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

So we do expect it to cross the blood-brain barrier, and there's really 3 pieces of evidence that suggest that it does. First, the cell penetrating peptide that we use has been used in carrying other cargo, but has been used to deliver cargo to the brain. In some of the studies that got into large monkeys, apes and chimpanzees, they were able -- they were looking at their cargo to prevent embolization during aneurysm surgery. And they were able to show that with an IV infusion, the CPP, the cell penetrating peptide, was able to carry it across the blood-brain barrier and into the brain. So it does seem that the cell penetrating peptides can cross the blood-brain barrier. Second, we did some work in the neuro knockout. So there are 2 models in this disease, 2 mouse models, one being the neuro knockout, which is brain -- knocked out in brain, dorsal root ganglia and then spinal cord. And Dr. Payne did this study for us at Indiana University. And what he did was he started dosing the mice at 7 days, and he was able to show that he could mitigate the development of the ataxic gait, so the animals continue to walk and walk normally. He could prolong their lives. And when he took out brain, dorsal root ganglia and then spinal cord, he was able to show that there actually was human frataxin in all of those tissues, which shows that it crosses the blood-brain barrier. Lastly, we did a study in monkeys. And these were normal monkeys. We dosed with vehicle for 2 days, and then prior to dosing the 1601, we did lumbar punctures. We dosed for another 2 weeks and then after dosing, did lumbar punctures again. There was no human frataxin in the CSF prior to dosing. And after dosing for 14 days, you do see human frataxin in the CSF, so again, evidence that it crosses the blood-brain barrier. All that said, we do believe it crosses the blood-brain barrier. But remember, this is a systemic disease. So these patients die from heart disease. They develop diabetes. Their skeletal muscle is affected. So there are huge components to all of this that could still be impacted positively even if we didn't cross the blood-brain barrier, that we do -- we believe that we will.

Right. Right. Okay. Great. I mean you started to touch on some of the preclinical data that got you to this point, Carole. So maybe that's a good transition. You have this data, very interesting, and that you put out in May. And then shortly after that, you were put on clinical hold. And it's seemingly unrelated to the data, the clinical data that you had, and more related to the animal data. Could you walk us through what happened and your understanding of the concern from FDA?

Yes. Sure. So in order to support long-term dosing, because our next study is an open-label extension that will continue until we either terminate the program or get approval, we needed data in a 180-day study, a 6-month study. We had already completed a 28-day study in rat and monkey, a 90-day study in rat and monkey, and now we were doing the 180-day to support long-term dosing. While that study was still dosing, almost concurrently with the clinical data coming out, we had some mortalities in the highest dose groups. We obviously report -- we told the -- our investors, but we also obviously reported that to FDA. It's important to note, we did not have any patients on drug at that time. And our next trial was not planned to start until the end of the year. But we obviously told FDA about it. The study was still ongoing. So we couldn't give them a lot of clarity and information on the cause or what was happening because we didn't have the data, we were continuing to dose the study. And so they decided to put us on clinical hold to ensure that we wouldn't dose patients until it all got resolved. What they've asked for really is the report so that they can see the discussion of what we think caused that data, caused that to happen, those deaths. We are in the process of collecting that data. We announced in our most recent Q that we have finished dosing at the end of July. The 180 days for the monkeys are done dosing. We are now collecting all the specimens and the samples. As a small company, we use vendors. So samples are getting shipped off wherever they need to go, getting analyzed. The data will be coming in over the next couple of months. We will crunch that data, evaluate that data, get a story together, make sure we're comfortable with it, figure out whether we need to make any modifications to our open-label extension. And then we'll be submitting that to FDA. FDA, because we're on clinical hold, the one good thing is they have some statutory obligations to us. We are entitled to have a Type A meeting if we want one, and that has to be scheduled within 30 days of our request. And once we submit the response, they have 30 days to respond to it. Obviously, they don't have to lift the clinical hold, but they have 30 days to respond to it. So we're very optimistic that we'll be able to describe what we think happened, that we'll have adequate safety margins given the doses and the exposure that we have in the animals versus the exposure we have in our patient population and also given the fact that these patients are so sick and really have no alternatives. And given our clinical data being so positive, we're optimistic that we'll be able to work with the agency to come to some consensus of how to move forward.

Got it. And once that resolution is met, the next step is the open-label extension. What -- just walk us through what your -- what that design was. Is that -- and how long, how many patients do you expect? Is that presumably all the patients rolling over from the SAD and MAD? Or how should we think about that?

So SAD patients were able to enroll in MAD, and there were 16 who participated in both. MAD patients can at any base -- as long as they participated in either SAD or MAD, they're eligible to screen for the multiple -- for the open-label extension. We call it JIVE, the JIVE study. That study is open-label. We will be checking frataxin levels. We will be checking pharmacokinetics and obviously looking at safety as well as some clinical outcomes, but it is an open-label extension. So that -- we'll have to see what that actually shows us. The design is a multicenter study. Like I said, open-label. There is a very large natural history database that the Friedreich's Ataxia Research Alliance has generated. It's over 1,000 patients for up to 13 years. And industry actually has access to that through an initiative out of FDA. And so we can utilize that database to help us construct a control arm from that database that goes in parallel to our JIVE study, open-label extension study. I don't -- again, because there's a very large placebo effect in this population, we'll have to see how that all works out and looks. But clearly, looking at maintenance of increases in frataxin, safety and pharmacokinetics are really important to understanding what dose to put into our Phase III program.

Got it. Very helpful, Carole. Maybe just to go back and think a little bit bigger picture here. You touched on some of this with your review of FA. Certainly, there are other companies, groups making approaches about FA. It's a large unaddressed population, so it's certainly worth the effort. You hear quite a bit of activity around gene therapy, trying to address the disease. I mean could you give some thoughts about why either CTI-1601 could be better or could coexist, why your perspectives around why gene therapy may not be the best approach? I would love to get some color from you on that.

Yes. So there are a lot of different approaches. Look, these patients have nothing. So I hope that -- I worked in the multiple sclerosis field back in the '90s when multiple sclerosis patients had nothing, and then there was Avonex, Betaseron and Copaxone. And now, there's a dozen drugs and combinations of drugs and what -- different patients prefer different options. So I hope that happens in FA. It's what's best for the patient. But gene therapy has its challenges given the fact that it's a systemic disease. You really have -- every cell, with very few exceptions in the body, have mitochondria. And every cell that has mitochondria has frataxin and has low levels of frataxin in these patients. So you really have to deliver this treatment systemically. That means it's got to get into the brain, it's got to get into the heart, it's got to get into the pancreas, into the skeletal muscle, and so -- into the retina. And so, really, that's a challenge for gene therapy, to be able to target so many tissues. Whereas a subcu injection that circulates in the bloodstream goes to all the different tissues. The other challenge is, as I said, there is toxicity associated with high levels of frataxin, so you need to be able to control the dose. You can't have too much in one cell and not enough in another cell because it is not a secreted protein. And so really being able to make sure that you have the appropriate amounts of frataxin in each cell is very important. And like I said, with subcu, you can titrate the dose. Look, there's a lot of very, very smart people working on gene therapy. There are a lot of programs with very sophisticated science. And again, having alternatives in my mind is what's best for the patients. But I do believe that we at least can coexist and in some ways, have some advantages over gene therapy.

That's great color. I mean certainly, in a world where I think we're still trying to figure out as an industry what -- how to dose AAVs safely and in a systemic disease, yes, agreed, I hope everything works. But you certainly got a great shot at it. Okay. And then maybe just -- we have a couple of minutes left. You talked about it at the start, Carole, that your cell penetrating peptide had been used in other settings. I know all the focus right now is on 1601, that getting that back into patients is your only main priority at this point. But any -- is the technology applicable, as your approach and capabilities, are they applicable in other diseases? Is that something you're thinking about? Any teasers you want to provide there?

So yes, we are thinking about it, and we're actually doing work on it. The patents that we originally licensed from IU and Wake were very specific to frataxin. And so we have spent, well, a couple of years, along with working on 1601, expanding our patent portfolio to make sure that we could cover the cell penetrating peptides with other cargo and other targeting sequences. Because, like I said, we think the key is that cleavage site. So there has to be, in our technology, some way to cleave off the cell penetrating peptide. Those patents have been filed. They are being prosecuted. And we are now looking at other diseases, all rare diseases. We're not looking at big multibillion -- millions and millions of people disease, these are all rare diseases. And they are all diseases where something has to cross the cell membrane, not necessarily a mitochondrial membrane, but a cell membrane. So the technology is targeted to be able to carry cargo either to the nucleus, to the endosome, to the lysosome, to the mitochondria. But clearly, places where diseases were getting the cargo across the cell membrane is important. We're doing a good bit of work on it. It's still very early. I'm not a big believer in releasing and listing about a lot of ideas. We want to have data to be able to show to support where we're going, but we are moving forward and starting to generate data and hopefully, in the near term, not too distant term, you'll be able to see some of that data.

Got it. Very helpful color. Carole, I think we're close to time here. Any closing remarks from you that you would like to share?

No. Just we're very excited about the clinical data. As we sort of said, we really are the first ones to be able to show that you can increase frataxin level substantially with a subcu injection. We're very optimistic about the FDA. We think that once we collect all the data and we have all the information, we'll be able to put together a benefit risk profile that is appropriate and acceptable to FDA and get back in the clinic. And that's really our goal. We always have to remember that these patients really are in need of treatment. And so as long as we have a safe product or a product that at least has a positive benefit risk assessment, we'll keep plowing along and moving forward. And we appreciate you having us at the conference. Thank you. We appreciate having all the investors who showed so much interest all day. And we look forward to having good news in the near future.

Great. Thank you, Carole Ben-Maimon, CEO of Larimar. Best of luck getting back into patients. We're pulling for you. Thanks, everyone, for joining. Have a good night.

Thanks. Have a good evening, everybody.