Larimar Therapeutics. Special welcome to Carole Ben-Maimon, CEO, and Mike Delano, CFO, here as well. Thanks so much for joining us.
Thanks for having us.
Maybe you can start us off by giving us the latest update on your FA drug development and the upcoming catalysts that we can look forward to for future de-risking there.
Yeah, we have completed three studies to date: a SAD, a MAD, and a dose exploration study. Ongoing, we have our open label extension. We reported data back in December off of that, with another data set coming out in the middle of this year. We have continued to enroll patients who were in our other studies, are eligible to screen for this study and be enrolled. Back in November, we increased the dose from 25 mg to our target of 50. At this time, all of our patients are now on 50. Everybody has either been switched or is starting on the 50 mg dose. In addition to the open label extension, we also have an ongoing adolescent study. It's the first cohort of two cohorts, but this cohort is 12 to 17-year-olds.
In January, we announced that we had started dosing that patient, the first patient in that study. Once that cohort completes, those patients will also enter the open label extension.
Okay. The 25 mg OLE data show that you're approaching 50% or more of healthy frataxin level, depending on how you look at it. What are the nuances here, and how should we think about the expression in different kinds of cells, and when you think you might reach steady state at that dose?
Yeah, so 25 mg, it looks like we are actually at steady state by 60 days. We sample for frataxin at baseline, one month, two months, and three months in buccal cells, and baseline, one month, and three months in skin biopsies. You just can't do that many skin biopsies. We are well into the trial. We are approaching 50% in a lot of the patients, but not in all. Our target is to get as many patients above the 50% mark, but not above the 100% mark. Based on our simulations, it looks like about 60% of patients at the 50 mg dose would be above 50%, with only about 7% or 8% above 100%. We are very happy with those numbers, and we look forward to looking at the data to see if that actually predicts what we will see.
Is that what we'll get in mid-2025?
You'll get some of that data in mid-2025, yes.
Can you walk us through what quantum of data we can expect then?
Sure, sure. We've continued to enroll. We haven't said exactly how many patients. Obviously, it'll be north of the number. We had 14 patients had been enrolled at the time of the last data release. There'll be more than that because we've continued to enroll. We'll be showing PK data, as always, but for frataxin and, importantly, safety with longer-term dosing. We dosed our first patient at 25 mg last March, so those patients are actually coming up on a year. Assuming they haven't dropped out, you'll see even data past a year on those patients, as well as the new patients.
Okay. How do you think about which of these doses makes the most sense to develop further, ultimately bring to market? What would you like to see? If you see what you project you'll see at the 50 mg dose, is that a dose for all patients, or would you think that both doses would be good to have as options?
Right now, we're thinking the 50 mg dose is probably the best for the vast majority of patients. As I said, the simulation shows that it really provides the best levels for the most patients without taking them to over the 100% mark. We are still looking at whether or not some patients need a lower dose and some patients need a higher dose. You can envision that if a patient starts lower, let's say they start at 10% of normal, they may need a higher dose to get to 50% as compared to somebody who starts at 30% of normal. Age of onset correlates with that, so you don't actually have to do frataxin levels.
You can actually look at age of onset, but we just don't have enough data to know whether or not somebody who, let's say, has age of onset of 25 and therefore has a higher level of frataxin may be able to do with a 25 mg dose. As the trial plays out, because we do have a wide range of patients with different levels of frataxin when they start, we'll be able to tease that out. For now, I think the 50 mg dose will be the dose in the BLA. It will probably be the best dose for the most patients.
Okay. Can you put the frataxin levels that these doses might get patients to into perspective for us relative to healthy carriers or healthy subjects?
Sure. We have done a study in healthy people. We actually did genetic testing in 60 people, and we were able to show that in buccal cells, you have about 8 pg/μg protein level of frataxin. In skin, it is about 16.2 pg/μg protein. We know that carriers, so people who are heterozygous, have one healthy allele and one abnormal allele. Those people walk around with somewhere between 50% and 60% of healthy volunteers, and they are phenotypically completely normal. They show absolutely no signs of the disease. The hypothesis is that if you can get patients to 50% or 60%, 70%, you could potentially halt the progression of the disease, but hopefully at least slow it. I mean, obviously that would be ideal. We get everybody to 50% to 60% to 70%, they stop progressing.
Even if we can't get them all to 50%-60%, it does appear that it's a continuum. There's actually good data out there published by academicians primarily that shows the lower your frataxin level, the earlier your onset. For example, a person who has 11% of healthy volunteers, their age of onset is 7 years old, their rate of progression is 2.9 points on the FARS scale. If you increase their frataxin level just to 22%, so not to 50% or 60%, just to 22%, the age of onset is delayed until 11 years old, so four years, and the rate of decline decreases by almost a full point. We think that any increase in frataxin could have a clinically meaningful outcome, but it would be great to get as many people as we can above the 50% mark.
Okay. Speaking of younger patients, you've just started dosing patients age 12 to 17 in the PK run-in study. Can you walk us through that study design?
Sure.
What will you be measuring and looking at there in order to evaluate success?
The purpose of that study is to evaluate safety, obviously, because this is the first time we've dosed anybody under the age of 18, but also to confirm that the calculated dose is the right dose in kids and gives us the same exposure that we get in adults. When you do a transition to children under 18, you basically do a mathematical exercise where you figure out, based on their body surface area and known metabolism and all that, what the equivalent dose would be. Kids are actually going to get a mg per kg dose, not a fixed dose. We have the mg per kg dose as well as this math exercise that we've done.
We're taking that dose, giving it to the adolescents, doing pharmacokinetics on day one and day seven at seven days daily, and then we'll be analyzing that data to confirm that at that dose, the exposures are what we would expect and are similar to adults. Once we confirm that, we will then transition those adolescents into the open label extension. Also, I just want to say, sometimes adolescents are pretty big, as we all know, those of us who have kids, and so it is capped at 50 mg. So it'll be a mg per kg dose, but if their mg per kg dose is above 50, it'll be capped at 50.
Okay. At what point can you get into younger kids?
Once we've confirmed that exposure, we plan to do a cohort of children age two to twelve, or I guess two to eleven.
I know that you've mostly treated relatively advanced FA patients to date. At what point will you be looking to evaluate clinical measures in patients that are less advanced and so you might be able to capture FARS data?
We have, you're right, we have a relatively progressed population. We did that on purpose. We wanted to, first of all, it helps us with enrollment because they're not eligible for other clinical trials. Most clinical trials are in ambulatory patients. It also, we felt, was the right thing to do because it gave these patients who don't have access to clinical trials some access to investigational drugs. More than half of our patients are actually non-ambulatory, which actually has provided a lot of insight that I think is somewhat new science into how they progress, what different parts of the analyses can you do, like the Nine-Hole Peg Test, which people don't really pay a lot of attention to because in ambulatory patients, you have the 25-Foot Walk and you have broader measures on the mFARS.
We think that there are measures that we can look at in these further along patients. That said, the kids are going to give us a lot of insight into some of the earlier stage patients. We do have some earlier stage patients. We accepted all comers into the trial. That said, I think the kids, especially the younger kids, tend to be earlier in the disease course and more likely to progress at a faster rate, so we would be able to hopefully see that we slow that rate. We are looking at clinical outcomes even in our population, and we're focusing primarily on upper limb dexterity, and we're using the natural history database, which also collects those measures to look at how the rate of progression occurs even in patients who are further along.
What kind of analyses will you be doing as part of a potential BLA filing?
We'll be doing frataxin levels, obviously. That's going to be the cornerstone, that and obviously safety. Obviously, we have to do PK. That's just part of the routine of any kind of a submission or application. We are doing clinical outcomes, so we are looking at mFARS. We are looking at modified fatigue index. We're looking at the activities of daily living, which is a patient-reported outcome measure, as well as nine-hole peg. We presented some of that data back in December where we showed some modest increases in eight people at 90 days. We'll see if that continues to hold. That's what will be in the BLA, along with we've also been doing lipid levels and lipid profiles, as well as gene expression in our patients.
The way we look at that, these patients have abnormal lipid profiles and abnormal gene expression, and this has been described in the literature outside of us. The way we look at that is if you increase frataxin and now you start to see normalization of some of the biochemical markers, which are not subject to a placebo effect because they're biochemical, you start to say, okay, there's some activity here. Lipids are very much linked to energy production and mitochondrial function, and in almost all mitochondrial diseases, you actually do see lipid abnormalities. They are somewhat relevant, and they are a suggestion that downstream mitochondrial function might be improving.
Can you give us some insight into your history of interactions with the FDA, and what was it that led the company to feel like the FDA was receptive to a BLA? What data really resonated with them, or was it, if it wasn't any one piece of data, if it was connections between different parts of different data sets? What is the piece of data or the constellation of data that you think could be part of a successful BLA?
First of all, there are very few neurodegenerative diseases where you actually know the cause, and this happens to be one of them. They know that they have a GAA repeat, and we know that that causes low levels of frataxin, and we know that's the pathophysiologic cause of the disease. It lends itself to, if you can increase frataxin, maybe you can slow the progression of the disease. Now, you have to prove that, obviously. There's a lot of animal data that we have generated and some of the academicians have generated that show that if you increase frataxin, you do change the course of the disease in animals. It's not just us.
I mean, we've shown it in the cardiac knockout mouse model and in the neuro knockout model, but the gene therapy folks showed that when they restored frataxin, they mitigated the outcome of the disease. There's a knockdown model actually at UCLA. They were able to show that when you knock down frataxin in those mice, they developed signs of the disease, and when you let the frataxin come back to normal by removing the insult, the animals got better. There is a good amount of animal data that suggests that if you restore frataxin to its normal, I mean, above the 50% level, you can actually impact the clinical course of the disease. The other thing that makes this disease unique is that 98% of the patients have normal frataxin. They have two GAA repeats.
They don't have a point mutation or anything else. Two or 3% have a point mutation on one allele, and they have abnormal frataxin. By having normal frataxin, just not enough of it, you're not creating competing binding and irreversible binding and all the kinds of complications that can occur when you have abnormal levels of a protein in a disease. These people just simply don't have enough. The frataxin we are actually supplying is the identical sequence. For those of you who don't know, we have a cell-penetrating peptide attached to a mitochondrial targeting sequence, which is naturally occurring and is the identical sequence to endogenous frataxin attached to the frataxin moiety, which is also the identical sequence.
Once the protein gets into the cell and ultimately into the mitochondria and gets processed, the patients are left with the identical sequence that they have in their normal healthy cells. I think that all of that lends itself to making it easier to talk to regulators about the path forward to the approval process because there's some logic to it. Back in late 2023, we had our first meeting with FDA on a surrogate endpoint. We obviously met with them many times before that on other things, but to talk about using frataxin as a surrogate endpoint and an accelerated approval. There are certain criteria for accelerated approval, right? First, you have to be able to have a severe disease. We clearly have a severe disease. That's pretty obvious. Second, there has to remain an unmet medical need.
We wanted to confirm that even with the approval of omaveloxolone, there remained an unmet medical need. They agreed that there remains an unmet medical need for a product that actually gets at the root cause of the disease. I think we also saw that, by the way, with the acceptance of the vatiquinone application, the NDA, where they gave them priority review, which suggests that, and that's still an oxidative stress mechanism, even though it's a different mechanism of action. That suggests that the agency does still believe there remains an unmet medical need in this disease. Third, they agreed that frataxin is the sole cause of the disease, so frataxin deficiency. Not having enough frataxin is what causes these patients to deteriorate.
What we were left with was, try now to convince us that by increasing frataxin, you are reasonably likely to predict a clinical outcome, and that's the regulatory requirement for accelerated approval. They also told us they would be comfortable if we did that using animal data. We did not have to have human data. We would like it, but we do not have to have it. We have spent the last year plus working on pulling together all the animal data that we already had, generating some new data to answer a lot of their questions, and we are now in the process of having dialogue with them under the START program, which has been really phenomenal, and dialoguing with them on using frataxin as a surrogate endpoint to support an accelerated approval.
Interesting. The FDA is willing to use or rely on the animal data as kind of to fill in the gap that might exist between your very robust increases in frataxin, but you do not have mFARS data or upright stability or survival or anything else.
Survival's forever, right?
Yeah.
Takes a long time. The only other thing I would mention , is we also, remember, we applied for START this time last, the first quarter of last year was when the application went in. That application contemplated an accelerated approval. In that application, you had to lay out your communications, what timeline was, what you needed to talk to them about, when the data would become available, and what your ultimate goal was. Our application had an accelerated approval in there with the timelines that we've given all of our investors that the second half of this year would be the filing, and we were accepted into the program with them knowing full well what we're contemplating. They can always change their mind.
Yeah.
They're regulators. They have the right to change their mind. At least to date, they've been very supportive, I think, of what we're trying to do.
Will you have another meeting with them in order to?
We'll have multiple more meetings.
Confirm this?
Yeah. We'll have multiple more meetings with them. We actually dialogue with them quite a bit. Look, the last time they would have to say yes is the pre-BLA meeting, which won't take place for several months at least. That said, we are dialoguing with them and talking to them throughout the course of the year. I have to say the one remaining piece of data that I think we still need to iron out with them is how many patients, for how long, what's the kind of a safety database they actually want to see. We didn't want to start that dialogue till we had started the 50 mg and had some data to present to them because obviously the safer the drug is, the less data they'll need, and what the safety profile looks like will dictate what they're willing to accept.
We are in the process of talking to, starting to initiate those conversations now that we have 50 mg safety data. We feel very confident that they know what we're planning, that they are aware of it. They've been really interactive, I have to tell you, and quite flexible as it's come to under the START program. For a Type C meeting, you usually have to wait 75 days. We've been getting meetings in a lot shorter than that, sometimes 40, 45 days, which is significant. It's half the amount of time, right? It's a significant improvement. They've been willing to look at, I'll give you another example, our confirmatory study. We have to have the confirmatory study underway and enrolling right before we actually submit for an accelerated approval. We need a protocol, and we need buy-in from the regulators.
We've talked to both EMA and FDA about the protocol. We've gotten their feedback. We know sort of where we're going and what that trial is going to look like, and we're planning to initiate that study in the middle of this year as well.
What might that look like?
It'll look like pretty much every other one of these that have been done, but it'll be between 100 and 150 people, all ambulatory, heavily weighted towards the young, adults, some of them, but the younger population, probably 18 months' worth of dosing because I don't, this is a very slowly progressive disease, and I hate to get a signal but not get a P-value in a pivotal study. The endpoint is still something we're thinking about. It'll either be upright stability or mFARS, as you alluded to. We're in the process of really locking that down, but that'll be the study design.
Okay. How much patient exposure will you have by the time of the BLA if it's in the second half that it's filed?
I can't tell you yet because we're still enrolling patients. What I can tell you is we announced last March that we started dosing, and we still have some of those patients on drug. They'll be out probably 18 months, 15-18 months. You remember in the December release, we had eight subjects who had hit 90 days and some more coming close right on board. Those patients are now out 180 days plus more. There are patients that have been taking the drug for quite some time and tolerating it well. We have injection site reactions. That's probably the most common adverse event. They tend to be mild to moderate. They resolve almost always on their own, usually within an hour, definitely within 24 hours. Nobody has dropped out due to an injection site reaction at all.
That really seems to be the thing we really need to quantify at this point.
Right. You will have less patient exposure than the one approved option and maybe soon to be two, but the effect might be more impactful in terms of moving the needle on the underlying biomarker. Maybe the FDA is okay with that.
I think that's right. When you talk about having a lot less, it's not going to be all that much less, quite honestly. Length of time, probably. If you figure, and I'm making up these numbers, for argument's sake, we have 20 patients, 25 patients, adults in the OLE. We have another 10-15 patients, adolescents, that are now going into that study. You're now talking about close to 40 patients. We have the children going in. There is a possibility we still have not made a decision that we could open that trial to some naive patients as well. You start to get to some pretty reasonable numbers that are not unusual for a rare disease.
Okay. Very, very interesting. How do you think nomlabofusp fits into the competitive landscape, which, as I mentioned, could soon have two treatment options? How would physicians and caregivers decide amongst the three different options?
I think the idea that you know what the cause of the disease is and you're replacing it, you're fixing it, I think is a very compelling argument and discussion. I think that all these things have their own place in the world. I think for us, starting young so that we could actually prevent the deterioration is really important and makes a lot more logical sense than some of these other products that may be better for later stage patients. I think they're all going to sort of, it's going to play out. Look, I'm really old, and so I remember Copaxone and Avonex and Betaseron in the 1990s. MS, it was very similar. MS, there was nothing. And then all of a sudden.
They can't be combined.
They can't be combined, correct. These can. All three of them came out pretty much within a year and a half of each other. Now you look at the MS market, it's about a dozen products, probably. Patients have choices. They have different routes of administration. That's what we hope for. That's why we do what we do. I think that each of these different products may have their own place in the therapeutic intervention space. Docs, a lot of the KOLs are actually talking about combination therapies. I don't know how insurers are going to feel about that, quite honestly, to be frank. I think if you're thinking about preventing the progression of the disease, the logical place to go is to something that gets at the root cause, which is a frataxin deficiency.
Makes sense. One more question for you. How is the company resourced, and what's the strategy to fund a phase III if the FDA gives you the go-ahead?
Yep. We had, at the end of September, $204 million, which is runway into the second quarter of 2026. That means starting the confirmatory study in the middle of this year, there's money all the way into that, but it takes us only till the first quarter, I mean, the second quarter of 2026. It includes the adolescents and the adolescents going into the OLE. It includes full execution on the open label extension study. Remember, the confirmatory study is a global study and may very well be our registration study in Europe because they're less open to surrogate endpoints. That's all contemplated in there. A lot of manufacturing spend. The BLA, I know people pay a lot of attention to clinical and all those other things, which are obviously very important.
If you have an effect and you can't make the drug, that's not a good thing. Clearly, being able to file requires certain things that you have to do from a manufacturing perspective. Clearly, we have to be at a scale where we can actually supply the market. We are switching now to lyophilized product, which is really important because right now it's a frozen solution, which is not tenable for patients. We are working really hard to keep to those timelines, and we're burning about $30 million of cash a quarter for 2025, and that's a lot of manufacturing.
Okay. Very helpful. I think we're out of time, but this was a great chat, so we'll stay tuned. Thanks again.
Thank you.