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

Good morning, and welcome to Larimar Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request, and a replay will be available on the company's website. I would now like to turn the call over to Mr. Chase Oswald of LifeSci Advisors. Please go ahead.

Thank you, operator, and thank you all for participating in today's conference call. Before we start, I'd like to point out that there is a slide deck that will accompany today's presentation. This slide deck can be viewed using webcast link provided on the Investors page of the Larimar Therapeutics website. Also posted on this web page is the news release issued earlier today announcing data from Larimar's Phase I double-blind, placebo-controlled, multiple ascending dose clinical trial evaluating CTI-1601 in Friedreich's ataxia patients. I'd like to remind all listening that some of the information contained in the news release and 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. All statements contained in the news release and on this call other than statements of historical fact are forward-looking statements, including, but not limited to, statements regarding the expectations and assumptions regarding the future of the business, the company's ability to develop and commercialize CTI-1601 and other planned product candidates; the company's planned research and development efforts and other matters regarding the company's business strategies, use of capital, results of operations and financial position and plans and objectives for future operations. In some cases, you can identify forward-looking statements by the words, may, will, could, would, should, expect, intend, plan, anticipate, believe, estimate, predict, project, potential, continue, ongoing or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. These 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 milestone. That clinical trial results may differ from the final clinical trial results that earlier nonclinical and clinical data in testing of CTI-1601 may not be predictive of the results or success of clinical trials, and that clinical trial data are subject to different interpretations and assessments. The ongoing impact of the COVID-19 pandemic on the company's clinical trials, manufacturing, regulatory and nonclinical study time lines, ability to raise additional capital and general economic conditions, the company's ability to optimize and scale CTI-1601's manufacturing process, the company's ability to obtain regulatory approval for CTI-1601 and feature product candidates, the company's ability to develop sales and marketing capabilities whether alone or with potential future collaborators and successfully commercialize any approved product candidates. The company's ability to raise the necessary capital to conduct its product development activities and other risks described in the filings made of the company with the Securities and Exchange Commission, including, but not limited to, the company's periodic reports, including the annual report on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K filed with or furnished to 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 by which it cannot be certain. As a result, the forward-looking statements may not prove to be accurate. These forward-looking statements are based on information currently available to management, and the company assumes no obligation to update any forward-looking statements, except as required by law. With that, I'd like to turn the call over to Dr. Carole Ben-Maimon, President and CEO of Larimar Therapeutics. Please go ahead, Carole.

Thanks, Chase. Good morning, everyone, and thanks to all of you who are listening. In addition to Chase, I am also joined by our Chief Medical Officer, Dr. Nancy Ruiz; and our Chief Financial Officer, Mike Celano, who will be available during the question-and-answer session following my presentation. For those of you who don't know Larimar, we are a clinical stage biotechnology company developing a novel protein replacement therapy platform for Friedreich's ataxia and other complex rare diseases. We were founded by Dr. Mark Payne and Tom Hamilton, and at the end of 2016, Deerfield management made the initial investment. We went public through a reverse merger and accompanying PIPE in May 2020, with a shareholder base made up of high-quality institutional investors. As I previewed above, our lead program is in Friedreich's ataxia, or FA, a rare and terribly debilitating genetic disorder. To address the unmet medical needs in FA, we are developing CTI-1601, a recombinant fusion protein designed to treat the root cause of the disease. Patients with FA are deficient in a protein called frataxin. Frataxin is a protein that is active in the mitochondria of the cell. CTI-1601 is intended to deliver frataxin to the mitochondria in patients suffering from FA. We recently completed dosing in 2 Phase I trials. These trials were a placebo-controlled single ascending dose trial and a placebo-controlled multiple ascending dose trial, evaluating CTI-1601 in patients with Friedreich's ataxia. The primary purpose of today's call is to announce the exciting data these trials have generated, which show dose-dependent increases in frataxin levels in all evaluated tissues with daily dosing of CTI-1601. The frataxin levels observed in these tissues actually met or exceeded the levels we would expect to see in phenotypically normal heterozygous carriers of FA. We believe this data demonstrates proof-of-concept for CTI-1601. In addition, the data also indicates that CTI-1601 is generally well tolerated when administered daily for 13 days. Looking forward, we believe we are well positioned financially to build on these promising results as we ended the first quarter with over $81 million in cash, which provides for a projected runway into the first half of 2022. Now before we dive into the details of our data and trial design, I wanted to first highlight the key findings from our Phase I program. With regards to safety, we saw that repeated subcutaneous injections of CTI-1601 appear to have been generally well tolerated at doses up to 100 milligrams administered daily for up to 13 doses. When looking at pharmacodynamic data, we saw dose-dependent increases in frataxin levels from baseline compared to placebo-controlled in all evaluated tissues with daily dosing of CTI-1601. And finally, our pharmacokinetic analysis, together with the PD data, I just mentioned, support evaluating a once-daily dosing regimen for CTI-1601. Before I leave this slide, I'd like to highlight one of the most important findings from this study. Notably, frataxin levels in buccal cells for the 2 highest dose groups were equal to or in excess of those we would expect to see in heterozygous carriers who show no signs of the disease. Given that insufficient frataxin levels are the root cause of Friedreich's ataxia, we believe that these exciting findings demonstrate proof-of-concept for CTI-1601. So now that I've introduced the main takeaways of today's presentation, I want to take a moment to provide some context for the detailed data I'll be presenting by giving some background on Friedreich's ataxia and CTI-1601. Friedreich's ataxia is a rare terribly debilitating disease caused by a genetic defect that results in insufficient levels of frataxin, a key mitochondrial protein. It is important to note that the vast majority of patients with FA have some normal frataxin. They just don't have enough frataxin. Past studies have shown that patients with FA produce only about 20% to 40% of normal frataxin levels depending on the tissue, sampling technique and assay utilized. FA is a terrible disease. This deficiency of frataxin causes patients, who are born appearing to be healthy, to develop heart disease and progressive neurological symptoms that will eventually force them into a wheelchair 7 to 10 years after diagnosis. The life expectancy for these patients is between 30 to 50 years of age with the primary cause of death being cardiomyopathy. If FA is truly a systemic disease, every cell in the body that has mitochondria has frataxin. In addition to the neurologic dysfunction in cardiac disease, patients with FA develop diabetes, they can go blind and deaf, and they lose the ability to speak. There is a substantial unmet medical need in FA as there are no approved therapies available and current treatment options are limited to symptom management. In response to this unmet medical need, we are developing CTI-1601, a recombinant fusion protein. Through the administration of CTI-1601, we are aiming to address the root cause of Friedreich's ataxia by delivering mature frataxin protein to the mitochondria. To understand how CTI-1601 does this, it's first important to understand the structure of endogenous frataxin. If you look on the left side of the slide, you can see that frataxin, which is coded in the nucleus, produced in the cytoplasm and then transported into the mitochondria is originally coded as, what I like to call, a pro protein. This pro protein includes mitochondrial targeting sequence, or MTS, that carries the protein across the mitochondrial membrane. Once in the mitochondria, the MTS is cleaved off by the mitochondrial processing peptidase enzyme, allowing mature frataxin to accumulate within the organelle to function. Now if you look to the right side of the slide, you can see what's significant about CTI-1601. This recombinant protein has been designed to allow exogenously administered frataxin to cross the cell membrane and the mitochondrial membrane. This is accomplished by attaching a cell penetrating peptide, or CPP, a small amino acid sequence to the mitochondrial targeting sequence and not to the frataxin molecule itself. This maintains the cleavage site between the MTS and the frataxin molecule. By maintaining this cleavage site, once CTI-1601 enters the mitochondria, the mitochondrial processing peptidase can now cleave off the cell penetrating peptide and the MTS, leaving the active frataxin molecule in the mitochondria. We believe that attaching the CPP to the MTS and preserving that cleavage site is what constitutes the secret sauce of CTI-1601. So now that I've set the stage by describing how CTI-1601's mechanism of action directly addresses the root cause of FA, I'd like to introduce the design of our Phase I program and talk in depth about the exciting data I previewed earlier in the call. As you can see on this slide, our Phase I program includes 2 double-blind, placebo-controlled trials in patients with FA. The first of these trials is a SAD study that evaluated the safety of single subcutaneous injections of CTI-1601. This trial has been completed with data from the study showing that single subcutaneous injections of CTI-1601 appear to be generally well tolerated at doses up to 100 milligrams. Eligible patients from the SAD trial had the opportunity to screen for a MAD trial, which is the primary focus of today's call. Patients in this trial were randomized to receive multiple increasing doses of CTI-1601 or placebo administered subcutaneously over 13 days. The primary endpoints of the trial were safety and tolerability with secondary endpoints, including frataxin levels in buccal cells and platelets as well as pharmacokinetic analyses. Dosing in the trial was completed in the first quarter of the year. Here on this slide, you'll notice that 16 of the 28 patients who participated in the SAD study went on to enroll in our MAD trial. This is important as the MAD study was conducted during the pandemic, throughout the winter and required patients and their caregivers to travel from across the country to the single clinical research unit, where the study was conducted. Once there, patients and their caregivers have to remain in the unit for more than 3 weeks. The fact that 16 out of 28 patients were willing to endure this is really a tribute to the patient's commitment and tenacity, and we want to thank them for their participation and perseverance. The MAD trial had 3 cohorts. With cohort 1 enrolling 6 patients into the active arm and cohorts 2 and 3, each enrolling 7 patients into the active arm. Collectively, the 3 cohorts enrolled 7 patients into the placebo group. Moving on to Slide 9. You can see that as we moved from cohort 1 to cohort 3 in the MAD trial, we increased both the dose of CTI-1601 as well as the frequency of administration. Patients in cohort 1 were dosed with 25 milligrams daily for 4 days, and then every third day after that until day 13. In cohort 2, we doubled the dose of CTI-1601 to 50 milligrams and administered the protein daily for 7 days before moving to a once every other day dosing schedule until day 13. Finally, patients in cohort 3 were given 100-milligram dose daily for 13 consecutive days. Looking now at the bottom half of the slide, I'll briefly explain how we will be presenting the data for each cohort. You'll notice from the tables that for cohort 1, we will be showing frataxin levels at baseline, day 4 and day 13, in both buccal cells and platelets. While in cohorts 2 and 3, the data presented for these tissues will be from baseline, day 7 and day 13. Looking at the data in this way allows us to capture the final day of the daily dosing period for both cohorts 1 and 2, which will be informative for the design of subsequent studies. Per the study protocol, skin biopsies were collected only at baseline and day 13. Thus, those are the 2 time points we will be looking at for this tissue in all 3 cohorts. In addition, skin biopsies were optional, so patients could elect not to have them performed. Here on Slides 10 and 11, you can see the demographics and disease characteristics of patients who participated in the MAD trial. I won't go through the data in detail now as the slides are posted on our website for those interested in taking a deeper dive. I will, however, point out that the patient demographics in the MAD trial were similar to those in the SAD trial, which is obviously not surprising given that there were 16 patients who participated in both studies. Additionally, approximately half of the patients enrolled in our trials used a wheelchair to move around and thus are considered non-ambulatory. This is different than many of the Phase II/III trials to date in FA, where patients who participated were required to be ambulatory. Having these patients in our Phase I trials as well as our open-label extension, the JIVE study, will provide important data on the long-term safety and tolerability of CTI-1601 as well as potentially allow detection of a signal of efficacy in this population. On Slide 12, you'll see the data I previewed at the beginning of the call, which shows the daily subcutaneous injections of CTI-1601 resulted in dose-dependent increases in frataxin levels from baseline compared to placebo. The data you are looking at now is from buccal cells. But as you'll see in a moment, these data are consistent with what we saw in all evaluated tissues. Looking in more detail now, we can start with the graph on the left, which shows absolute frataxin concentrations in collected buccal cells normalized to total protein. The points on the graph represents the median from each group, while the error bars represent the 25th and 75th percentile. You'll also notice that as we move from baseline to the next measurement, which again was day 4 for the 25-milligram dose group and day 7 for the 50 and 100-milligram dose groups, we see an increase in frataxin levels in the second 2 highest dose groups, with the highest median frataxin level being in 100-milligram dose group, the highest dosing group. That said, in the 100-milligram dose group, we saw an approximately 2.5 fold increase in frataxin levels from baseline. Importantly, we see little to no change in frataxin levels in the placebo group or in the 25-milligram dose group, which received the lowest dose of CTI-1601. I'd like to draw your attention now to what was seen between day 7 and day 13 measurements. As this shows something that is a bit subtle, but quite informative. You can see from the graph that between day 7 and day 13, frataxin levels in the 100-milligram dose group remain relatively constant, while the frataxin levels in the 50-milligram dose group decrease. The important thing to remember here is that patients in the 50-milligram dose group were receiving CTI-1601 daily for the first 7 days, but then they were switched to receiving the protein every other day between day 7 and day 13. Conversely, patients in the 100-milligram dose group received both a higher dose of CTI-1601 and remained on the daily administration schedule throughout the 13 days. This is important because it suggests that a once-daily dosing schedule may be appropriate for subsequent studies. Turning our attention now to the graph on the right. We see the same data, but presented as a change from -- so this represents the additional frataxin that is being supplied by administration of CTI-1601. Once again, we see little to no change from baseline in buccal cell frataxin levels from patients in the placebo group or the 25-milligram dose group. On day 7, when both the 50 and 100-milligram dose groups were on daily dosing schedules, we see increases in frataxin levels with the greatest increase coming from patients in the 100-milligram dose group. As I will show you in a moment, these frataxin levels are at or above what we would see in heterozygous that show no signs of the disease. On Slide 13, you can see the frataxin levels measured in skin biopsies, which were collected both at baseline and on day 13. These results are consistent with what we saw in buccal cells, but with a more pronounced approximate threefold increase in frataxin levels compared to baseline in patients in the 100-milligram dose group. The increases in frataxin levels were observed -- the increases in frataxin levels observed were once again dose-dependent with daily dosing, with little to no change from baseline seen in the placebo group or the 25-milligram dose group. On Slide 14, you can see the results we obtained from platelets, which was the last tissue we evaluated. While results here were generally consistent with what was seen in other tissues, we did see a good deal of variability in the baseline measurements of all groups. However, when looking at change from baseline in the 100-milligram dose group, in the graph on the right, it becomes clear that we are, once again, seeing increases in frataxin levels at the highest dose when compared to placebo. Now if we look here on Slide 15, we can see a different representation of the data with a bit more detail on how increases in frataxin levels from baseline correlated with CTI-1601 dose. The 3 graphs represent the change from baseline on day 13 with each bar representing an individual patient. As you can see from the color coding, as you move from left to right, the largest increases from baseline tended to come from higher dosing cohorts with more frequent dosing. Collectively, these patient-level data further supports the dose-dependent effects of CTI-1601 that were observed with daily dosing in all tissue studied. So once we establish that we could increase frataxin levels in peripheral tissues, we then asked ourselves 2 questions. The first being are peripheral frataxin levels clinically relevant? And the second thing how do the frataxin levels we achieved with CTI-1601 administration in our clinical trial compared to frataxin levels from healthy controls and heterozygous carriers who show no signs of the disease? To answer the first question, we were able to look at the literature, which has shown that frataxin levels in buccal cells and blood are predictive of disease severity. It has been shown that the lower the frataxin level in these tissues, the longer the GAA repeat and the earlier the onset of the disease. Further, while published data varies on the level of frataxin in patients, we have referenced a study that shows that patients with FA produce approximately 20% to 40% of normal frataxin levels in buccal cells and blood. While heterozygous carriers who show no disease symptoms display frataxin levels that are about 50% of those seen in healthy controls. Collectively, these findings suggest that peripheral frataxin levels are clinically relevant, highlighting the significance of the results we have presented here today. Now to answer our second question, we can look at data from a noninterventional study we began conducting prior to the coronavirus pandemic. This study, which included healthy controls, measured frataxin levels in buccal cells using the same sampling technique and assay employed in our Phase I MAD trial. While we ended up terminating this noninterventional study due to the COVID-related restrictions, we have data from the first 8 healthy control subjects. If you look at the graph on the right, you'll notice the dashed green line, which represents 60% of the median frataxin levels measured in these 8 healthy controls. You can see from this graph, the patients in the 50 and 100-milligram dose groups both achieved median frataxin levels at or above this line, which notably exceeds the frataxin levels we would expect to see in buccal cells of phenotypically normal heterozygous carriers. Although others have reported toxicity with very high levels of frataxin, the levels we are reporting here do not approach the levels reported in those studies. As we advance the development program for CTI-1601, we will continue to monitor frataxin levels in these tissues and optimize dosing regimen. Given what is known about the predictive nature of buccal frataxin levels or neurological function in FA patients, we believe the favorable comparison speaks to the significance of our Phase I results and the extent to which they demonstrate proof-of-concept for our clinical program. Looking forward, we are planning to collect additional data from healthy controls in a separate noninterventional study utilizing the same sampling techniques in our proprietary assay in order to better inform CTI-1601's continued clinical development. Shifting gears a bit now, I'd like to talk about some of the safety findings from our MAD trial. Based on these findings, CTI-1601 appears to be generally well tolerated when administered daily for 13 days. Of the 27 patients who enrolled in the MAD trial, 26 completed the study with 1 patient in the 50-milligram dose group withdrawing after experiencing mild-to-moderate nausea and vomiting. Notably, we observed no serious adverse events, important medical events or treatment-related severe adverse events in the trial. The most common adverse events were mild and moderate injection site reactions. At least 1 injection site reaction was noted in 43% of placebo patients and in 100% of CTI-1601 patients. I should also note that the number and severity of adverse events did not increase with increasing exposure to CTI-1601. Shifting our focus now to our pharmacokinetic analysis. We found that CTI-1601 was quickly absorbed following subcutaneous administration. Notably, we saw dose proportional increases in exposure with increasing doses of CTI-1601 and a mean half-life of approximately 11 hours. Although we have flexibility and can increase the dose if necessary, these analyses support evaluating a once-daily dosing regimen for CTI-1601. So to summarize our top line Phase I findings. Repeated subcutaneous injections of CTI-1601 appear to be generally well tolerated at doses up to 100 milligrams administered daily for 13 days with no serious adverse events reported in either of the SAD or MAD trials. Pharmacodynamic assessment showed that daily subcutaneous administrations of CTI-1601 resulted in dose-dependent increases in frataxin levels from baseline compared to placebo in all evaluated tissues, which included buccal cells, skin and platelets. This finding was particularly notable given that frataxin levels in buccal cells have been shown to correlate with neurological function in patients with FA. Moreover, we were able to achieve frataxin levels that exceed the frataxin levels we would expect to see in phenotypically normal carriers of the FA gene based on data and 8 healthy controls obtained from a noninterventional trial using our collection techniques and proprietary assay. Finally, our pharmacokinetic assessments showed that CTI-1601 was quickly absorbed with dose proportional exposure supporting the evaluation of once-daily dosing in future clinical studies. Collectively, we believe these results demonstrate proof-of-concept for CTI-1601 as they establish its ability to deliver the critical protein to peripheral tissues that patients with FA are missing. Let me switch gears for a moment. We have several events coming up this year. In particular, we are planning to discuss this data and our future clinical development plans with both the FDA and the European Medicines Agency. As you may also have seen in our 10-Q filed last night, we have an ongoing 180-day nonhuman primate study in which mortalities were observed in the highest dose groups. FDA is aware of these findings and as dosing in the study is ongoing, we continue to collect relevant data, and we'll share it with the agency prior to the initiation of future clinical trials. While the cause of these findings has not yet been determined, what I can say now is that based on all of the information we have from our clinical and nonclinical programs to date plus extensive input from toxicologists and other relevant experts, we do not expect these nonclinical findings to impact our previously disclosed time lines with regards to our JIVE open-label extension and pediatric MAD trials, both of which we expect to initiate in the second half of the year. Looking a bit further down the road, we are planning for a global pivotal study as early as the second half of 2022. In addition, we will also be engaging in conversations with the regulatory authorities so that we are pursuing the most expeditious development path in an attempt to provide access to CTI-1601 as soon as it's feasible. Let's now refocus on the clinical program. Slide 21 provides an overview of our JIVE trial, which is a multicenter open-label extension trial that we expect to initiate in the second half of the year. Patients from both our SAD and MAD trials will be eligible to screen for JIVE as will patients from a pediatric MAD trial, which is also expected to begin in the second half. While the exact dosing levels evaluated in JIVE will be determined based on additional analysis from our Phase I program. We expect to treat patients in JIVE for up to 24 months with any necessary extensions. We expect to enroll up to 50 patients who will likely be given once-daily doses of CTI-1601 administered subcutaneously. While there will be no placebo group for the JIVE trial, we will utilize an external control arm derived from the critical path institute data. The primary endpoint of JIVE will be safety and tolerability, while key secondary endpoints include long-term measurements of frataxin levels and efficacy assessments. The long-term data we gained from this study will be very useful as we work to advance the CTI-1601 development program. Now before we move to Q&A, I just wanted to once again sum up the key findings and conclusions from our Phase I data. First, we saw that repeated subcutaneous injections of CTI-1601 appear to have been generally well tolerated at doses up to 100 milligrams administered daily for 13 days. Second, we saw dose-dependent increases in frataxin levels from baseline compared to placebo controls in all evaluated tissues with daily dosing. And third, our pharmacokinetic and pharmacodynamic analysis support evaluating a once-daily dosing regimen for CTI-1601. As I mentioned several times throughout the call, the frataxin levels achieved in buccal cells with CTI-1601 administration were equal to or in excess of those we would expect to see in heterozygous carriers who show no signs of disease. Given that insufficient frataxin levels are the root cause of Friedreich's ataxia, we believe that these exciting findings demonstrate proof-of-concept for CTI-1601. It is also important to note that to the best of our knowledge, CTI-1601 is the only drug candidate in clinical development that is designed to supplement frataxin levels in patients with FA, thus addressing the root cause of the disease. Finally, I would like to take a minute to acknowledge that none of the progress we have discussed here today would have been possible without the commitment of our patients, the great work being done by the Friedreich's ataxia research alliance or the talent of our employees, partners and investigators. I am extremely grateful to all of these individuals for the important roles they have played in advancing CTI-1601's clinical development. With that, I'd like to extend one last thank you to all of those listening to our call today. We will now open the call to questions. Operator?

[Operator Instructions] Our first question comes from Myles Minter of William Blair.

Congrats on the data. It's really nice to see this frataxin expression, and it's a great outcome for patients, really. My first question is on cohort 2. It seems as if there's been a slight decline in expression from day 7 to day 13 across the tissues. Just trying to clarify whether that's just due to the reduction in the dosing frequency in week 2 versus week 1? Or is that variability in the frataxin expression of the patients or maybe even the assay? And is it safe to say that when you switch those patients over to JIVE, they'll all be pushing up to the 100 milligram dose? That's the first one.

Myles, it's good to hear your voice. So we believe that the decrease in cohort 2 between day 7 and 13 is because those patients were switched to every other day dosing. So we do believe that it's probably going to at least initially be a daily dose of CTI-1601 that's required. And we think that's borne out by the 100-milligram dose group, where you really don't see that decrease. And so yes, we do think it's because of the change in regimen, which was part of the reason why we designed the trial the way we did. With regard to JIVE being 100 milligrams. We really can't answer that question yet. We're still looking at a whole bunch of other pieces of data. And this is really top line data, and there's still a lot of number crunching that needs to go on, looking at the pharmacodynamic data by patient, looking at it by weight, things like that. So I don't think we really know at this point what dose will be in JIVE. But I do think it's fair to say that it is likely to be daily dosing, at least initially.

Okay. That makes sense. And then on the injection site reaction frequency, I'm wondering whether the incidence rates changed over the 2-week treatment period? Do they occur more frequently or with greater severity upfront as opposed to dosing throughout that second week? Any indications there?

Not that we can tell right now. It was pretty random. Some patients -- like we said, all the patients on the active had at least 1, but not every time they injected do they have an injection site reaction. And I don't think they necessarily change with frequency. We have not looked at yet at site. We used -- we actually administered the drug at 4 sites, both thighs and either side of the abdomen, and those sites were rotated, which is pretty traditional with subcutaneous injections. And so we still have to look at things like site of administration. But these -- the injection site reactions were really very transient, and were -- like we said, mild or moderate.

Okay. The last one before I jump back in the queue, just on the monkey talks. I know you can't really comment too much on it. But when you notified the FDA of this, was there any back and forth commentary with the agency that we should be aware about? And then sort of when you're going to update the agency? And can you give us a sense for the dose ranges that the mortalities occurred in the monkey relative to that, that you're using in the clinic, say, the 100-milligram dose in patients?

Yes. So we don't really like to give a lot of detail with our conversations with FDA. But I can tell you that they have been notified, and they're okay with us submitting the data when we need to and when we're ready to. This trial is still ongoing. So until it's complete and we can get all our data in, I think it's premature to continue to have a lot of conversation with the agency because we have to obviously determine what we think is the cause and have -- make sure that we have all of the data. With regard to dose, I wouldn't focus on dose. I would focus on exposure because that's what's really relevant and what most of the regulatory authorities will look at. And from the standpoint of exposure, we don't have the exposure yet in the 180-day because they're still being dosed. It's still ongoing. But we did complete, as you well know, a 90-day study. And based on the exposure seen in that study, we do have significant safety margins. And so -- and it's the same species of monkey. It's the same size monkey. So I would anticipate that what we saw in the 90-day is relevant. And like I said, we have significant safety margins.

Our next question comes from Jonathan Wolleben of JMP Securities.

Congrats on the data. Just a few for me. When you take a look at the baseline frataxin levels, I'm wondering if this is consistent with what you'd expect based on some of the other characteristics, like you mentioned, 50% of patients being non-ambulatory?

Yes. I think it is. It's really hard to compare frataxin levels across trials because they use different sampling techniques and there's different assays. And I think what's really consistent is that patients usually have somewhere around 20%. We've said 20% to 40%. But I think if you talk to the patient community, they actually think it's closer to 20% or maybe even a little bit less. But I do think it's consistent. And as you saw, it's consistent between patients. I mean the baseline numbers all look pretty similar in all the different tissues with the exception of platelets, which seem to have more variability.

Was there anything besides dose when you look across demographics or patient characteristics for those who seem to have more frataxin observed? And then when you think about the time course, obviously, we're -- it's very short right now, and I have 2 time points. But do you think there's a leveling off here already? Or do you expect to see kind of more increases over time if you continue to dose?

Yes. It's a hard question to answer, Jonathan, and a good one and an important one. I think we really need to get into the JIVE study and go out further to know whether we're actually at steady state or not. There is a theory that frataxin has a longer half-life than probably CTI-1601 does. And even then iron sulfur cluster enzymes may even have a longer half-life. So I think until we actually get into a chronic dosing, like we will in the JIVE study. It's really hard to know whether we could even, at some point, switch to every other day or whether we see -- we're really at steady state and we need to dose daily. But I think we need more data.

And I guess last one for me, to that point. Do you have any sense based on literature or natural history when seeing these increases and levels might translate to some kind of clinical benefits?

Yes. I don't, because nobody else has replaced frataxin. So we've really -- at least historically -- I mean in the animals, you can actually see it relatively quickly. We do, as you may recall, have some clinical data. We did time 25-foot walk for those patients who could walk. We did the 9-hole PEG repeatedly. We've also looked at speech and modified. That data has not yet been analyzed. It's in the process. And we'll be releasing that data later in the year. And so I think that will give us some hint, like I said -- I've said many times, after 13 days, I really don't anticipate to see a clinical outcome. But obviously, we are going to look and evaluate that data. And then once we get into the JIVE study, we'll be able to compare some of that clinical data to our natural -- to the natural history database into our control arm.

Our next question comes from Yatin Suneja of Guggenheim Partners.

Just a couple for me. So it seems like you are emphasizing that only in buccal cells you are achieving frataxin level that are similar or exceeds the heterozygous carrier. What about skin and/or platelets?

Yes. So Yatin, nice to hear your voice again. The reason we talk about buccal cells is because that's the only data we have in the -- first from the literature, it's really just buccal cells. But as importantly, it's the fact that we did this noninterventional study, and we didn't do skin biopsies or platelets. We just did buccal cells. And so that's where we have that control. We are going to be doing a noninterventional study looking at healthy volunteers, where we will be collecting skin and platelets and buccal cells. But it's not because we're so much emphasizing the buccal cells. It's because that's the data we have at this point. I think actually skin is highly relevant. You may -- I'm sure you know the buccal cells are mucosal membranes, so these cells turn over very quickly. And skin is a much more stable tissue as well as the sampling techniques. When you do buccal swabs, how hard you swab, how long you swab, obviously, we tried to control that and we were at a single unit, so it was a bit more easier to control it in our study. But skin biopsies are routine, you're using a specific device. So you always get the same amount of tissue and the same depth of tissue. And so I actually think the skin biopsies are really interesting. And obviously, in those tissues, we saw a threefold increase between days -- baseline and day 13. So I actually really like the skin. Platelets, I think, are a little less indicative, and I think I've said this before to you, because they're intravascular, right? And we know the drug gets into the intravascular space, and we know it's absorbed quickly, and the half-life is about 11 hours. So I think platelets are variable for a whole host of reasons, and I think probably not as relevant because they're not really a peripheral tissue. Buccal swabs and skin are peripheral tissues, and we show that the process protein is in those tissues.