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

Greetings, and welcome to the Larimar Therapeutics conferenc call. [Operator Instructions] As a reminder, this end is being recorded. It is now my pleasure to introduce your host, Grant Weingarten. Please go ahead.

Thank you, operator, and thank you all for participating in today's end call. Before we start, I would like to point out that there is a slide deck that accompany today's presentation. It can be viewed using a 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, announcing top line data from the 25-milligram cohort of Larimar's Phase II dose exploration trial with CTI-1601 and Friedreich's Ataxia. Involves an update on next steps for the CTI-1601 program. This press release also includes Larimar's first quarter financial results. So these are not the topic of today's call. Before passing off to company management for prepared remarks, I would like to remind all listening that some of the information disclosed on this end call contains forward-looking statements that are based on the company's beliefs and assumptions and on the 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, the company's plans to -- and ability to develop and commercialize CTI-1601 and other matters regarding company's 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, company's ability to successfully engage with the FDA and respond to requests from FDA for further information and data regarding the CTI-1601 clinical program, preliminary and top line clinical trial results may differ from final clinical trial results that 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 that 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 in the filings made by the company with the Securities and Exchange Commission and available at 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, 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. Let me start by getting right to today's news. Earlier, we announced preliminary top line data from the 25-milligram cohort of our placebo-controlled Phase II dose exploration trial of CTI-1601 in participants with Friedreich’s Ataxia. This cohort evaluated a 25-milligram dose of CTI-1601 administered daily for 14 days and then every other day until day 28. Safety data from the 25-milligram cohort indicate CTI-1601 was generally well tolerated and pharmacokinetic results suggest that steady state was achieved by day 14. There were no serious adverse events and one participant discontinued due to an allergic reaction that resolved with standard treatment. When looking at changes from baseline in frataxin in skin biopsies of each trial participants, a median placebo-adjusted increase from baseline of 3.5 picograms per microgram protein was seen with 14 days of daily dosing. In addition, I'll note that 7 of 9 CTI-1601 participants had quantifiable levels of frataxin at both baseline and day 14. All 7 of these participants had increases in frataxin and skin biopsies on day 14. Comparatively, all 4 placebo participants had quantifiable levels of frataxin at each time point, and none had an increase in frataxin. To provide context for the frataxin increases absorbed in skin in our Phase II trial, I'll note that we conducted a non-interventional study in 60 homozygous healthy volunteers. In this study, the median frataxin level observed in skin biopsies with 16 picograms for microgram protein. Based on the published literature, we would then expect phenotypically healthy heterozygous carriers to have a median skin frataxin concentration of approximately 8 picograms per microgram protein or roughly 50% of the levels of healthy homozygous. I'll also note that this study utilized the same sampling technique and assay as all of our clinical trials, allowing us to compare between our studies. Therefore, we believe, the median placebo-adjusted increases from baseline in skin frataxin observed in our Phase II study speak to CTI-1601's potential, particularly given that we did not see increases in frataxin in our Phase I study when 25 milligrams was dosed for only 4 days daily. We look forward to sharing more detailed data from our non-interventional study in a future publication or at a future medical meeting. In buccal cells, which we believe are more prone to variability due to the sampling technique used to collect them as well as their high turnover rate, we saw a median placebo-adjusted increase from baseline of 0.9 picograms per microgram protein, increase in frataxin concentration from daily dosing for straight 14 days. Like in skin, 7 of 9 CTI-1601 participants had quantifiable levels of frataxin at both baseline and on day 14. Of these 7 CTI-1601 participants, 5 had increased buccal cell frataxin concentrations on day 14. For placebo participants, 2 had quantifiable levels of frataxin in buccal cells at baseline and day 14, with neither showing an increase in frataxin. Comparing back to the aforementioned non-interventional study, the median frataxin concentration in buccal cells for the 60 homozygous healthy volunteers assessed was 8 picograms per microgram protein. Therefore, we would expect phenotypically healthy heterozygous carriers, to have a median buccal cell concentration, frataxin concentration of approximately 4 picograms per microgram protein. Again, we believe comparing these findings to our Phase II results speaks to CTI-1601's potential. These Phase II pharmacodynamic results build upon our proof-of-concept Phase I data, which showed increases in skin and buccal cell frataxin concentrations with daily dosing of 50 and 100 milligrams of CTI-1601 for 7 days. The data from our Phase II trials 25-milligram cohort have been submitted to the FDA for review as requested by the agency in their September correspondence. We have scheduled a meeting with the FDA later this quarter to discuss whether the data submitted are sufficient to gain clearance to initiate a 50-milligram cohort in our Phase II dose exploration study. We expect to provide an additional update on the CTI-1601 program in the first quarter of the year after we have received feedback from our upcoming meeting. Before I go on to provide some background on Larimar as well as additional details on our new clinical results and planned next steps for CTI-1601, I would like to provide some additional context for today's announcement. Those of you who follow Larimar closely, like we recall that we originally planned for a regulatory update this quarter that did not include an announcement of top line results from our trials 25-milligram cohort. This plan was based on the expectation that FDA would be -- only be reviewing blinded data from the study. During the course of our interactions with FDA, the agency requested unblinded data from the trial. Given the results that arose from analysis of unblinded data, we felt it was important to share them with the investment community in a timely fashion. Looking ahead, if the FDA clears us to move forward with the second cohort, we expect to report top line safety pharmacodynamic and pharmacokinetic data from the second cohort after its completion. We plan to provide guidance on the expected timing of that data release after we have our meeting with the FDA and come to a consensus on the next steps for CTI-1601. For those listening who are less familiar with Larimar, let me provide some background on the company and what led us to today's announcement. Larimar is a clinical stage biotechnology company with a novel protein replacement therapy platform. Our lead therapeutic candidate is CTI-1601, a recombinant fusion protein that is being developed as a treatment for Friedreich’s Ataxia or FA as I'll sometimes refer to it. FA is an orphan disease that results from a genetic defect that causes patients to have insufficient levels of frataxin, which is a crucial mitochondrial protein. CTI-1601 is designed to directly address frataxin deficiency by delivering frataxin to mitochondria. In Phase I trials and participants with FA, we saw dose-dependent increases in frataxin levels in peripheral tissues with daily dosing of CTI-1601, providing clinical proof of concept for the program. Importantly, our Phase I data also indicated that CTI-1601 was generally well tolerated when administered via subcutaneous injections daily for 13 days at doses up to 100 milligrams with one participant in the 50-milligram cohort discontinuing due to mild to moderate nausea and vomiting after the first dose. There were no serious adverse events and the most common adverse event was mild to moderate injection site reactions. No participants discontinued due to injection site reactions. After the conclusion of our Phase I trials, the CTI-1601 program was pushed -- placed on an FDA clinical hold due to mortality in a 26-week nonhuman primate toxicology study. These mortalities occurred in the 2 highest doses of the 4 total dose groups that were studied. We subsequently performed and submitted extensive analysis from our clinical and nonclinical studies to FDA, ultimately receiving clearance to initiate the 25-milligram cohort of a 4-week Phase II placebo-controlled dose exploration trial of CTI-1601 in participants with FA. In accordance with the partial hold imposed by the FDA as part of their decision to lift the prior full clinical hold, we were required to submit data from this 25-milligram cohort to the FDA prior to dose escalating in the Phase II study or initiating any other studies of CTI-1601. The requested data have been submitted and the FDA now is now reviewing the information ahead of the meeting, we will be having with the agency later this quarter. During this meeting, we plan to discuss the proposed dose escalation to 50 milligrams in a second cohort in our Phase II trial, as well as gain additional insights on the optimal development path for CTI-1601 as we move the program forward. As we work towards our upcoming FDA meeting, we are doing so with cash runway that we expect will extend into the second half of 2024. Thanks to our cash balance of approximately $111.5 million as of the end of the last quarter. Next, I'd like to briefly give some background on FA and the current treatment landscape to put some context around the new data we shared today. I'll start with some background on Friedreich’s Ataxia, which is a rare autosomal recessive genetic disease with truly devastating symptoms. FA 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. The longer a patient's GAA repeat, the less frataxin he or she will produce. With a typical patient with FA producing about 20% to 40% of the frataxin levels seen in homozygous healthy people. Not having enough frataxin leads to a myriad of debilitating symptoms and complications, 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 symptoms and complications of FA include loss of musculoskeletal function, blindness, deafness and inability to speak clearly and diabetes. Unfortunately, patients with FA have a life expectancy of only 30 to 50 years with the most common cause of death being heart disease. While omaveloxolone was approved as the first therapy indicated for FA earlier this year in what was a critically important breakthrough for patients, there are still no approved agents designed to increase frataxin and address the deficiency underlying FA's horrible symptoms. Because of this, key opinion leaders and 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 the key findings from our Phase I program, which informs the design of our Phase II study and provided clinical proof-of-concept for CTI-1601. These earlier results provide important context for the findings we are sharing today. I'll start by drawing your attention to the graph on the left side of your slide. This graph shows changes in frataxin levels from baseline in skin normalized to total protein for the placebo, 25-, 50- and 100-milligram dose groups in our Phase I multiple ascending dose trial. We chose skin as one of the evaluated tissue types in our clinical program because skin cells have a relatively low turnover rate and a standardized collection method is available. This makes data obtained from skin less variable than data obtained from tissues such as buccal cells, which are subject to more turnover and do not have a standardized collection method. Of course, skin biopsies cannot be performed frequently as they are invasive and therefore, burdensome for trial participants. Thus, in our Phase I trial, we collected skin samples only at baseline and day 13 and in our Phase II study only at baseline, day 14 and day 28. As you can see in the [ regime ] at the bottom of the slide, participants in the Phase I trials 25-milligram group were dosed daily for 4 days and then every third day through day 13. Participants in the 50-milligram group were dosed daily for 7 days and then every other day through day 13. Participants in the 100-milligram group were dosed daily for 13 consecutive days. With this in mind, I should note that for the Phase I study, the results for skin at day 13 reflect frataxin levels measured after patients switched to intermittent dosing regimens, with the exception of the 100-milligram dose group, where they were dosed daily for the full 13 days. On the graph on the left, you see results from skin biopsies that showed a dose-dependent increase in frataxin from baseline compared to placebo at day 13 and in the 50-milligram and 100-milligram dose groups. In the graph, the dots represent a median and the horizontal lines the 25th and 75th percentile. Moving to the graph on the right, you can see data from buccal cells. We chose to evaluate buccal cells because there is a body of literature on frataxin levels in these cells, including published studies indicating buccal cells frataxin levels correlate with neurological function in patients with FA. As explained before, the inherent variability in buccal cell sampling and the high turnover rate of these cells can make the resulting data on frataxin concentrations, a bit noisy, which is why it is important to evaluate multiple tissue types and look at data in its entirety. Taking our Phase I data from skin and buccal cells together, you can see that results between tissue types were consistent, though we observed increase in median frataxin was more pronounced in skin. Importantly, this aligns with what we've seen in our Phase II trials 25-milligram cohort Taking a closer look at the Phase I data from buccal cells, you'll notice that in the first section or data on day 4 for the 25-milligram cohort and day 7 for the 50 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 clear and dose-dependent increase in frataxin from baseline compared to placebo with daily dosing for 7 days at 50 and 100 milligrams. Similar to skin, we did not see increases in frataxin in buccal cells in the 25-milligram cohort. Though I'll again remind you that participants in this cohort were dosed daily for only 4 days. Now let's focus on the data from the 50-milligram cohort, which is relevant, given that assuming FDA agrees, this will be the next dose we aim to study. As I mentioned earlier, we see a clear increase in frataxin levels from baseline on day 7, which is the last day of daily dosing. If we then look at the data between day 7 and day 13, we can take away a key insight that informs the design of our Phase II trial. As you can see, while moving to every other day dosing -- to every other day dosing regimen between day 7 and day 13, it led to a slight decrease in buccal cell frataxin, though levels still remained above baseline. These findings led us to explore a regimen that included an initial period of daily dosing followed by every other day dosing in our Phase II trial. On this next slide, you can see graphs where each bar represents an individual participant from our Phase I trial. Looking at the color coding and moving from left to right in each graph, you'll notice that the largest increases in frataxin concentration from baseline came from higher dosing cohorts with more frequent administration. These data speak to the dose dependency of the encouraging pharmacodynamic results from our Phase I trial, which we believe provides proof of concept for CTI-1601. Shifting gears. This slide shows the design of our Phase II trial. As I mentioned earlier, this trial was informed by our Phase I results with key questions being, whether frataxin levels could be raised with extended daily dosing of 25 milligrams of CTI-1601 and weather increased for taxing levels achieved with 2 weeks of daily dosing, could be sustained by following up with less frequent dosing. The trial enrolls ambulatory and non-ambulatory participants with FA, who are at least 18 years old. Participants are randomized 2:1 to receive CTI-1601 or placebo, with the first cohort enrolling 13 participants, 9 on active treatment and 4 on placebo. Participants are dosed daily via subcutaneous injection for the first 14 days and then every other day thereafter through day 28. With this design, we aim to further characterize the PK/PD and safety profiles of CTI-1601, to enable its continued clinical study and inform the long-term dose and dose regimen. Here on Slides 9 and 10, you can see the demographics and disease characteristics of participants to enroll in the Phase II trials 25-milligram cohort. Since these slides are posted on our website, I won't go through this in detail now, but we'll note that the demographics in this trial are similar to those in our Phase I program. In addition, I'll note that 5 participants in our Phase II trial previously participated in the Phase I program. Here on Slide 11, you can see the key takeaways of the Phase II trial safety and pharmacokinetic data, both of which are encouraging. With our latest data, our safety database is up to 37 different patients with FA treated with CTI-1601. Overall, data from both our Phase I and Phase II trials are consistent with results from each indicating that CTI-1601 has been generally well tolerated. Of the 13 participants who enrolled in our Phase II trials, 25-milligram cohort, 9 were randomized to active treatment and 4 to placebo. Of the 9 participants randomized to active treatment, 8 completed dosing with 1 withdrawing due to an allergic reaction to the steady drug, which resolved with standard treatment. There were no serious adverse events nor important medical events observed in the cohort. There was a single severe adverse event reported in the cohort, which was the aforementioned allergic reaction that resolved with standard treatment. The most common adverse events were mild and moderate injection site reactions with at least 1 injection site reaction seen in 2 of 4 placebo participants and 9 of 9 CTI-1601 treated participants. No participants discontinued the study due to injection site reactions. With regards to the pharmacokinetics, data from the trial suggest steady state was achieved in the 25-milligram cohort by day 14, which was the last day of daily dosing before participants were switched to an every other day dosing regimen. This is an important finding that will inform CTI-1601's long-term dose and dose regimen. On this next slide, you can see the preliminary top line data from skin biopsies in our Phase II trials, 25-milligram cohort with the graph showing change from baseline in frataxin concentrations normalized to total protein. These results, therefore, represent the additional frataxin supplied by administration of CTI-1601. As with the Phase I results, I reviewed, the points in the graph on the left represent medians while the horizontal lines represent the 25th and 75th percentiles respectively. Looking at the graph on the left, you can see a median placebo-adjusted increase from baseline of 3.5 picograms per microgram protein and frataxin concentrations on day 14 for CTI treated participants. If you then look at the data from day 28, you can see how frataxin levels changed during the period when participants switched from daily to every other day dosing. Looking between these time points, you can see that frataxin levels in skin decreased though the median remains above baseline levels. Taken together with day 14 skin data, these results provide us with 2 important learnings; first, they suggest we can increase frataxin in skin with daily dosing of CTI-1601 at only 25 milligrams. Given frataxin deficiency is what underlies FA's devastating symptoms, we believe this is a crucial finding that speaks to CTI-1601's potential to provide a clinical benefit. Second, these results suggest that when dosing at 25 milligrams, a daily dosing regimen may be preferred to maintain increases in frataxin levels. They, therefore, provide a preliminary answer to both of the key questions we had going into our Phase II trial, 25-milligram group. Additional data from future cohorts and studies will enhance this understanding. Moving on to look at the graph on the right. You can see a more detailed representation of the data on changes in frataxin in levels from baseline. Each bar shown represents an individual participant with participants who had for tests and concentrations below the limit of quantification either at baseline or day 14 excluded from these representations. Of the participants with all quantitative data available, 7 of 7 receiving CTI-1601 achieved an increase in skin frataxin levels at day 14, while no placebo participants had increased skin frataxin levels. I'll also point out that there was one CTI-1601 treated participant who had quantifiable levels of frataxin at baseline but not on day 14. And there was one participant with no day 14 sample because they discontinued from the study due to an allergic reaction. Here on Slide 13, you can see data from buccal cells, again, with the data shown as changes in frataxin concentration from baseline. As you can see, there was a median placebo-adjusted increase from baseline of 0.9 picograms per microgram protein in frataxin concentration at day 14, consistent with what we saw in skin. I should note, however, that the data in buccal cells are a bit noisy likely due to the inherent variability of the sampling technique used to collect these cells and their rapid turnover. Turning our attention to the next section of the graph, we can see that frataxin levels decreased back to approximately baseline on day 28 after 14 days of alternate day administration of CTI-1601. Looking at buccal cell data from individual participants, 5 out of 7 CTI-1601 participants with quantitative data available at both baseline and on day 14 has increased frataxin concentrations on day 14 compared to neither of the 2 placebo patients. I'll also note that 2 placebo participants do not have quantifiable levels of frataxin at either baseline or on day 14. Taking our results together, we are very pleased that the data from skin and buccal cells from both our Phase I and Phase II trials show consistency in the observation of frataxin increases throughout the data sets, as well as the preference for daily administration when aiming to maintain increases in frataxin. Given the central role, frataxin deficiency plays in FA's pathophysiology, we view this as an encouraging finding. As we look ahead, we plan to provide our next regulatory update on CTI-1601 in the third quarter after we have had the chance to get feedback from our upcoming FDA meeting. Our goal is to gain FDA clearance to move to a 50-milligram cohort in the Phase II trial which would evaluate the same dosing schedule utilized in the 25-milligram cohort. Looking a bit further down the road, assuming we receive FDA clearance to proceed, our current clinical development plan for CTI-1601 also includes our open-label extension trial and a multiple ascending dose trial in individuals with FA who are in between 2 and 17 years old. We believe this pediatric study will be particularly exciting from a clinical perspective as there are currently no drugs approved for individuals with FA who are under 16. Collectively, the results of our Phase I, Phase II open-label extension and pediatric trials are expected to provide valuable information related to CTI-1601 safety, potentially effective dose, dose regimen and ability to increase frataxin levels and impact clinical function. This information is in turn expected to inform the design of a global double-blind placebo-controlled pivotal trial. To summarize today's presentation, we are at an important and exciting point in CTI-1601's development as the first therapeutic intended to increase frataxin levels and address the protein deficiency underlying Friedreich’s Ataxia. We believe our Phase I data first demonstrated CTI-1601's potential to do this as we saw increases in frataxin and peripheral tissues when CTI-1601 was dosed daily for -- at 50 milligrams for at least 7 days. We have now built on these proof-of-concept data with Phase II results that demonstrate we can increase frataxin in skin and buccal cells with daily dosing of 25 milligrams for 14 days. We are now preparing to meet with the FDA to discuss our latest Phase II results with the goal of gaining clearance to initiate a subsequent cohort evaluating a 50-milligram dose with a regimen identical to that of our first cohort. We expect our next update will be in the third quarter. Finally, before we open the call for questions, 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 all the talented Larimar employees, partners, 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, we will now open the line for questions. Operator?

[Operator Instructions] And our first question comes from Yatin Suneja with Guggenheim Partners.

Thank you for providing such a comprehensive view. So, couple for me. So the first one is, could you talk about the differences in increases in frataxin level that you are seeing in skin versus the buccal cells because in skin, you're definitely bringing it up a lot more than in the buccal cell? So that's the first question. I have a couple more.

Thanks, Yatin. Good to talk to you. Thanks for joining. So in our non-interventional study, which is we did genetically test. So we know people -- the participants in that study are healthy and homozygous. You do see higher levels of frataxin in skin than you see in buccal cells. In skin, it was about 16 picograms for microgram and buccal cells, it was about 8. And so skin is a more stable tissue. And quite honestly, may be more reflective of the tissues that we're trying to target because you don't have as much turnover in heart, neurological tissue, CNS or muscle as you do in buccal cells, which turn over really quickly because they need to be replenished. You also have a bit noisier environment from when you actually do the sampling. That's actually been reported in the literature as well. So the fact that we see differences in frataxin levels in different tissues, I don't think it's surprising. I think that was your question.

Yes. Got it. So then in terms of the increases that you are seeing between -- in patients that are showing increases in skin. So the question is, are the patients that are showing a robust increase in skin are also showing a similar sort of increases in buccal cells? Or are there differences?

No, they're similar. And you can tell that by the fact that 7 out of 7 had increases in skin and 5 out of 7 had increases in buccal cell. So everybody that completed the study had increases with the exception of one.

Got it. Got it. And then so going into this readout, we didn't expect it to show any increases in frataxin level. So based on better-than-expected increase in frataxin level that you are seeing, even at the 25-milligram dose, would you want to study it further in maybe more chronic therapy, maybe more -- maybe on a 28-day continuous basis? Or would you just go to the 50 milligram? And even for the 50 milligram, would you propose at 14 days chronic versus and then the next 14 days intermittent? Or would you do a chronic for 28 days?

Yes. I think we are obviously having conversations with the FDA on some of these points, right? I do think that looking at 25 milligrams for extended periods of time, I would say, longer than 28 days might very well be useful because, again, we did not assess whether we're actually at steady state. We may still be getting some increases. So -- or that some of the patients who didn't have as robust increase may have a greater increase if they dose for longer. With regard to the 50 milligram, I think we're still planning to go ahead with 2 weeks of daily dosing and then 2 weeks of every other day. And the reason for that is that part of the challenge with our Phase I study was the different dosing regimens. And so maintaining the same dosing regimen will allow us to do a lot more modeling and get a lot better understanding of the PK/PD relationship. If we start to switch it around, it becomes a lot harder to compare between the cohorts. So I think at least for now, the plan is to do 50 milligrams for 14 days daily and then go to every other day.

Got it. Then final question for me. Could you articulate a little bit more about the allergic reaction that we're seeing? What was it? What about preclinical studies? Was there a signal there?

Yes. It's not a signal. You're dosing a protein to people, you often get a reaction. And it was a typical allergic reaction. The person developed a rash and was treated with standard therapy with antihistamines and steroids and it resolved on his end on its own. He was rechallenged and then had a similar reaction. So we do believe it was an allergic reaction. Probably to the drug, it could have been to an excipient as well, but probably to the drug.

Our next question comes from Myles Minter with William Blair.

Congrats on the data. Maybe from a regulatory perspective, when was the request made by the FDA that they did definitively want to see this data unblinded from a frataxin expression perspective because obviously, the narrative going into this was that they were going to see unblinded safety data and then make a decision. So just wondering when that changed? And did that give you any indication as to why they wanted to see the data? Is it just like you have it in-house, therefore, we'd like to see everything we can? Or was it more pointed that they wanted to see some sort of exposure relationship and frataxin expression relationships in individual patients?

So Myles, obviously, we don't want to disclose a lot of our conversations with the FDA. They're currently reviewing our data. We felt like we needed to put this out there because we think it was so positive and so interesting and so insignificant or so important, I should say. But the conversations with the FDA are still really going on. You're right, they originally -- or I shouldn't say, we originally thought that unblinded data will suffice. They did come back and ask for the data to be unblinded. I can't tell you, honestly, for sure why they wanted that. We obviously looked at the frataxin data in a blinded fashion, and there were some subtle suggestions that something might be going on. But it's hard when you're looking at the entire group of 13 and the placebos are sort of mixed in with the non [indiscernible] I don't know whether -- I can't really speak to what their motivation was. But obviously, this drug is supposed to increase frataxin levels. So I don't think it's odd that they would want to see the PD data as well.

Okay. That's fair. Then maybe a more technical question. Just what is the lower limit of quantification on the frataxin assay that you're using? Just interesting to see a couple of patients drop below that, regardless of whether they're on or off therapy, given that I thought frataxin -- FA patients have about 20% of frataxin levels of normal at any given time. So just wondering what that lower limited of quantification is?

It's pretty low. I have to get it for you, but it's obviously in picograms per microgram. I mean it's pretty low. These are small numbers. But we quote that 20% to 40%, but patients who have early onset before the age of 14 really have much lower numbers. And if you talk to some of the KOLs, they will even say that the patients with the really aggressive course who present early have levels of 5%. Because remember, in our trial, we're including late onset patients as well. We have patients -- I have to look at the demographic, but well, there are 60, which are laid on to patients. And they actually have higher levels of frataxin, we've been able to look at that and it does curly. So I think you're going to have -- you have a pretty wide spread here and the fact that some of these patients with early onset have very low levels or maybe below the limit of quantification, I don't think is surprising.

And final one for me is just back on the potential allergic reaction here. Did that patient just receive a single dose of 1601? Or is it somewhere later down the treatment course?

That patient actually participated in trials prior to as well in our Phase I program. And he received more than a single dose.

Congrats on the data.

Our next question comes from Jon Wolleben with JMP Securities.

Just piggybacking on the park comment, Carole, any differences in baseline characteristics, frataxin changes or safety in the 4 patients that previously participated in the 1601 studies?

I think they were 5 and no, the demographics from the Phase I, the Phase II trial are pretty -- very, very similar. But like I said, it is a broad population. It's not -- it's not the population you're used to seeing in the Phase III trial, where they're all ambulatory and the age range is reduced. These are ambulatory and non-ambulatory, as you recall, half of the patients in the Phase I program were actually non-ambulatory in wheelchairs. And then we have a relatively broad age range. Obviously, nobody below 18 but we do go all the way up and include later on some patients who are over [indiscernible].

Okay. And you mentioned steady state in the prepared comments in one of your answers. Want to confirm if it was at steady state at day 14? And then based on the preclinical data, would you expect to see continued increases in frataxin if dosing was maintained at a daily regimen and you were at steady state?