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

Hello, ladies and gentlemen. Thank you for standing by, and welcome to 4D Molecular Therapeutics 4D-310 and 4D-110 Clinical Data Conference Call. [Operator Instructions] As a reminder, today's call is being recorded. With that, I will hand over the call to Mike Zanoni, Vice President, Head of Investor Relations, who will make introductory comments.

Thank you, Van, and welcome, everyone, to 4D Molecular Therapeutics 4D-310 and 4D-110 Clinical Data Conference Call. Today's webcasted presentation as well as this afternoon's press release describing the initial results from our Phase I/II clinical study of 4D-310 in patients with Fabry disease as well as an update on the 4D-110 choroideremia Phase I/II clinical trial are accessible in the Investors section of the 4D Molecular Therapeutics website. With me today are Dr. David Kirn, our Co-Founder and Chief Executive Officer; Dr. Robert Fishman, our Chief Medical Officer; Dr. [ Rafi ] Schiffmann, our SVP and Clinical Therapeutic Area Head, Lysosomal Storage Diseases and Cardiology; and Augie Moretti, our Chief Financial Officer. As a reminder, we'll be making forward-looking statements regarding our clinical data from our 4D-310 Fabry disease Phase I/II clinical trial, our 4D-110 choroideremia Phase I/II clinical trial, regulatory and product development plans and research activities. These statements 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 our most recent Form 10-K and Form 10-Q, both of 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 Dr. David Kirn, Co-Founder, Chief Executive Officer. David?

Thanks, Mike. Good afternoon, everyone, and thank you for joining us. Today, we reported initial clinical data from the ongoing 4D-310 Phase I/II clinical trial as well as updated clinical data from the ongoing 4D-110 Phase I/II clinical trial. With respect to 4D-310, these data are the first evidence of clinical activity reported from an intravenous product candidate utilizing our proprietary vector C102, a targeted and evolved vector invented at 4D through Therapeutic Vector Evolution. These data support our belief that 4D-310 is generally well tolerated and has potential to deliver patient benefit after a single intravenous injection. Importantly, the post-treatment mean a-Galactosidase A, or AGA, enzyme activity in patients' blood was within or more than 20-fold above the normal range. To our knowledge, these may reflect the highest protein levels achieved in humans to date with any gene therapy for any indication. Of note, approximately half of all patients with Fabry disease on ERT will develop anti-AGA antibodies. And hence, this is a large Fabry patient population with high unmet medical need. Importantly, our results were achieved despite the presence of pre-existing anti-AGA antibodies in all 3 patients. Now prior to delving into these results in detail, I'd like to provide a brief overview of our pipeline. As you can see on this slide, our Therapeutic Vector Evolution platform and its vector modularity have allowed us to develop a diverse pipeline for both rare and large market diseases, including patient populations that other gene therapies are unable to address. Our initial product candidates are focused in ophthalmology, pulmonology and cardiology. In cardiology, we're initially focused on Fabry disease, a systemic lysosomal storage disease that results in significant heart disease, heart failure and even death. Our product candidates in each therapeutic area leverage a targeted and evolved vector that we invented, allowing us to build out a product portfolio using an efficient modular approach. We believe the diversity of our pipeline increases our likelihood of commercial success. Now I'd like to give you an overview of our clinical data with 4D-310. 4D-310 had a manageable safety profile with no dose-limiting toxicities. And importantly, evidence of clinical activity was demonstrated in all 3 patients. First, in the 2 patients with low and intermediate baseline anti-AGA antibody titers, the mean post-treatment AGA enzyme activities were over 2,000% of the mean normal AGA in the population. Of note, these levels were achieved despite anti-AGA antibody positivity in these patients. In addition, in the third patient who had very high baseline anti-AGA antibody titers prior to treatment, sustained AGA activity was demonstrated at all time points with a mean AGA activity within the normal range. This patient had significantly elevated serum lyso-Gb3 substrate levels at baseline, and following treatment, lyso-Gb3 levels decreased by over 50%. Now before we get into the trial details, we'd like to briefly remind you that Fabry disease is an X-linked monogenic recessive disease where a lack of AGA enzyme activity leads to Gb3 substrate accumulation, causing damage systemically, including to kidneys, heart and blood vessels. There are 2 phenotypes: classic patients who have minimal enzyme activity and account for approximately 50% of the population, and late onset patients who have approximately 5% to 20% of normal enzyme activity and represent the other 50% of the population. Notably, anti-AGA antibody positivity is induced by ERT in approximately 50% of all patients, including approximately 80% of classic patients. Prior to turning the call over to Dr. Bob Fishman, I'd first like to highlight the differentiating attributes of our targeted and evolved C102 vector, which along with the GLA transgene and a strong ubiquitous promoter, is utilized in our 4D-310 product candidate. In the upper right panel, this illustration shows the limitations of conventional AAV for IV infusion to the heart. Conventional AAV vectors are cleared by physiologic and anatomical barriers, such as the liver and the spleen, and thus, IV treatment requires extremely high doses that are associated with potential toxicities as well as a high cost of goods. In contrast, in the lower right panel, we see that C102 was designed for targeting of the heart at significantly lower doses while retaining delivery to other important tissues, including kidney, blood vessels and liver. Here, we show that our 4D-310 product candidate was designed for a unique dual mechanism of action after a single IV administration. The product is designed to generate both high sustained blood levels of AGA for systemic cross-correction of tissues, as well as for a complementary high local production of AGA directly within the key target organs themselves, including heart, blood vessels and kidney. This design has the potential to address the significant unmet medical needs in patients with Fabry disease, and we believe either mechanism would represent a significant clinical advancement on its own, and together, these mechanisms could be synergistic. The 4D MT clinical team with us today includes Dr. Robert Fishman, our CMO; and Dr. Raphael Schiffmann, a world leader in the management of Fabry disease patients. Now with my comments as background, I'd like to turn the call over to Dr. Robert Fishman, who will give a detailed presentation on the clinical data. Bob?

Thank you, David. The data described are as of the data cutoff date of October 12, 2021. Three patients with classic Fabry disease due to GLA gene mutations had been treated at the 1E13 vg/kg dose in cohort 1. We expect to continue enrolling patients on the 1E13 dose. In addition, the protocol allows for either dose escalation to 3E13 or dose deescalation to 3E12 vg/kg dose. In this study, key inclusion criteria include classic Fabry disease or late onset Fabry disease with left ventricular hypertrophy. Of note, patients were enrolled regardless of anti-AGA antibody status. Patients were also enrolled regardless of ERT status. Patients were categorized as ERT-on, ERT-naive or ERT-off, meaning ERT was received and then stopped prior to the study. The primary endpoint of the study is safety and tolerability with key secondary endpoints, including serum AGA enzyme activity and serum lyso-Gb3 substrate levels over time. These endpoints were assessed at an independent central laboratory at the Mayo Clinic. These assays have been validated, and the laboratory is CLIA certified and is a leading site for these Fabry disease-related assays. On Slide 11, we provide an overview of baseline pretreatment characteristics of these 3 patients. All 3 patients have classic Fabry disease and all 3 had received prior ERT. Two remained on ERT at the time of study entry, whereas 1 had discontinued ERT 13 months earlier. All 3 were positive for anti-AGA antibody titers across a wide range; 1 to 947, 1 to 13,900 and 1 to 99,900. This wide range allowed us to assess the association between baseline antibody titers and AGA activity levels following treatment. On the next 2 slides, we'll focus on mean serum AGA enzyme activity relative to antibody titers. Patients 1 and 3 with low and intermediate baseline antibody titers demonstrated mean serum AGA activity levels during post-treatment follow-up that were over 2,000% of the mean normal in the population. As we'll show you in the individual patient graph, following discontinuation of ERT, positive effects on serum lyso-Gb3 substrate were demonstrated in both patients. Patient 2 is the highest titer on the study and the highest in screening. And this patient demonstrated a mean serum AGA activity level within the normal range. Now let's look at each of the patients in more detail. Patient 1 had an antibody titer of 1 to 947 at baseline and was receiving ERT at the time of enrollment, indicated as ERT-On in the table. This patient had 6 months follow-up at the time of data cutoff. Serum AGA increased to significantly above the normal range for all time points. AGA activity levels at all time points were more than tenfold above the mean normal level in humans. The serum lyso-Gb3 was relatively low at baseline due to ERT. The lyso-Gb3 levels remained low and did not significantly increase after discontinuation of ERT at week 14. Patient 3 had the antibody titer of 1 to 13,900 at baseline and was receiving ERT at the time of study entry. This patient had 6 weeks of post-treatment follow-up at the time of the data cutoff. Serum AGA activity increased to significantly above the normal range for all time points. All AGA activity levels were well above the mean normal level in humans. The serum lyso-Gb3 was relatively low at baseline due to ERT. The lyso-Gb3 levels remained low and did not significantly increase after discontinuation of ERT on day 14. So now let's move to patient 2. Patient 2 had, by far, the highest antibody titer at baseline and was no longer receiving ERT. After receiving the 1E13 vg/kg dose, the patient had 12 weeks of follow-up at the time of data cutoff. Serum AGA was within the normal range for most time points measured. The serum lyso-Gb3 was elevated at baseline due to discontinuation of ERT 13 months earlier. The lyso-Gb3 levels decreased by 50% over the first 4 weeks following 4D-310 and have remained stable thereafter. On Slide 17, we summarized the initial safety and tolerability profile from this Phase I/II clinical trial. 4D-310 showed a manageable safety profile with no dose-limiting toxicities and no clinically significant liver toxicity. On these next few slides, we will take a more granular look at the laboratory results that focus on class effects associated with systemically administered AAV gene therapies, namely atypical hemolytic uremic syndrome or atypical HUS and liver toxicity. Patient 2, who had the highest antibody titers, had laboratory results consistent with self-limited and transient atypical HUS at day 8, including an increase in creatinine and decrease in platelets. After diagnosis, the patient was admitted for observation, received fluids for hydration and was discharged after 4 days. This patient did not receive complement inhibitors, and kidney function fully recovered without further intervention. Creatinine decreased steadily, and platelets increased steadily until both had normalized within 4 weeks. The 2 other patients did not experience atypical HUS. Patient 3 had transient proteinuria. Creatinine, platelets and hemoglobin all remained within the normal range. As shown here, no patients had significant liver toxicity. Patient 2, who had the aHUS, also had grade 1 transaminase elevation at a protocol-specified time point, this resolved promptly. To summarize our initial 4D-310 clinical data in patients with Fabry disease, 4D-310 clinical activity was observed in all 3 patients at all time points following treatment. This clinical activity was achieved despite the presence of positive anti-AGA antibody titers prior to treatment. In patients 1 and 3, who had low and intermediate anti-AGA antibody titers, mean post-treatment AGA enzyme activity levels were greater than 2,000% of mean normal levels. Low baseline serum lyso-Gb3 levels were maintained following discontinuation of ERT in both of these patients. In Patient 2, who had the highest anti-AGA antibody titer, AGA activity was within the normal range, and this was associated with a significant reduction in the lyso-Gb3 levels in serum. 4D-310 showed a manageable safety profile with no dose-limiting toxicities. Transient, self-limited atypical HUS was noted in 1 patient. Treatment with complement inhibitors was not necessary and kidney function recovered without further intervention. No significant liver toxicities were demonstrated. Before passing things back to David, I'd like to take a moment to thank our patients, their families, our investigators and their teams and our central laboratory colleagues at the Mayo Clinic for their efforts and support of the program. Thank you. David?

Thank you, Bob. Before we move on, I'd like to underscore that these data support our belief that 4D-310 has the potential to benefit a broad Fabry disease patient population. 4D-310 is differentiated from both ERT and other experimental gene therapies for Fabry disease. First, as shown in the left panel, we believe that 4D-310 treatment can result in sustained therapeutic levels of AGA in patients after a single dose. This figure shows the mean AGA levels from patients 1 and 3 on the Phase I/II trial over time and published data on the pharmacokinetics of ERT in patients. The sustained levels with 4D-310 after a single dose are in marked contrast to the very short half-life and rapid clearance of ERT in patients requiring biweekly ERT infusions. 4D-310 has the potential to drive enhanced systemic tissue cross correction after a single dose. In the right panel, we show published data from other gene therapy programs as compared with the results from this trial. This figure shows the AGA levels in patients at their latest time point after treatment with either 4D-310 or other experimental gene therapy approaches for Fabry disease. These data suggest the unique dual mechanism of action design used for 4D-310, including our proprietary targeted and evolved vector C102 may result in higher sustained levels at commercially reasonable doses. Longer follow-up and treatment of additional patients will be required to demonstrate the full potential of 4D-310 for patients with Fabry disease. The next steps for this program are outlined on this slide. First, we plan to continue enrolling patients at the 1E13 vg/kg dose level. And based on the AG activity in all patients, we may elect to explore a lower dose in the future as well. Second, we plan to enroll patients with all Fabry disease subtypes. To date, we've dosed a difficult-to-treat population classic Fabry disease patients with positive anti-AGA antibody titers. We plan to treat patients with and without anti-AGA antibody titers, both classic and late-onset patients and those on and off of ERT. Third, at this time, we plan to exclude patients with the most extreme anti-AGA antibody titers similar to those seen in patient 2, with a threshold cutoff of a titer of 1 to 25,000. We may revisit the treatment of these patients in the future. Based on our internal data and published data, we believe this excluded population may only constitute approximately 5% of all patients with Fabry disease. Meaning that we believe that approximately 95% of all Fabry disease patients will still be eligible to enroll on this trial. Today, we're also pleased to announce the clearance of our IND in Taiwan as part of a new Asia-Pacific Rim Phase I/II clinical trial with 4D-310. This trial will include post-treatment heart biopsy analyses, including assessments of transgene delivery. I'd now like to give an overview of our clinical data with the intravitreal product candidate 4D-110 in patients with choroideremia. As you may recall, our last update on this program was in June, where in addition to announcing that we would regain full rights to 4D-110, we also provided an initial clinical data update on this program. Patients on the 4D-110 trial have less follow-up than those on the trial with our lead inherited retinal dystrophy program, 4D-125 for XLRP. We therefore characterized the clinical data package at this time as preliminary. A total of 6 patients have been enrolled and treated. Intravitreal 4D-110 was not associated with dose-limiting toxicities at either of 2 dose levels. First, we'll walk through the detailed clinical activity and inflammation data. In the context of this slowly progressing retinal dystrophy, preliminary evidence of clinical activity was demonstrated. Two patients at the low dose are evaluable for clinical activity after 12 months minimum follow-up at this time. For context, retinal pigment epithelial cells, or RPE, are the target in choroideremia. Therefore, we measured fundus autofluorescence area, or FAF area, in order to assess the viable RPE cell layer over time. We compared FAF area loss over time in the treated eye versus the untreated control eye in both of these evaluable patients. In these patients, both the percent and absolute FAF area loss were less in the treated eye versus the control eyes in the same patient. As a result, we believe this suggests RPE cell preservation was associated with 4D-110 treatment. Of note, we also demonstrated a reduction in photoreceptor loss as measured by ellipsoid zone area over time. Inflammation scores were assessed over time using the SUN and NEI standard scores for the anterior chamber and vitreous, respectively. In the anterior chamber, Grade 2 plus cells were observed in 2 of 6 patients at a single protocol-defined time point, and Grade 1 plus cells were observed at a single protocol-defined time point in 1 additional patient. In the vitreous chamber, 3 patients had 1 plus cells at a single protocol-defined time point. Now we'll summarize the data and key takeaways by dose cohort. In cohort 1, at the 3E11 vg per eye dose level, 4D-110 was generally well tolerated and inflammation was manageable with corticosteroids. No DLTs or SAEs were reported, and clinical activity was demonstrated as we just showed you. Based on the totality of clinical activity data in all patients, we elected to expand enrollment at the preferred dose level of 3E11 vgs per eye. At the Cohort 2 high dose level of 1E12 vgs per eye, inflammation was similar to that in Cohort 1. In mid-October, iris pigment dispersion and transillumination was reported in all 3 patients at this dose level, approximately 7 to 9 months following treatment. Investigator reported these events as SAEs, although both 2 patients were asymptomatic and 1 patient reported only mild glare. Of note, no hospitalizations or medical interventions were initiated. We believe these findings are most likely due to efficient transduction of iris pigmented epithelial cells, or IPE, resulting in over-expression of the REP1 transgene product in these cells. These cells are phenotypically and functionally similar to the target RPE cells in this disease. Its finding was not associated with inflammation severity. This finding was not reported in any patients at the 3E11 vg per eye dose level. And this finding was not reported in any of the 8 XLRP patients treated with 4D-125, including in 5 patients treated at the same high dose level. In summary, 4D-110 was associated with clinical activity and a manageable safety profile at the 3E11 vg per eye dose level. We plan to continue enrollment at this dose level. Now take a step back. I'm proud to say that 4D continues to relentlessly execute. This month, we've delivered clinical data updates across 2 4DMT invented vectors from 3 different clinical programs. Notably, today, we reported first ever clinical data from our 4D-310 product candidate utilizing our C102 targeted and evolved vector that was invented through 4DMT's Therapeutic Vector Evolution platform. To our knowledge, these initial clinical data are not only the first demonstration of consistent serum AGA activity significantly above the normal range, but also may reflect the highest protein levels achieved in humans to date with any gene therapy for any indication. In ophthalmology, and with our R100 vector, we've announced clinical data from both 4D-125 and 4D-110, and we recently received clearance of our IND for 4D-150, our large market product candidate for wet AMD. In addition to the R100 and C102 vectors, we've also received clearance of our IND for our 4D-710 cystic fibrosis program candidate, which utilizes the A101 vector. 4DMT began with a vision, to unlock the full potential gene therapy through innovation and through harnessing the power of directed evolution. Our initial clinical data demonstrates the potential of the Therapeutic Vector Evolution platform to overcome the hurdles faced by conventional gene therapy vectors. And so with that, we welcome your questions. Operator?

[Operator Instructions] Your first question comes from the line of Salveen Richter from Goldman Sachs.

Could you talk a bit about the impact of the ERT on the data set that you saw with the gene therapy and how you think about a path forward, given the synergistic nature that you discussed? And then secondly, if you could just talk about what you need to show on liver biopsies as well as kind of functional outcomes you think about going forward here?

Sure. Well, thank you for the question, Salveen. We're thrilled with the AGA levels we're seeing. And certainly, the lyso-Gb3 responses are consistent with the high level of activity. In patient 2, where the lyso-Gb3 was elevated at baseline, we saw a significant reduction of more than 50%. And then in the 2 patients who had come into the study on ERT and had low lyso-Gb3, those levels were maintained stable and low after discontinuation of ERT. In terms of next steps for this program, we think we really have an opportunity to benefit tissue systemically through both mechanisms of action. Clearly, high sustained levels of AGA should lead to a strong cross-correction of tissue systemically. And then with gene expression directly in the target tissues themselves as well that [indiscernible] of AGA should be also a strong mechanism for patient benefit. And again, we hope that together those could synergize. Certainly, we believe these levels of AGA enzyme activity in the blood should result in benefit in the kidney. We need to prove that over time. But certainly, we would expect the potential to slow the eGFR slope as well as eventually to show biopsy evidence of clearance of substrate from the kidney on [indiscernible] biopsies. So that's something we're considering as well.

Your next question comes from the line of Tazeen Ahmad from Bank of America.

Congratulations on the initial data. I just have a couple here. How do we know whether or not ERT co-administration is going to be needed for patients forever, let's say? Or is this something that can be weaned over time? Secondly, can you give us a sense on how we get comfortable with durability of response? The initial data does look promising. Do you think you calculated the right amount of observation period to give a sense of what longer-term durability will be? And then if I could squeeze in the last one. Is there any potential risk from overactive AGA activity in your mind? And is that a potential reason to dose lower?

Thanks for the questions, Tazeen. So first of all, we do believe that ERT can be discontinued in these patients if we continue to see these sorts of results. So as we said, 1 patient came into the study off of ERT and had a really highly significant response. And then 2 patients to date -- the other 2 patients, we've discontinued ERT and lyso-Gb3 levels look nice and stable and low. So we would expect long term to have the goal of replacing ERT and not using a combination. So that's the goal there. And then I think you asked about durability. And yes, so I think in terms of durability, we need more follow-up. We want to get more follow-up. We're extremely pleased with the levels we're seeing. We're obviously starting at extremely high level. So we expect to have a durable effect for quite a while. We do know from other gene therapy programs that AAV gene therapy once it's in a stable post-mitotic tissue, like heart or lung or kidney, should give nice long-term stable expression. So we look forward to proving that, but obviously, we want additional follow-up to really demonstrate that. In terms of the levels we're achieving, this is a very high level. We achieved about 500% of normal levels in primates. That was safe and well tolerated. So we're doing significantly better than we did in primates, which is great for translatability of our programs. We do know in mice, we've achieved levels that are 1,000x normal, and those were safe and well tolerated. We know in primates, high levels were safe and well tolerated. And even in transgenic mice, AGA has been over expressed about 1,000 fold above normal and then well tolerated. In the clinic, AGA enzyme therapy has been very well tolerated. And as you saw in one of those slides, the AGA with ERT, the spike is actually 10 to 100-fold higher than what we're seeing. It's just that it's rapidly cleared. And so we think a sustained continuous expression of ERT -- of AGA is a superior approach. But nevertheless, we have that safety data with ERT that's extremely promising and comforting. And then finally, pegylated AGA does give a pretty continuous exposure with every 2-week dosing and that's been safe and well tolerated. So we think, based on our safety data to date and the totality of the data with AGA enzyme, there appears to be a very large therapeutic index with AGA. And at this time, we're comfortable with this dose. Now again, with additional patient treatments and experience, we may elect to explore a lower dose. That's certainly something we're open to. But at this point, we feel comfortable with this dose level.

[Operator Instructions] There are no further questions at this time. I would now like to turn the conference back to our presenters for the closing remarks.

Well, thank you, everyone, for your time today. We really appreciate it, and look forward to further meetings in the future.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and have a wonderful day. You may all disconnect.