4D Molecular Therapeutics, Inc. (FDMT) Earnings Call Transcript & Summary

Hello, ladies and gentlemen. Thank you for standing by, and welcome to 4D Molecular Therapeutics' update from INGLAXA Phase I/II clinical trials and development plans for 4D-310 genetic medicine for Fabry disease cardiomyopathy webcast. As a reminder, today's call is being recorded. With that, I will hand the call over to August Moretti, Chief Financial Officer, who will make introductory comments.

Thank you, operator, and welcome, everyone, to 4D Molecular Therapeutics 4D-310 program update webcast. A press release describing the results and development plans related to 4D-310 is accessible in the Investors section of the 4D Molecular Therapeutics website, and a recording of this webcast will be accessible on our website after completion of this call. With me today are Dr. David Kirn, our Co-Founder and Chief Executive Officer; and Dr. PJ Utz, Professor of Medicine, Immunology and Rheumatology at Stanford University. As a reminder, on this call, we will be making forward-looking statements regarding our clinical data from our 4D-310 Phase I/II clinical trial, product development plans, research activities and business plans. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to materially differ from those forecasted. A description of these risks can be found in the Risk Factors sections of our most recent Form 10-K and Form 10-Q, which are on file with the SEC. We will reference a slide presentation during the call today. Shortly after the call, we will post the presentation to the Investors section of the website. With that, I'd like to turn the call over to our CEO, David Kirn. David?

Thank you, Augie, and thank you, everyone, for joining us today. We're excited to provide an update on our Fabry disease cardiomyopathy program today. As many of you know, our company is boldly innovating to unlock the full potential of genetic medicines for millions of patients. Our platform technology is based on Nobel Prize-winning technology 'directed evolution', to invent targeted and customized sectors with superior therapeutic profiles compared to wild-type vectors. To-date, we've demonstrated human clinical proof-of-concept for our platform with 3 vectors across 3 therapeutic areas and by 3 different routes of administration. We are currently developing 5 clinical-stage product candidates for 7 patient populations and markets. On this slide, you can see that we have a broad and deep pipeline across the ophthalmology, pulmonology and cardiology therapeutic areas, each of which leverages a proprietary and optimized 4DMT vector. Today, we'll be focusing on cardiology, and I'm excited to be discussing detailed interim clinical data from our INGLAXA Phase I/II clinical trials of 4D-310 for Fabry disease cardiomyopathy. Now before we go through the slides, I'd like to summarize the key takeaways from today's presentation. Number 1, with 4D-310, we've demonstrated clinical proof-of-concept for low-dose IV delivery and efficacy within the heart in humans. This is now our third 4DMT-invented vector with clinical proof-of-concept data. We're seeing clear evidence of improvement in functional cardiac endpoints and biomarkers within the heart. Number 2, the therapy was generally well tolerated with no significant liver, heart or dorsal root ganglia toxicity. Number 3, we saw a signal transient acute atypical hemolytic uremic syndrome, or aHUS, a known class effect of intravenous AV therapies that led to a single dose-limiting toxicity and clinical hold. We intend to implement a rituximab and sirolimus immunosuppressive regimen that is highly effective at preventing aHUS. And number 4, based on interactions with and feedback from the FDA, we believe that our Phase III development pathway is clear. Now let's take a quick refresher on Fabry disease cardiomyopathy. Fabry disease is a monogenic X-linked disease caused by mutations in the gene encoding AGA enzyme. The prevalence of this disease is more than 50,000 across the U.S. and the EU-5, and cardiac disease is the primary cause of death for these patients accounting for roughly 75% of death. The current standard of care for these patients is enzyme replacement therapy, or ERT, which does not adequately address the cardiomyopathy. The cardiomyopathy progresses despite ERT, and therefore, there remains a significant unmet medical need for these patients. Now before we dive into the data, a quick note on known problems with intravenous conventional AAV gene therapies for organs other than the liver. These tissue targets include skeletal and cardiac muscle, the CNS and others. First, these IV AAV gene therapies have inefficient delivery and inefficient transduction capabilities for target tissues. As a result, high doses of anywhere from 7E13 to 4E14 vg/kg are required for efficacy, and this can result in dose-limiting toxicities and very high cost of goods. For example, high doses of these therapies are known to have significant liver, heart and DRG toxicities in some patients. Finally, pre-existing antibodies to the capsid can limit delivery and transduction and can result in exclusion of many otherwise eligible patients. At 4DMT, overcoming these limitations with gene therapy through innovation is in our DNA. Our solution for genetic medicines targeted to the heart is a low-dose intravenous AAV vector, C102. C102 was invented through directed evolution in primates for targeting cardiomyocytes. As seen in the top-left diagram, gene therapies utilizing conventional vectors are largely cleared by the liver resulting in limited delivery to the heart. As seen in the lower left, we evolved C102 for enhanced tropism to the heart and specifically to cardiomyocytes, allowing us to use much lower doses while achieving a high degree of delivery to the heart, including in patients with Fabry disease. The bottom right diagram shows our vector's highly significant superiority for human cardiomyocyte transduction versus conventional vectors AAV9, AAV8 and AAV1. Here, you can see that our Genetic Medicine 4D-310 has unique mechanism of action versus current approved therapies and therapies under development. To our knowledge, 4D-310 is the only biologic designed to treat the heart in these patients. With a single dose, we are able to preferentially target the disease tissues of interest in Fabry disease, primarily the heart and secondarily, the kidney and blood vessels. Importantly, with the ability to induce intracellular production of enzyme within targeted disease cells, we are able to avoid AGA neutralization in the blood by anti-AGA antibodies which are present in approximately 50% of patients receiving ERT. In addition, we evolved the C102-capsid in the presence of human neutralizing antibodies, allowing us to potentially dose patients in the presence of low titer neutralizing antibodies to C102. This slide summarizes our INGLAXA Phase I/II open-label studies. We studied 4D-310 across 2 trials in the U.S., Taiwan and Australia. The dose level explored for all patients dose was 1E13 vg/kg, which is much lower than standard IV AAV doses for muscle tissues and other programs. Our dose is only approximately 3% to 14% of doses used with other products. Our prophylactic immunosuppressive regimen in these patients was corticosteroids. This will change going forward. In addition to safety and tolerability, cardiac efficacy endpoints are based on cardiac imaging, function, quality of life and cardiac biopsies. Here we summarize the baseline characteristics for the 6 study participants dosed with 4D-310 to date. 3 patients had classic Fabry disease and 3 had late onset, 3 patients entered the study on ERT, 3 patients had baseline anti-AGA antibody titers that range from approximately 1 to 1,000 to 1 to 100,000. Now we'll delve into the cardiac outcomes data of the patients who've had at least 12 months of follow-up at the time of the data cutoff or who underwent cardiac biopsy. On this slide, you can see the cardiac assessments we evaluated in our studies. The first 2 exercise capacity measured by CPET and Cardiac Quality of Life measured by the Kansas City Cardiomyopathy Questionnaire are both FDA recommended primary end points. Cardiac contractility measured by echocardiogram is an FDA recommended supportive endpoint. The last 2 substrate accumulation measured by MRI and transgene delivery and expression by cardiac biopsy are exploratory endpoints. Before we describe how patients did on 4D-310, I'll reiterate that ERT does not address the heart disease of Fabry patients. You can see summarized here in natural history studies, Fabry patients worsened over 12 months on all cardiac assessments. We're excited to report that after treating patients with 4D-310, we see meaningful improvement across all 5 cardiac endpoints, including exercise capacity, cardiac quality of life and cardiac contractility, which, again, our FDA recommended primary and supportive pivotal trial endpoints. In our biopsy results, we demonstrated widespread delivery and transgene expression within cardiomyocytes. Again, this is in marked contrast results with ERT. We'll now go into these results in detail. Global Longitudinal Strain or GLS, assesses left ventricular function. All results were scored by an independent reading center. GLS was measured in 3 apical views on ECHO and reported as the average value. More negative values reflect improved function. 2 study participants had evidence of impairment in ventricular function by GLS at baseline. At month 12, both participants demonstrated meaningful improvements in GLS that exceeded the minimum detectable difference as defined by this assay. The third patient who had normal baseline values nevertheless exhibited improvement in GLS that was substantial when compared to worsening in natural history controls on ERT. As shown here, evidence from the published literature shows worsening in GLS at 12 months in individuals with Fabry disease on long-term ERT. Now on to cardiopulmonary exercise testing, or CPET, which is used to assess subjects exercise capacity through determination of peak VO2. All results were scored by an independent reading center. At month 12, 2 of 3 participants showed a meaningful improvement in peak VO2 that exceeded the minimum clinically important difference for this assay. Patient 3 experienced a modest decline in peak VO2. By way of comparison, individuals with Fabry disease receiving ERT showed a mean decline of 1.8 units at 12 months. The Kansas City Cardiomyopathy Questionnaire is a validated instrument for the assessment of heart-related health status, including symptoms, physical limitations and overall quality of life. Scores range from 0% to 100% with higher scores indicating less severe impairment. Changes in KCCQ scores have been shown to correlate with peak VO2, 6-minute walk distance and the risk of hospitalization and mortality in patients with heart failure. At month 12, clinically meaningful improvements in KCCQ score were observed in both participants with evidence of baseline impairment. Improvements were observed across multiple domains is reflected by changes in the overall summary score, the physical limitation score and the total symptom score. As you can see, these improvements were greater than the clinically meaningful difference of 5 for this instrument, signifying the importance of these improvements. The third patient remained at a score of 100% throughout 12 months after dosing. Now let's move on to cardiac biopsy results. All cardiac biopsy samples were obtained from the patient at week 6 following a single dose of 4D-310. These samples were then assessed by independent experts. Tissue samples exhibited normal histology and no evidence of inflammation. All 4 samples were positive for ISH and IHC for 4D-310. ISH showed robust 4D-310-mediated expression of transgene RNA, an expression was exclusively seen within cardiomyocytes. Approximately 50% of all cardiomyocytes were estimated to be positive. All sample sections were positive for 4D-310 transgene delivery by quantitative PCR with an estimated 4 genomes per cardiomyocyte. Transgene RNA expression by RT-qPCR was demonstrated in all samples with an estimated 16 transcripts for cardiomyocyte. These data demonstrated widespread delivery in transgene expression in cardiomyocytes using our cardiotropic vector C102 at a relatively low dose of 1E13 vg/kg. Next, we'll discuss the safety and tolerability findings to-date, including an in-depth discussion of our aHUS investigation and earnings to-date. At a high level, 6 participants received a single dose of 4D-310 with a prophylactic corticosteroid immunosuppression regimen. The therapy was generally well tolerated with none of the classic organ toxicities found with high-dose conventional AAV therapies in liver, heart or DRG. Three participants experienced transient and acute aHUS, the last 1 of which qualified as a dose-limiting toxicity. The DLT in this patient in the Australia study led us at 4DMT to pause further enrollment in both studies. We promptly initiated discussions with the safety committee and U.S. FDA, and we embarked on a detailed investigative process. Hematology lab findings demonstrated that the aHUS process started within the first 3 to 7 days after dosing as expected, and the acute process was starting to resolve within the next 1 to 4 days. Patients were discharged from the hospital within 4 to 7 days. Recovery from the acute self-limited process occurred over approximately 2 to 4 weeks in all 3 subjects with 2 of them receiving Eculizumab and patient 6 requiring temporary hemodialysis. Now I'll review our investigative process regarding aHUS events on these trials and our plans to prevent these in the future. I will now turn the presentation over to Dr. PJ Utz, Professor of Immunology and Rheumatology at Stanford University and a Member of our Scientific Advisory Board. He will discuss the mechanism of aHUS with IV AAV delivery and our investigative findings. I would also like to acknowledge our other immunology experts who have contributed, including Dr. Mastellos and Byrne who have been instrumental in our understanding and planning. With that, thank you for joining us, Dr. Utz, and we'll turn it over to you.

Thank you, David. In summary, aHUS is a known class effect related to IV delivery of AAV at relatively high doses, including for SMA-1 and cardiac and muscle indications such as Duchenne muscular dystrophy. Generally, the timing of onset is 3 to 7 days after administration, and the acute active process is short-lived. The onset is believed to be due to a rapid rise of IgM antibodies to the foreign protein in the blood, in this case, the AAV capsid, which leads to antigen antibody complex formation and activation of the classical complement pathway. These complexes can cause transient damage within the kidneys and potentially other organs. AAV induced aHUS is dose-related with almost all reports occurring with relatively high doses of the AAV in the 7E13 to 4E14 vg/kg dose range. The dose level on the 4DMT INGLAXA trials is significantly lower at 1E13 vg/kg. Therefore, we asked the question as to whether there was anything unique about the C102 vector used in 4D-310 and/or whether there was anything in these patients that predisposed them to aHUS at these low and otherwise safe doses. First, we demonstrated that the C102 vector itself does not activate the complement pathways directly. Next, we hypothesized that the 3 patients who had aHUS, including patient 6 who had the DLT could have underlying conditions that predisposed to aHUS, such as pre-dosing complement activation. Now let's discuss our investigation of patients on INGLAXA trials. So how does AAV activate the complement pathway? We start with the IV infusion of AAV. After the introduction of AAV or any foreign antigen for that matter, the first line of defense for the immune system is a rise in IgM antibody titers. When IgM binds to AAV, this activates the classical complement pathway, which can lead to transient acute aHUS until the AAV capsid is cleared from the blood. The alternative pathway can be activated by other factors and attacks to significantly amplify activation of the classical pathway. We see on this slide the findings on complement activation from patients on the INGLAXA studies. These assays were added as a protocol amendment, and we therefore have complement data on patients 3 through 6 only. The Y axis represents residual complement function, which therefore decreases as the complement pathway activates in the patient and consumes plasma complement factors, thus reducing function. The orange band represents the normal range. The classical complement pathway is shown on the left and the alternative complement pathway is shown on the right. On the left, you can see that in 3 patients, the classical pathway is being activated at only a low level after dosing. In contrast, in the patient 6 DLT classical complement pathway activation is highly significant 7 days after dosing. Importantly, when we then look at the graph on the right showing the alternative complement pathway, you can see the same patient 6 DLT started far below the normal range at the time of dosing. This means the patient had pre-dosing activation of his complement system, which represents a major risk factor for aHUS. This was not known at the time of dosing. We believe this is the first description of pre-dosing alternative complement pathway activation in a patient dosed with AAV. On this slide, we see additional aHUS related immune data for patients 4 to 6. Anti-C102 IgM levels in serum are induced after dosing as expected, overlapping with the presence of capsid in the blood. Of note, Patient 6 clearly had hyperacute induction of IgM antibody titers. Higher anti-capsid IgM titers are a potential risk factor for aHUS. Here, we summarize our current understanding. On the left, we see the typical classical complement pathway activation with AAV. On the right is a diagram of what happened with the DLT patient. First, pre-dosing activation of the alternative pathway was present and second, a pronounced IgM antibody response to the vector occurred. We believe that activation in 2 critical pathways could have been a synergistic mechanism that led to severe aHUS in this patient. Now I would like to hand things back to David. David?

Thanks, Dr. Utz for a great discussion of aHUS and the events we observed. I'd like to now go over what we believe is a well understood and highly effective solution to prevent aHUS in our program going forward. We're collaborating directly with Dr. Barry Byrne, who pioneered a new immunosuppression regimen for IV AAV administration. The regimen involves administering rituximab and sirolimus or RS prior to and after AAV dosing. This total regimen blocks the rise of IgM response to AAV and as a result, prevents activation of the classical complement pathway and aHUS. On the right is work that Dr. Byrne and Manuela Corti presented at a joint ASGCT FDA event in January of this year. These data from 38 patients demonstrate that the RS regimen prevented the rise in anti-AAV IgM and the subsequent activation of complement in 15 RS patients, a marked contrast to 23 controls. On this slide, we see additional clinical data on these 38 patients, confirming that the RS regimen prevented aHUS. In addition to using the RS regimen to prevent aHUS by blocking the classical pathway, we're also amending the protocol to prescreen for complement activation and exclude those patients who have it. By excluding patients who have heightened risk for developing aHUS and implementing the RS immunosuppressive regimen, we believe we can ensure patient safety and work with the FDA to lift our clinical hold and resume dosing patients as soon as feasible. In summary, today, we discuss promising interim 4D-310 clinical data. We reported cardiac endpoint improvements in all 3 patients at 12 months across 4 diverse endpoints, including efficacy endpoints that could support approval in the future. On cardiac biopsy, we reported widespread gene delivery in transgene expression within cardiomyocytes. 4D-310 was generally well tolerated and was not associated with significant liver and heart or DRG toxicities. Transient acute aHUS was noted with the corticosteroid immunosuppressive regimen in 3 patients. Our investigation patients, dosed to-date, including patient 6 with the DLT identified 2 important contributing factors. First, we identified pre-dosing complement pathway activation. Second, in post-dosing, we observed heightened production of IgM. In patient 6, we believe both of these mechanisms may have synergized to further accelerate complement activation leading to severe aHUS. In addition, the C102 vector was shown to not activate the complement pathways directly. In terms of next steps, we are in close communication with the FDA, sharing our data and working on a full response to FDA feedback to remove the clinical hold and reinitiate enrollment. Our response plan includes 2 key pillars: first, excluding patients with risk factors for aHUS; and second, implementing a short-term immunosuppressive regimen to block IgM production and therefore, prevent aHUS and all patients dosed. We have identified an assay that is routinely available to detect pre-dosing activation of complement pathways, allowing us to exclude patients with activation who would be at higher risk for development of aHUS. Second, we plan to implement the short-term RS immunosuppressive regimen, a highly effective regimen consisting of 2 widely used FDA-approved agents with extensive safety records. In parallel, we're continuing to follow treated patients on all assessments, including their cardiac endpoints. Finally, we've gained alignment with the FDA on our Phase III plans, including CMC activities and clinical trial design. Lastly, I'd like to highlight the incredible opportunities we believe our data unlocks. First, we believe the data differentiate 4D-310 as the only product to our knowledge that can address the cardiac manifestations of Fabry disease. Given the relatively low dose of our product, this represents an attractive commercial opportunity. Second, we believe the C102 vector is now validated as a superior cardiotropic vector that enables the ability to target many diseases with cardiac involvement. Finally, we have validated the ability of our directed evolution platform to generate superior vectors now demonstrated in all 3 of the first 3 vectors we've taken from concept into the clinic. Now with that, and before we move into Q&A, I'd like to acknowledge and thank Dr. Utz, Byrne and Mastellos for their contributions to us and the field and the entire 4D-310 team at 4D, including Dr. Raphael Schiffmann and Mitra Tavakkoli. Lastly, I'd like to thank the investigators, clinical trial staff, patients and their families. Operator?

[Operator Instructions] And our first question comes from Josh Schimmer from Evercore.

I guess, first, I think you indicated you have alignment with the FDA on the Phase III trial design. Can you elaborate on what that might look like? And then you've previously shown MRI data, the T1 signal. Why have you not shown an update for that in this data set?

Right. Thanks for attending, and thanks for the questions, Josh. So first of all, with regard to our alignment with Phase III with FDA, we specifically have alignment on the following. First of all, primary endpoints will be peak VO2 by cardiopulmonary exercise testing and quality of life by KCCQ, and those could potentially be co-primary endpoints. Also, we have alignment that cardiac contractility as defined by global longitudinal strain or GLS on ECHO would be supportive. We also have alignment on our manufacturing process being acceptable for initiation of Phase III, and we also have alignment importantly on potency assays to support Phase III, which is, as you know, in gene therapy can often lead to some delays. So we're thrilled to be aligned on that. In terms of the MRI, that is very exploratory. We did see significant improvements in 2 of the 3 patients that was in the table. We didn't call it out as a separate slide just because, again, we think that these approvable endpoints are more important clinically. But it's a great point. The MRI is able to detect substrate reduction over time in the heart. And again, 2 of the 3 patients showed an improvement by that assay.

Our next question comes from Nalin Tejavibulya from Jefferies.

So the first question is, given that Fabry disease patients have underlying kidney risks anyway. So in addition to the inclusion/exclusion criteria that -- how are you thinking about the patient population that you recruit in the pivotal trial? And in addition to that, in the real world, what percent of the Fabry disease patients would not be eligible for 4D-310?

Thank you for the question, Nalin. So -- we think this is going to be quite rare to have frank activation of the alternative pathway. So we'll see over time, but we would be very surprised, I think, if that was more than a handful of patients. We really don't think that that's going to be common. It's certainly not been commonly described. So we think that we still have likely the broadest enrollment criteria in the field for Fabry disease. We accept both classic and late-onset patients, males and females. Because of our mechanism of action, we allow patients on with or without preexisting AGA antibody titers as well. So we think that we have quite broad enrollment criteria still regardless of this adjustment. So we think we'll be able to treat the vast majority of Fabry disease patients, both in the Phase III and also in the real world.

Got it. And 1 more question, if I may. From the limited data that you've shown thus far, there doesn't seem to be a definitive correlation between peak VO2 improvement, which is the primary endpoint of the pivotal trial and the other parameters such as GLS improvements and cardiac quality of life. So what would you need to see a 12-month follow-up in the 6 patients in order to proceed to a pivotal trial?

That's a great point. I think the peak VO2 there are other factors beyond just cardiac health that can contribute to that endpoint. So it's a little bit noisier in a small data set like this as opposed to something like the GLS on ECHO is very, very clear, and that's exclusively focused on cardiac health. So I think we'd like to see across all 6 patients. And you correctly point out, there are 3 more that we're following currently, and we'll get the similar data set on those. We'd like to see trends along the same lines that we're seeing as a general improvement across all of these end points. I think what's impressive to us and exciting to our investigators is that these all look at very different aspects of a patient's health and outcome. And nevertheless, all 4 of them are telling us the same thing that we're having a significant effect and benefit on the heart. And also, I think that the biopsy also confirms that that mechanism is almost certainly due to delivery of the vector to the cardiomyocytes themselves and expression within the cardiomyocytes, which only our therapy can uniquely achieve, we believe.

[Operator Instructions] Our next question comes from Kostas Biliouris from BMO Capital Markets.

A couple from us. One is on the dosing. I'm wondering whether you considered using a lower dose. I know you saw that typically you need 7E13 to activate these safety signals, but I'm wondering if lowering the dose even further would help and whether redosing is a possibility here? And then I have a second question.

Thanks, Kostas for the question. So first of all, the dose that we come back into the clinic with after the resumption of enrollment is still to be determined. That's something we want to discuss with FDA. We do believe that with the Rituximab/Sirolimus regimen, there is a strong possibility that that may increase delivery to the heart. Barry Byrne has reported data on that, and that would presumably be due to the block and the IgM coming up in a longer circulatory time and better delivery that way. He's also shown the ability to block IgG coming up and has shown at 3 months, it's still feasible to redose. So we think with the RS regimen, it certainly has the potential of not only blocking the aHUS, but also increasing delivery and potentially also allowing for redosing if that's something we want to do. So I think it gives us a lot of flexibility. Whether when we go back into the clinic, we drop the dose initially or not, I think it just remains to be discussed with FDA, and we'll certainly make that clear once we know.

Very helpful. And my second question is on the cardiomyocyte. You saw that 50% were positive in the biopsies. Can you please talk a little bit more about this number? What is the target here, whether 50% is sufficient? Would you like to go higher or lower? Any color around that?

Yes, thanks for that question as well. We think 50% is a very attractive number for us to be able to achieve. We're excited by that. Our investigators are excited and we think that that's a therapeutic. That's a level of transduction in cardiomyocytes that we think would translate into therapeutic benefit on the endpoints we're looking at. So we're really thrilled to be at 50%. What also was interesting is, again, given the way this vector has evolved for cardiomyocytes is that we really see highly selective cardiomyocyte transduction in the heart. There are a number of other cell types, including fibroblasting the heart. And what we saw is a high-level transduction specifically of the cardiomyocytes, which is the target cell for cardiac diseases such as Fabry. So we think we're in a great dose -- a great range in terms of the transduction efficiency, and we think that that's going to translate into clinical benefit.

We have no further questions. I would like to turn the call back over to David Kirn for closing remarks.

Well, thank you, operator, and thank you, everyone, for your attention today. We appreciate the interest and the questions from our analysts, and we look forward to more successful calls like this in the future, and we're excited about the future of 4D-310 as well as our C102 vector for other cardiac diseases. We really believe that this opens up a number of other diseases for us to treat alone and with partners. And finally, again, this is a third vector that we validated across 3 different therapeutic areas and 3 different routes of administration, which we think is a really important milestone for the company. So thank you for your time today, and we'll wrap it up there.

This concludes today's conference call. Thank you for your participation. You may now disconnect.