Yes. Yeah. It's the difference. Hey, everybody. Good afternoon, and thanks for joining us at the Citizens Life Sciences Conference. My name is Jon Wolleben, Senior Analyst here, and we're pleased to have Larimar Therapeutics and CEO Carole Ben-Maimon. Carole, thanks for joining us.
Thank you for having me.
The way I usually like to start, 'cause we don't always know if people are familiar with the company, tell us what you guys are working on at Larimar, and then we can dig into the details.
We're working on a protein replacement therapy for Friedreich's ataxia. Friedreich's ataxia is a autosomal recessive disease. Kids are born looking healthy. They're in wheelchairs around puberty. Well, they start to get clumsy around puberty. They're in wheelchairs usually in their 20s and they die in their 30s and 40s. It's caused by a missing protein called frataxin that is active inside the mitochondria. It's important to get this protein across the cell membrane and into the mitochondria, which is another membrane where it's active. We have a technology to do that, to basically give a sub-Q injection, and the protein travels into the cell and then ultimately into the mitochondria where it can be active. The goal is to slow or stop or even reverse some of the progression in this disease.
What I really liked getting familiar with the story is we know biology, we have a missing or deficient protein, and you guys are replacing what is causing this disease.
Yeah, I think that's what's exciting. It's one of the things that got me interested in it 10 years ago. I think it's also important because there's no abnormal protein floating around, so it's not like you're competing with a, with a bad protein that you have to worry about still being there.
Mm-hmm.
It's simply these patients have normal frataxin, they just don't have enough of it.
Talk to us about kind of patient numbers, prevalence, what do we know about progression?
We know that there are about 5,000 patients in the United States, about 20,000 throughout the world. It is mostly a European disease, so it's in the U.K., concentrated in other parts of Europe. There are patients also in Australia. There's a population, a smaller population in Canada. And then there's smattering of patients in other parts of the world, mostly in the Middle East, and probably a population in India that's completely underdiagnosed.
We did see an approval for Friedreich's ataxia with SKYCLARYS. I can't remember. It was a year and a half ago or so, two years ago. Time's flying. Talk to us a little bit about kind of remaining unmet need, learnings from that development program, and how it's being used in the community, how your drug may be different.
Yeah. SKYCLARYS was approved in 2023.
Geez.
Because of the mitochondrial dysfunction, there's a lot of free radicals floating around in this disease, and so they get oxidative stress, and a lot of the damage to the tissue is a result of that. SKYCLARYS works downstream. It has absolutely no effect on frataxin, the missing protein, but it does have an effect on oxidative stress mechanisms, and it has been shown in their clinical trials to slow the progression of the disease. The disease usually progresses about two to three points per year in the ambulatory population using mFARS as a measure, which is the tool. They did show a 1.5-point reduction in the rate of decline. They were approved, I think, February 29, 2023.
That's a good memory.
Day before my birthday.
Oh. Tell us a little bit about the data you guys have generated, 'cause you guys for having a really cool technology have also generated really interesting data as well. Walk us through kind of your clinical program so far.
Yep. We filed our IND in 2019, and since then we've completed four clinical trials, a SAD, a MAD, a dose exploration study, and a PK run-in study in adolescents. We have an ongoing study, which is our open label study, and that's the data I'll talk about. Both in the MAD and the dose exploration study, we were able to demonstrate increases in frataxin levels. We were able to demonstrate that it gets into the mitochondria, and we were able to look at PK and safety, obviously. In the pediatric PK run-in study, the intention of that study was simply to show that the kids were getting the same exposure to the drug that the adults were. In the open label extension study, we also look at frataxin, but over longer periods of time.
We currently have patients who are out well over a year. We have said that there will be at least 10 patients when we do another data cut in the second quarter. There will be at least 10 patients at a year, and we will be looking at mFARS, activities of daily living, nine-hole peg test, and fatigue scale as clinical outcomes. We'll also be looking at frataxin levels and the correlation between the two, obviously safety as well. When we did the data cut back in September, we had data from eight patients at one year. The reason one year is important is that there's a natural history database that's very, very rich in data. It's almost 1,000 patients for, like, 13 or 14 years.
Those patients are only seen annually, so you don't have any comparison except but annual comparisons. Once you have your annual look, you can actually look at 18 months and two years because you can see if the effect is maintained or even improved, but the only reference group you're gonna have is at annual visits. Back in September, we were able to show that the frataxin levels increased. We were able to show that at six months, 100% of the patients, so 10 out of 10, who had frataxin at that time point, were over the 50% mark. 50% is relevant because parents who are carriers who have no symptoms of the disease have 50%-75% of normal levels.
If you can get over 50%-75%, you should be in a place where patients should be able to live normal lives. It was very exciting to see that at day 180, 10 out of the 10 patients were above the 50% mark. We also, as I said, looked at the clinical outcomes, and we showed a 2.25-point improvement in mFARS, which is significant because, as I said, the approved drug had a 1.5-point improvement. We're, you know, in a really good place with that. That was as compared to a reference data set similar to our patient population of a deterioration of one point.
All of the other measures, the eight activities of daily living, the nine-hole peg, and the fatigue scale also showed improvement as compared to deterioration in the reference population. We were very excited about that data. That was the data that we used to submit to FDA, which got us the Breakthrough Therapy designation that we just talked about.
Mm-hmm.
A couple of weeks ago.
That was a lot. You guys have generated-
We've generated two data.
You guys have generated a lot of data, and you've learned a lot. When you guys first got in the clinic, when we talk about, you know, frataxin levels, at first you guys were measuring in buccal cells, cheek swabs, and now you're focused on skin. Another question we get is like, okay, so it's in the skin, but how do we know that it's going to you know, for Friedreich's ataxia affects organs, most notably, you know, a lot of cause of death is cardiac. Talk to us about, you know, why you're measuring the skin. You mentioned about the levels you wanna get to, but then also your confidence that the drug isn't just, you know, fixing the skin.
Yeah. It's correct. The target organs are. First of all, it's a systemic disease, so every cell that has mitochondria is deficient in frataxin. I'm sure that if we treat just heart, for example, and we keep people alive longer, you'll see disease in other tissues, and that happens a lot of times when you prolong life, you get new, different outcomes that you didn't anticipate. Right now, the target organs that people really focus on are dorsal root ganglion, brain, heart, skeletal muscle, pancreas because they do develop diabetes, and those are probably. They also go blind and go deaf, and it's not because of active, optic nerve damage, it's because of retinal damage. There are a lot of. It's really systemic, is the bottom line. We do skin and buccal cells.
The reason we started with buccal cells is there's a lot of data in the literature produced mostly out of CHOP and Penn, with FARA, the Friedreich's Ataxia Research Alliance. Those tissues, the buccal cells, have been shown to correlate with disease burden. The lower your frataxin level in your buccal cells, the earlier the onset of the disease and the faster the progression. It's important to have that correlation, and we didn't have that correlation with any other tissues. With regard to skin, we started doing skin because it's a peripheral tissue that we could sample frequently. You know, people talk about heart biopsies, they talk about skeletal muscle biopsies. The fact of the matter is you can only do two of those, one at baseline and one at some other time point.
Mm-hmm.
Skin, we do it at baseline one month, three months, and then every three months for the first year. You're getting a lot more data. You can track the fact that the levels are maintained over time. The question comes up, as you're saying, how do you know, since skin doesn't have any abnormalities in these patients, how do you know that it's getting to some place that matters? We did a lot of animal work. We actually worked closely with the FDA, because we were talking to them about using frataxin levels as a novel surrogate endpoint, either buccal cells or skin. We pulled together a lot of studies that were able to demonstrate that increases in frataxin in either buccal cells or skin, one, are highly correlated with each other, and two, are highly correlated across animal species.
Monkeys, rats, mice all have the same relationships between frataxin levels in the various tissues, and they all go up in one, they go up proportionally in another one. We did sample heart, skeletal muscle, dorsal root ganglion, and we've seen increases in frataxin in all of those tissues. All of that data was published last summer. There were two publications that we put out, and they're both on our website.
In the patients, did you see an association between, you know, the amount of frataxin increases and some of the functional benefits you mentioned? Also, can you talk a little bit about the lipid data you got?
Yeah. We just started looking at the correlations between frataxin and change in the clinical outcomes. We only had eight patients, so I wanna just make sure people realize the data's limited. There does seem to be a clear correlation between the level of frataxin and the improvement on the mFARS and other scales. Remember what I said, though. At six months, everybody is above 50%, and we know that heterozygous carriers have around 50%, maybe a little bit more. Which means that if you get to 85%, you may not improve anymore because you're already okay.
Sure.
The correlations have to be done when the patients we're testing are at lower levels to be able to see the progression, and we do see the correlations. We'll be doing another cut of the data in the second quarter for the BLA, and that data will also be released to the investment community.
In the lipid markers, how does that add some more context to the story?
Lipids are mostly triglycerides that we're looking at, and they tend to be energy sources and energy storage resources. Most mitochondrial diseases have abnormalities in lipid profiles. That means it's not just your triglycerides are higher, it's that when you look at your triglycerides, the specific triglycerides are abnormal. They either have shorter fatty acid chains or longer fatty acid chains. They may be hypersaturated, and so they're not produced in a normal function in a normal way. We did a healthy volunteer study in 60 people. We genetically tested them, and we took obviously only people who were healthy, who had two normal alleles. We did find one person who didn't know they were a carrier.
Hmm.
We did skin biopsies, buccal cells, and we also did lipid profiles on them. We took the lipid profiles, and we compared those lipid profiles to our patient baseline lipid profiles. What you see is in very specific triglycerides, you see an upregulation of the triglycerides compared to normal healthy volunteers. The patients are actually upregulated.
Mm-hmm.
With treatment at 25 mg or 50 mg, you see a dose-dependent decrease in those lipid profiles. It's just another way of looking at a biomarker, and there are correlations, by the way, with frataxin, very clear correlations with frataxin. The higher the dose, the higher your frataxin level, and the more your lipids move towards normalization.
I think that's another point. Now, you guys have found the 50 mg target dose, but we should, you know, at least acknowledge that you guys did see dose-response on multiple metrics as you were getting there.
That's absolutely true.
Which I think is important. Talking a lot about efficacy and efficacy markers, but safety, what have you guys learned so far?
We have learned that in general, the drug is relatively well-tolerated. Most common adverse events are injection site reactions, local injection site reactions. We inject in the four quadrants of the abdomen, two sites on each thigh, and they rotate, so each site gets used once every eight days. The injection site reactions are mild to moderate. They resolve pretty much on their own. There's a lot of itching, is what they really are really constitute how people describe them. They just itch.
Mm-hmm.
They seem to decline in frequency and severity after about three months, and nobody has dropped out because of an injection site reaction. The drug is self-administered or given by a caregiver. The problem we have had is we have had some allergic reactions. It's a protein. It's a biologic. It's not uncommon for proteins to be immunogenic. We had a phase I MAD study actually stopped and was finished. It was completed in the first quarter of 2021. We didn't start our open label extension study, which was for those patients who had participated in prior studies until the first quarter of 2024. Some of our patients have had three years of no drug.
Hmm.
They had exposure, they were off the drug for long periods of time, and then they were re-exposed to the drug. We've had seven cases of anaphylaxis as of September, and six of those seven cases were on patients who received the drug, took a hiatus, a break because we weren't doing trials, and then received it again in the open label study. The events occur relatively quickly.
Mm-hmm.
W ithin a couple of months or so. We don't see it late after once the drug is being continued late. We have 10 patients who were not on drug in the prior study. They were on placebo. They were in a prior study, but they weren't on the drug. They only received placebo, and only one of those patients actually had anaphylaxis. Also, 65 patients have been exposed to at least one dose, and we have had the seven cases of anaphylaxis out of that 65. Total doses administered over the course of development, it's almost 8,000 doses. There is an issue with the anaphylaxis if you stop taking your drug for probably more than six months, but that is probably the rationale. We're in the process of thinking through now how we might get patients back on drug. We do discontinue those patients.
Mm-hmm.
It's not like some other studies where they're continued. We discontinue them if they have anaphylaxis.
It seems like you've identified a, at least a reasonable pattern, and that's not gonna be reflective of real-world use.
I think that's right.
Okay. Now we got to talk about the fun FDA stuff because you guys are going after a novel path in a rare disease, and it's not a week goes by we don't hear something going on at FDA about chaos or refusals. I think a lot of people have questions about what you guys are doing. First tell us about how you're moving forward and then why people should be confident in that strategy.
Yeah. There are very few neurodegenerative diseases where you actually know the root cause of the disease and somebody has an idea of how to fix it. That's really important because knowing the mechanism and the cause of the disease, and then having a strategy to go right after that mechanism is really critical. We started in the end of 2023 talking to the FDA about the use of frataxin as a novel surrogate endpoint. That was when we had our first meeting with them. They were open to it. They agreed that this was a severe disease. They agreed, which was very important since it was six months after omaveloxolone was approved, that there remained an unmet medical need even though there was an approval, and it was unmet because they needed something that would go after the root cause of the disease.
Also, remember that omaveloxolone is only approved in patients 16 and over, so patients under 16 years do not have an approved therapy. Most importantly, they agreed that the sole pathophysiology of this disease is deficient frataxin.
Mm-hmm.
There's nothing else that has to be fixed, essentially. They asked for some animal data to support the use of skin and buccal cells to look at the how high we needed to go, what the magnitude of effect should be, and the correlations between the tissues. We pulled all of our animal data together, which was a lot. We designed another study to fill some of the gaps, and we published all of that data last summer. We submitted that data last year, a little over a year ago, and last end of winter, they came back and said that they were willing to consider using frataxin as a novel surrogate endpoint and that it would be a review issue when they got the data.
We were really excited about that, and we think it really warrants that. They've reiterated that now. We had another meeting with them in the first quarter, sort of concurrently with submitting the data for breakthrough, and they basically came back and said, yes, they agree that we should submit for an accelerated approval for the treatment of patients, adults and children, with Friedreich's ataxia. They were very clear.
Mm-hmm.
Using frataxin as a novel surrogate endpoint.
For all the noise that we hear, it seems like they've been extremely collaborative based on your communications to us. With your communication with you and what you told us about it, and then also, like, your involvement in the START Pilot Program as well. You got Breakthrough Therapy designation. Sounds like a pretty smooth, consistent messaging with FDA, at least in your instance.
Yeah. I would call out the fact that we're in DN1, so we're in CDER. We're not in CBER. Second, we have been working with the same reviewers literally since our pre-IND meeting. Teresa Buracchio, who runs the office of DN1, and Emily Freilich, who is the division director of DN1, both have been with the program since the pre-IND meeting. They know us well. They've been in every meeting. Teresa doesn't come to every meeting, but Emily's in every meeting. They've been in the program in the FDA for years. They've been promoted throughout their course. There really doesn't appear to be a lot of drama in that division. They just seem very supportive. They did award us the START Pilot Program, which has been invaluable.
We get meetings. You would normally have 75 days. We get them in 60 or 45 days, even some of them. We get a lot of CMC feedback.
Mm-hmm.
In a timely fashion, which is also really helpful because everybody knows the CRLs, yeah, your drug works, but you can't make it because of this, and this.
Mm-hmm.
We pay a lot of attention to CMC. We have not experienced the quote-unquote chaos that others have. I think sometimes the FDA tells you something and you just don't hear it necessarily.
Funny how we learn about that down the road.
Yeah. I mean, no, it is. They speak in what I call FDA-ese.
Yeah.
You know, when they say-
It's called, like, willing to consider.
Right.
Yeah.
We strongly recommend. Well, strongly recommend means you better do it.
Yeah. So you talk about an update in 2Q with your data. How about the submission? What's the timing and what you guys have to do between now and then?
June will be the submission. We have to finish some of our manufacturing work. We're at full scale for commercial scale in the United States. We have the lyophilized product in the clinic. FDA has reviewed all that comparability data. We have all of our assays validated, and our potency assay has been reviewed by the agency. We feel very good about CMC. The PPQ is now underway, and that's the final piece. We have to complete that and put it into the BLA. Now we're actually getting prepared for the review process. We're getting prepared for inspection readiness, preparing our sites and our manufacturing sites. We're getting prepared for the questions that will come back.
Mm-hmm.
Very importantly, we're preparing to initiate and execute the phase III program, which we said we'll start screening in the second quarter and dosing shortly after.
It was interesting when we caught up, I can't keep track, a couple weeks ago, you mentioned that FDA actually kind of eased the safety requirements for you guys. What's kind of changed on that front, and what do you have to do in terms of follow-up for the submission?
Yeah. Back in the spring, you may remember, they came out, and they said they wanted 30 patients at six months and 10 at a year. We will have over 10 at a year, for sure. The six months we might be tight. We may fall short. I mean, there are patients coming on board, we're continuing to enroll, and they continue to dose, so eventually we'll get there. It's not gonna be forever.
Yeah.
It's like a couple of months. We may not have it at the time of submission. We told them that, and we laid out when we thought we would get there and what the impact could be, and we laid out for them the benefit/risk assessment. We sent them all of the efficacy data 'cause they'd only seen it sporadically, and we laid it out in light of all the safety issues. We did an update, so they got more data than even we've put out to investors. They came back, and they said that they could not give us a minimum, and we have it in writing, we have it in minutes. They said they could not give us a minimum. It would really be a benefit-risk assessment.
Mm-hmm.
A labeling issue and that it would be a review issue. We would submit the BLA, and as they review the benefits in contrast to the risks, they'll be able to make a decision. Now, remember, we also have the 120-day safety update, which is a requirement. It's not an amendment. It's a requirement. We'll be able to update the safety data three months after the BLA goes in, and then if they really want more data, we can always put in a major amendment, have a three-month delay in approval.
Mm-hmm.
The application still remains under review. I'm very comfortable that we'll be able to meet the standards that they want, and I'm very reassured that they felt the safety, the efficacy data was convincing enough that they felt that the safety can be dealt with. By the way, we do have. I said we'll have more than 10 patients in a year. We have some patients out 18 months, and we have just a few, but we have a few even heading two years.
In terms of timing, we got the June submission, we got confirmatory trials starting second quarter, we got data update coming second quarter, and I think what's important for people to keep in mind is you don't have kind of an efficacy clinical hurdle you have to hit anymore, correct?
That's correct. I mean, we do have to do the data cut. Until you see the data.
Sure.
You never know what's in it.
Yep.
Um, but-
There is no, like, endpoint we have to hit.
No.
Success to move forward.
No, just the correlation. We would like to see some correlations between frataxin levels and efficacy. We saw them in the eight patients in September. That data was reviewed by FDA. They did see it. They thought it was convincing, and they said they just wanna see the patients at the time we submit.
Then the last one for you and will be the last question always is, you know, the balance sheet reminder and then also runway that gives you.
Yep. I'll take the quotes from Mike Celano. We raised $108 million a couple weeks ago. Pro forma, as of the end of December, we had $244 million, and that will take us into the second quarter of 2027. We have some big quarters coming up because of the PPQs.
Manufacturing, yeah.
The manufacturing exactly, and obviously the filing of the BLA itself. That should take us into the second quarter of 2027. If you do the math, and if we don't have an amendment, you know, sometime in the first half of next year.
An approval.
An approval, yeah.
Yeah.
It could be longer given the fact that if we did need to put in a major amendment for safety, for more safety data.
Okay. Well, very conservative assumption there, but we'll keep an ear to the ground. We'll have a lot of updates soon. This will be a really exciting year for Larimar. Carole, thanks so much for coming and telling us more about it.