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

Hello, and welcome to the Larimar Therapeutics conference call. [Operator Instructions] Please be advised this call is being recorded and a replay will be available on the company's website. [Operator Instructions] It's now my pleasure to turn the call over to Grant Weingarten of LifeSci Advisors. Please go ahead, Grant.

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 can be viewed using the webcast link provided on the Investors page of the Larimar Therapeutics website. Also posted on this web page 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 the expectations and assumptions regarding the future of the company's business, company's plans and ability to develop and commercialize CTI-1601 and other matters regarding the company's planned 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 CTI-1601 clinical milestones and continued interactions with the FDA. The earlier nonclinical and clinical data and testing of CTI-1601 may not be predictive of the results or success of later clinical trials and assessments and the clinical trial data are subject to different interpretations and assessments. The company's ability to raise the necessary capital to conduct its product development activities and other risks described by 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. Carole Ben-Maimon, President and CEO of Larimar Therapeutics. In addition, Larimar's Chief Financial Officer, Mike Celano, Chief Development Officer; Dr. Gopi Shankar, and newly appointed Chief Medical Officer, Dr. Rusty Clayton will be available during the question-and-answer session following the prepared remarks. With that, I will now turn the call over to Carole.

Thanks, Grant, and good morning, everyone. In the past, we have told you that we would be providing an update on the CTI-1601 development program once we had feedback from FDA after our meeting in the second quarter of this year. We are now excited to provide that update. The FDA has provided their decision to our complete response to our partial clinical hold, which we submitted after the meeting. We are happy to provide what we believe represents truly exciting development for both Larimar and the Friedreich's ataxia community. First, our placebo-controlled 4-week Phase II dose exploration trial of CTI-1601 in patients with Friedreich's ataxia has been clear to proceed to a 50-milligram cohort evaluating a daily dosing regimen for 14 days and then every other day dosing through day 28. This milestone comes following a review of unblinded data from the trial's 25-milligram cohort by the FDA and which included safety, PK and frataxin levels in buccal cells and skin cells. Second, the FDA has also cleared our open-label extension trial for initiation with 25 milligrams daily dosing. Patients who participated is in either of our Phase I studies were in our Phase II dose exploration study will be eligible to screen for this trial. After screening, participants enrolled in the trial will receive daily subcutaneous injection of 25 milligrams of CTI-1601 with injections being self-administered or administered by a caregiver. Collectively, these regulatory accomplishments represent a major step forward for our CTI-1601 program, which aims to deliver the first Friedreich's ataxia therapy designed specifically to increase frataxin levels in patients deficient in this protein. With our Phase II and open-label extension trial, we aim to identify CTI-1601's long-term dose and dosing regimen for future studies, while building upon prior clinical proof-of-concept data demonstrating increases in frataxin levels in peripheral tissues. As we work to advance these two U.S. trials, we have also begun to engage with regulators and investigators outside the U.S. These efforts are part of preparations to expand our clinical programs to international geographies so that we can position ourselves to address the unmet needs of the Friedreich's ataxia community around the globe. As a reminder, CTI-1601 has been granted orphan drug designation in the United States and Europe, rare pediatric disease and FastTrack designation in the United States and prime designation in Europe. Looking ahead, upon completion of our Phase II trial 50-milligram cohort, we will submit additional unblinded data to the FDA with the intent of continuing to advance the development program for CTI-1601. Independent of that submission, as we have discussed before, we want to include pediatric patients in our trial and also want to initiate discussions with FDA on appropriate endpoints for our future pivotal study. This will include discussions on the value of measurable frataxin levels and the role these levels may have in relation to the clinical course of patients with Friedreich's ataxia. With that brief summary of today's exciting news complete, I'd now like to take a step back to provide an overview of Larimar as well as what led to today's news. As you can see on this slide, Larimar is a clinical stage biotechnology company with a novel protein replacement therapy platform with first-in-class potential. Our lead program is in Friedreich's ataxia, a rare 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 Friedreich's ataxia, or FA, as I'll often refer to it. We are developing CTI-1601, a recombinant fusion protein designed to directly address frataxin deficiency by delivering the protein to the mitochondria. In Phase I trial in participants with FA, daily doses of CTI-1601 resulted in dose-dependent increases in frataxin levels in peripheral tissues, providing clinical proof-of-concept. Data from these trials also indicated that CTI-1601 was generally well tolerated when administered via subcutaneous injection daily for 13 days at doses up to 100 milligrams. The initiation of a second cohort at 50 milligrams in the dose exploration study will occur as soon as possible, and the initiation of the open-label extension will occur in the first quarter of next year. This has us moving towards key anticipated milestones, including topline safety, PK and frataxin data, from our Phase II trial, 50-milligram cohort anticipated in the first half of next year. We will be able to clarify timing once enrollment is completed. We believe our current cash runway will extend beyond those anticipated milestones with our current cash balance in excess of $100 million, which is expected to fund operations into the fourth quarter of 2024. Dose escalation above 50 milligrams in the Phase II trial and the initiation of clinical trials in addition to the Phase II trial and the open-label extension, are contingent upon FDA review of results from the Phase II trial 50-milligram cohort as the program currently remains on partial clinical hold. With this next slide, I'd like to briefly provide some background on FA and the current treatment landscape for those listening who may be less familiar with the disease and the Larimar story. As you can see here, Friedreich's ataxia is caused by a genetic defect consisting of an increase in the repeat of the GAA codon that prevents patients from producing enough of the critical mitochondrial protein frataxin. A typical patient with FA produces about 20% to 40% of the frataxin levels seen in homozygous healthy people. Not having enough frataxin leads to a myriad of debilitating effects, which are summarized on the left side of the slide. Symptoms will often present before the age of 14 and are progressive, typically causing patients to be wheelchair-bound 7 to 10 years after the initial diagnosis. The complications of FA include loss of musculoskeletal function, blindness, deafness and an inability to speak clearly as well as diabetes. Unfortunately, patients with FA have a life expectancy of only 30 to 50 years, and the most common cause of death is heart disease. Earlier this year, omaveloxolone was approved by FDA as the first therapy indicated for FA in what was a critically important breakthrough for patients. However, there are still no approved agents designed to increase frataxin and address the deficiency underlying FAs devastating pathophysiology. Because of this, key opinion leaders, FA patients and advocates have made it clear that there is still a pressing unmet need for novel therapies to treat the underlying cause of FA. Next, I'd like to briefly summarize some of our key clinical findings to date from both our Phase I multiple ascending dose study and our Phase II dose exploration study. Shown on this slide are results from our Phase I multiple ascending dose trial with the graphs showing changes from baseline in frataxin levels normalized to total protein in skin and buccal cells. Each of these tissue types has its own advantages and challenges for measuring frataxin. In tissue provides a more stable measurement due to it having a lower turnover rate and a standardized collection method. Buccal cells can be collected through less invasive techniques and there is a body of medical literature that supports the association between buccal cell frataxin level and age of onset and rate of progression of disease in patients with FA. Turning our attention to the legend below the graph. You can see that in this study, participants in the 25-milligram group were dosed daily for 4 days and then every third day through day 13. Participants in the 50-milligram cohort were dosed daily for 7 days and then every other day through day 13. And participants in the 100-milligram dose group were dosed daily for 13 consecutive days. Within the graph, the dots represent medians and the horizontal lines, the 25th and 75th percentile. On the graph on the left, you see results from skin cells that showed a dose-dependent increase in frataxin from baseline compared to placebo at day 13. While we did not see an increase in frataxin levels in the 25-milligram cohort, I'll remind you that day 13 was well after these patients switched from a daily dosing regimen to an every third-day dosing regimen. Moving to the graph on the right, we see consistent dose-dependent changes from baseline in frataxin levels in buccal cells. In the first section of the graph, we show frataxin levels on day 4 for the 25-milligram cohort and day 7 for the 50-milligram and 100-milligram cohort, as this allows us to capture the final day of daily dosing for the 25- and 50-milligram cohort. Looking at these data, we see a dose-dependent increase in frataxin from baseline compared to placebo as the dose is escalated to 50 and 100 milligrams. As you'll see shortly, although we do not see increases in the 25-milligram cohort in this study, data from our Phase II study showed that increases in frataxin levels can be achieved with extended daily dosing of 25 milligrams of CTI-1601. Next, I'd like to turn your attention to data from the 50-milligram cohort in our Phase I trial, which, as mentioned, will be the next dose studied in our Phase II trial. Starting at day 7, you can see the daily dosing led to a clear increase in frataxin levels from baseline compared to placebo. Based on these data, the initial cohort of the Phase II study was intended to determine, first, if extended daily dosing with 25 milligrams of CTI-1601 could lead to increases in frataxin. And second, if the frataxin increases achieved with 14 days of daily dosing are sustained after switching to an every other day dosing regimen. Now let's transition to the Phase II trial. On this slide, you can see the top line data from its 25-milligram cohort, with the graph showing changes from baseline and frataxin concentrations normalized to total protein. Starting all the way on the left, you can see that after 14 days of daily dosing, we observed a clear increase in frataxin levels from baseline compared to placebo and skin cells. When participants were then switch to every other day dosing for 14 days, we observed a slight decrease in frataxin levels, though the median remained well above baseline. If you then turn your attention to the graph on the right, you can see that our results in buccal cells were similar to those observed in skin with an increase in frataxin observed after 14 days of daily dosing. However, one difference in the buccal cell data was the frataxin levels return to near baseline values following the switch from daily to every other day dosing. Looking at the totality of frataxin data, reported to date from both our Phase I and II trials. We are very pleased that CTI-1601 seems to consistently drive increased frataxin concentration in peripheral tissues at a dose as low as 25 milligrams. These results demonstrate CTI-1601's potential to directly address the frataxin deficiency underlying the development of Friedreich's ataxia. With regards to the dose and dosing regimen for increasing and maintaining frataxin concentration, this is a subject we will be evaluating further in our Phase II trials next cohort and in our open-label extension study. Here on Slide 8, you can see a summary of Phase I and Phase II safety data from our clinical program, which indicates that CTI-1601 is generally well tolerated. In total, 37 individuals with FA have received at least 1 dose of CTI-1601. Across our Phase I and II trials, there have been no serious adverse events or important medical events reported to date. There was one allergic reaction, which was considered to be a severe adverse event in the Phase II study. The most common adverse events reported in our clinical program have been mild and moderate injection site reactions. All of the reactions resolved without any intervention. After a thorough review of these Phase I and Phase II results, the FDA has responded to our complete response and has cleared us to proceed to our Phase II trial 50-milligram cohort. As you can see here, this cohort will utilize an identical dosing regimen as the 25-milligram cohort. We expect the 50-milligram cohort will enroll 12 to 15 adult participants with FA, randomized 2:1 to receive CTI-1601 or placebo. Top line unblinded safety pharmacokinetic and frataxin data from the cohort are expected in the first half of next year. In addition to our data package and request to proceed to a 50-milligram cohort in our Phase II trial, our most recent complete response also included a proposed protocol for our open-label extension trial of CTI-1601. As mentioned at the top of the call, this trial has also been cleared for initiation by the FDA. As you can see in the trial schematic shown on this slide, patients who previously completed a CTI-1601 clinical trial are eligible to screen for a multicenter open-label extension trial. After screening, participants enrolled in the trial will receive daily subcutaneous injections 25 milligrams of CTI-1601 with injections being self-administered or administered by a caregiver. If you turn your attention to the bottom of the slide, you'll notice that the safety and pharmacodynamic objectives of our open-label extension trial are to evaluate the safety and tolerability of long-term subcutaneous injections of CTI-1601 and as well as the long-term pharmacokinetics. The open-label extension study will also continue to collect and analyze frataxin levels and other pharmacodynamic markers, including lipid profiles and gene expression. Data will be collected periodically over the first year and every 3 months thereafter. In this study, Other objectives include the evaluation of the long-term subcutaneous administration of CTI-1601 on measures of clinical function. To provide a point of comparison for measures of clinical function, we will utilize 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 will be prospectively defined. We expect the open-label extension study to begin in the first quarter of next year and that we will report interim data from the trial in Q4 2024. On this slide, you can see some more information on our future plans for the CTI-1601 clinical program. which we anticipate will include a pediatric placebo-controlled multiple ascending dose trial in individuals with FA who are between 2 and 17 years old. Participants in this planned trial will be eligible to roll into our open-label extension trial, and we are particularly slated by this prospect of generating data in a pediatric FA population as the only approved treatment for FA is not indicated for use in those under 16 years old. Prior to initiating the pediatric MAD study, we will need to submit additional data from adult patients to the FDA for review. Together, our Phase I, Phase II open-label extension and planned pediatric trial are designed to generate data characterizing CTI-1601safety and tolerability and to identify the dose and dosing regimen with the greatest potential to increase frataxin levels and improved clinical outcomes for patients. After achieving this goal, we would then seek to reinforce our early and mid-stage clinical findings in a global double-blind placebo-controlled pivotal trial evaluating both frataxin levels and clinical outcomes. As we look ahead for CTI-1601, the next key data readout for the program is expected from our Phase II trial in the first half of next year. At that time, we expect to report top line unblinded safety, PK and frataxin level data from the trial's 50-milligram cohort. In terms of what we hope to see from this readout, we will first want to see safety data that continue to indicate CTI-1601 is generally well tolerated. For frataxin level, data we aim to build upon existing evidence demonstrating CTI-1601 dose-dependent effect. In summary, the news reported today represents a major step forward in CTI-1601's clinical development as the first therapeutic intended to increase frataxin levels and address the protein deficiency leading to FA's devastating clinical course. After reviewing our complete response that included the unblinded clinical data from cohort 1 of our Phase II trial indicating that CTI-1601 in was generally well tolerated, describing the pharmacokinetic profile and also showing that daily treatment led to frataxin increases in skin and buccal cells. The FDA cleared us to initiate our second cohort at a dose of 50 milligrams in adult patients as well as to initiate our open-label extension trial at 25 milligrams daily in patients who participated in our Phase I studies or in our Phase II dose exploration study. In addition, we have begun to engage with regulators and investigators outside the U.S. as we prepare to expand our clinical program to international geographies. As we look ahead for our CTI-1601 program, we remain on track to initiate the second cohort at 50 milligrams in the Phase II dose exploration study as soon as possible and the initiation of the open-label extension will occur in the first quarter of next year. We expect to report unblinded top line safety, pharmacokinetic and frataxin data, from our Phase II trial 50-milligram cohort in the first half of 2024, and expect to report preliminary interim data from the open-label extension trial in the fourth quarter of 2024. With these milestones ahead of us and a robust clinical data set demonstrating CTI-1601's differentiated mechanism of action as well as the current cash balance in excess of $100 million, we believe we are well-positioned as we seek to address the urgent unmet need 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 CTI-1601 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 Mike, Gopi and our newly appointed Chief Medical Officer, Dr. Rusty Clayton. Rusty recently expanded his role at Larimar and was appointed as Chief Medical Officer after spending the last 5 years as 1 of our closest advisers and Chair of our Scientific Advisory Board. He has attended every meeting with FDA, including the [indiscernible] meeting, and I know he will be an important addition to our already highly effective Larimar team. We are thrilled to have Rusty as part of our team and also wish our former Chief Medical Officer, Dr. Nancy Ruiz, all the best in her retirement. We will now open the line for questions. Operator?

[Operator Instructions] Our first question today is coming from Yatin Suneja from Guggenheim Partners.

Congrats on the update. A couple for me. So Carole, you highlighted on the 50-milligram cohort. Obviously, safety is important. But I'm just curious to learn from you what the expectations are in terms of frataxin increase based on your PK/PD model. So that's one. And then in terms of the patient population in the 50-milligram cohort, should there be any difference relative to the 25-milligram cohort, what about Omav will patients be allowed to have Omav? And then I have one more.

Thanks for the questions. So with regard to the 50-milligram cohort, I think we're expecting to see increases similar to what we saw in our Phase I program. where frataxin was significantly increased over 25. I think it's a little hard to know exactly where that's going to fall given the fact that we're dosing, again, for longer. It is possible that with 50 milligrams for 14 days instead of 7 days daily that we actually see greater increases than we saw in the Phase I. But obviously, we're doing the study, so we can figure that out. But we do expect to see significant increases over the 25-milligram cohort. With regard to the population, it should be similar to the 25-milligram group. They are not the same people. So although patients can participate in multiple studies so they can -- some participated in the SAD and the MAD some participated in the MAD and the dose exploration study some participated quite honestly, in all 3, they will not be the same patients that were in the first cohort. They will be different patients, but they may be either naive patients or patients who have previously been exposed to CTI-1601. With regard to Omav, we will not be allowing omaveloxolone in the second cohort of the Phase II study. We don't think there is enough safety data to ensure that patients could be safe if both drugs were being given simultaneously. We are starting to try and collect some of that data so that we can better anticipate what should be the protocol for the open-label extension as we start to initiate that in the first quarter but we'll update you as we get more and more data. And we also obviously watch the rollout and the launch of omaveloxolone. But obviously, we're very sensitive to the fact that patients are very excited and we'll be starting to take it, and we will do what we can to work with them.

Got it. And then just -- there is one more. In terms of the cohorts or doses above that, I mean how are you thinking about, let's say, the next dose above 50, do you have to go? Would that also require an FDA feedback or I mean if obviously 50 show -- if 50 can achieve the required frataxin level you probably don't have to go. But just curious your articulation around going next on the dose.

Yes, I think that's a great question. the agency has not capped us. So I think that is important that if we do believe, based on the data from the 50, both the safety data, obviously, in the pharmacokinetic and frataxin data, that we need to go higher. We will be submitting to FDA. We need to submit that data at FDA prior to because the partial hold is still in place. But we can -- it's definitely an option, assuming the data supports it. And just to make it clear to everybody, it is possible we could want to go to a higher dose, even if we don't -- even if we think the 50 milligrams is completely adequate, that study is open. And so it's just easier to collect that data now than it would be to close that study down and start again if we found that we really did want to go to a higher dose, even some people. And so it is possible that we move forward decide to do a higher dose concurrently with collecting the data in the open-label extension, which is why we're so excited about that. That study will give us a lot of information on frataxin and dosing and what to anticipate with long-term dosing. So we'll keep that option open, Yatin, but we will need to submit the data -- the safety data, PK data and frataxin data unblinded to the FDA and work with them to try and make the decision as to whether -- and to go up and to what dose.

Your next question today is coming from Myles Minter from William Blair.

Congrats as well. Maybe just the first one is, are you going to be enrolling any new placebo patients? I'm just wondering whether you do the frataxin expression here and you will still be running new placebo samples on that same assay or whether they're just going to be frataxin expression in 1601 treated patients when you run that assay in the 50-milligram cohort, that's the first one. The second is on [ Omav ] usage, particularly in the OLE, I know that's a work in progress. But I'm curious because you [ tout ] the fact you're going to be comparing this data to the FACOMS cohort as well. And I doubt whether FACOM has experience or data with Omav usage. So just wondering whether there's any potential discrepancies there.

So with regard to placebo, we will have placebo patients in the second cohort. The randomization is 2:1 the same as it was in the first cohort. It's really important to keep the placebo patients. It's a short-term study. So obviously, there's no ethical issues there. And from the standpoint of placebo, it's very helpful when you're looking at safety data in particular. Obviously, they don't have increases in frataxin because they don't -- we're not supplying CTI-1601, but it is important as we assess safety data. With regard to the open-label extension and the clinical outcomes, it's a really important question, and we're still sort of working with that. What we do know is that omaveloxolone does not increase frataxin levels that's known. And so we're pretty comfortable the frataxin data that we'll be getting out of the OLE will be very useful. The other question is how many of those patients who are already -- have been in our trials will be actually still on Omav or will be on Omav. I think that's yet to be seen. Obviously, patients are very excited and there's going to be a quick uptake. But you never know what happens as you start to take a new drug. And so we'll have to see how many -- whether there's a subset of patients that aren't on Omav that we can assess. And again, it will provide also if we can do it, I don't want to commit to doing it. So if we can do it, if we deem it safe -- we will also provide information on concurrent -- [ concomitant ] administration, which is very important for labeling and for doctors to know how to use those drugs if they are going to use them together. So it still will be important data. I want to also highlight that we did mention in the prepared remarks that we are starting to think about how to look at frataxin levels long-term as a clinical outcome. And we -- now that we're moving forward, I think, pretty aggressively with the agency. I think now is the time to start talking to them about whether frataxin can [ pay ] itself can actually play a role as a clinical outcome as well as talking to them about how the gene expression and lipid data that we're collecting as we start to understand it better, can act as a mechanism. I don't want to use the word marker, but as a mechanism to assess activity of the frataxin that we're administering. So all those conversations -- I mean we're -- we think this is a huge path forward. Our meeting with them was incredibly positive and incredibly interactive. They have really made sure to say that just because the partial hold is being maintained, doesn't mean we can't move forward and have -- continue to have conversations with them and move this program forward and they made that very clear. And so I'm very -- we're very excited about not only initiating both of these studies, but also being able to continue active communications with FDA as well as ex U.S. regulators and investigators to really get the program now on track moving forward and continuing to progress.

And just one quick one. Just with the ex U.S. geographies and starting up trials there. Would you just immediately request starting at 50 milligrams or even 100 milligrams in those ex U.S. geographies?

Good question, Myles. We haven't gotten there yet. We'll let -- as we get a little further down the path, we'll be -- we'll keep everybody informed. But we really haven't initiated those conversations -- we're just excited to be able to move forward with the 50-milligram cohort and the OLE. I think before we would decide -- we really would like to see the cohort -- and obviously, we're moving aggressively to start to get that trial going and start enrolling.

Your next question is coming from Jon Wolleben from JMP.

A couple for me on the open-label extension. Just wondering about timing of the start and first quarter next year versus potentially sooner. What kind of work needs to be done to get that up and running and could it come sooner?

It is possible, Jonathan. We run into the holidays at the end of December, and Thanksgiving, which is always as issue with vendors and things like that. Logistically, we've been working on it. It's a harder study to start than a single center study that's conducted as [ CRU ], but Dr. Clayton over here has been brought on board full time to make sure that we do it as expeditiously as we possibly can. We're very comfortable with the first quarter date, but we are obviously working very closely. It's also a study that's done at mostly academic centers. And you know as well as I do, a lot of the academic centers can be a bit slower with their contracting and their [ IRBs ] but we are moving as aggressively as we can. And like I said, Rusty has been asked to join and I know it has been engaged with investigators and we'll continue to work with our team we have a really, really good clinical operations team that actually reports into Gopi. And so as a team Gopi and Rusty together along with our operational teams that are just you've seen them perform, right? You saw how they executed on the Phase I through COVID. You've seen what happened. We were up and running weeks after. We got clearance from FDA for the first cohort. So we'll do everything we can to move as quickly as we can.

Okay. And it seems like a good sign that FDA cleared you to do daily dosing, open-label extension. Can you talk about how you're collecting frataxin samples and open-label data that could give us more confidence that maybe even longer dosing could see further increases? Is that your expectation? And also how frequently is FDA requesting the safe safety updates from the open-label extension.