they just couldn't comply with the protocol.
Got it. With regard to the BLA filing, could you maybe articulate for us what would be needed?
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?
Yeah. Sure. So we are in discussions with the FDA on what will be needed. I think it'll be frataxin levels, and I think we've pretty much put that to bed. I mean, we have patients out well over 180 days that frataxin levels are maintained. We didn't present that data because 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 non-clinical 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.
Got it. Thank you. I'll get back in the queue.
The next question is from the line of Joori Park with Leerink. Let's see if there are questions. Moving on, our next question is from the line of Myles Minter with William Blair. Please proceed with your question.
Hey, thanks for taking the questions. 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 timeline at which the seizure did happen in that one 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 ICAR that the median levels of the 50 milligram dose was projected at 8.17 picogram per microgram. So just wondering, given today's data and 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 very much.
Thanks, Miles. Good to talk to you. You're right about the allergic reaction. Obviously, that occurred early. The patient who had the 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 with every because we're going to have SAEs. 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 in skin because we only have two time points. And as you're suggesting or as you noticed, the frataxin levels do increase 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 the frataxin levels, we're very comfortable that we can increase it to 50 and be in the range that we anticipated with our modeling simulations. The data doesn't really change that much at all.
Cool. Thanks for the questions.
Thank you. The next question is from the line of Samantha Semenkow with Citi. Please proceed with your question.
Hi.
Good morning, and thanks very much for taking the questions. 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, compare with, say, omaveloxolone?
Yeah. Sam, I can't really compare it with omaveloxolone simply because we only have 90 days of data, and they had either 48 weeks or three years. So it's really hard to compare it. I think this is early in the going, and we're very excited because, quite honestly, with this number of patients and this length of time and at the 25 milligram dose, I honestly did not, as I said in my prepared remarks, honestly did not expect to see very much. I think it's very encouraging that we're seeing this movement.
I think also the fact that this upper limbs in a population that we knew wouldn't be able to do a lot with 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'll 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 enough follow-up for some of these scales that you can take at FDA to start really solidifying the trend or the connection, rather, between frataxin increases and improvement? Is it necessary to show that, and is that sufficient follow-up for the BLA? Thank you.
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 just close the book. We would have a novel surrogate endpoint. But I also think the agency is willing to accept non-clinical 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 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 - thank you. We still have to have our conversations with the agencies.
Our next question is from the line of Joori Park with Leerink. Please proceed with your questions.
Hi. Thank you for taking our questions. And I apologize for getting disconnected earlier. And apologies. These questions have been asked. But the first one is on safety. I was just wondering, of the two patients who had the serious adverse events, do you know when the safety signal arose? And then how long have you dosed the six 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 in the 50-mg. And I have a follow-up. Thank you.
I think I stated earlier, the two SAEs occurred early in the course. One was immediate, obviously. It was 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 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 there's just not a lot of data yet.
Okay. Understood. And then finally, when can we expect to get an update on how the progress is going with the regulatory agency on pursuing an accelerated approval pathway? Thank you.
I'm hesitant to give you a timing simply because dependent on them. You know what I mean? It depends on their schedules and their availability. But 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, 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.
Okay. Thank you very much.
The next question is from the line of John Wolleben with JMP Securities. Please proceed with your questions.
Hey. Thanks for taking the question and 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? Y
eah. The 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 unique patients who've been in our trials. Not all of them are eligible. 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 the study. They're getting biopsies every month and then every three months. It's a very cumbersome study, so there'll be those patients who just aren't interested in being in the study or maybe patients are on that and they have omaveloxolone and they're satisfied, so it'll 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 FDA? And then can you talk a little bit more about the non-clinical 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.
What was your first question? I'm sorry.
Your expectation for safety database necessary.
Oh, 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 eight 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 out. 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. I have to tell you there were two 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 way. I think it's less. We have 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.
Yeah. Thanks so much, Carol.
Our next question is from the line of Laura Chico with Wedbush Securities. Please proceed with your questions.
Good morning. Thanks very much for taking the questions. Just two from me. Were there any skin sample biopsies that exceeded 100% of normal or healthy volunteer in the analysis?
Yes, there were. There were.
We fully anticipate, based on our simulations, Laura, of 50 milligrams, we figure there'll be about 13% that are above 100. But they're not double or triple. They're just above. And we don't see a signal with those. The animal data that was presented years ago by the gene therapy folks that suggested toxicity wasn't until you hit like 20 times normal. So we're nowhere near that level. Got it. Okay. 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? It will include some, but it'll be very limited because we are switching everyone. So we have, obviously, if we have data of 260 days, we have very few, but some patients that are at 180 days.
So it'll include some data, but it'll be mostly 50-mg because we're switching everybody. Right, right. Rolling everybody to the 50-mg d ose.
Okay. Got it. Maybe I'll sneak one last one in there. Did you screen for anti-drug antibodies at this point?
We have been screening for anti-drug antibodies. We have not actually run the samples, obviously. We're batching the samples. But the fact that we maintain frataxin levels suggests that even if there are ADAs, they're not neutralizing because the frataxin levels are being maintained.
P erfect. Okay. Thank you very much. I'll hop back in queue.
Our next question is from the line of Cory Jubinville with LifeSci Capital. Please proceed with your questions.
Thanks for taking our questions. And congrats, Carol and Mike, on this really exciting update.
The trends that you've been seeing in MFARS are particularly exciting in kind of building off of the question that was asked earlier. How does this improvement compare against matched patients from the FACOMS database? And is MFARS worse linearly, or does it have a similar rate in ambulatory versus non-ambulatory patients? And how should we be thinking about that as it relates to a potential confirmatory study where I would presume patients that you would be enrolling on average would be less severe than patients that are enrolled presently?
So we can't compare it to the natural history database until we fully enroll. I learned this from my statisticians. Because what happens is you actually match the patients to a particular patient in the database based on your criteria. And if you do it before, the matches will change. So the data will change.
Once all the patients are enrolled, we'll be able to perform those analyses. With regard to MFARS change, the rate of change probably does change with different patient populations. We know for sure that children with early onset change much more quickly than people with later onset. We also know that the rate of change, the driver of the rate of change, changes when you're ambulatory, where it's more lower limb dexterity and lower limb function versus upper limb dexterity and upper limb function when you're non-ambulatory. For the confirmatory study, that will be in ambulatory patients. We'll be looking at the similar things that everybody else has pretty much looked at, and that will be ambulatory patients. Somebody asked, and I don't think I actually answered it, that the outcome measure will either be upright stability or MFARS.
We're still discussing that with multiple regulatory authorities, but it'll be one or the other.
Got it. That's really helpful. And if I could sneak in a follow-up, you previously discussed this idea that the 25-mg nominal dose might be ideal for some patients. So I guess in light of the data that we're seeing today, can you walk us through your thoughts on specifically which patient groups might be the best suited for a potential 25-mg dose, and how are you thinking about implementing that, whether it be in your BLA submission or future studies, etc.?
Yeah. As we collect more data, we'll be able to look at the correlations better and see whether or not patients who start out at higher levels will increase to a target of, let's say, 60%, 70%, whatever the target is, with a lower dose. But we just don't have enough data.
We don't have enough spread in the dataset to really look at that yet. But it may be that based on your age of onset, you can try a lower dose or a higher dose. So patients who have early onset who we know have lower levels of frataxin, maybe they need a higher dose. They need the 50, whereas patients who are later age of onset and have a higher frataxin level, which we know from history, right, could use 25. But we just don't have enough data to be able to tease that out yet.
Excellent. Thanks. That's really helpful. And congrats again.
Thanks.
Our next questions are from the line of Joel Beatty with Baird. Please proceed with your questions.
Hey. Thanks for that update. The first question is kind of a follow-up to that last question. You just talked about 25 milligrams.
Could we talk about 75 milligrams? And is there a potential, after seeing this data, that a higher dose than 50 could be needed for some patients?
I don't know the answer to that yet, Joel. I think it's possible. But we are not precluded from dosing 75 milligrams. Remember, in our multiple ascending dose study, we went up to 100 milligrams for 14 days. So we have safety data that if we do believe that there is a subpopulation, that we can go up to 75 and check it out. But right now, I think the 50 will be adequate. We know that based on our simulations, 59% of patients would be over 50. And I think it was like 90 somewhere over 30. So it's a pretty good safety. Sorry, the 50 milligrams should be a dose that fits the most patients. Got it.
That's helpful.
And then the frataxin levels at day 90, how much do they correlate to frataxin levels at day 30? For example, patients with the highest frataxin levels at day 90, do they also tend to have the highest frataxin levels at day 30?
I honestly don't know. I don't think we looked at that.
Okay. Great. Thank you.
Our next questions are from the line of Catherine Novack with Jones Trading. Please proceed with your questions.
Hi. Morning. Thanks for taking my questions. The first question is just around the SAE. Since this is the second severe allergic reaction you've seen, is there any identifiable drug component that could potentially be used as part of exclusion criteria going forward? And then also, have you done analyses to see if this is maybe related to manufacturing, potentially residual impurities on the protein purification method?
Any color on that would be helpful.
Yeah. It's not the manufacturing, and I can't tell you that it's any one specific component. This is very, very common with proteins. I mean, if you listen to any of the ads, the DTC ads that are on television, every drug has a warning against, "Don't take it if you're allergic to the drug." It's not uncommon at all. And we have dosed close to 60 patients. Some of those were placebos, so it's close to 60 patients. And I don't think this, to me, is expected and nothing to be alarmed about. People are allergic to small molecules, but they tend to be much more reactive to proteins.
Okay. That's helpful. And then just one more. So you mentioned 50% of the patients were non-ambulatory.
Is that of the total safety population or of the patients that were included in the efficacy readout? And then if it's just if it's for the total population, how many efficacy patients were ambulatory versus non-ambulatory?
Half of the efficacy patients were ambulatory and not exactly half. And it is for the entire population as well.
Okay. That's very helpful. Thanks for taking my questions.
Thank you. The next question is from the line of Andreas Argyrides with Oppenheimer. Please proceed with your questions.
Hi. Good morning. And thanks for taking our questions and congrats on all the positive updates here. A lot of good questions were asked, so I'll ask just a couple here. Quickly, have you guys moved patients on the lyophilized version of nomlabofusp in the OLE? Do you expect similar safety compared to the frozen liquid form?
And then just back to the BLA submission and all the data you're going to accumulate between now and then, what are some of the, I guess, additional gating factors? How are you thinking about your confidence in that? And you made comments around that too. But what updates do you need again from the FDA to just make sure you're still on track for that timeline? Thanks.
So we have not started switching to LYO yet, so everybody's still on frozen solution. That will happen sometime early next year, maybe the middle of next year. And with regard to the conversations with FDA on the BLA, they continue. I mean, there's a lot that goes into a BLA, as you obviously know. We have to lock down the novel surrogate endpoint piece.
We have to lock down the safety data, how large and for how long they need to see patients, as well as all of the CMC work that's getting done. But that's all on track. We have a very detailed timeline. Thanks to START, we have a very detailed communication plan with the agency, and so I think we're pretty comfortable that we'll be able to get the answers we need and have the conversations we need with the agency. I also don't want to ignore the European authorities. We are also talking to the European authorities and working with them on the design of the confirmatory study, what their needs are for submissions and other outcomes, so FDA is a key component, for sure, but we're also talking to the EMA as well as the UK authorities.
As you saw, we got ILAP designation. So they also are interested in an expedited process. So all of those designations actually are very helpful.
Just a quick follow-up and just a clarification. Do you plan to communicate the conversations with the FDA prior to BLA submission, or can we assume BLA submission aligns with the FDA?
I didn't understand your question. I'm sorry, Andreas.
Just in terms of the process of how you're going to plan to communicate to us whether or not is it just a BLA submission, or are you going to have a formal press release on discussions with the FDA and their communication to you on accelerated approval?
If we can get a definitive answer from them that we're comfortable is not a moving target, then yes, we'll absolutely communicate it to investors. There's no question.
Just sometimes with FDA, everything's a review issue. And we respect FDA completely, and we, I think, have a really nice relationship with them. And we'd like to keep it that way. It's very constructive. They give us really good feedback, and they've given it to us in a really timely fashion. So if we have something that's definitive, we will absolutely tell investors. But until we do, until we're absolutely sure that it's not going to change, I think we'll just continue our conversations with them.
Thanks, Carol. Appreciate all the color. Congrats on all the positive data today.
Thank you.
Thank you. Our final question is from the line of Ed White with H.C. Wainwright. Please proceed with your questions.
Good morning. Thanks for taking my question. I guess most of them have been asked already.
So, maybe just looking at the data, you have mentioned many times in the past that there's less frataxin in buccal cells than in skin cells. But can you explain why there's the big difference in the magnitude of change between the buccal cell data and the skin cell data?
And I think it's just that there's a good amount of noise in the dataset because it's just a small population. And because the numbers are so limited, we see some variability. But the change in frataxin level between buccal and skin is very highly correlated. Not including this data because we haven't done it with this data yet, but based on the data we have from our other trials, the coefficient of correlation is about 0.8. So the change from baseline in both of those cell types is really highly correlated.
Okay.
Has the FDA indicated that they will be looking at the skin data, or is the buccal data seem to be more of their focus?
We haven't talked about one versus the other yet. We will as we get into the discussion on frataxin levels as a surrogate endpoint. What I have said publicly is that to date, it's the skin and buccal, and they seem very comfortable with. They haven't asked for any other tissues. That doesn't mean they won't, but as of now, they have not. And so we think that both of these tissues, although we really rely on skin because of its reproducibility and its less variability, and it's easier sampling. It's harder sampling because it's a biopsy, but it's easier sampling because it's not dependent on how hard you push or how long you swab for.
So we think skin is probably the better tool. But right now, given the clinical correlation that buccal cells have from the literature, we think you need to really look at both at this point.
Okay. Thanks for taking my question.
Thank you. At this time, we've reached the end of our question-and-answer session. I'll turn it back over to management for closing remarks.
Thank you all for participating in the program, and we look forward to talking to you again.
Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.