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spk06: Welcome everyone to the Q2 2024 RegenX Bioearnings Conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question, simply press the star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one. At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of BeginXBio. Please go ahead.
spk04: Good afternoon, and thank you for joining us today. Earlier this afternoon, Regenexx Bio released financial and operating results for the second quarter ended June 30, 2024. The press release is available on our website at www.regenixbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the risk factors in the management's discussion and analysis section of Regenexx BIO's annual report on Form 10-K for the full year ended December 31st, 2023, and comparable risk factor sections of Regenexx BIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, August 1st, 2024, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I will now turn the call over to Kern Simpson, President and CEO of Regenexx Bio.
spk10: Thank you, Patrick. Good afternoon, everyone, and thank you for joining us. I'm pleased to be leading today's call, my first one as Regenexx Bio's Chief Executive Officer. Today we'll be sharing a number of exciting, positive updates and discuss the momentum happening across our pipeline of differentiated AV therapeutics. I'll begin with a recap of our business highlights, as well as an update of our corporate goals and key milestones that we have achieved. Dr. Steve Piccola, our Chief Medical Officer, will provide an update on our clinical programs, and then Vince Assista, our Chief Financial Officer, will provide an overview of financial results for the second quarter ended June 30, 2024. At the end of the call, we'll open up the line for questions. It's been a productive first half of the year for Regenexx Bio as we make significant progress advancing each of our programs toward pivotal stage clinical trials and future commercialization. Our priority programs are RGX202 for the treatment of Duchenne, AbbVie RGX314 program for the treatment of wet AMD and diabetic retinopathy, or DR, being developed in collaboration with AbbVie, and RGX-121 for the treatment of MPS II or Hunter syndrome. Our lead programs, specifically 202 and 314, represent large commercial opportunities where our product candidates are differentiated from current standard of care, can be expedited via accelerated approval due to significant unmet need, and support meaningful value generation soon and for the long term. Let me begin with RGX202, which represents the next generation of microdystrophin gene therapies and is poised to potentially be the second AAV-based product to reach the market. There are a number of exciting developments for RGX202. Steve will share more details about the positive data reported today, demonstrating consistent, robust microdystrophin expression across treated patients reflecting a broad range of ages. But I first want to highlight the differentiating factors that we believe will make RGX202 a best-in-class product and the excellent progress we are making to both expedite its development and maximize its commercial potential. RGX202 is a differentiated product candidate utilizing an advanced microdystrophin construct with potential for improved functional benefit, as shown in our preclinical data. It is the only microdystrophin product that includes the C-terminal domain, a key region of the naturally occurring dystrophin gene, which has been shown in preclinical studies to protect the muscle from contraction-induced stress and improve the ability of the muscle to repair itself. As I mentioned, RGX202 is demonstrating consistently high levels of microdystrophin expression across patients of all ages. But I want to note that it is in older ambulatory boys where we're seeing the highest levels of microdystrophin expression reported in older ambulatory patients, especially compared to other published data. And RGX202 has been well tolerated and no SAEs have been reported, which is a significant element of the overall risk-benefit analysis for patients, caregivers, and regulatory agencies, and a meaningful differentiator versus other Duchenne gene therapy trials. As I mentioned, our goal is to be the next approved gene therapy in Duchenne, and we are taking all of the necessary steps towards this goal. We recently completed a successful end-of-phase two meeting with the US FDA and walked away from this meeting confident in our plans to file a BLA using microdystrophin as the primary endpoint for accelerated approval. The meeting also involved discussion of our industry-leading NavXpress suspension-based commercial-ready manufacturing process used in this trial. At our in-house manufacturing facility, we have the capacity and yields to produce 2,500 doses of RGX202 per year. Given the differentiating characteristics of RGX202 and the significant ongoing unmet need in the Duchenne community, plus our manufacturing expertise, we are well positioned to advance this program towards commercialization. Turning to AbbVie RGX314, Our gene therapy being developed in chronic retinal diseases with our partner, AbbVie, we have made several advancements across the supracoroidal trials in diabetic retinopathy and wet AMD. First, with regard to the altitude trial of 314 for the treatment of DR using supracoroidal delivery, we are accelerating plans for our end of phase two meeting with the FDA. This meeting is now expected to take place in the fourth quarter of this year versus our initial guidance of first quarter 2025. The new timeline supports the rapid acceleration towards pivotal trials with initiation expected in the first half of 2025. Importantly, Regenexx Bio will be entitled to a $200 million milestone payment upon successful dosing of the first patient with AbbVie RGX 314 in DR, which again is anticipated in 2025. We are also excited to announce that working with our partners at AbbVie, we will be expanding the broad multi-indication global potential of 314 by initiating a new cohort in the altitude trial for patients with diabetic macular edema, DME, 314 is well positioned to become the standard of care to treat and progression of diabetic retinopathy. Broadening the altitude trial to include patients with DME further expands the global potential of 314. We have also made important progress on our 314 programs for wet AMD, as well as in our RGX121 program for MPS2, as we approach potential approval and becoming the first gene therapy for Hunter Syndrome. We remain on schedule to initiate a rolling BLA filing in the third quarter of 2024. Approval of the planned BLA could result in receipt of a priority review voucher in 2025. Overall, we are making excellent progress and have provided positive updates across all programs with a number of additional catalysts on track to be shared later this year. We remain excited by our progress as we continue on the strategic plan. We are accelerating the development of our pipeline and expanding their value for shareholders while bringing potentially life-changing therapies to patients facing great unmet needs. With that update, I'd like to now turn the call over to Steve for an update on our clinical programs. Steve?
spk05: Thank you, Curran. I'll start with RGX202, a potential one-time gene therapy for the treatment of Duchenne. Today, we reported new microdistributed expression data from the two new patients, age 5.8 and 8.5 years, who received RGX202 at dose level 2, the dose we are advancing to pivotal phase. Microdistributant expression was measured to be 77.2 and 46.5% respectively, compared to control at three months. As of July 8, 2024, RGX202 continues to be well-tolerated with no serious adverse events, and all patients who reach three-month trial assessments indicate meaningful increases an expression of RGX202 microdistrophin, and reduction from baseline in serum creatinine kinase levels, supporting evidence of clinical improvement. We are very excited as today's data adds to the totality of evidence demonstrating consistent high microdistrophin expression across all treated patients. In addition, early evidence of strength and motor function improvement were observed via trial clinic assessments and home videos shared by caregivers. On the continued strength of our data, in June, we announced the expansion of the Affinity to Duchenne trial to include a new cohort of patients aged one to three years. This is a cohort of boys where there remains no approved gene therapy products and a cohort that represents a significant portion of the untreatable prevalent population of Duchenne boys. As we ultimately seek a broad label for RGX202, we will continue to produce data where limited or no data exists to further establish a differentiated product profile that can enhance RGX202's commercial potential. Moving to 314, which is being developed in collaboration with AbbVie to treat wet AMD, DR, and DME via subretinal and suprachoroidal routes of administration. I'll start with 314 for DR, being evaluated in the Phase II altitude trial using in-office supracoroidal delivery. As Curran mentioned, with our partner, AbbVie, we have accelerated our end-of-Phase II meeting with the FDA and believe this puts us in an excellent position to initiate our first pivotal trial in DR. Today, we announced that we are now enrolling a new cohort of the ALTITUDE trial to evaluate 314 in patients with center-involved diabetic macular edema, or CI-DME. DME is a vision-threatening complication of diabetic eye disease and impacts more than 30 million patients globally. We are also evaluating 314 for the treatment of wet AMD via subretinal delivery in two ongoing pivotal trials, Atmosphere and Ascent, in the U.S., Europe, and Japan. These trials continue to progress well. Our long-term follow-up data from the Phase I-II subretinal trial out to four years have set the gold standard in clinical development for wet AMD gene therapies. We have also fully enrolled the Open Label Fellow Eye Study, evaluating 314 in patients previously treated with 314 in the other eye. This study is expected to support a label inclusive of bilateral use, representing a meaningful option for the significant number of patients with wet AMD in both eyes. Also in wet AMD, today we announced 314 was well-tolerated at dose level 3 in the AVA trial for wet AMD using in-office supracoroidal delivery. In patients who received short-course prophylactic steroid eye drops, there were no drug-related SAEs and no cases of intraocular inflammation, endophthalmitis, vasculitis, retinal artery occlusion, choroidal effusion, or hypotony. We are encouraged by the positive safety profile seen to date, and we plan to enroll a new cohort at dose level four as we evaluate dose levels on a path toward pivotal stage. We continue to be encouraged by the progress on our 314 programs, and I'd like to particularly highlight the safety profile observed, including in our supracoroidal programs. We are confident in our plan to advance into new disease states and dose levels because of this safety profile, particularly in the setting of short-course, seven-week prophylactic steroid eye drops. In more than 130 patients treated in office, we're seeing a differentiated safety profile for ocular gene therapies, representing a meaningful potential treatment option for patients and physicians globally. on RGX121 being developed for the treatment of MPS2 or Hunter syndrome. In February at the World Symposium, we announced that the campsite pivotal trial met its primary endpoint with high statistical significance. Patients treated with RGX121 achieved decreased cerebrospinal fluid, CSF, levels of heparin sulfate D2S6, a key biomarker of brain disease activity to below maximum attenuated disease levels. We plan to share new data from the campsite trial in the second half of this year. We believe RGX121 is well-positioned to be the first gene therapy and one-time treatment for Hunter syndrome. We've completed a successful pre-BLA meeting with the FDA that finalized details of our planned rolling BLA submissions. The key takeaways from the meeting included alignment on the use of CSF D2S6 as the key biomarker and surrogate endpoint reasonably likely to predict clinical benefit to support accelerated approval. We also reached alignment on CMC manufacturing requirements and on the confirmatory trial design. To conclude, we continue to make significant progress with data updates in trial progression across all programs in our pipeline. Lastly, I'd like to thank the patients, families, clinicians, and patient advocacy representatives who have been involved in and supported all of these trials. And with that, I'll turn the call over to Vit to review our financial guidance. Vit?
spk23: Thank you, Steve.
spk07: Regenexx file ended the quarter on June 30th, 2024 with cash, cash equivalents and marketable securities of $327 million compared to $314 million as of December 31st, 2023. The increase was primarily attributable to $131 million in net proceeds received from an upsized public offering of common stock and pre-funded warranted completed in March 2024, partially offset by cash fees to fund operating activities in the first half of 2024. R&D expenses were $49 million for the second quarter of 2024, compared to $60 million for the second quarter of 2023. The decrease was largely driven by reduced manufacturing and clinical supply costs for AbbVie RGX 314 and RGX 202, and personal related costs as a result of reduced headcount. The decrease was partially offset by increases in clinical trial expenses for AbbVie RGX 314 and RGX 202. Regenexx Bio expects its balance in cash, cash equivalents, and marketable securities of $327 million as of June 30, 2024, to fund its operations into 2026. This cash runway guidance is based on the company's current operational plans and excludes the impact of any payments that may be received from AbbVie upon the achievement of development or commercial milestones under AbbVie RGX 314 collaboration, including a potential $200 million milestone for achievement of the first patient dose in the pivotal trial for supracordial delivery for treatment of DR. Additionally, our one-way guidance excludes the potential monetization of a priority review voucher that may be received for RGX121. With that, I will turn the call back to Curran to provide his first set of final thoughts.
spk10: Thanks, Bitt. Today was another exciting day for our 202 program with additional positive data. As we look ahead to the rest of the year, we are encouraged by our discussions with the FDA and our finalizing pivotal plans that will enable us to utilize the accelerated approval pathway to rapidly advance 202 as a potential best-in-class treatment for Duchenne. Additionally, we are pleased to be accelerating the end of Phase II meeting for DR in partnership with AbbVie to enable a pivotal start next year. As we close today and reflect on the first half of the year, I'll emphasize that our plans are on track and we continue to expand value as we make excellent progress in advancing therapies that address significant unmet needs. Thanks everyone for your time today. I'll turn the call over for questions. Operator?
spk06: Thank you. We will now begin the question and answer session. At this time, I would like to remind everyone in order to ask a question, press the star and then the number one on your telephone keypad. If you are called upon to ask your question and are listening by a loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. We do request for today's session that you please limit to one question and one follow-up. We will pause for a moment to compile the question and answer roster. Your first question comes from the line of Gina Wong of Barclays. Please go ahead.
spk02: Thank you. Congrats on the new data regarding the 202 in DMD. So I have two questions. One is the 202. I know you will meet with the FDA, finalize the pivotal study. Do you have a goal of a protein level you wanted to achieve? And do you expect FDA will set some threshold in order for accelerated approval? And another question is regarding the 314, a supercorridor indication in DR and the wet EMD. What's the reason for dose level 4? And will you also include patients with existing neutralizing antibody?
spk10: Thank you for the question, Gina. In terms of, can I clarify the first question? A goal for protein level, microdistribute level. We've proposed a threshold with FDA, and that's one of the things that we'll be waiting for the minutes and sort of final agreement in addition to the back and forth that will occur with the pivotal plan that will be submitted. We feel that just in general, thinking about the field and what we've been able to glean from our investigators, that A level above 10% is likely to result in functional benefit. I think that will be a discussion that we have going forward, but that's, if you think about our data, to date every patient that we've published data on is above that threshold. I'll field the second question to Steve if that's okay.
spk05: Hi, Gina. Thanks for the questions. So 314 and going to dose level 4 in our phase 2 studies, why do that? We've certainly met our target product profile in diabetic retinopathy, and that's why we're so excited with the advancement towards pivotal that Curran and I have summarized. We've also seen, as I have highlighted, excellent safety. So I think the key consideration is we're going higher in part because we can. We really have the flexibility given that the excellent safety that we believe is due to the compartmentalized route into the suprachoroidal space as opposed to less compartmentalized spaces like the intervitreal space. and particularly with our product, RGX314. So in collaboration with AbbVie, we're doing this. And I think it also fits just general basic drug development, where if you have good safety to really fully characterize a product, it makes sense to continue looking at higher doses if you can.
spk25: Thank you.
spk06: Your next question comes from the line of . Please go ahead.
spk24: Great. Thanks for taking our questions. We had two first on 202. Could you just speak a bit more about the functional assessment data we're going to be getting later this year, what your guidance is to best interpret that to get a sense of differentiation, real-world differentiation, and how that data set might play into discussions with regulators on next steps? And then secondly on 314, for suprachoroidal and wet AMD, could you talk a bit about how you see that program moving towards a pivotal program and how that pivotal program potentially for 314 and wet AMD could overlap with efforts with the subretinal approach? Thanks.
spk10: Okay. I can take the first question. Steve, do you want to start with the second one?
spk05: I missed the second one. Could you repeat the second one?
spk24: Sure, yeah. It was about 314 supercoital and wet AMD. Just wondering what the path is to a pivotal program there and how you see a potentially pivotal effort for 314 and wet AMD overlapping with your efforts with the subretinal program you currently have underway.
spk05: Sure. So with all the experience we have with wet AMD, we... have a pretty good sense of assessing both safety and efficacy, both from our subretinal experience and also the prior cohorts we've done with supracoroidal. So I think it's the usual endpoints that we think of. We get to take advantage of the totality of evidence on top of, of course, having good safety. So biomarkers like retinal thickness, where we get a very good objective measure, BCBA, and of course, reduction in treatment burden. So we'll really look at all of those to see what type of response we get at six months and longer, and really compare that to what's been seen, for example, even in our subretinal program, where we want to see good durability and really maintain a anatomic control as measured by retinal thickness, and BCVA control while dramatically reducing injection burden. And we've often talked about at least 50% of patients not needing any injections and over 50% of reduction in injection burden.
spk10: And this is current to the first question. In terms of functional data in the fall, just to To baseline, we measure microdystrophin at a three-month time point. And then on the functional assays, we measure generally every three months a number of functional assessments that you've seen historically with other programs. And in the fall, I would expect to see a significant amount of functional data out to 12 months for the dose level one patients. And for some of the early dose level two patients, you'll see six and probably nine month data for them. Things like Time to Rise and NSAA as an example. We haven't finalized exactly what data will come out because it's still emerging, but that's the plan for the fall.
spk05: Vikram, you also had the question of how do we see this in the context of our ongoing pivotal subretinal program for wet AMD when thinking about supracoroidal. I think it's fair to say that both we and AbbVie really see opportunities in both, and that's why we both are together advancing further evaluation of SCS at DL4. for this while we continue with the pivotal program with subretinol. Certainly, the opportunity that we see with subretinol given the gold standard in safety and efficacy that we've shown in excellent durability has us very excited about that. There's, of course, the opportunity to expand the optionality by having an in-office procedure And we look forward to gathering more data in the additional cohort to keep evaluating that option.
spk11: That's helpful. Thank you.
spk06: Your next question comes from the line of Paul Choy of Goldman Sachs. Please go ahead.
spk21: Hi. Good afternoon and thanks for taking our questions. My first is I was wondering if you could maybe just elaborate on interest levels in the patient community and clinical community for 202, a potential pivotal trial later this year or early next year in the wake of the recent Alevitis label expansion and approval there. And then my second question on 314 is with regard to dose cohort 4 here. I know you specified that there would be prophylactic steroid use here, but could you maybe comment on a view whether there would be potentially reduced need for rescue VEGF use? A competitor recently provided some updated data for their program, and I think this came as a bit of a surprise, so just any thoughts there as to whether dose cohort four could potentially either increase the injection-free frequency or reduce the rescue usage as you prosecute that cohort. Thank you.
spk10: I can take the first one and then I'll have Steve address the second question. I think on patient recruitment for 202, we've been able to check in with sites and investigators at meetings like PPMD. and we've seen nothing but really strong interest in the program. Many of these centers have up to 100 patients and just having discussions with the investigators around are people still interested in our study given that there's a product on the market, the resounding answer is yes. There are many patients that are looking at our program and seeing the differentiation that it offers, seeing the safety, that's been demonstrated to date, and I would say that there's strong interest, and therefore, on our end, strong confidence in our ability to recruit the study. So early days, I feel very confident in our ability to recruit the pivotal program, and I'll turn it over to Steve to address the 314 question.
spk05: Sure, so regarding DL4, assessment in these indications, we certainly think there's the opportunity that we could decrease rescue use further than what we've seen while maintaining visual acuity benefit and stability and also anatomic control. As I mentioned to one of the earlier questions, we have the flexibility to do that. You referred to some other data that's that's come out earlier this year, and I think one always has to look at that issue of can you go up higher on dose, and if there's either a concern about additional safety issues, including immune response and inflammation, and also if you start to run into the issue of how long a duration of prophylactic steroids can really be tolerated, So that's why we're very excited about our safety profile where we don't need extended prophylactic steroids. So I think the totality of that does give us the chance to go up higher and see if we can reduce injection burden further.
spk10: And just one follow-up, Paul, to the question on recruitment. One of the purposes of the data release we did today was really to show people the differentiated level of microdystrophin in some of the older patients that have been treated. So that's just another piece of information that a patient can use when they're deciding what therapy to have their child treated with. So that was one of the purposes of that release is to help people understand our product a bit more.
spk22: Great. Thanks for taking our questions.
spk06: Your next question comes from the line of Alex from Bank of America. Please go ahead.
spk03: Hi, good afternoon. This is Mary Kate on for Alex today. Thanks for taking our question. Just one on DMV. Given questions around safety for others in the field, what kind of safety database do you expect you'll be required to collect for approval in terms of size and duration of follow-up? Thank you.
spk10: Yeah, that's, I think, something that we're still working on and probably will tie out completely in the pivotal plan that we'll submit to FDA. So we're really not able to comment in terms of various specifics there. I think in general, our proposal on sample size is in the 30 to 40 patient region, but that's really a discussion that's ongoing with FDA. But I think The reasons that we feel that's a valid number is, number one, we have a commercial-ready process that we won't make changes to in terms of product profile during the pivotal studies, and so that should reduce the sample size. And second, the initial safety record that we've already demonstrated in the trial to date should be a positive in terms of how FDA might view the program and how they assess what the sample size should be. So we feel like we're in a good position there, and I think that gives us a good feeling that the recruitment will be accelerated into next year.
spk30: Understood. Thank you.
spk06: Your next question comes from the line of Annabel Salmoni of STIPO. Please go ahead.
spk01: Hi. Thanks for taking my question. We also have two. First on DMD, just bringing back the question of functional data and what you might be looking for. Given the broad age group that you're looking at and maybe the different levels of ambulation, are you giving any consideration to stratifying those patients based on age group and measuring them on different metrics depending on their age and then matching against the natural history for that specific age group. So how much granularity might we see already and maybe what are you possibly baking into phase three? And then on 314, I guess I'm trying to understand how you're thinking about this dose level four in light of, you know, other competitors in the space, do you feel that the benchmark for you is your subretinal? Is it the benchmark for you, other competitors in the space? And, you know, given, I guess, maybe a little bit of a race in the gene therapy space, is there less urgency to be the first one out there or the one to get it right? Because the population is large and maybe they're a little bit less desperate than, say, in the rare disease area. Are people looking at this competitive landscape the wrong way? So a little broader question. Thanks.
spk10: I can start with 202. And I think we think about functional data in sort of two dimensions. As it relates to accelerated approval, you know, our primary driver will be measuring microdystrophin at three months as our primary endpoint. But along with that, of course, we're measuring functional data along the way. And initially what I would expect in the fall is likely a reference of functional data to baseline levels for the specific patient. Now, if we think about a confirmatory study, you're absolutely correct that studying natural history and matching patients either by age or by age disease progression would be part of that strategy that we're having discussions on. So it's actually, I would expect to see both sort of views as it relates to functional data. I'll turn it over to Steve for the 314 question.
spk05: Thanks, Annabelle. So as far as benchmarking, as I mentioned, we got a lot of experience, many of us from prior programs as well, but certainly in-house with our subretinal program, really the target is pretty similar in terms of what you have to show when we think of supracoroidal, perhaps slightly a little broader given the non-surgical in-office opportunity of supracoroidal. I think an important context when thinking of different programs is really assessing how much durability has really been shown. So really being able to look out to six months and beyond relative to when the last loading dose may have been given, for example, in indications like wet AMD. And I think with certain agents that require repeat injection, even though they have greater durability, there's the reality that at some point you're going to need the reinjection. And if you're looking at a time point that's too early to see that, are you going to start seeing the need for rescue creep up? And that's why we're excited about a gene therapy approach where you have stable, consistent anti-VEGF activity that can allow for really the ultimate goal of having in a sizable proportion of patients not needing any injections. So we feel good about this approach, and we know how to look at the safety and efficacy to really know when we're in a position to move forward. Okay.
spk27: Thank you.
spk06: Your next question comes from the line of Manny Purujar of Learing Partners. Please go ahead.
spk15: Hi, good afternoon. This is CJA on for Mani. Thanks for taking our question. Could you please comment on your strategy in DMD? Are you targeting younger patients than surreptitious current label since you've announced you've expanded the age range to one to three while surreptitious youngest age is four? Thanks.
spk10: Hi, this is Curran. I think it's safe to say we want to build an adequate safety database at a minimum for the patients in ages one to three, but we'll be enrolling across a wide variety of ages in the studies.
spk05: And we had made the decision to expand and look at this broad age range, including one to three, before any elevatous label expansion. We've seen this opportunity, and now with the results, safety that we've seen and the microdystrophin expression we've seen across a wide age range on the upper end, it's a great opportunity to look at one- to three-year-olds.
spk14: Perfect. Thanks for the commentary.
spk06: The question comes from the line up. Eliana Merle of UBS. Please go ahead.
spk20: Hi, this is Eric Massandra calling in for Eliana. Thanks so much for the question. My first one's on 202. Do you have any in-house data from patients already dosed with 202 beyond the three months to help us better understand variability and what the effects might be over time? And what do you expect to see over time? Do you expect labels to be stable for three months or more, or do they deepen over time? I have one follow-up.
spk10: I'm sorry. Are you referring to micro dystrophin levels beyond three months or other functional data, for example? Micro dystrophin, yes. Okay. No, we're taking a biopsy prior to treatment and then at three months. We don't have biopsies beyond that time point, basically per direction with FDA. However, we'll obviously be measuring durability in terms of functional outcomes in the out periods. Yes, we don't have data beyond three months, but I think our preclinical data would suggest really excellent durability. And the construct that includes the C-terminus has a longer half-life than microdystrophin that's devoid of that. So I would expect both higher levels of microdystrophin and perhaps sustained levels of relative to what you've seen in other literature.
spk20: Got it. And just one quick follow-up. Is there anything that you've been able to identify in terms of patient characteristics that's correlated so far with a higher microdiscipline expression or higher functional assessment?
spk05: So the usual caveat that there aren't enough patients to really have confidence in terms of predictors. I'd say the biggest learning so far is actually that age is not predicting a lower microdystrophin as you go up on age, which has been a concern that the community has had, whether that might be the case. And some data from other programs suggest that That may be an issue, but we've not seen that at all. So I think the striking thing from our data is even in eight and older, we're seeing very robust microdystrophin levels. Beyond that, we're seeing microdystrophin levels across the patients. So no clear differentiator or predictor in this sample to date.
spk17: Got it. Thank you.
spk06: Your next question comes from the line of Luca Eze of RBC. Please go ahead.
spk18: Oh, great. Thanks so much for taking my question. Congrats on the progress, maybe current. Can you just expand a bit more on your recent end-of-Phase II meeting with the FDA? I appreciate it. You're still waiting for the minutes, but can you confirm that your read is that you can get accelerated approval and expression across all patients with DMD and not only patients that are excluded from the Sarepta label today, either because of age or existing immunity. I think that's an important distinction, so any caller, much appreciated. And then maybe still in DMD, how are you thinking about a confirmatory trial? Will you still use North Star as the primary endpoint, or do you think there are other endpoints that could be more sensitive here? Any caller, much appreciated. Thanks so much.
spk10: I can work a bit in reverse. We'll use North Star, but we're obviously measuring a number of additional functional indicators that you've seen, as I mentioned earlier, time to rise and some of the timed walks that are associated. So I would characterize it as we're measuring everything because there are, you know, it's still a field where I think the functional assays are evolving and Each product is different, and I think we want to be able to capture as much functional data as we can across as many indices as we can. Related to accelerated approval, our strategy is to approach this for a broad approval, not a narrow approval for only patients that are ineligible for current therapy. And the basis for that is simply the differentiation of the product. That's, I think, one of the basic tenets of the accelerated approval is unmet need. And we feel we have a really strong evolving case that addresses unmet need, and our ambition will be to obtain as broad a label as possible.
spk00: Got it. Thanks so much.
spk06: Your next question comes from the line of Brian Scarnia of Baird. Please go ahead.
spk19: Hey, thanks for taking the question. On the phase three plans for diabetic retinopathy, just trying to engage sort of your level of confidence in Abby's level of confidence in the first half initiation next year. What are sort of the primary questions that the company's supposed to get answered by the FDA or the FDA hopes you think the FDA will need answers to at the end of phase two meeting? to sort of ensure that this phase three gets kicked off. And maybe just some color on the DME cohort and is the consideration, is there a consideration to pursue these more progressed patients or is the thought here really just to supplement with some data in patients who have progressed on to DME?
spk10: I'll give a brief comment and then turn over to Steve. I certainly think we and Abby have a really high level of confidence in DR progressing into Pivotal next year. And I think that's shown in the acceleration of the end of phase two meeting into this year. We're eager to get this study up and going. And I think I'll let Steve comment on the details of the pivotal approach, but we feel like there's a very standard approach to developing in diabetic retinopathy established endpoints and precedent. But I'll let Steve comment on the details of what we're thinking and and how that study should go.
spk05: Yeah. Fortunately, as Karin mentioned, there's a roadmap for diabetic retinopathy that's been laid by repeat injection anti-VEGF that has really allowed us to know what do you expect from a negative control arm if you're not receiving an active agent. And that, of course, really helps us to power studies in combination with the actual proof-of-concept data that we have. We also know a lot about the endpoints that are accepted. So we feel very confident that this has really de-risked quite a lot from a regulatory standpoint. So it's really assessing some things around the edges and some definitions and the like, frankly, when it comes to the pivotal designs So I think that's one of the aspects that, given the positive results that we've seen, why we have been able to accelerate and bring this into Phase 2 meeting into Q4 instead of Q1 next year.
spk19: And then you're... I was just going to ask about the DMA cohort.
spk05: Yeah. Yeah, so... We are looking at center-involved DME. Of course, that's the traditional indication. So we don't see a need to go outside the box in terms of the type of patient population that we'd be looking at so that we can really have the context of what others have looked at and what others have seen. So yeah, it's just a great opportunity. We do know diseases like DME or the complication of DME and wet AMD that there's a little higher VEGF drive than exists with, say, nonproliferative diabetic retinopathy without DME. So we think we're right around the dose response range where this is going to be very interesting to look at DL4 in this patient population.
spk12: Great. Thank you.
spk06: Your next question comes from the line of Daniel Gataulin of Chardon Capital Markets. Please go ahead.
spk13: Hey, guys. Thank you for taking the question. Congrats on your role. I have a quick question on the WET-AMD program, the retinal delivery. When do you anticipate sharing data from the fellow eye study? And as a follow-up to that, how it translates to suprachoroidal injections, given those are are more likely to interact with the immune system. What is your long-term strategy for treating fellow eyes using superchloroidal delivery? Thank you.
spk09: I'll turn that over to Steve.
spk05: Hi, Dino. So as far as when we would have fellow eye results, we have the update today that we completed enrollment of the fellow eye study. So if you add on you know, up to six months or so from that would give you kind of a rough range of when we traditionally have been comfortable releasing data in this type of indication to really show a stable effect at least. We were excited to have this study not just from a regulatory standpoint to have that label expansion to allow bilateral disease, but As you referred, the immune response, whether you would have a greater immune response that could affect safety and or efficacy when you dose the second eye. Subretinal, I think, is the most straightforward to feel confident that you won't have an issue dosing the fellow eye because of the immune privilege status of the subretinal space. Superchoroidal, we've seen much less inflammation and no safety issues in terms of inflammation compared to, say, intravitreal administration. So that gives us confidence that supracoroidal would have that opportunity as well. So we decided to take it one step at a time, first look at subretinal fellow eye, but over time certainly it would make sense to assess fellow eye with supracoroidal as well.
spk13: Got it. Thank you very much for taking the question.
spk06: Ladies and gentlemen, there are no questions. That concludes today's call. Thank you all for joining. You may now disconnect. Thank you. © transcript Emily Beynon Thank you. you Thank you. Bye. you Welcome everyone to the Q2 2024 Regen X Bioearnings Conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question, simply press the star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one. At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of BeginXBio. Please go ahead.
spk04: Good afternoon, and thank you for joining us today. Earlier this afternoon, Regenexx Bio released financial and operating results for the second quarter ended June 30, 2024. The press release is available on our website at www.regenixbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the risk factors in the management's discussion and analysis section of Regenexx Bio's annual report on Form 10-K for the full year ended December 31, 2023, and comparable risk factor sections of Regenexx Bio's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, August 1st, 2024, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I will now turn the call over to Curran Simpson, President and CEO of Regenexx Bio.
spk10: Thank you, Patrick. Good afternoon, everyone, and thank you for joining us. I'm pleased to be leading today's call, my first one as Regenexx Bio's Chief Executive Officer. Today we'll be sharing a number of exciting, positive updates and discuss the momentum happening across our pipeline of differentiated AV therapeutics. I'll begin with a recap of our business highlights, as well as an update of our corporate goals and key milestones that we have achieved. Dr. Steve Piccola, our Chief Medical Officer, will provide an update on our clinical programs, and then Vic Vecista, our Chief Financial Officer, will provide an overview of financial results for the second quarter ended June 30, 2024. At the end of the call, we'll open up the line for questions. It's been a productive first half of the year for Regenexx Bio as we make significant progress advancing each of our programs toward pivotal stage clinical trials and future commercialization. Our priority programs are RGX202 for the treatment of Duchenne, AbbVie RGX314 program for the treatment of wet AMD and diabetic retinopathy, or DR, being developed in collaboration with AbbVie, and RGX-121 for the treatment of MPS II or Hunter syndrome. Our lead programs, specifically 202 and 314, represent large commercial opportunities where our product candidates are differentiated from current standard of care, can be expedited via accelerated approval due to significant unmet need, and support meaningful value generation soon and for the long term. Let me begin with RGX202, which represents the next generation of microdystrophin gene therapies and is poised to potentially be the second AAV-based product to reach the market. There are a number of exciting developments for RGX202. Steve will share more details about the positive data reported today, demonstrating consistent, robust microdystrophin expression across treated patients reflecting a broad range of ages. But I first want to highlight the differentiating factors that we believe will make RGX202 a best-in-class product and the excellent progress we are making to both expedite its development and maximize its commercial potential. RGX202 is a differentiated product candidate utilizing an advanced microdystrophin construct with potential for improved functional benefit, as shown in our preclinical data. It is the only microdystrophin product that includes the C-terminal domain, a key region of the naturally occurring dystrophin gene, which has been shown in preclinical studies to protect the muscle from contraction-induced stress and improve the ability of the muscle to repair itself. As I mentioned, RGX202 is demonstrating consistently high levels of microdystrophin expression across patients of all ages. But I want to note that it is in older ambulatory boys where we're seeing the highest levels of microdystrophin expression reported in older ambulatory patients, especially compared to other published data. And RGX202 has been well tolerated and no SAEs have been reported, which is a significant element of the overall risk-benefit analysis for patients, caregivers, and regulatory agencies and a meaningful differentiator versus other Duchenne gene therapy trials. As I mentioned, our goal is to be the next approved gene therapy in Duchenne, and we are taking all of the necessary steps towards this goal. We recently completed a successful end-of-phase two meeting with the U.S. FDA and walked away from this meeting confident in our plans to file a BLA using microdystrophin as the primary endpoint for accelerated approval. The meeting also involved discussion of our industry-leading NavXpress suspension-based commercial-ready manufacturing process used in this trial. At our in-house manufacturing facility, we have the capacity and yields to produce 2,500 doses of RGX202 per year. Given the differentiating characteristics of RGX202 and the significant ongoing unmet need in the Duchenne community, plus our manufacturing expertise, we are well positioned to advance this program towards commercialization. Turning to AbbVie RGX314, Our gene therapy being developed in chronic retinal diseases with our partner, AbbVie, we have made several advancements across the supracoroidal trials in diabetic retinopathy and wet AMD. First, with regard to the altitude trial of 314 for the treatment of DR using supracoroidal delivery, we are accelerating plans for our end of phase two meeting with the FDA. This meeting is now expected to take place in the fourth quarter of this year versus our initial guidance of first quarter 2025. The new timeline supports the rapid acceleration towards pivotal trials with initiation expected in the first half of 2025. Importantly, Regenexx Bio will be entitled to a $200 million milestone payment upon successful dosing of the first patient with AbbVie RGX 314 in DR, which again is anticipated in 2025. We are also excited to announce that working with our partners at AbbVie, we will be expanding the broad multi-indication global potential of 314 by initiating a new cohort in the altitude trial for patients with diabetic macular edema, DME, 314 is well positioned to become the standard of care to treat and progression of diabetic retinopathy. Broadening the altitude trial to include patients with DME further expands the global potential of 314. We have also made important progress on our 314 programs for wet AMD, as well as in our RGX121 program for MPS2, as we approach potential approval and becoming the first gene therapy for Hunter Syndrome. We remain on schedule to initiate a rolling BLA filing in the third quarter of 2024. Approval of the planned BLA could result in receipt of a priority review voucher in 2025. Overall, we are making excellent progress and have provided positive updates across all programs with a number of additional catalysts on track to be shared later this year. We remain excited by our progress as we continue on the strategic plan. We are accelerating the development of our pipeline and expanding their value for shareholders while bringing potentially life-changing therapies to patients facing great unmet needs. With that update, I'd like to now turn the call over to Steve for an update on our clinical programs. Steve?
spk05: Thank you, Curran. I'll start with RGX202, a potential one-time gene therapy for the treatment of Duchenne. Today, we reported new microdiscipline expression data from the two new patients, age 5.8 and 8.5 years, who received RGX202 at dose level two the dose we are advancing to pivotal phase. Microdistrict and expression was measured to be 77.2 and 46.5% respectively, compared to control at three months. As of July 8, 2024, RGX202 continues to be well-tolerated with no serious adverse events, and all patients who reach three-month trial assessments indicate meaningful increases in an expression of RGX202 microdistrophin, and reduction from baseline in serum creatinine kinase levels, supporting evidence of clinical improvement. We are very excited as today's data adds to the totality of evidence demonstrating consistent high microdistrophin expression across all treated patients. In addition, early evidence of strength and motor function improvement were observed via trial clinic assessments and home videos shared by caregivers. On the continued strength of our data, in June, we announced the expansion of the Affinity to Duchenne trial to include a new cohort of patients aged one to three years. This is a cohort of boys where there remains no approved gene therapy products and a cohort that represents a significant portion of the untreatable prevalent population of Duchenne boys. As we ultimately seek a broad label for RGX202, we will continue to produce data where limited or no data exists to further establish a differentiated product profile that can enhance RGX202's commercial potential. Moving to 314, which is being developed in collaboration with AbbVie to treat wet AMD, DR, and DME via subretinal and suprachoroidal routes of administration. I'll start with 314 for DR being evaluated in the Phase II altitude trial using in-office supracoroidal delivery. As Curran mentioned, with our partner, AbbVie, we have accelerated our end-of-Phase II meeting with the FDA and believe this puts us in an excellent position to initiate our first pivotal trial in DR. Today, we announced that we are now enrolling a new cohort of the ALTITUDE trial to evaluate 314 in patients with center-involved diabetic macular edema, or CI-DME. DME is a vision-threatening complication of diabetic eye disease and impacts more than 30 million patients globally. We are also evaluating 314 for the treatment of wet AMD via subretinal delivery in two ongoing pivotal trials, Atmosphere and Ascent, in the U.S., Europe, and Japan. These trials continue to progress well. Our long-term follow-up data from the Phase I-II subretinal trial out to four years have set the gold standard in clinical development for wet AMD gene therapies. We have also fully enrolled the open-label fellow eye study evaluating 314 in patients previously treated with 314 in the other eye. This study is expected to support a label inclusive of bilateral use, representing a meaningful option for the significant number of patients with wet AMD in both eyes. Also in wet AMD, today we announced 314 was well-tolerated at dose level 3 in the AVA trial for wet AMD using in-office supracoroidal delivery. In patients who received short-course prophylactic steroid eye drops, there were no drug-related SAEs and no cases of intraocular inflammation, endophthalmitis, vasculitis, retinal artery occlusion, choroidal effusion, or hypotony. We are encouraged by the positive safety profile seen to date, and we plan to enroll a new cohort at dose level four as we evaluate dose levels on a path toward pivotal stage. We continue to be encouraged by the progress on our 314 programs, and I'd like to particularly highlight the safety profile observed, including in our supracoroidal programs. We are confident in our plan to advance into new disease states and dose levels because of this safety profile, particularly in the setting of short-course, seven-week prophylactic steroid eye drops. In more than 130 patients treated in office, we're seeing a differentiated safety profile for ocular gene therapies, representing a meaningful potential treatment option for patients and physicians globally. on RGX121 being developed for the treatment of MPS2 or Hunter syndrome. In February at the World Symposium, we announced that the campsite pivotal trial met its primary endpoint with high statistical significance. Patients treated with RGX121 achieved decreased cerebrospinal fluid, CSF, levels of heparin sulfate D2F6, a key biomarker of brain disease activity to below maximum attenuated disease levels. We plan to share new data from the campsite trial in the second half of this year. We believe RGX121 is well-positioned to be the first gene therapy and one-time treatment for Hunter syndrome. We've completed a successful pre-BLA meeting with the FDA that finalized details of our planned rolling BLA submissions. The key takeaways from the meeting included alignment on the use of CSF D2S6 as the key biomarker and surrogate endpoint reasonably likely to predict clinical benefit to support accelerated approval. We also reached alignment on CMC manufacturing requirements and on the confirmatory trial design. To conclude, we continue to make significant progress with data updates in trial progression across all programs in our pipeline. Lastly, I'd like to thank the patients, families, clinicians, and patient advocacy representatives who have been involved in and supported all of these trials. And with that, I'll turn the call over to Vit to review our financial guidance. Vit?
spk23: Thank you, Steve.
spk07: Regenexx Bio ended the quarter on June 30, 2024, with cash, cash equivalents, and marketable securities of $327 million, compared to $314 million as of December 31, 2023. The increase was primarily attributable to $131 million in net proceeds received from an upsized public offering of common stock and pre-funded warranted completed in March 2024, partially offset by cash fees to fund operating activities in the first half of 2024. R&D expenses were $49 million for the second quarter of 2024, compared to $60 million for the second quarter of 2023. The decrease was largely driven by reduced manufacturing and clinical supply costs for AbbVie RGX 314 and RGX 202, and personal related costs as a result of reduced headcount. The decrease was partially offset by increases in clinical trial expenses for AbbVie RGX 314 and RGX 202. Regenexx Bio expects its balance in cash, cash equivalents, and marketable securities of $327 million as of June 30, 2024, to fund its operations into 2026. This cash runway guidance is based on the company's current operational plans and excludes the impact of any payments that may be received from AbbVie upon the achievement of development or commercial milestones under AbbVie RGX 314 collaboration, including a potential $200 million milestone for achievement of the first patient dose in the pivotal trial for supracordial delivery for treatment of DR. Additionally, our one-way guidance excludes the potential monetization of a priority review voucher that may be received for RGX121. With that, I will turn the call back to Curran to provide his first set of final thoughts.
spk10: Thanks, Vint. Today was another exciting day for our 202 program with additional positive data. As we look ahead to the rest of the year, we are encouraged by our discussions with the FDA and our finalizing pivotal plans that will enable us to utilize the accelerated approval pathway to rapidly advance 202 as a potential best-in-class treatment for Duchenne. Additionally, we are pleased to be accelerating the end of Phase II meeting for DR in partnership with AbbVie to enable a pivotal start next year. As we close today and reflect on the first half of the year, I'll emphasize that our plans are on track and we continue to expand value as we make excellent progress in advancing therapies that address significant unmet needs. Thanks everyone for your time today. I'll turn the call over for questions. Operator?
spk06: Thank you. We will now begin the question and answer session. At this time, I would like to remind everyone in order to ask a question, press the star and then the number one on your telephone keypad. If you are called upon to ask your question and are listening by a loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. We do request for today's session that you please limit to one question and one follow-up. We will pause for a moment to compile the question and answer roster. Your first question comes from the line of Gina Wong of Barclays. Please go ahead.
spk02: Thank you. Congrats on the new data regarding the 202 in DMD. So I have two questions. One is the 202, I know you will meet with FDA, finalize the pivotal study. Do you have a goal of a protein level you wanted to achieve and do you expect FDA will set some threshold in order for accelerated approval? And another question is regarding the 314, a supercorridor indication in DR and the wet EMD. What's the reason for dose level four? And will you also include patients with existing neutralizing antibody?
spk10: Thank you for the question, Gina. In terms of, can I clarify the first question? A goal for protein level, microdistribute level. We've proposed a threshold with FDA, and that's one of the things that we'll be waiting for the minutes and sort of final agreement in addition to the back and forth that will occur with the pivotal plan that will be submitted. We feel that just in general, thinking about the field and what we've been able to glean from our investigators, that A level above 10% is likely to result in functional benefit. I think that will be a discussion that we have going forward, but if you think about our data, to date, every patient that we've published data on is above that threshold. I'll field the second question to Steve, if that's okay.
spk05: Hi, Gina. Thanks for the questions. So 314 and going to dose level four in our phase two studies, why do that? We've certainly met our target product profile in diabetic retinopathy, and that's why we're so excited with the advancement towards pivotal that Curran and I have summarized. We've also seen, as I have highlighted, excellent safety. So I think the key consideration is we're going higher in part because we can. We really have the flexibility given that the excellent safety that we believe is due to the compartmentalized route into the supracroidal space as opposed to less compartmentalized spaces like the intravitreal space and particularly with our product, RGX314. So in collaboration with AbbVie, we're doing this. And I think it also fits just general basic drug development, where if you have good safety to really fully characterize a product, it makes sense to continue looking at higher doses if you can.
spk25: Thank you.
spk06: Your next question comes from the line of . Please go ahead.
spk24: Great. Thanks for taking our questions. We had two first on 202. Could you just speak a bit more about the functional assessment data we're going to be getting later this year, what your guidance is to best interpret that to get a sense of differentiation, real-world differentiation, and how that data set might play into discussions with regulators on next steps? And then secondly on 314, for suprachoroidal and wet AMD, could you talk a bit about how you see that program moving towards a pivotal program and how that pivotal program potentially for 314 and wet AMD could overlap with efforts with the subretinal approach? Thanks.
spk10: Okay. I can take the first question. Steve, do you want to start with the second one?
spk05: I missed the second one. Could you repeat the second one?
spk24: Sure, yeah. It was about 314 supercoital and wet AMD, just wondering what the path is to a pivotal program there and how you see a potentially pivotal effort for 314 and wet AMD overlapping with your efforts with the subretinal program you currently have underway.
spk05: Sure. So with all the experience we have with wet AMD, we have a pretty good sense of assessing both safety and efficacy, both from our subretinal experience and also the prior cohorts we've done with supracroidal. So I think it's the usual endpoints that we think of. We get to take advantage of the totality of evidence on top of, of course, having good safety. biomarkers like retinal thickness, where we get a very good objective measure, BCBA, and of course, reduction in treatment burden. So we'll really look at all of those to see what type of response we get at six months and longer, and really compare that to what's been seen, for example, even in our subretinal program, where we want to see good durability and really maintain a anatomic control as measured by retinal thickness, and BCVA control while dramatically reducing injection burden. And we've often talked about at least 50 percent of patients not needing any injections and over 50 percent of reduction in injection burden.
spk10: And this is Curran. To the first question, in terms of functional data in the fall, just to to baseline, we measure microdystrophin at a three-month time point. And then on the functional assays, we measure generally every three months a number of functional assessments that you've seen historically with other programs. And in the fall, I would expect to see a significant amount of functional data out to 12 months for the dose level one patients. And for some of the early dose level two patients, you'll see six and probably nine month data for them, things like Time to Rise and NSAA as an example. We haven't finalized exactly what data will come out because it's still emerging, but that's the plan for the fall.
spk05: Vikram, you also had the question of how do we see this in the context of our ongoing pivotal subretinal program for wet AMD when thinking about supracoroidal. I think it's fair to say that both we and AbbVie really see opportunities in both, and that's why we both are together advancing further evaluation of SCS at DL4. for this while we continue with the pivotal program with subretinol. Certainly the opportunity that we see with subretinol given the gold standard in safety and efficacy that we've shown in excellent durability has us very excited about that. There's of course the opportunity to expand the optionality by having an in-office procedure And we look forward to gathering more data in the additional cohort to keep evaluating that option.
spk11: That's helpful. Thank you.
spk06: Your next question comes from the line of Paul Choy of Goldman Sachs. Please go ahead.
spk21: Hi. Good afternoon, and thanks for taking our questions. My first is I was wondering if you could maybe just elaborate on interest levels in the patient community and clinical community for 202, a potential pivotal trial later this year or early next year in the wake of the recent Alevitis label expansion and approval there. And then my second question on 314 is with regard to dose cohort 4 here. I know you specified that there would be prophylactic steroid use here, but could you maybe comment on a view whether there would be potentially reduced need for rescue VEGF use? A competitor recently provided some updated data for their program, and I think this came as a bit of a surprise, so just any thoughts there as to whether dose cohort four could potentially either increase the injection-free frequency or reduce the rescue usage as you prosecute that cohort. Thank you.
spk10: I can take the first one, and then I'll have Steve address the second question. I think on patient recruitment for 202, we've been able to check in with sites and investigators at meetings like PPMD and we've seen nothing but really strong interest in the program. Many of these centers have up to 100 patients and just having discussions with the investigators around are people still interested in our study given that there's a product on the market, the resounding answer is yes. There are many patients that are looking at our program and seeing the differentiation that it offers, seeing the safety, that's been demonstrated to date, and I would say that there's strong interest, and therefore, on our end, strong confidence in our ability to recruit the study. So early days, I feel very confident in our ability to recruit the pivotal program, and I'll turn it over to Steve to address the 314 question.
spk05: Sure, so regarding DL4, assessment in these indications, we certainly think there's the opportunity that we could decrease rescue use further than what we've seen while maintaining visual acuity benefit instability and also anatomic control. As I mentioned to one of the earlier questions, we have the flexibility to do that. You referred to some other data that's that's come out earlier this year, and I think one always has to look at that issue of can you go up higher on dose, and if there's either a concern about additional safety issues, including immune response and inflammation, and also if you start to run into the issue of how long a duration of prophylactic steroids can really be tolerated. So that's why we're very excited about our safety profile where we don't need extended prophylactic steroids. So I think the totality of that does give us the chance to go up higher and see if we can reduce injection burden further.
spk10: And just one follow-up, Paul, to the question on recruitment. One of the purposes of the data release we did today was really to show people the differentiated level of microdystrophin in some of the older patients that have been treated. So that's just another piece of information that a patient can use when they're deciding what therapy to have their child treated with. So that was one of the purposes of that release is to help people understand our product a bit more.
spk22: Great. Thanks for taking our questions.
spk06: Your next question comes from the line of Alex from Bank of America. Please go ahead.
spk03: Hi. Good afternoon. This is Mary Kate on for Alex today. Thanks for taking our question. Just one on DMV. Given questions around safety for others in the field, what kind of safety database do you expect you'll be required to collect for approval in terms of size and duration of follow-up? Thank you.
spk10: Yeah, that's, I think, something that we're still working on and probably will tie out completely in the pivotal plan that we'll submit to FDA. So we're really not able to comment in terms of various specifics there. I think in general, our proposal on sample size is in the 30 to 40 patient region, but that's really a discussion that's ongoing with FDA. But I think The reasons that we feel that's a valid number is, number one, we have a commercial-ready process that we won't make changes to in terms of product profile during the pivotal studies, and so that should reduce the sample size. And second, the initial safety record that we've already demonstrated in the trial to date should be a positive in terms of how FDA might view the program and how they assess what the sample size should be. So we feel like we're in a good position there, and I think that gives us a good feeling that the recruitment will be accelerated into next year.
spk30: Understood. Thank you.
spk06: Your next question comes from the line of Annabel Salmoni of STIPO. Please go ahead.
spk01: Hi. Thanks for taking my question. We also have two. First, on DMD, just bringing back the question of functional data and what you might be looking for, given the broad age group that you're looking at and maybe the different levels of ambulation, are you giving any consideration to stratifying those patients based on age group and measuring them on different metrics depending on their age and then matching against the natural history for that specific age group. So how much granularity might we see already and maybe what are you possibly baking into phase three? And then on 314, I guess I'm trying to understand how you're thinking about this dose level four In light of, you know, other competitors in the space, do you feel that the benchmark for you is your subretinal? Is it the benchmark for you, other competitors in the space? And, you know, given, I guess, maybe a little bit of a race in the gene therapy space, is there less urgency to be the first one out there or the one to get it right? Because the population is large and maybe they're a little bit less desperate than, say, in the rare disease area. Are people looking at this competitive landscape the wrong way? So a little broader question. Thanks.
spk10: I can start with 202. And I think we think about functional data in sort of two dimensions. As it relates to accelerated approval, you know, our primary driver will be measuring microdystrophin at three months as our primary endpoint. But along with that, of course, we're measuring functional data along the way. And initially what I would expect in the fall is likely a reference of functional data to baseline levels for the specific patient. Now, if we think about a confirmatory study, you're absolutely correct that studying natural history and matching patients either by age or by age disease progression would be part of that strategy that we're having discussions on. So it's actually, I would expect to see both sort of views as it relates to functional data. I'll turn it over to Steve for the 314 question.
spk05: Thanks, Annabel. So as far as benchmarking, as I mentioned, we got a lot of experience, many of us from prior programs as well, but certainly in-house with our subretinal program, really the target is pretty similar in terms of what you have to show when we think of supracoroidal, perhaps slightly a little broader given the non-surgical in-office opportunity of supracoroidal. I think an important context when thinking of different programs is really assessing how much durability has really been shown. So really being able to look out to six months and beyond relative to when the last loading dose may have been given, for example, in indications like wet AMD. And I think with certain agents that require repeat injection, even though they have greater durability, there's the reality that at some point you're going to need the reinjection. And if you're looking at a time point that's too early to see that, are you going to start seeing the need for rescue creep up? And that's why we're excited about a gene therapy approach where you have stable, consistent anti-VEGF activity that can allow for really the ultimate goal of having in a sizable proportion of patients not needing any injections. So we feel good about this approach, and we know how to look at the safety and efficacy to really know when we're in a position to move forward. Okay.
spk27: Thank you.
spk06: Your next question comes from the line of Manny Purujar of Learing Partners. Please go ahead.
spk15: Hi, good afternoon. This is CJA on Vermont. Thanks for taking our question. Could you please comment on your strategy in DMD? Are you targeting younger patients than surreptitious current label since you've announced you've expanded the age range to one to three while surreptitious youngest age is four? Thanks.
spk10: Hi, this is Curran. I think it's safe to say we want to build an adequate safety database at a minimum for the patients in ages one to three, but we'll be enrolling across a wide variety of ages in the studies.
spk05: And we had made the decision to expand and look at this broad age range, including one to three, before any elevatous label expansion. We've seen this opportunity, and now with the results, safety that we've seen and the microdystrophin expression we've seen across a wide age range on the upper end, it's a great opportunity to look at one- to three-year-olds.
spk14: Perfect. Thanks for the commentary.
spk06: The question comes from the line up. Eliana Merle of UBS. Please go ahead.
spk20: Hi, this is Eric Massanza calling in for Eliana. Thanks so much for the question. My first one's on 202. Do you have any in-house data from patients already dosed with 202 beyond the three months to help us better understand variability and what the effects might be over time? And what are you expecting to see over time? Do you expect labels to be stable for three months or more, or do they deepen over time? I have one follow-up.
spk10: I'm sorry. Are you referring to micro dystrophin levels beyond three months or other functional data, for example? Micro dystrophin, yes. Okay. No, we're taking a biopsy prior to treatment and then at three months. We don't have biopsies beyond that time point, basically per direction with FDA. However, we'll obviously be measuring durability in terms of functional outcomes in the out periods. Yes, we don't have data beyond three months, but I think our preclinical data would suggest really excellent durability. And the construct that includes the C-terminus has a longer half-life than microdystrophin that's devoid of that. So I would expect both higher levels of microdystrophin and perhaps sustained levels of relative to what you've seen in other literature.
spk20: Got it. And just one quick follow-up. Is there anything that you've been able to identify in terms of patient characteristics that's correlated so far with a higher microdiscipline expression or higher functional assessment?
spk05: So the usual caveat that there aren't enough patients to really have confidence in terms of predictors. I'd say the biggest learning so far is actually that age is not predicting a lower micro dystrophin as you go up on age, which has been a concern that the community has had, whether that might be the case. And some data from other programs suggest that That may be an issue, but we've not seen that at all. So I think the striking thing from our data is even in eight and older, we're seeing very robust microdystrophin levels. Beyond that, we're seeing microdystrophin levels across the patients. So no clear differentiator or predictor in this sample to date.
spk17: Got it. Thank you.
spk06: Your next question comes from the line of Luca Eze of RBC. Please go ahead.
spk18: Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe current. Can you just expand a bit more on your recent end-of-Phase II meeting with the FDA? I appreciate it. You're still waiting for the minutes, but can you confirm that your read is that you can get accelerated approval and expression across all patients with DMD and not only patients that are excluded from the Sarepta label today, either because of age or existing immunity. I think that's an important distinction, so any caller, much appreciated. And then maybe still in DMD, how are you thinking about a confirmatory trial? Will you still use North Star as the primary endpoint, or do you think there are other endpoints that could be more sensitive here? Any caller, much appreciated. Thanks so much.
spk10: I can work a bit in reverse. We'll use North Star, but we're obviously measuring a number of additional functional indicators that you've seen, as I mentioned earlier, time to rise and some of the timed walks that are associated. So I would characterize it as we're measuring everything because there are, you know, it's still a field where I think the functional assays are evolving and Each product is different, and I think we want to be able to capture as much functional data as we can across as many indices as we can. Related to accelerated approval, our strategy is to approach this for a broad approval, not a narrow approval for only patients that are ineligible for current therapy. And the basis for that is simply the differentiation of the product. That's, I think, one of the basic tenets of the accelerated approval is unmet need. And we feel we have a really strong evolving case that addresses unmet need. And our ambition will be to obtain as broad a label as possible.
spk00: Got it. Thanks so much.
spk06: Your next question comes from the line of Brian Scarnia of Baird. Please go ahead.
spk19: Hey, thanks for taking the question. On the phase three plans for diabetic retinopathy, just trying to engage sort of your level of confidence in Abby's level of confidence in the first half initiation next year. What are sort of the primary questions that the companies want to get answered by the FDA or the FDA hopes you think the FDA will need answers to at the end of phase two meetings? to sort of ensure that this phase three gets kicked off. And maybe just some color on the DME cohort and is the consideration, is there a consideration to pursue these more progressed patients or is the thought here really just to supplement with some data in patients who have progressed on to DME?
spk10: I'll give a brief comment and then turn over to Steve. I certainly think we and Abby have a really high level of confidence in DR progressing into Pivotal next year. and I think that's shown in the acceleration of the end of Phase II meeting into this year. We're eager to get this study up and going, and I think I'll let Steve comment on the details of the pivotal approach, but we feel like there's a very standard approach to developing in diabetic retinopathy established endpoints and precedent, but I'll let Steve comment on the details of what we're thinking and and how that study should go.
spk05: Yep. Fortunately, as Karin mentioned, there's a roadmap for diabetic retinopathy that's been laid by repeat injection anti-VEGF that has really allowed us to know what do you expect from a negative control arm if you're not receiving an active agent. And that, of course, really helps us to power studies in combination with the actual proof of concept data that we have. We also know a lot about the endpoints that are accepted. So we feel very confident that this is really de-risked quite a lot from a regulatory standpoint. So it's really assessing some things around the edges and some definitions and the like, frankly, when it comes to the pivotal designs So I think that's one of the aspects that, given the positive results that we've seen, why we have been able to accelerate and bring this into Phase 2 meeting into Q4 instead of Q1 next year.
spk19: And then you're... I was just going to ask about the DME cohort.
spk05: Yeah. Yeah, so... We are looking at center-involved DME. Of course, that's the traditional indication. So we don't see a need to go outside the box in terms of the type of patient population that we'd be looking at so that we can really have the context of what others have looked at and what others have seen. So yeah, it's just a great opportunity. We do know diseases like DME or the complication of DME and wet AMD that there's a little higher VEGF drive than exists with, say, nonproliferative diabetic retinopathy without DME. So we think we're right around the dose response range where this is going to be very interesting to look at DL4 in this patient population.
spk12: Great. Thank you.
spk06: Your next question comes from the line of Daniel Gataulin of Chardon Capital Markets. Please go ahead.
spk13: Hey, guys. Thank you for taking the question. Congrats on your role. I have a quick question on the WET-AMD program, the subretinal delivery. When do you anticipate sharing data from the fellow eye study? And as a follow-up to that, how it translates to suprachoroidal injections, given those are are more likely to interact with the immune system. What is your long-term strategy for treating fellow eyes using superchloroidal delivery? Thank you.
spk09: I'll turn that over to Steve.
spk05: Hi, Dino. So as far as when we would have fellow eye results, we have the update today that we completed enrollment of the fellow eye study. So if you add on... you know, up to six months or so from that would give you kind of a rough range of when we traditionally have been comfortable releasing data in this type of indication to really show a stable effect at least. We were excited to have this study, not just from a regulatory standpoint to have that label expansion to allow bilateral disease, but As you referred, the immune response, whether you would have a greater immune response that could affect safety and or efficacy when you dose the second eye. Subretinal, I think, is the most straightforward to feel confident that you won't have an issue dosing the fellow eye because of the immune privilege status of the subretinal space. Superchoroidal we've seen much less inflammation and no safety issues in terms of inflammation compared to, say, intravitreal administration. So that gives us confidence that supracoroidal would have that opportunity as well. So we decided to take it one step at a time, first look at subretinal fellow I, but over time certainly it would make sense to assess fellow I with supracoroidal as well.
spk13: Got it. Thank you very much for taking the question.
spk06: Ladies and gentlemen, there are no questions. That concludes today's call. Thank you all for joining. You may now disconnect.
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