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

Greetings, and welcome to the Larimar Therapeutics conference call. [Operator Instructions] I would now like to turn the conference over to your host, Grant Weingarten of LifeSci Advisors. Thank you.

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 will accompany today's presentation. This slide deck can be viewed using the webcast link provided in the Investors page of Larimar Therapeutics website. Also posted on this web page is a news release issued earlier today announcing Larimar's planned next steps for the CTI-1601 clinical program following the receipt of FDA clearance to initiate the 25-milligram cohort of a Phase 2 dose exploration trial of CTI-1601 in Friedreich's ataxia patients. In addition, the web page also includes a separate press release announcing the pricing of a $70 million underwritten offering of Larimar common stock. Before passing it off to company management for prepared remarks, I would like to remind all listening that some of the information contained in these news releases 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 included 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 company's business. Company's plans 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. The earlier nonclinical and clinical data and testing of CTI-1601 may not be predictive of the results or success of clinical trials 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 in the filings made by the company with the Securities and Exchange Commission available at www.sec.gov. These forward-looking statements are based on a combination of factors currently known by the company and its projections of the future about which it cannot be certain and 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. Carole is joined by Lamar's Chief Financial Officer, Mike Celano who will be available during the question-and-answer session following the prepared remarks. With that, I will now turn the call over to Carole.

Good morning everyone. I'd like to begin my remarks by thanking the FDA for their engagement throughout the clinical hold process and by expressing my enthusiasm for CTI-1601's upcoming return to the clinic. Given the urgent need for disease-modifying Friedreich's ataxia therapies and the strength of the clinical data we've generated to date. We believe the agency's decision is an important event for both the Larimar team and the entire Friedreich's ataxia community. Our upcoming Phase 2 trial is expected to generate additional clinical data that will allow us to better characterize the pharmacokinetics and pharmacodynamics of CTI-1601 and identify the dose and dose regimen for future long-term clinical trials. This data will help us move this program forward towards our goal of improving the lives of patients with Friedreich's ataxia and their families. Now taking a step back for those less familiar with Larimar. CTI-1601 is a recombinant fusion protein derived from our novel protein replacement platform. It is designed to address the root cause of Friedreich's ataxia or FA as I'll sometimes call it. FA patients are deficient in frataxin, a crucial mitochondrial protein. CTI-1601 is intended to deliver frataxin to the mitochondria patient, thereby improving this deficiency. Last year, we announced the top line results from placebo-controlled single and multiple ascending dose Phase 1 clinical trial evaluating CTI-1601 in patients with Friedreich's ataxia. These results which we believe demonstrated clinical proof of concept for CTI-1601 showed dose-dependent increases in frataxin levels in all evaluated tissues. After daily dosing, the frataxin levels observed in these tissues actually met or exceeded the levels we would expect to see in phenotypically normal heterozygous carriers of the FAG. In addition, the data also indicated that CTI-1601 was generally well tolerated when administered daily for 13 days at doses up to 100 milligrams administered subcutaneously. On today's presentation, we will be discussing our upcoming clinical plans for CTI-1601 following the FDA's decision to lift the program's full clinical hold which was put into place after mortalities were observed in the 2 highest dose groups of a 26-week nonhuman primate toxicology study and imposed a partial hold on the program. With this decision, the FDA cleared CTI-1601 for a return to the clinic and the initiation of the 25-milligram dose cohort of a Phase 2 dose exploration trial. The design of this upcoming trial was submitted to FDA as part of our complete response. The only change the FDA requested was to review the data from the 25-milligram cohort prior to escalating the dose in the second cohort. Initiation of the Phase II trial is expected in the fourth quarter of this year with top line data expected in the second half of 2023. As we work towards CTI-1601's continued development we are fortunate to be doing so with the support of a strong shareholder base that includes our founding investor, Deerfield Management and additional top-tier institutions. We had approximately $54.9 million in cash as of June 30. And earlier today, we're very pleased to announce the pricing of a $70 million underwritten offering of common stock. Based on our current projections the anticipated proceeds from the offering announced today together with our existing cash resources will provide us with runway into the second half of 2024. So now that I've introduced the main takeaways of today's presentation, I want to briefly provide context for our clinical plans by providing an overview on Friedreich's ataxia, CTI-1601 and our exciting clinical proof-of-concept data. Friedreich's ataxia is a devastating rare disease caused by a genetic defect consisting of a repeat of the GAA codon that prevents patients from producing sufficient amounts of frataxin which as I mentioned earlier is a key mitochondrial protein. Typically, a patient with FA will produce about 20% to 40% of normal frataxin levels. The amount of frataxin a specific patient produces is dependent on the length of their GAA repeat. The longer the GAA repeat, the lower the frataxin levels. It is also important to note that the vast majority of FA patients are producing some normal frataxin. They just do not have enough. Insufficient levels of frataxin cause a host of truly terrible and debilitating systemic symptoms. These symptoms often present before age 14 and include heart disease, progressive neurological symptoms that typically force patients into a wheelchair about 7 to 10 years after diagnosis. In addition, patients may develop diabetes, they may go blind and deaf and may lose the ability to speak. Unfortunately, there are no approved therapies for FA. Current treatments are limited to symptom management. There is, therefore, a pressing unmet need for disease-modifying therapies that can slow, halt or even prevent progression of the disease. CTI-1601 was designed specifically with this need in mind as it seeks to address FA's root cause by delivering mature frataxin to the mitochondria. To best explain how CTI-1601 does this I'll turn your attention to the left side of this slide. Here you'll see the structure of endogenous frataxin which is coded in the nucleus and produced in the cytoplasm as what I often call a pro protein. This pro protein includes a mitochondrial targeting sequence or MTS which will enable the transport of frataxin from the cytoplasm into the mitochondria as its name implies. Once within the mitochondria the MTS will be enzymatically removed by mitochondrial processing peptidase leaving mature frataxin behind to function. Turning your attention to the slides right panel. You can see the design of CTI-1601 which consists of 3 portions. The blue and green portions are those making up endogenous frataxin and include the MTS and a mature frataxin segment. The magenta portion consists of a small amino acid sequence known as the cell-penetrating peptide or CPP, intended to carry the molecule across the cell in mitochondrial membranes. This peptide is importantly attached on the end of the MTS rather than to the mature frataxin segment. This elegant design maintains the cleavage site between the MTS and mature frataxin. This allows the fusion protein to be transported into the cell and then delivered to the mitochondria where the mitochondrial processing peptidase can enzymatically remove both the CPP and MTS, leaving behind mature frataxin to address FA's root cause. So with that overview of FA and CTI-1601's mechanism of action complete, let's move on to our planned next steps for the clinical program. As I previewed in my opening remarks, we are now working to initiate a placebo-controlled Phase 2, 4-week dose exploration study in Friedreich's ataxia patients. The design of the trial which builds on our prior clinical proof-of-concept data is shown here. Similar to any Phase 2 study, this trial aims to further characterize pharmacodynamics, pharmacokinetics and safety to inform on the best long-term dose and dose regimen. Eligible patients will include ambulatory and non-ambulatory individuals with FA who are at least 18 years of age. Patients may be CTI-1601 treatment-naive or have previously participated in our Phase 1 SAD or MAD trials. The first cohort of the upcoming Phase 2 trial will evaluate a 25-milligram dose of CTI-1601 with dose escalation to 50 milligrams in the second cohort, contingent on the submission and review of the data from the first cohort by the FDA and the review by the trial's independent data monitoring committee. Patients in each cohort will be randomized 2:1 to receive CTI-1601 or placebo daily via subcutaneous injection for 14 days and then every other day until day 28. We expect to enroll a total of approximately 24 to 30 patients in the trial, 12 to 15 patients per cohort. Key endpoints in the trial will include safety and tolerability assessments as well as measures of frataxin levels in buccal cells and skin. In addition, we will be looking at CTI-1601's effects on the patient's lipid profile and gene expression. With this design we are looking to answer several important questions including whether frataxin levels can be raised with extended daily dosing of 25 milligrams of CTI-1601. As I'll show you shortly data from cohorts 2 and 3 of our Phase 1 MAD trial showed that subcutaneous injections of 50 milligrams or 100 milligrams of CTI-1601 administered daily for at least 7 days resulted in frataxin levels in buccal cells that were at or in excess of those that would be expected and phenotypically normal heterozygous carriers. Cohort 1 of the MAD trial which evaluated a 25-milligram dose explored a daily dosing regimen for only 4 days before switching to a regimen that dose patients once every 72 hours. Starting the Phase 2 trial with 14 days of daily dosing at 25 milligrams will therefore provide data that will be crucial towards understanding CTI-1601's minimum effect dose. A visual representation of the Phase 1 MAD trial design can be seen here. As I just mentioned, Cohort 1 in the MAD trial evaluated daily dosing of 25 milligrams of CTI-1601 for 4 days and then every third day after that until day 13. In Cohort 2, we administered 50 milligrams of CTI-1601 daily for 7 days before moving to a once every other day dosing schedule until day 13. Finally, patients in Cohort 3 were given a 100-milligram dose daily for 13 consecutive days. The study was designed in this fashion to ensure that safety was established at lower doses with less frequent dosing before doses and dosing frequency were increased. In addition, this allowed for the pharmacokinetics of CTI-1601 to be characterized at the lower doses before escalating to the next higher cohort. This is typical of a first-in-human study that seeks to establish a study drug's clinical safety and pharmacokinetic profile such as this one. Turning our attention to the bottom half of the slide, I'll now quickly explain how we have been presenting the data for each cohort. I'll focus on our data from buccal cells today and will note that we saw consistent results when examining frataxin levels in skin and platelets. Those interested in data from these tissues can find the relevant graph in the appendix of this deck which is available on our website. As you can see in the table in Cohort 1, we show frataxin levels at baseline day 4 and day 13. In Cohorts 2 and 3, we show frataxin levels at baseline day 7 and day 13. This allows us to capture the final day of daily dosing in each cohort as well as the levels of frataxin after intermittent dosing helping to inform the design of our upcoming Phase 2 trial. On the next slide, you can see the Phase 1 MAD data from buccal cells I previewed at the top of the call. This shows dose-dependent increases in frataxin levels from baseline compared to placebo with daily subcutaneous CTI-1601 injections. On the left is a graph showing absolute frataxin levels normalized to total protein with the dots representing the median frataxin level for each dose group and the horizontal lines representing the 25th and 75th percentile. On the right is the same data depicted as change from baseline which highlights the additional frataxin being supplied by CTI-1601. For today's presentation, I'll focus first on the 25 and 50 milligram cohorts since these are the doses we plan to explore in our upcoming Phase 2 trial. Starting with the graph on the left you can see dose-dependent increases in frataxin levels compared to placebo as we move from baseline to the next measurement, which again was 4 days for the 25 milligram cohort and 7 days for the 50- and 100-milligram cohorts. These data show that we can increase buccal cell frataxin levels by administering 50 milligram doses of CTI-1601. While we did not see increases in frataxin in the 25-milligram cohort, it's important to remember that the data we have for this cohort is only after 4 days of daily dosing. As I mentioned earlier, the first cohort of our upcoming Phase 2 study has been designed to inform whether extended periods of daily dosing with 25 milligrams of CTI-1601 may lead to relevant increases in frataxin levels. We believe getting this answer will help us establish CTI-1601's minimum effective dose as well as the frequency of dosing required to maintain frataxin levels. This information is key to informing the preferred dose and treatment regimen for late-stage clinical trials. If we now turn our attention back to the 50-milligram cohort, we can see some additional data that informed the design of our upcoming Phase 2 study. As I just mentioned, there is a clear increase in frataxin levels in this cohort on day 7 which was the last day of daily dosing. However, on day 14 which was after patients switched to an every other day dosing regimen these levels decreased, but still did not return to baseline. This is in contrast to what we're seeing with daily dosing for 13 consecutive days in the 100-milligram cohort where frataxin levels remained relatively constant. These findings suggest that at least for the first 13 days a daily dosing regimen may be preferred for increasing levels of frataxin in peripheral tissues. These findings were key factors that shape the design of our upcoming Phase 2 trial. An additional factor was our nonclinical pharmacokinetic data set where we saw accumulation of CTI-1601 with daily dosing over longer time periods. This, along with other factors, raises the possibility that daily dosing may only be needed to maintain increases in frataxin levels to a certain point after which a less frequent dosing regimen could be employed. We believe exploring both daily and every other day dosing over 2-week periods in the Phase II trial will provide valuable data that can be fed into our PK/PD models as we work to determine an appropriate treatment regimen moving forward. If we were to simply look at daily dosing for the whole 28-day period, we would have less information as we work to move towards ensuring we study the preferred dose and dose regimen in later-stage trials. Now before I move on to recap the safety data from our Phase 1 trial, I'd like to take a minute to provide important context on the pharmacodynamic results I just discussed. To do this, I'll note data published in the literature that have shown frataxin levels in buccal cells and blood to be predictive of FA disease severity, age of onset and overall neurologic function in patients. An additional study referenced on this slide indicates that patients with FA produce only 20% to 40% of normal frataxin levels depending on the tissue considered. In contrast, heterozygous carrier showing no signs of disease have frataxin levels that are about 50% of what is seen in unaffected healthy persons. Together, these studies suggest that frataxin levels in peripheral tissues may be a clinically relevant marker of pharmacologic activity against FA. Next, I'll ask you to turn your attention to the graph on the right which compares the frataxin levels achieved with CTI-1601 administration in our clinical trial to frataxin levels from healthy controls. On this graph you'll see a dashed green line which represents 60% of the median frataxin levels measured in the buccal cells of 8 healthy control subjects who participated in a non-interventional study we began conducting before the COVID-19 pandemic. When making these measurements and designing our Phase 1 trial, we purposefully utilized the same sampling technique and assay to measure buccal cell frataxin levels. This allowed us to directly compare results in buccal cells obtained in the Phase 1 and non-interventional clinical trials. This would not have been the case if a different tissue type assay or sampling technique was used in one of those studies. When comparing data from the 2 studies, we see the daily dosing of 50 or 100 milligrams of CTI-1601 for 7 days resulted in median buccal cell frataxin levels that were at or above the aforementioned green line which exceeds the frataxin levels we would expect to see in the buccal cells of phenotypically normal heterozygous carriers. That said, there are key opinion leaders that believe that even moderate increases in frataxin may provide a clinical benefit. Given the predictive length between peripheral frataxin levels and the onset and progression of FA, we believe this is a powerful result that demonstrates CTI-1601's potential as a disease-modifying therapy. One additional point I'll make about our Phase 1 data is that although very high levels of frataxin have been associated with toxicity in published non-clinical studies. We are not approaching these levels nor do we believe we need to approach these levels with CTI-1601 administration to achieve a clinical effect. Further safety data from the Phase 1 program showed that CTI-1601 was generally well tolerated at doses up to 100 milligrams administered daily for 13 days. No serious adverse events, important medical events or treatment-related severe adverse events were reported in the trial. The most common adverse events observed were mild and moderate injection site reactions. There were no study discontinuations due to these reactions and all reactions resolved on their own, with most resolving within an hour. With the exception of injection site reactions, the number and severity of adverse events in the trial did not increase with increasing exposure to CTI-1601. We also did not observe accumulation of CTI-1601 with the doses and regimen studied. Given the data from the 26-week toxicology study in non-human primates, including the death of 3 out of a total of 34 animals in the 2 highest dose groups which led to the clinical hold, it is important to assess safety margins. All non-human primates in the 2 lower dose groups survived to the end of the study and received all of their doses. Based on AUC, Cmax and Ctrough from the Phase 1 studies at the 25 and 50-milligram levels and the no observed adverse effect levels from the 4-week 13-week and 26-week NHP toxicology studies. The safety margins calculated for CTI-1601 are generally greater than 10. Though the precise mechanism of toxicity in the NHPs was not determined, we believe the toxicity was associated with accumulation and high levels of exposure as demonstrated by the safety margins just discussed. We believe the presence of persistent edema at the injection site in some of the non-human primates may explain this accumulation as it appears to be associated with the adverse events in the non-human primates as well as higher plasma levels of CTI-1601. In the clinic, the injection sites will be closely monitored and we intend to avoid the use of injection sites where persistent edema is present. With the FDA clearing CTI-1601 for a return to the clinic to initiate the 25-milligram dose cohort for our Phase 2 dose exploration trial following a review of the extensive clinical and nonclinical data submitted, we are now focused on initiating the trial which we expect to begin in the fourth quarter of this year. Once the Phase II study is complete and the appropriate dose and dose regimen have been identified, we intend to initiate our Jive open-label extension trial as well as a multiple ascending dose trial in patients between the ages of 2 and 17 in the second half of 2023. Dose escalation in the Phase 2 trial and initiation of the Jive and pediatric MAD trials will be subject to the FDA lifting the partial clinical hold. Together with the upcoming Phase 2 study, these 2 planned trials will be designed to enhance the data generated by our prior Phase 1 trial. We believe this will allow us to gain valuable information on safety, dose and increases in frataxin levels over longer periods of time in order to inform the design of a global pivotal trial. In closing, I would like to summarize a few key points from today's presentation. First, we are optimistic about the outlook for our lead therapeutic candidate CTI-1601, which is designed to address the root cause of FA by delivering mature frataxin to the mitochondria. This optimism is fueled in part by our Phase I clinical data. We believe these data demonstrated proof-of-concept for CTI-1601 by showing the daily subcutaneous injections of 50 or 100 milligram doses for at least 7 days resulted in buccal cell frataxin levels that met or exceeded those we would expect to see in phenotypically normal heterozygous carriers of the FAG. Buccal cell level frataxin levels have notably been shown to correlate with neurologic function in FA patient. With CTI-1601 now cleared for a return to the clinic at a 25-milligram dose level, we are working to gather information on its minimum effective and preferred long-term dose in a placebo-controlled Phase II dose exploration trial in FA patient. The trial will begin by evaluating extended daily dosing of 25 milligrams of CTI-1601 with planned dose escalation to 50 milligrams in Cohort 2 contingent upon submission and review of the data from the trial's first cohort by the FDA and the review by the trial's independent data monitoring committee. We expect the Phase 2 trial to begin in the fourth quarter and to report top line data in the second half of 2023. Lastly, and very importantly before opening it up for QA, I would like to once again express my excitement for CTI-1601's return to the clinic and extend my gratitude to all those who helped further its development. This includes not only our employees, partners and investigators but also all those affiliated with the Friedreich's Ataxia Research Alliance and of course, the patients participating in our trials and their families. Addressing the unmet needs of the FA community remains the ultimate goal of our CTI-1601 program and we look forward to moving the development program forward. With that, we will now open the line for questions.

Our first question comes from the line of Myles Minter with William Blair.

Congrats on the news. Great day for patients and hopefully we'll see some benefit beginning in the fourth quarter here. My question is I've 2 of them. The first one is just what percentage increasing frataxin levels are you defining as what would be minimally clinically effective? I mean in our KOL conversations, I think it's about 5% maybe even a 10% increase. And I guess what's your rationale that this 25-milligram dose is kind of in the ballpark to get in there. Can you talk to any sort of PK modeling that you've done of this increased duration of dosing frequency and the accumulation factor here and what we can kind of expect from that cohort?

Thanks for the question. It's obviously a real important one. And I think you're right that there are several key opinion leaders who are speaking to the fact that you may not actually need to get to levels of heterozygous carriers. And that really modest increases may actually be enough to have a clinical benefit. I think we really are just going to have to sort of wait and see. We do have in the trial some additional exploratory outcome measures like lipid profiles and gene expression. And they may be very helpful in helping us in the short term see whether the amount of frataxin that's actually being delivered is enough to actually either normalize or start to normalize those abnormalities. And so we will be looking at lipid profiles. There's actually a nice article out of Penn from a couple of months ago that shows that these patients do have a dyslipidemia. We actually did look at lipid levels in our MAD study as well. That data has not been released yet but will be presented at a scientific conference at some point. So I think it is a good question. Obviously, we'll try and see and hopefully get our frataxin levels high up to where we want. But clearly, it may not be necessary to get them to 50% to 60%. With regard to the modeling for the 25 milligram we just don't have a lot of data. I mean we have modeled it out, but we don't really have a lot of data. But we do think that it is worth at least making sure that if you dose the 25 milligram for longer, you don't see increases because we do want to have a minimum effective dose. As you know, the concentration of the drug is 50 milligrams per CC. And so 1 CC is a 50-milligram dose but the 25 milligrams is a half of CC. So it would be nice to decrease the volume if possible for patients. Obviously, not necessary a 1 CC dose is fine but it would be nice if we could dose it at a lower dose. So we want to explore the 25-milligram dose but we'll have to see what we actually see.

Is there anything additional that the agency wanted you to look at in this trial from a safety perspective that wasn't captured or wasn't focused on in the original SAD and MAD study? Just given we now have the autopsy reports for those non-human primates and the whole injection site reaction edema accumulation issue here?

No, they didn't ask. We submitted a protocol and they pretty much accepted what we submitted and we really didn't have anything additional to what we had in the MAD study. So not really.

Our next question comes from the line of Yatin Suneja with Guggenheim Partners.

Congratulations on getting the hold lifted and getting the asset back into the clinic. So a couple of questions from me. Carole, you mentioned about the safety margin at the 25 and the 50 which will be above 10. I'm particularly interested about the 50. Could you just articulate what is the margin at the 50 dose? Because if you look at the data that you are showing here, you definitely hit the green line with the 7-day continuous dosing at the 50. So particularly interested about your comment on the 50-milligram dose? And then I have a follow-up.

The safety margins that we quoted are generally greater than 10 apply to 50 as well as the 25. So it's pretty much the same. They really weren't that different. The exposures in the animals even at the NOAELs were quite high.

In terms of the collection of buccal cell data for this Phase 2, how often you will be collecting? Could you do a daily collection just to see the trend? That's one question. The second is I think in this study, you are including both ambulatory and non-ambulatory patients and they both have a different rate of progression. So can you just talk about any differences in these patient population? Any differences in the baseline frataxin level across these 2 group? And should we expect a similar treatment effect in these patients?

So with regard to the frataxin levels in buccal cells we do collect them quite frequently. Obviously, we present the data where it's relevant but we will be able to collect them frequently and we do. We're also going to be collecting skin biopsies. Obviously, we can't do those daily or as frequently as the buccal cells. But we will be collecting several skin biopsies. We're not doing platelets this time primarily because it's a long study and it requires a lot of blood. And so it limits us for other parameters that we can collect. With regard to ambulatory versus non-ambulatory patients in the Phase 2 trial like this where we don't really expect to see a clinical outcome. We're doing some functional clinical outcome measures but a limited number. We're really more focused on the objective outcomes like the frataxin levels and the lipids and gene expression. And obviously, most importantly, the safety and pharmacokinetics. So we don't think that whether they're ambulatory or non-ambulatory has as much of effect. You're right that the baseline frataxin levels may differ in the different populations given the age of onset. But we do collect age of onset and we do analyze for that as we look at the data. And so we're pretty comfortable that we can look at the frataxin levels. In the MAD study, we also had both ambulatory and non-ambulatory patients.

So as you move to the 50-milligram dose in this study, can you just talk about how you are thinking about the frequent or the regimen that regimen? Will it going to be very similar to the 25 milligram where you gave the drug data for 14 days and then every other day? Or are their other regimens that you have in mind or you might have proposed to the FDA?

No, at this point without any data we anticipate that the 50-milligram dose regimen will be identical to the 25 milligram. Now that could change once we see the 25 and get the pharmacokinetics. But at least at this point we really want to get as much PK data as we can so that we can enhance the PK/PD model. And we want to see whether the frataxin levels are maintained after a longer daily dosing when you switch to every other day because, obviously, again, I alluded to the fact that people are injecting themselves. And so if we can minimize the number of injections or the volume it would be useful. But we do intend at this point to go 14 days daily and then 14 days every other day.

Our next question comes from the line of Jon Wolleben with JMP Securities.

Sharing my congrats as well. Obviously, a positive day for patients. Just wanted a couple of questions. Do you have clearance to dose higher than 50 milligrams if you're not hitting the exposures that you're targeting? Just wondering what kind of clearance you might have above that dose level?

We have no cap as far as we know. It will obviously be based on the safety and the pharmacokinetics. I would anticipate that if we did want to go higher, we would submit the 50-milligram dose data after it was collected and propose that to the agency. But at this point, we don't have any intention of going higher. The 50 milligram at least from the data we have from the MAD study seems to accomplish more than what we need to accomplish. And as [indiscernible] sort of alluded to, there is a lot of talk out there amongst the KOLs, that getting to 50% or 60% of normal people may not even be necessary. We really just at this point don't intend to go to 100. If we should need to though we're not capped but I know we would submit the data at FDA first.

And it sounds like your readout is going to include both the 25 and 50 milligram cohorts. But wondering if you're going to communicate any data after you complete the 25 milligram whether it's detailed frataxin levels or simply that FDA has cleared you to move to the 50-milligram dose sometime early in 2023.