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spk02: Hello, and thank you for standing by. Welcome to the Q3 2022 Regenexx Bio, Inc. Earnings Call and Update on Altitude. At this time, all participants are in the listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 11 on your telephone. It is now my pleasure to introduce Chief Legal Officer Patrick Christmas.
spk14: Good morning, and thank you for joining us today. Earlier this morning, Regenexx Bio released financial and operating results for the third quarter ended September 30th, 2022, as well as new data from our altitude trial. The press releases and data presentation are available on our website at www.regenexxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook and our development of RGX 314, 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 and the management's discussions and analysis sections of Regenexx BIO's annual report on Form 10-K for the full year ended December 31st, 2021. And comparable risk factor section of Regenexx BIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the FCC's website. Any information we provide on this conference call is provided only as of the date of this call, November 3rd, 2022. 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 in 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 would now like to turn the call over to Ken Mills, CEO of Regenexx Bio. Ken?
spk11: Thank you, Patrick. Good morning, everyone. Thanks for joining us. I'm pleased to begin today's call with a recap of the recent business highlights, as well as an update on our corporate goals. VIT FASISTA, our chief financial officer, will provide an overview of financial results for the third quarter ended September 30th, 2022. We're bi-coastal today. Steve Ficola, our chief medical officer, is on the West Coast, recently attending Retina Society. He'll provide an in-depth overview of the data that was presented yesterday at the Retina Society meeting from our Phase II altitude trial, evaluating RGX314 for the treatment of diabetic retinopathy, or DR, using suprachoroidal delivery. Towards the end of the call, we'll be joined by altitude investigator Leila Vasovich from Duke University and independent retina expert Dr. Peter Kaiser from the Cleveland Clinic. Leila and Peter will stay on with us as we open up the line for questions. At Regenexx Bio, our mission is to improve lives through the curative potential of gene therapy, focused on developing therapies for diseases that have significant unmet need. We continue to be a leader in gene therapy. There are thousands of patients who have been dosed with AAV therapeutics derived from our NAV technology platform and hundreds more receiving treatment every quarter. I'm very proud of how our company has been advancing our internal pipeline, and I believe our fundamentals have never been stronger. We put into place our five by 25 strategy to progress five AAV therapeutics from our internal pipeline and licensed programs into pivotal stage or commercial products by 2025. I'm now going to summarize some of the program highlights and operational updates from our announcements this morning. Our global eye care collaboration with AbbVie to develop and commercialize RGX314 for retina disease continues to advance. and is on track for a first BLA filing in 2024. Progress in trial enrollment and emerging clinical trial data also supports excellent progress in our suprachoroidal delivery program. At AAO, RGX314 subretinal delivery for the treatment of wet AMD was reported to be well tolerated with long-term durable treatment effects now observed up to four years. We expect this trial, along with the two ongoing pivotal trials, Atmosphere and Ascent, to support our planned VLA submission in 2024. In October, we also announced positive interim data from the Phase II AVA trial of RGX314 for the treatment of wet AMD using superchoroidal delivery. These data show that RGX314 was well-tolerated, with stable BCVA and a meaningful reduction in anti-VEGF treatment burden at all dose levels out to six months. We announced the expansion of this trial to further explore the third dose level in a sixth cohort with a short course of prophylactic ocular steroid following RGX314 administration in order to potentially prevent the observed incidence of mild to moderate intraocular inflammation. Yesterday, as I mentioned at the Retina Society meeting, new positive interim data was presented from our phase two altitude trial of RGX314 for the treatment of DR using suprachoroidal delivery and Steve will lead a review and discussion of these data in greater detail shortly. We've been working diligently to prepare on the initiation of our first in-human trial of RGX202 for the treatment of Duchenne and continue to expect to dose the first patient in the Affinity Duchenne trial in the first half of 2023. RGX202 is a potential one-time gene therapy for the treatment of Duchenne and being developed as a highly differentiated product designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-terminal domain, domains found naturally occurring in naturally occurring dystrophin. RGX202 is designed to support the delivery and targeted expression of genes throughout the skeletal and heart muscle using our NAV AAV8 vector. RGX121 is our candidate for the treatment of mucopolysaccharidosis type 2, also known as Hunter syndrome. This is currently being evaluated in an expanded pivotal phase program called Campsite. We are dosing patients in this pivotal program. Most recent positive interim data update from this study of this candidate reported that RGX121 was well-tolerated across all cohorts studied. Biomarker data from the patients in all three cohorts indicated encouraging dose-dependent reductions of cerebral spinal fluid GAGs. following one-time administration of RGX121. Improvements in neurodevelopmental function and caregiver-reported outcomes demonstrated CNS activity up to two years after RGX121 administration. The expanded pivotal phase of this program is expected to enroll up to 10 MPS II patients using commercial-scale GMP material to support a BLA filing in 2024 using the accelerated approval pathway. with the potential to enroll additional patients. This is our second active pivotal program and another opportunity for a BLA filing by 2024. Our ongoing phase 1-2 trial of RGX111 for the treatment of severe MPS1 or Hurler syndrome continues with plans to enroll additional patients in cohort 2 expansion R. Our manufacturing innovation center in GMP capacity Capability remains a key differentiator for Regenexx Bio and a key element of our strategy. Our in-house facility is cutting edge and allows us to move quickly from candidate selection to production of clinical grade material, which supports accelerating the early development of AAV therapeutics. Additionally, we believe our approach focuses early on product quality and process control, which lessens the need for changes during clinical development to enable efficient transition from clinical trials to commercial readiness. I would now just like to take this time to thank our entire Regenexx Bio team, all of our investigators and their site support staff, and the patient communities for their commitment to the continued development of our AAV therapeutics. We certainly believe that one-time gene therapy can address a whole range of unmet needs in both chronic and rare diseases, and we remain dedicated to these patients and their families. Reflecting on this quarter at this point in the year, I'm very proud of the progress we've made to advance our 5 by 25 strategy. And with that, I will now turn the call over to Vit for a review of our third quarter results and financial guidance.
spk09: Thank you, Ken. Regenexx Bio ended the quarter on September 30, 2022, with cash equivalents and marketable securities totaling $617. compared to $849.3 million as of December 31st, 2021. The decrease was primarily the result of cash used to fund operating activities and capital expenditures, as well as temporary unrealized losses on marketable debt securities during the nine months ended September 30th, 2022. R&D expenses were $63.3 million for the quarter-ended September 30th, 2022, compared to $47.9 million for the quarter-ended September 30th, 2021. The increase was primarily attributable to personnel costs and expenses associated with clinical trials and manufacturing-related activities for our lead product candidates, and was partially offset by Regenexx 314 development costs reimbursable by AbbVie under our iCare collaboration. In accordance with the collaboration agreement, Regenexx Bio will continue to fund certain ongoing clinical trials for RGX314 through the end of 2022, while other 314 development costs are shared with AbbVie. Beginning in 2023, AbbVie will be responsible for funding the majority of all Regenexx 314 development expenses. Based on our current operating plan, we expect the balance in cash equivalents and marketable securities of $617 million as of September 30, 2022, to fund our operations into 2025. And now we would like to return the call over to Steve for an in-depth discussion of the recently announced altitude data.
spk16: Thank you, Pat. As Ken shared, we recently presented interim data updates for our RGX314 trials for the treatment of wet AMD using subretinal and suprachoroidal delivery. RGX314 is also being developed for the treatment of DR, and we're pleased to be sharing new interim data from our Phase II altitude trial of RGX314 using suprachoroidal delivery that was presented yesterday at the Retina Society meetings. Slides from that presentation can be found in the Media, Presentations, and Publications section on our website. Joining me this morning, we have Dr. Leila Vojcevic, Associate Professor of Ophthalmology and Director of the Duke Vitreo-Retinal Fellowship Program, and the lead investigator who presented the altitude data yesterday. We're also joined by Dr. Peter Kaiser, Director of the Center for Ocular Research and Evaluation at the Cole Eye Institute at the Cleveland Clinic. DR is a complication of diabetes and is the leading cause of blindness in adults between the ages of 24 and 75. An estimated 27 million patients are affected by this debilitating disease worldwide. DR is a slowly progressing disease that can lead to vision-threatening complications, including diabetic macular edema, or DME, and neovascularization that can lead to blindness. Like in wet AMD, patients with DR are treated with anti-VEGF therapy, which has proven to reduce the risk of developing vision-threatening complications. However, due to the unsustainable treatment burden using anti-VEGF therapies, primarily the result of the frequent intraocular injections required, many patients with this condition put off receiving any treatment until symptoms become unavoidable. We believe a gene therapy like RGX314 could potentially overcome this hurdle and provide an important therapy for DR patients to significantly alter their disease progression. Altitude is a multicenter, open-label, randomized controlled dose escalation phase two trial evaluating the efficacy, safety, and tolerability of supracoroidal delivery of RGX314 using the SCS microinjector in patients with a DR diagnosis of moderately severe or severe non-proliferative diabetic retinopathy, NPDR, or mild proliferative diabetic retinopathy, PDR. Patients in cohort one received RGF314 at a dose level of 2.5E11 genome copies per eye, which we refer to as dose one, while patients in cohorts two and three received RGF314 at an increased dose level of 5E11 GC per eye, which we refer to as dose 2. Patients in cohorts 1 through 3 did not receive prophylactic corticosteroid therapy before or after RGF314 administration. As of October 17, 2022, RGF314 was reported to be well tolerated in cohorts 1 through 3, Five serious adverse events were reported, none of which were considered drug-related. For the total group of cohorts, one through three receiving RGX314, 50 patients in total, common ocular adverse events in the study eye through six months were predominantly mild and included conjunctival hemorrhage, conjunctival hyperemia, and episcleritis. In addition, three patients experienced intraocular inflammation, IOI, all of which were mild and resolved on topical corticosteroids. There were no meaningful differences in safety outcomes observed for patients who were MAP positive. Best corrected visual acuity remained stable in cohorts one through three through six months. At six months, patients treated with RGF314 demonstrated clinically meaningful improvements in disease severity versus observational control as measured by the diabetic retinopathy severity scale or DRSS. Specifically, 20% of patients representing 40% of patients in dose one and 11% of patients in dose two achieved two-step or greater improvement in DRSS score versus 10% in observation control. Additionally, 54% of patients representing 60% of patients in dose level one and 51% of patients in dose level two achieved any level of DRSS improvement versus 20% in control. And it's important to note that zero out of 50 RGX314-treated patients had at least a two-step worsening in DRSS score, while 20% of patients in the control arm experienced at least a two-step worsening. So with that, I will now turn the call over to Dr. Leila Bosovich, who is sitting next to me in lovely Pasadena. where Layla, we were really excited to hear your presentation yesterday at the Redmond Society meeting here. So now it's really a great opportunity for us to hear your clinical perspective as lead investigator in the trial on the interim results that you presented.
spk13: Thank you, Steve. It's a pleasure to be here today. I'm very excited about interim data that was presented yesterday and discussing this morning. Primarily, as Steve nicely highlighted, diabetic retinopathy is a tremendous problem, a huge public health problem globally, and that relates to very busy clinics with diabetic retinopathy patients who, unfortunately, because of their status and working age, cannot keep up with the treatment burden of frequent injections. So that results typically in my clinic, about 90% of my patients are being watched and not treated, and often not even coming for the appointment. So clearly there is a tremendous need for better treatment, more sustainable treatment. And having a one-time treatment in office may provide that solution. So I'm excited to see the interim data results. First of all, the efficacy looks very promising with improvements in all cohorts, including improvements in diabetic retinopathy severity scores, and no disease worsening that we saw in the data results. But even more importantly, the safety results looks promising as well. The fact that we're seeing good results with minimal evidence of inflammation was encouraging to me. So overall, this translates to me for hopefully one day having a treatment option for 90% of my patients that are currently being observed who are potentially going to have a disease affecting visual decline in the future, and this option may provide a solution to their vision worsening.
spk16: Great. Thanks so much, Leila, for that perspective. As the audience can hear, we're very excited about this interim data that Leila presented and the potential of RGX314. for patients with DR. As we continue to build upon the drug profile of RJX314 in DR, we've made the decision to expand the altitude trial to include a higher third dose level of 1E12GC per eye. And Layla outlined that as well yesterday at the presentation. The trial is currently enrolling two new cohorts, cohorts four and five, at this third dose level. Cohorts four and five are enrolling patients stratified by DRSS levels, with patients in cohort four having moderately severe to severe NPR, which is DRSS levels of 47 to 53. And patients in cohort five have mild to moderate PDR, which is DRSS levels of 61 to 65. So we're excited at that ability to evaluate in an expanded DRSS range Patients in these cohorts will receive a short course of prophylactic ocular steroids following RGX314 to evaluate the ability to prevent or reduce the incidence of the mild intraocular inflammation seen to date in a setting of no prophylactic steroids. Patients will be enrolled in these cohorts regardless of baseline AAV8 NAV status. So now we also have sitting here with us in Pasadena this morning, Dr. Peter Kaiser, who, in addition to being an expert clinician and clinical trialist and expert across the retina space, is also a very experienced central reading center grader and expert and overseer, including assessment of diabetic retinopathy and use of the standard DRSS scale. So, Peter, really a perfect opportunity to really blend your expertise both clinically but also how you think of endpoints when it comes to diabetic retinopathy and use of the DRSS scale. We'd love to hear your key takeaways from this interim data update.
spk05: Sure, yeah, and thanks for inviting me. Leila really outlined it great, which is we have two products that are FDA approved for treatment of diabetic retinopathy, and the regulatory endpoint that we use is diabetic retinopathy severity score, which really is something that we do at a reading center level. In general, at a clinical level, Leila and I won't be counting microaneurysms and looking at it as closely as we do at a clinical study. It's important to understand that the DRSS was developed a long time ago, almost 30, 35 years ago now, for the early treatment diabetic retinopathy study. It was one of the first randomized studies done across medicine. The importance of a two-step change is that's a very significant change in the level of retinopathy. That's why the FDA and the EMA use that for regulatory approval. However, in clinical practice, what we want to see is overall our patients getting better. And as Leila correctly pointed out, the reason we don't use the FDA approved products, both at least not just that often. You know, there are a few patients we do use it on, but in general we don't, is because it requires very frequent injections, and these working-age patients simply can't take the time off from work to get these injections, or they have burnout. You know, they just don't want to do it. Most of these patients actually have very little changes in vision, so they don't really see an improvement with these injections, but as physicians we can see the improvements. And that really brings out the point of RGX314. This is, to me, is a killer app for gene therapy, the idea of doing an in-office procedure to allow these patients to have an improvement in the diabetic retinopathy severity scores, which we saw very nicely with the presentation by Leila yesterday of the altitude interim study results. This is very exciting for all of us in the retina field. Wonderful.
spk16: Thanks so much, Peter. And with that, we are ready to turn the call over for questions. Operator?
spk02: Thank you. As a reminder, to ask a question, you will need to press star 1-1 on your telephone. Once again, to ask a question, please press star 1-1. And our first question comes from the line of Gina Wang with Barclays.
spk00: Hello, thank you very much for taking our questions. This is Shuyang for Gina. I have two questions. The first question is about the inflammation. So the inflammation rate at 5E11 dose cohort seem to be pretty similar to the wet AMD at the same dose. Could it give more colors like the onset duration and how the inflammation was resolved, like what steroid and how long it's used and how long does it take to dissolve. Then I have a follow-up question on the new prophy cohort. So can you give more colors on the short course steroid? Is it similar or same as the AVF for wet AMD, such as administration? Like do you plan to use both topical and one-time subtenual injection, and what steroid will be used, and what will be the dose regimen? Thank you very much.
spk10: Steve, I think those questions are best directed to you and the experts there.
spk16: Great. Hi, Shia. Thanks for the questions. I'll give an initial comment. and pass it over to Layla to give her perspective of what she experienced within the trial firsthand. So in terms of inflammation, you're exactly right. We didn't see anything unanticipated, so we were quite pleased with the low rates of mild intraocular inflammation and the characteristics were what we've seen previously, nothing concerning in that. generally within two to six weeks of RGX314 and very easily managed with a short course of topical corticosteroids. Our investigators, and we'll hear Layla's perspective, very happy with the profile that we're seeing that's consistent with what we've seen previously. But we also have this great opportunity to evaluate and further characterize in a setting of prophylactic steroids where that allows the clinicians to assess how these patients do and potentially mitigate even further the risk of inflammation. And we're doing that with topical ocular steroids in the expansion of the altitude study. And it'll just be a standard short course with typical taper over weeks. which our investigators and our thought leaders are very comfortable with that type of prophylactic regimen. But we have Leila here who actually dosed patients in the trial and is very aware of the data we saw across the trial. What was your perspective as you think of your own experience and your colleagues' experience in the trial as far as inflammation?
spk13: Thank you, Steve. Yeah, exactly like you highlighted. Having had patients in this trial and watching them very careful for any evidence of inflammation, I would say it was really mild. It presented exactly two to four weeks after the injection, potentially up to six, and really very rare to maybe a little more frequent than that anterior segment cells. So what does that translate? Really asymptomatic for the patient. This was something because these patients are in clinical trial settings, we're closely watching and noting. And if we did see any hint of it because of our sensitivity to inflammation gene therapy trials, we were proactive in treating them. So I think the treatment, like you mentioned, is very reasonable, very effective as well in topical steroid formats. And it was a short paper that was used as well for patients who did. And I'll point out, in this cohort, it's about 6% of patients overall across actually all three cohorts that had the inflammation, very manageable with topical stairs. And I think what that translates to my clinical setting, I think the safety profile is promising and very manageable by a retina specialist.
spk16: Great. Thanks, Layla. Next question.
spk02: Thank you. And our next question comes from the line of Vikram Perhit with Morgan Stanley.
spk04: Good morning. This is Gaspol on for Vikram. We have two questions. So the first one is when doctors treat patients with DR, how are they measuring progress? Are they generally looking at a two-step improvement in DRSS or for any level of improvement? And then also, too, how do you believe the addition of a dose of prophylactic steroid will impact the commercial opportunity for IGX214 in DR, if at all?
spk10: Thanks, Steve, again. Right at you.
spk16: Great. Thanks, Gospel. And I'm going to direct it right away to Peter, because I think both these questions fit very well for getting a a clinical perspective independently of how DR patients are managed and also how to think about topical steroids.
spk05: Yes, I'll handle the second question first. When you look at any new treatment as a retina specialist, we've been heightened sensitivity to intraocular inflammation. That term is a catch-all phrase, obviously. It includes anything that we could possibly see. When I look at the results of the supracoital treatment, both in AMD and diabetic retinopathy of RGX314, this is mild IOI. I served on a safety review committee for Novartis, and this is not the same thing. There's no retinal artery occlusions, retinal vein occlusion, retinal vasculitis. This is very mild intraocular inflammation that's treated with a short course of steroids. To me, that's not a big deal, so I'm not concerned about that. Certainly, we have to see more patients, but so far, none of the data concerns me in any way. In terms of the first part of your question, DRSS, we do that at a reading center level. This requires really carefully counting microaneurysms, venous feeding, et cetera. In clinical practice, the average geo-retina specialist is absolutely not going to do that, but what we are going to do is look at these patients over time to make sure that they're improving. If they have early neovascularization, so like level 61, which was enrolled in this clinical study, we're gonna be watching that neovascularization very closely with any of our treatments for that matter to make sure that that area is resolving. So in other words, we would expect with our treatment that that neovascularization would disappear because that neovascularization is what leads to future vision problems, traction retinal attachments, vitreous hemorrhage, And that's what causes, eventually, blindness untreated. So that's what we are most worried about. Over time, we would watch to make sure they disappear. But we also like to see the hemorrhages and the microorganisms disappear also. And this is something we can very easily do with a clinical exam. So most retina specialists are not doing a formal DRSS evaluation. We're just looking at the patient through a dilated fundus exam.
spk04: Got it. Thank you very much.
spk02: Thank you. And our next question comes from the line of Alex Stranahan with Bank of America.
spk15: Hey, guys. Thanks for taking our questions. Just a couple from us also on DR. First, maybe you could talk about the rationale for adding the higher dose level in altitude. Is there a certain bar on DRSS or some other metrics that you'd ideally like to hit that you're not already? Just trying to understand how you're thinking of the data. thus far, given it looks like there was actually a step down in DRSS improvement from dose one to dose two, but maybe there's a bullet for one-step improvers in cohort three. And secondly, could you talk about the observational control in the study? Is this an appropriate comparator arm for your discussions with the FDA? I guess looking at a pivotal study, do you think you would need to run a head-to-head similar to what you're doing in the wet AMD program? Thanks.
spk03: Thanks, Alex.
spk16: So, in terms of rationale for the higher dose, these are both the ABA study and altitude. These are the first two studies ever evaluating suprachroidal delivery of gene therapy for these indications. So, this is really an exciting time for the field and for us to really characterize RGX314 via this route of administration. We actually have interim data that we've presented with dose level 3 in the wet AMD setting from the ABH study. So we, in effect, have a head start of evaluating this. So it made perfect sense for us and our strategic partner, AbbVie, to continue to evaluate in this study. Regarding dose level 1 and dose level 2, as Peter mentioned, there are various cuts and ways to look at change in DRSS. And the reality is when we look at the totality of this data, we see what we want to see in terms of both dose level one and dose level two. That aspect as far as what we would need to do in a pivotal study, there we are very confident in an observation control for the reasons that Leila and Peter both nicely elucidated, that even though we know available repeated injections work, quote unquote, in terms of improving DRSS and improving DR and preventing vision-threatening complications, those treatments are simply not used only in a rare proportion of patients, as Leila mentioned. So standard of care is really still watchful waiting So an observation control is ideal for this setting and one of the nice things about DR development. And it's nice that we have the concurrent control in this trial where we see what you'd expect to see. And I think either, you know, Layla or Peter, it'd be great when you look at our observation control and you think of, precedents, controls in the literature and your own clinical experience, what do you expect to see if you don't treat patients?
spk13: Thank you, Steve. Yeah, I know exactly what you've highlighted. I would expect to see progression over time to vision worsening and complications from diabetic retinopathy. I similarly will echo I think observational arm is very acceptable because that is the real-world setting currently. We are observing these patients, not treating them with frequent injections. So from my personal opinion and really experience in the clinic across the board, it's quite acceptable.
spk05: Yeah, I fully agree. The current clinical standard from a regulatory standpoint is not to do a head-to-head study against intravitreal anti-VEGF injections. That would not be required. A sham control in this disease is not only regulatory reasonable, It's also a very doable study. You know, my patients, the opposite, if you put anti-veg efforts to control, it would be very hard for me to get a patient into this study. So it's the opposite of what you would think. But from a regulatory standpoint, absolutely, totally fine to do a sham control. And in terms of numbers, you know, I think the beauty of this data set is that there is a control group. So you can kind of see what happens over time. And what's happening to this control group at a six-month interim data is sort of what we'd expect. About 20% or so are having a pretty significant worsening. A few patients get better, and if you look at the control groups, say VividVista, RideRide, etc., some of Panorama, some of these other studies that have been done, it's about 10% to 15% will actually improve a little bit. And largely, that's not due to the fact that the disease is getting better. In general, what that is is that the patient in that study suddenly realized, oh, wait a minute, I actually need to... do better control my sugars, better control my blood pressure because I'm in this study. And that's what leads to that improvement. It's nothing to do with, like, in general, as Leila said, these patients are going to go downhill. They don't improve. But if you do improve your sugars and blood pressure, that will improve things. And we've seen that in, like, the UK PDS and the DCCT studies in the past.
spk02: Thank you. Thank you. And our next question comes from the line of Ellie Merle with UBS.
spk01: Hi. This is Sarah. I'm for Ellie. Thanks so much for taking our question. I guess looking at the change in DRSS score that you see at month six, differences across cohorts between sort of no worsening or no change on a greater than two-step or even one-step improvement, I guess, do you look at this as an effect of the neutralizing antibody status and thoughts about that moving forward into a potential phase three or labeling? And then I guess a second question is any detail or color that you can provide on the five SAEs that occurred during treatment would be great. Thanks so much.
spk16: Great. Thanks, Sarah. So on your first question about the different cohorts and the different dose levels and the NAB status, very similar to what we see in the ABA study, we've not seen an impact as we look at this data. Of course, with 15 to 20 patients per cohort, you're going to have some variability that you would anticipate and also thinking of baseline DRSS, how severe you are at baseline is a variable that can impact whether you can improve two steps or not. I think this actually would be a good question. I'll turn it over to Peter to talk about that nuance of of grading and how to think of data based on baseline characteristics. But certainly if you take that into account, we find, and again, looking at the totality of the data that in each of the dose levels in each of the cohorts that patients are moving in the right direction, unlike the control arm, if you really take into account all the variables of not worsening by a lot, like a couple of the control subjects, and having improvements on average in the others. So then again, we in AbbVie get to not only look at these results, but also our APA study to really assess how do NABs matter or not. And that's why we chose in the expansion to enroll patients independent of their NAP status, we'll still measure it and we'll still be able to assess that to see if we continue to see no impact there. I think before I go to the next question, I'll... I think, Peter, I think it's a nice question to really get your sense when you tease into the data, how do you look across cohorts, based on the baseline characteristics, for example?
spk05: Yeah, I think, you know, whenever you look at interim data, especially in Phase II with relatively small numbers of patients, you don't want to read too much into it. You want to look at the totality of the data. And to me, if you look at all the cohorts, you know, they're trending in the right direction. There's right shifts in every single cohort, whereas in the control group you don't see a shift at all, which is what you expected, maybe even a slight shift. left shift, which eventually untreated you'd expect to occur over time. But if you look at, say, cohort one versus two and three, there's actually a very large imbalance at baseline with DRSS scores, and it's a very important imbalance. So in cohort one, there's more patients in early PDR, so level 61. And level 61 is a really minimal amount of neovascularization at the disc. So to move that two steps forward is actually very easy with just a little bit of anti-VEGF. Like any anti-VEGF given to a patient with mild NVD, that NVD is going to disappear and they quickly go to 57 and then drop even further thereafter. Whereas you take somebody who's, say, severe NPDR and try to improve them two steps, that's a much bigger change in terms of what needs to be done to the eyes. You know, if you have a lot of PDRs, early PDRs, it's going to be easier to show a two-step change. But that's not what we care about. We care about the overall population of patients. And to me, that's what I said at the beginning, that the right shift of all these patients is what's more exciting than really looking, you know, gradually at a few patients who just kind of went one way or the other way right at a six-month time point.
spk16: Great. And, Sarah, your other question on SAEs. So here, none of the five SAEs were considered drug-related. And they're really the types of things that happen to patients, diabetic patients, who on average are older, not quite as old as the wet AMD patients. But just to give you an example, broken femur, other unrelated aspects. And in fact, the only ocular SAE happened in the fellow eye for the patient who had worsening vitreous hemorrhage. So overall, very clean from a safety standpoint.
spk01: Great. Thanks so much.
spk02: Thank you. And our next question comes from the line of Luca with RBC Capital Markets.
spk12: Oh, great. Thanks for taking our questions. This is Lisan for Luca. Just two questions from us. Wondering if you can elaborate more on the decision to include prophylactic steroids. Was this due to the diabetic retinopathy data alone or the totality of the data between the diabetic retinopathy and wet A&D program? And as well, you know, on the baseline characteristics, I noticed that the cohort two and three patients had no prior ATVEGF injections. but the cohort one patient did, and they appeared to respond a little bit better. So just wondering, going forward for the high-dose cohort, will you enroll patients who are anti-VEGF experienced versus anti-VEGF naive? Thanks.
spk16: Thanks, Lisa. So to elaborate more on the decision to expand, Again, we take advantage of all the data we have, so that's one of the nice aspects of having both a wet AMD AVH study ongoing as well as this altitude study in DR patients. So it really gives us a chance to look at safety and tolerability and also biologic effect for these VEGF-driven retinopathies And we're very pleased with our partner, AbbVie, and we look in concert at these interim data. And I think it was a very natural decision to go up on dose, to dose level 3, as we did with the same exact dose in AV8. The second question, Lisa, on previous treatment, yes, as you mentioned, there were some patients in one of the cohorts who had previous treatment. What we do in these types of studies is we make sure there's a certain washout window, so even if that patient is not, quote-unquote, treatment naive, they at least have not had an anti-BET-GEF. injection in at least six months to minimize the risk of a confounding factor there. And there were actually some interesting presentations yesterday getting into and from other programs thinking about treatment naive versus not. So we'll follow with that same approach going forward so we haven't amended that part of the protocol where a patient can have had prior anti-VEGF but not within a recent timeframe.
spk12: Great. Thanks for taking our questions.
spk02: Thank you. And our next question comes from the line of Andreas with Wedbush.
spk06: Good morning, and thanks for taking our question. Two for us. So on the bottom of slide nine, it says that a couple of patients received anti-VEGF therapy here. Could you tell us how we determine if patients receive standard of care and what's the criteria? And then I have a follow-up.
spk03: Sure.
spk16: So, in patients with this disease, of course, we look for complications and the investigators look for complications. And at the end of the day, the investigator and we, of course, the sponsor, agree if it's indicated to treat a patient that they should proceed with treatment. And it certainly, with the longer we follow these patients, that's one of the key potential benefits of a sustained anti-VEGF treatment is the ability to prevent patients from developing vision-threatening complications. So we have the one patient in the control group who did need treatment that we elaborate on in the footnote who even with treatment wound up with four-step worsening at the end and we had a lone patient in the 50 RGX 314 treated eyes that had a single anti-VEGF injection early in the course and and you see how that patient did. So if you look at the totality of this data, that also directionally goes in the same shift in terms of outcomes that Peter discussed in terms of how we look also at the imaging basis of how severe the diabetic retinopathy is. Layla, as you presented this data, you have a perspective on thinking of retreatment and the realities of that aspect when you think of this kind of patient population that goes up to 61 and then 65 where we're including those patients because they're at very high risk of advancing. How do you think of that in terms of the risk of going to DME and high-risk PDR and needing treatment?
spk13: Other historic diabetic retinopathy trials have not typically included mild PDR or moderate PDR, as you are doing that in this trial. And with that inclusion, there may be significant gains to have. There's also risk of progression, especially early on in the treatment protocol. So as you point out, the one patient that did receive anti-digest injection was really quite soon after enrollment. So one wonders whether there was any response to the treatment that early in enrollment period. And it was also higher diabetic retinopathy severity towards the mild PBR patients. So we are right there set up for, unfortunately, already progressing to complication. So I think that could be very well explained by that.
spk06: Okay, great. And then you might have touched on this a bit in the previous questions here, but Just so thinking about or observing the decrease in greater than two-step improvement observed from cohort one to cohort two and three, how are you thinking about or what are your expectations for the higher dose?
spk03: Thank you.
spk16: Andres, we'll have to see, of course, so that's why we do the trial, we are encouraged that with dose level one and dose level two, we're seeing what we want to see. And now to have this opportunity to look at a higher dose level. And as Layla mentioned, we're also expanding to include not only the mild PBR, but also the moderate PBR. And stratifying based on that, so we're going to have a lot more patients and a lot more data to really assess dose response here as well as how we can assess it in wet AMD and really learn from both.
spk03: Thank you.
spk02: Thank you. And as a reminder, to ask a question, please press star 1-1. Our next question comes from the line of Danil Gadolin with Chardon.
spk07: Yes, good morning. Thank you for taking the question. I have one on potential improvement from six to 12 months. So you previously shared the data on improvement from three to six months and compared that to the standard of care . I wanted to see if you know how that continues to progress beyond six months and what would be your expectations for three and four.
spk16: So in the existing cohorts and then going forward, we care about these time points that we've presented to date and we certainly look forward to compiling and cleaning and being able to report in the future on longer-term follow-up time points for these cohorts, including the one-year time point. As far as expectations, I think One aspect is for illustrative reasons, one can think of what's been done before, how repeat injection with existing therapies impacts diabetic retinopathy severity and the realities of as treatment frequency decreases and patients fall off, use that the diabetic retinopathy severity returns and I think as our guests have highlighted, we know without treatment, which would be the observation control in a future study, that patients in general do not get better, and it's just that small percentage of patients that get better due to other factors that Peter highlighted. So it really puts us in a good position in terms of a regulatory standpoint if we think of bigger studies that are powered and take out the risk of imbalances in terms of hitting a regulatory bar while also hitting what ultimately matters to the investigators and the patients, which is shifting the severity to the right into the favorable direction and keeping patients from getting worse and developing the blinding complications that Peter highlighted.
spk07: Got it. Thank you very much.
spk02: Thank you. And I'm showing no further questions. So with that, I'll hand the call back over to CEO Ken Mills for any closing remarks.
spk11: Thanks, Operator. I appreciate that. Steve, thanks for walking us through that overview, and really grateful to Dr. Zafisovic and Kaiser for both their time early this morning, their perspectives on treatment paradigms in DR, and perspectives and weighing in on the new interim data from the altitude trial. I just want to reiterate that Regenexx Bio continues to perform at a very high level. We have an amazing team, one that's dedicated to expanding the understanding and the applications of AAV vectors, developing and generating new innovative AAV therapeutics that have the potential to significantly impact patients' lives. We've had several data updates over the past month. from both our eye care collaboration with AbbVie as well as our rare disease portfolio. We have a foundation of capital over 600 million to fund our mission and operations into 2025 and through multiple filings and other anticipated data milestones. So truly believe we have a clear and definable path to achieve our five by 25 vision to advance five AAV therapeutics from our internal pipeline and license programs into pivotal stage or commercial products by 2025. We look forward to keeping you all updated on our progress as we finish the year, begin to look ahead at 2023. Again, thanks very much to our guests and the entire team, and have a great rest of the day.
spk02: Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.
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