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

My name is [ Henry Chang ]. I'm with the banking team here at JPMorgan, and it's my pleasure to introduce Larimar Therapeutics today. Presenting today will be Dr. Carole Ben-Maimon, President and CEO of Larimar. Just a quick note, we'll have time for Q&A after the presentation. So please wait until then for any questions, and we'll get you a microphone. But without further ado, I'll turn it over to you, Carole.

Thank you. Thank you, everybody, and welcome, and thanks for coming to learn more about Larimar. We're excited to be here today. These are our forward-looking statements. I'm not going to go through them, obviously. So let me tell you a little bit about Friedreich's ataxia.

Sorry about that.

It's okay. So Friedreich's ataxia is a neurodegenerative disease that is really devastating. It's a rare disorder. It is an orphan disorder. There are about 5,000 patients in the United States, about 20,000 throughout the world. Patients are usually diagnosed about 70% of them before the age of 14. So it is a disease that occurs in pediatric patients and really continues to progress throughout life with an early death. It is caused by a deficiency in frataxin, a protein that's active in the mitochondria of the cell. And so therefore, the goal here is to restore frataxin. Patients with FA walk around with about 20% to 40% of frataxin, but the severely affected actually have much less, around 5% to 10%. The heterozygous carriers, so the parents of these children are essentially phenotypically normal. They have no signs of the disease, but they do walk around with about 50% to 75% of normal healthy people. So the goal here is you don't have to get to 100%. If you can just get over the 50% mark, you can actually hopefully slow or stop the progression of the disease, which is the target. The patients are actually born looking healthy. It's actually a really tragic disease. And as they start to get towards puberty 5, 7, 10, 11 years old, they start to become clumsy. They can't ride their bikes as well as they used to. They can't run as well as they used to. By the age of 20, most of them are in wheelchairs. And by the age of 30 to 50, they die. It is a systemic disease. Any cell in the body that has mitochondria, which is essentially every cell in the body with one exception, erythrocytes, has frataxin. And so they have the neurodegenerative part of the disease, but they also suffer from a Hypertrophic Cardiomyopathy. Many of them develop diabetes. They have skeletal muscle issues. They develop scoliosis and often need surgery for the scoliosis. They have problems swallowing. And so treating the entire body is really critical. Most of them die from a Hypertrophic Cardiomyopathy. So it is the heart disease that ultimately they succumb to. Many of these families actually have more than 1 child with the disease, which is really devastating. We actually had a family in our office a couple of months, maybe 6 months ago, 4 children and 3 of them are in wheelchairs. And that happens because most of these families have had all their kids by the time the first one is diagnosed. So it really is an incredibly devastating and tragic disease. There remains an unmet medical need. It's very important to note there is one approved therapy, but it works downstream. It does not attack the root cause of the disease, frataxin deficiency. So we believe that we will be potentially the first disease-modifying therapy for FA. Let me tell you how we do what we need to do. The challenge here is getting the protein into the cell, but then also getting it into the mitochondria. So what you see on the left is Endogenous frataxin. It's the normal frataxin that 95% or more of these patients have. Frataxin is actually coded in the nucleus. It's produced in the cytoplasm, and it's produced is what I like to call a pro protein. So it has the frataxin moiety, which you see in blue here, but the green is the mitochondrial targeting sequence. And that's the part of the cell -- of the protein that takes it into the mitochondria. And once in the mitochondria, a specialized enzyme cleaves off the mitochondrial targeting sequence, leaving the active human frataxin. On the right, you see nomlabofusp, the molecule that we're developing. And you can see that the cell-penetrating peptide that's going to get it into the cell is not attached to the frataxin moiety, it's attached to the cell -- to the mitochondrial targeting sequence. That's important because that maintains the cleavage site between the MTS and the frataxin moiety. And so when the cell crosses -- when the protein crosses the cell membrane, the mitochondrial targeting sequence is there to get it into the mitochondria where the cleavage site is still in existence so that MPP, the mitochondrial processing peptidase can actually cleave off the cell penetrating peptide and the MTS, leaving the identical sequence to the normal endogenous frataxin. So both the MTS and the frataxin moiety are identical to endogenous frataxin. We've done some market research, and it's important to note that clinicians actually really do understand that there still is an unmet need for something that targets the root cause of the disease. And so they understand that the root cause is a deficiency in frataxin and that getting at the deficiency in frataxin could very well be disease modifying. And so we're very excited about that. We actually launched a disease awareness campaign back in the fall. And we do know that people really do realize that there is a need for further therapies. A little bit about the levels of frataxin in patients. It's important to know that if you have lower frataxin levels, so the lower your frataxin level, the earlier the onset, but as importantly, the faster the progression. So what you see in the table on the left is if you have 11% of frataxin, your disease -- your age of onset is about 7 years old, with about a 3-point progression every year in the FARS score, which is just a tool that's used to measure progression. If you increase to 22%, so you don't have to go all the way up to 50%, you increase to 22%, you delay the onset of the disease by 4 years. But as importantly, you actually slow the progression of the disease by a full point. So what we're looking to do is provide enough frataxin to these patients that they will either halt the disease progression or slow significantly and delay the loss of speech and delay the loss of ambulation. So again, we have the potential to be the first disease-modifying therapy in a terrible neurodegenerative disease. We have completed 4 studies, a SAD, a MAD, a dose-exploration study and a PK run-in study -- PK study in adolescents. We have one ongoing trial right now, which is our open-label study, where we're collecting frataxin at various time points to demonstrate the increase in frataxin. We're also collecting obviously, safety and clinical outcomes as well. We are pursuing an accelerated approval with a filing in the second quarter of this year, and it will be based on using frataxin levels as a novel surrogate endpoint. We -- and the BLA will go in and launch is planned for early '27. From the standpoint of regulatory, we have Orphan Drug designation in the U.S. and the EU. We have Rare Pediatric Disease and should the voucher system be extended, we will be eligible for a Pediatric voucher at the time of approval. We have Fast Track. In Europe, we have PRIME and in the U.K., we have ILAP. And we were very excited to receive start designation back in 2024, which has allowed us to have incredible conversations with FDA. They have just been really, really engaging and really, really constructive in all of our meetings. The time line for announcements is we do plan to have a regulatory update. There will not be data, but a regulatory update after conversations with the FDA that will occur this quarter. And the BLA will be submitted seeking accelerated approval in the second quarter. There will also be a data release once we have the final data for the BLA and then launch is targeted for early '27. From an IP perspective, we have Composition of Matter patents in the United States to take us out to 2020. We also have a Formulation patent, and we have some Platform patents that provide that people can't just tweak the molecule by changing a couple of amino acids. But most importantly, we got our first European patent issued for -- which is a Composition of Matter patent. And so we're very excited now to also have patent protection in Europe. A little bit about the ongoing open-label study. So this study started as a study, an extension study. So the initial population was only patients who had participated in prior studies. And those patients were in a study, they stopped dosing until we opened this study in the first quarter of '24, and then they restarted the drug. And that's important because some of these patients have shown an allergic reaction. And I'm going to talk more about that as we get forward. But that's why the regimen that you're seeing up here is now the new regimen. We have recently expanded the population to include the adolescents who participated in the PK run-in study, so children 12 to 17 years old. And we've also now expanded it to include patients who have not participated in other studies. And that's important because we are expanding our population. We do plan to enroll children 2 to 11. That amendment is in progress, and we're working to get that started as early as we can. We -- the dose regimen is antihistamines. They start them 5 days prior to initiating their first dose. They get -- in the doctor's office, they get a 5-milligram test dose. If they do well after an hour, they get a 25-milligram dose, which they take then at home, self-administered or administered by a caregiver for 25 days, and then they increase the dose to 50, which is our target dose and what we think our final dose will be. This is the frataxin data in skin. I'll talk a little bit about skin. We have submitted to FDA a whole package that included all of that data to support the novel surrogate endpoint, and they accepted it, and they said it would be an issue for review only. And so we know that skin -- changes in skin frataxin actually correlate very nicely with dorsal root ganglion, skeletal muscle and heart, all target tissues for the disease. And you can see on this slide, the dot is the median. The horizontal bars are the 25th and 75th percentiles. The dotted line on the left is where heterozygotes gets lived, that 50% mark, which is where we really would like to get above. And you can see that by day 180, all of the patients who have been treated are above the 50% mark. The number, the 50% mark, we did a normal healthy volunteer study where we genetically tested 60 people to make sure they had 2 normal alleles. And we know that normal skin frataxin levels are around 16 picograms per microgram protein. And as you see here, the 50% would be 8 picograms per microgram protein. And you can see we're well above that mark with the treated patients by day 180. This is the same data just shown in a table form. On the right, though, are the absolute numbers. We have this in here for [ pay pilled ]. It's on our website, obviously, but we're excited to see the response we've gotten. This is another way of animating this, and I'll focus on the right. As we had our normal healthy volunteer study, we were able to divide the frataxin levels into quartiles. And what we see here is the patients at baseline, and those are the patients represented in black, are very low. Actually, in this population by day 180, there was like less than -- sorry, at baseline, they were less than 17%. By day 180, you can see that the treated patients, which is all of them, have increased to over the 50% mark. And those are the patients that are represented in green. You can also see that at day 90, some of the patients have increased by 1 quartile, which is the blue and -- but many of them have also gotten to greater than 50%. So we're very comfortable that the 50-milligram dose is the best dose for most patients. I'll talk a little bit about safety now. We've had 65 people who have been exposed to at least 1 dose of drug. 39 of those patients have enrolled in the open-label study. The most common adverse events are injection site reactions, local injection site reactions. They are mild to moderate. They resolve pretty much on their own. They seem to decrease over time, and nobody has dropped out due to an injection site reaction. I think that's really important because we have patients now as of March, who will be out 2 years, and these people are staying on the drug, and I'm going to show you that in a little bit. But 7 patients have actually had anaphylaxis. They respond to standard therapy, EpiPen. We do provide epinephrine auto-injectors to all of the patients so that they have them if they need them. All of the patients have returned to their normal state of health. All of these events have occurred within the first couple of months of dosing, most of them on the first day of dosing. And once they get past the first couple of weeks, we have not seen any allergic events, quite honestly. They return to their normal state of health, and they have no further sequela. 6 of the 7 patients had been exposed to nomlabofusp in the prior study. There was one who had not -- who had received placebo. There are also 10 participants in the study that had only received placebo. They never received nomlabofusp. And only that one patient has seen anaphylaxis. So we think the incidence is much, much lower in patients who have not been -- had prior exposure with a long break. Some of these patients had a break of over 3 years. So it's important to note that we think -- important to get into the trial, some of these naive patients so we can actually follow them for longer. Long-term safety, it's generally well tolerated. Other than this, we don't really see anything novel except for the injection site reactions, which I said decrease over time and don't cause withdrawal. We have 14 patients at 6 months as of the data cut in August, so those patients are now further along and 8 patients at a year. So that data continues to progress, and we continue to enroll. What are we doing to try and mitigate the risk? So first thing is education. Getting people, patients and doctors to know how to recognize anaphylaxis, how to treat it and make sure that they understand and they have all the tools at their bed sides to make sure that they can take care of it. We started the histamine blockers. We modified the dosing regimen to allow for that test dose, which we think is important, not only because it's a lower dose. So hopefully, the reactions will be less severe, but more importantly, because it could very well prevent by desensitizing the mast cells and basophils, the release of histamine actually prevent the anaphylaxis. And then finally, we give everybody an epinephrine auto-injector to make sure that they have something that they can treat themselves and it works very well. This is the -- a chart of dropouts. And what I want to focus you on is here. This is the first 90 days of treatment. And this is really where most of these events occur. Once you get out past 90 days, there is an occasional discontinuation, but they really are few and far between. And as I said earlier, we now have patients who are going on 2 years' worth of dosing. One thing I learned a couple of days ago from our statistician that I hadn't realized, we've given almost 8,000 doses of drug across our trials. So that's like a really a lot of -- in a rare disease to be able to say that you've given 8,000 doses is tremendous. And that's partially because the patients who are going on 2 years, they would have over 7,000 doses each. And so it's really quite a remarkable, in my mind, data package for a rare disease. In addition to looking at frataxin, we've also looked at clinical outcomes, and that's really important. And we've -- most of our patients are in wheelchairs. They are more progressed than some of the Phase III studies. And what we've done here is we've basically looked at the baseline characteristics of our patient population, then looked into the natural history study, the FACOMS database, which is the natural history study that was conducted by the Friedreich's Ataxia Research Alliance, the patient advocacy group. And we pulled out a subset of patients as a reference population that matched our patients. And what we see here, the blue is the clinical -- the nomlabofusp group. The tan is the FACOMS data. And so if we focus on mFARS, which is the outcome measure used in most clinical trials, you see that the improvement and down is better, higher scores are worse. So if you go -- if you look at the first look here, right here, we have an improvement of 2.25 in our population, while the same population, the reference population in the FACOMS database worsens by 1 point. That's important to put into context. So the only approved therapy, omaveloxolone, had an improvement at 1 year of 1.56 points. We have an improvement now of 2.25. So we at least know that from a regulatory perspective, that is considered clinically meaningful. In addition to mFARS, we looked at activities of daily living, which is here. And we looked at 9-hole PEG test, which is an upper arm dexterity measure, which is very important in our population since so many of them are wheelchair bound. And we looked at a fatigue score, which is the bar one on the right. And you can see that all of the measures improved in our patient population and in the FACOMS database, all of them worsened. So we are making a difference. And I have to tell you, I was incredibly surprised when I looked at this data. I really thought this drug would halt the progression of the disease. I never ever thought that it would improve patients and patients are continuing it looks like to actually improve. And that probably due to creating a more efficient system in the cells so that they can make more ATP and they can actually normalize the healthy cells that they still have. So we basically believe that we could be the first disease-modifying therapy. We are attacking the root cause of the disease. The data suggests that increasing frataxin levels may halt the disease progression and potentially even improve it. We do have to deal with the anaphylaxis, but it's totally treatable with an EpiPen and patients do well once they are treated, and they have all known how to handle it. And overall, the drug is generally well tolerated with the most common adverse events, injection site reactions, which don't -- which seem to decrease over time and do not lead to withdrawal. This is a very busy slide, and I'm not going to go through it. I would focus you first on the very top. We have agreement with the FDA that we can use frataxin as a novel surrogate endpoint, and it would be a review issue. We also have a recommendation from the FDA that we should use and focus on skin frataxin levels and not buccal cells, which we also collect, although they show pretty much the same thing, but the skin is just less variable and clearly, changes in skin frataxin correlate very, very nicely with dorsal root ganglion, skeletal muscle and heart, all target tissues. I'll focus also, we are pursuing an accelerated approval, which means that we are required to do a Phase III confirmatory study. And I'll spend a little time on that in the next couple of minutes. But finally, we're working very aggressively on our CMC to make sure that we have all of the things completed that need to be done for the filing. And we've been interacting very closely with FDA and routinely with FDA to make sure that we don't have any hiccups in our CMC. With regard to the Phase III trial, we're looking at ambulatory patients, so a different population than we're currently in. Patients 2 to 40 years of age with 2/3 of them being under 21 because that's a population that progresses more quickly. So we'll make the placebo group more -- progress more quickly so we can differentiate our drug. And we are looking at about 100 to 150 patients, probably close to 130 or so. It will be 50-milligram dose for 18 months with mFARS in Europe and upright stability in the U.S. Both EMA and FDA have reviewed this protocol. They have both given us comments. Those comments have all been incorporated. We did propose upright stability for Europe. The EMA wants very much to have a broader score. And so we'll be -- we are using upright stability in the U.S. and mFARS in Europe. Otherwise, they are identical protocols. The trial is being initiated. We had to amend the protocol for the new regimen, but it's now complete and amended. Our sites are all selected. There'll be U.S. sites followed by European sites, U.K. sites and then a little bit later, Australia and Canada. Regulatory submissions are going in and have gone in, and we're interacting now with the EMA through the [ CEDAS ] system and we'll be announcing the first dose when we achieve that. So all in all, we're very excited about where we are. We think that this could be -- very well be the first disease-modifying therapy. We believe it will really change the lives of some of these patients, and we really are very hopeful. We believe this is the beginning of the journey, not the end of the journey. We're planning for a second quarter submission to the FDA with an early 2027 launch. So with that, I'll turn it over to you, and you can ask whatever questions you need to.

Yes. Thanks, Carole. Really appreciate having you with us here today. So I'll open it up. If anyone has any questions, please raise your hand, and we can get you a microphone. Otherwise, I can also kick us off. You mentioned there's a regulatory update in Q1 of this year. Could you just provide a little bit more color on what that update will entail?

So it won't be data because we're not going to do another data cut, but we will be having conversations with the FDA. We've been very actively talking to them, and we've had periodic conversations with them for some time. But we do want to make sure we pull all of the package together and they see exactly what they're going to get in the BLA. And so we're making those submissions. We'll be scheduling a meeting to talk to them about those submissions, and we'll be providing an update once we have better clarity on what their thoughts are.

Great. And also just given the severity of FA and the lack of disease-modifying options, you mentioned the benefit risk profile to regulators, but how would you frame that towards families and families of patients as well as physicians?

Yes. One of the things I can just say to you is we have never had a problem with enrollment. There are patients who want to get into these trials. And quite honestly, the limitation is not the number of patients. It's the capacity of the sites to actually conduct the trials. They can only handle so many patients at a time. And so it's really important, I think, to recognize that people understand that this is a devastating disease. They lose their children day in and day out. Any of us who have kids, we all know what that must look like when every day you wake up and you think your kids going to be worse off than they were the day before. And from a patient perspective, I think it's really important to think about what happens. At 20 years old, these kids are starting to lose their speech. They're cognitively completely healthy, but they start to lose their ability to communicate. That must be so isolating in a population of kids who are so social -- we're all so social at 20 years old. And so it's really important to put this in context. These kids have trouble swallowing. These patients have trouble swallowing. They can't eat, they can't drink. And what happens, they become dehydrated and they lose weight. And so as we -- if we can even treat some of those things that are really part of the ADL score, the activities of daily living, it's really important. We have -- we talk to a patient -- parent actually a while ago at the beginning of the summer and they have a 20-something year old with FA. She's in a wheelchair. And she happened to be starting an internship, and she was -- the father was very upset about and very concerned about how she was going to get to the internship, it was in the city. How should we get the elevators. And what was the child interested in. She was afraid that they were going to think she was stupid because she couldn't -- she slurred her speech. So these people really, really suffer. And so I think the FDA is very aware of this disease. They understand it. This division, DN1 that we're in has already reviewed 2 applications and approved 1. So they're very familiar with the disease. They understand the unmet medical need. And I think that shows in their interactions with us and the fact that they gave us a start designation. We do have to deal with the anaphylaxis. There's no question. But let's remember that once that's treated and if they don't go back on the drug, they don't suffer from any other sequelae. It's not like liver function tests where if you damage your liver, you now have to live with a damaged liver. They go right back to the usual state of health, which isn't great, but it's the usual state of health. So I think the benefit risk here is very clear, and I think the agency sees that.

Maybe one more for me is what are your plans for the confirmatory Phase III trials?

Yes. So we're starting that study. Obviously, we all know that it needs to be enrolling at the time we make our submission. We are in discussions with FDA as to what our -- what the plan will be and what our commitments will be. But as I said, the regulatory authorities have all reviewed it. It's in the process of being initiated -- very far into the process of being initiated. And we fully anticipate that we'll be dosing our first subject definitely this year and probably early in the year.

Great. Well, I think that's all our questions. So once again, Carole, thank you very much being here.

Thanks for having us.

Thank you all for joining.

Have a good morning.