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spk10: Good day, ladies and gentlemen. Thank you for standing by. Welcome to the second quarter of 2022 Regenexx BIO Incorporated earnings conference call. At this time, all participants are on a listen-only mode. After the speaker's remarks, there will be a question and answer session. To ask a question during the session, you will need to press star 1 1 on your telephone keypad. At this time, I would like to turn the conference over to Mr. Vit Vasista, Chief Financial Officer, Regenexx BIO. Sir, please begin.
spk05: Good afternoon and thank you for joining us today. With us today are Ken Mills, Regenexx BIOS President and Chief Executive Officer, and Dr. Steve McCullough, our Chief Medical Officer. Earlier this afternoon, Regenexx Bio released financial and operating results for the second quarter and the June 30th, 2022. The press release reporting our financial results is available on our website at www.regenexxbio.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 and the management's discussion and analysis sections of Regenexx file's annual report on Form 10-K for the full year ended December 31st, 2021 and comparable risk factors sections in Regenexx FIO'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 3rd, 2022. And we undertake no obligations 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 performant financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Natural results may differ materially. I would like to now turn the call over to Ken Mills. Ken?
spk06: Thank you, Bitt. Good afternoon, everyone, and thanks for joining us. I'm pleased to begin today's call with a recap of our recent business highlights, as well as an update on our corporate goals. Steve will then provide an update on our clinical programs and VIT will provide an overview of financial results for the second quarter ended June 30th, 2022. At the end of the call, we will open up the line for questions. Before Steve gets into the pipeline progress in detail, I'd like to provide some context on the gene therapy industry. Last quarter, I mentioned how encouraged I was about the future of the industry, and this past June, I believe we witnessed the impact of many effects, including with the FDA Advisory Committee unanimously endorsing two new gene therapies for the treatment of rare diseases. Clearly, this is great news for the gene therapy industry, and most importantly, for patients needing these potentially life-saving therapies. I believe the panel's approach to reviewing the risk-reward profile of these products and the Committee's acknowledgment for the product's construct and its role in both safety and efficacy highlights the willingness of these experts to take a more flexible approach when evaluating products for patients with large unmet needs. In addition, in the past couple of months, the European Commission has granted marketing authorization for one AAV therapeutic, and the EMA has also adopted a positive opinion recommending conditional market approval for another AAV therapeutic, both indicated for rare diseases. So overall, I find these endorsements encouraging for the industry as well as for Regenexx Bio as we advance our AAV therapeutics for patients with large unmet needs. Moving on to some of our internal highlights for the quarter, we continue to make excellent progress advancing RGX314 using both subretinal and suprachoroidal delivery. With RGX314 for the treatment of wet age-related macular degeneration using subretinal delivery, we remain on track for a BLA filing in 2024 based on two pivotal trials, Atmosphere and Ascent. We've also progressed our RGX314 trials using supracoroidal delivery for the treatment of wet AMD and diabetic retinopathy, or DR. And in May, we announced completion of enrollment of a Phase II altitude trial evaluating RGX314 for the treatment of DR. And more recently, in July, we announced completion of enrollment in Cohort 5 of our Phase II ABA trial evaluating RGX314 in the treatment of wet AMD. We plan to present additional super-choroidal data later this year, and we're pleased with the progress we've made across the entire RGX314 program this quarter. We continue to take full advantage also of our global partnership with AbbVie to bring RGX314 to market. Taking a moment to update on RGX202, our candidate for the treatment of Duchenne. Last quarter, we announced that we made the difficult decision to delay dosing of patients in our first in-human Duchenne clinical trial. This decision was due to an unexpected isolated observation in the final vial filling stage of the manufacturing process at a third-party contract manufacturer that didn't meet our quality criteria. The unexpected delay, among other things, reinforced the importance of investment toward in-house GMP manufacturing capabilities and the facility. This is why I would like to highlight that this past quarter we celebrated the opening of our new CGMP manufacturing facility called the Regenic Biomanufacturing Innovation Center. This 21,000 square foot facility is located in our headquarters building in Rockville, Maryland. This marks our successful expansion into a company with full end-to-end capabilities from research and development to commercial scale infrastructure. We are one of only a few gene therapy companies worldwide with a CGMP facility capable of production at scales up to 2,000 liters. The first runs in our Manufacturing Innovation Center support our clinical supply for the RGX202 program. New process improvements that we plan to use in our facility are expected to produce, for example in RGX202, an approximately five-fold improvement in vector yield per patch than previously used processes. I want to reiterate our strong commitment to the Duchenne community. Preparation for the initiation of our first in human trial with RGX202 continues, including ongoing manufacturing of additional clinical supply for the trial. We continue to anticipate dosing the first patient in this trial in the first half of 2023. Finally, our newest update comes from earlier this morning when we announced that the pivotal program in MPS II is now active and enrolling patients and our intention to file a BLA in 2024 using the accelerated approval pathway. MPS II or Hunter syndrome is a debilitating disease with a large unmet need that significantly impacts a child's daily life and life expectancy and is inadequately treated by any drugs on the market today. We are developing RGX121, a potential first-in-class one-time AAV therapeutic for the treatment of MPS II to treat the CNS manifestations of MPS II for which there are currently no available treatment options. Recent discussions with the FDA support this plan. The accelerated approval pathway was created to allow for expedited development of drugs that treat serious conditions and provide a meaningful advantage over available therapies based on a surrogate endpoint. I would note that following our announcement in November 2021 of the launch of the Pathway Development Consortium, co-founded by Regenic Bio and Solid Biosciences, which brings together key stakeholders, including the FDA, with the goal of expediting patient access to AAV therapeutics, we've seen an increased interest in the accelerated approval pathway across the gene therapy industry. This is an important advancement for rare disease communities, and especially those like the MPS II community. Our pivotal program will measure GAGs in the CSF, which we believe can be considered a surrogate biomarker that is reasonably likely to predict clinical benefit in MPS II disease under the accelerated approval pathway, as the buildup of GAGs or glycosaminoglycans in the central nervous system of MPS II patients leads to clinical manifestations, including neurodevelopmental deficits. We believe the accelerated approval pathway will allow us to advance RGX121 as quickly as possible with the aim of providing a much-needed new treatment option for the MPS II community. So with that, I will now turn the call over to Steve to talk in greater detail about the internal programs.
spk09: Thank you, Ken. I'll begin with an update on RGX314, which is being developed in collaboration with AbbVie to treat multiple ocular indications, including wet AMD and diabetic retinopathy. RGX314 uses the NAVAVA vector to deliver a gene encoding a therapeutic antibody fragment to inhibit vascular endothelial growth factor, or VEGF. Wet AMD is the leading cause of vision loss in people over 60, affecting more than 2 million patients in the US, Europe, and Japan. The current standard of care for wet AMD patients are anti-VEGF treatments, which require patients to receive frequent injections into the eye. Real-world evidence shows that patients with wet AMD are severely undertreated due to the unsustainable treatment burden of these frequent injections. As a result, the majority of wet AMD patients experience significant vision loss over time. RGX314 is being developed as a one-time treatment for wet AMD that has the potential to reduce the frequency of anti-VEGF treatments and preserve vision for wet AMD patients. We continue to enroll patients in Atmosphere and Ascent are two pivotal clinical trials evaluating the efficacy and safety of RGX314 in patients with wet AMD using the subretinal delivery approach. Combined, these two pivotal trials will enroll approximately 765 subjects and evaluate for non-inferiority the mean change in BCVA for RGX314 compared to repeated intravitreal injections of anti-VEGF treatment at one year. These two trials are expected to support a BLA submission for RGX314 in 2024. Overall, we believe RGX314 represents a significant potential advancement for the treatment of wet AMD. We are also advancing two additional RGX314 programs that are part of our collaboration with AbbVie for the treatment of wet AMD and diabetic retinopathy using in-office superchoroidal delivery approach. In wet AMD, we recently announced that we completed enrollment in cohort five of our phase two AVA trial, a randomized dose escalation study evaluating the efficacy, safety, and tolerability of RGX314 in 95 subjects with wet AMD. To date, we have presented six-month data for the first two cohorts that demonstrated evidence of the emerging clinical profile of RJF314 using suprachoroidal delivery, with the most recent data from cohort two showing stable visual acuity and retinal thickness, as well as a 72% reduction in anti-VEGF treatment burden compared to the mean annualized injection rate during the 12 months prior to receiving RJF314. The safety profile for RJH314 across all cohorts, as of the last update from November 4, 2021, was reported to be well-tolerated in 50 patients with no drug-related serious adverse events. Mild intraocular inflammation was observed on slit lamp examination at similar incidents across both dose levels in cohorts 1 and 2, in 4 out of 15 patients in cohort 1, and 3 out of 15 patients in cohort 2. and resolved quickly with topical corticosteroids. Patients in this trial did not receive prophylactic steroids before or after administration of RGX314. Moving to RGX314 for the treatment of DR. DR is a complication of diabetes and is the leading cause of blindness in adults between the age of 24 and 75 worldwide. 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 can be treated with anti-VEGF therapy, which is 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 injections required with today's available treatments, many people with this condition either elect to forego treatment or 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 patients to significantly alter their disease progression. We recently completed enrollment of the Phase II Altitude Trial, a randomized dose escalation study in 60 subjects across three cohorts to evaluate the efficacy, safety, and tolerability of RGX314 in subjects with DR. The trial's primary efficacy endpoint is the proportion of patients achieving at least a two-step improvement in DR measured by the DRSS scale at one year. Six-month data from Cohort 1 demonstrated, after a single superchoroidal RGX314 administration, a clinically meaningful two-step improvement from baseline on the DRSS scale in 47% of the 15 treated patients compared to 0% in the observational control. As of the data cutoff of January 18, 2022, RGX314 was reported to be well-tolerated in the 15 patients' dose, with RGX314 in cohort one with no drug-related SAEs and no intraocular inflammation observed. We are encouraged by what we are seeing at this stage. Shifting to our rare disease portfolio, RGX202, our potential one-time gene therapy for the treatment of Duchenne, is 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 or CT domain found in naturally occurring dystrophin. In preclinical studies, the presence of the CT domain has been shown to recruit key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice models. Additional design features, including codon optimization and reduced CPG content, which has the potential to improve gene expression, increase translational efficiency, and reduce immunogenicity. RGX202 is designed to support the delivery and targeted expression of genes throughout skeletal and heart muscle using our NAV-AADA vector and a well-characterized muscle-specific promoter, SPC512. The Affinity Duchenne Phase 1-2 trial will measure safety and tolerability of RGX202, as well as microdiscipline protein expression levels, muscle strength, and functional assessments, including the North Star ambulatory assessment and muscle MRI. Preparation for this trial is ongoing, including readying clinical trial sites for the upcoming trial, which we anticipate dosing in the first half of 2023. Finally, as Ken mentioned earlier, we are pleased to announce that the ongoing Phase 1-2 trial of RGX-121 has been expanded into a pivotal Phase 1-2-3 trial called Campsite. The Campsite trial, which is now active, is a multi-center, open-label trial enrolling boys with MPS II aged four months up to five years of age. The trial is expected to include up to 10 MPS II patients to support the BLA filing using the accelerated approval pathway with the potential to enroll additional patients. These patients will receive a dose of 2.9E11 GC per gram of brain mass of RGX-121 using commercial scale CGMP material, which is the same dose being evaluated in cohort three of the phase 1-2 trial. The BLA filing is expected to be supported by endpoints in the pivotal program, including changes from baseline of glycosaminoglycans, or GAGs, in the cerebrospinal fluid, CSF, at four months. The trial will also continue to collect neurodevelopmental data and caregiver-reported outcomes. The campsite trial is a global trial and is expected to include sites in the U.S., Brazil, and Canada. we have begun dosing patients in this pivotal program. Behind RGX121, we are developing RGX111 for the treatment of severe MPS1, or Hurler syndrome, where we continue our ongoing Phase 1-2 open-label trial. We continue with plans to enroll additional patients in a Cohort 2 expansion arm of this trial. And tomorrow, our team is proud to join the National MPS Society's 36th Annual Family Conference taking place in Nashville. This is one of the largest MPS advocacy conferences and it is held each year to support research, education, and awareness for this debilitating group of diseases. We look forward to connecting with the MPS community and discussing our RGX121 Pivotal Program Plan with more physicians, caregivers, and patient stakeholders. So to conclude, we have made significant progress in the first half of 2022, and we look forward to further progress over the course of the rest of the year. Now I turn the call back to Ken.
spk06: Thank you, Steve, for the good updates and to the entire team for the progress over this past quarter. and throughout the entire year so far. I'm really proud of how our company's been advancing our pipeline, and I believe that the fundamentals that Regenexx Bio have never been stronger. We've 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. With Steve's update, I hope you can all see how important progress we've made in executing on this plan. And beyond the internal programs, 5x25 may also include programs being developed through our NAV technology licensees. Our NAV technology platform is driving the field of AAV gene therapy forward with over 60 clinical trials utilizing NAV vectors registered in the National Institutes of Health clinical trials database since 2015. Overall, I believe we've laid out a clear and definable path to achieving this goal by advancing our key programs that have the potential to treat very high unmet need in areas where our NAV technology platform can be used to develop and potentially commercialize AAV therapeutics as soon as possible. So with that, I'm now going to turn the call over to Vit, who will review our financials and guidance.
spk05: Thank you, Ken. Quarter ended on June 30th, 2022 Regenexx file with cash, cash equivalents and marketable securities totaling $682 million 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 first six months ended June 30, 2022. R&D expenses were $61 million for the quarter ended June 30, 2022, compared to $45.9 million for the quarter ended June 30, 2021. The increase was primarily attributable to personal costs and expenses associated with clinical trials and manufacturing related activities for 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 5 will continue to fund certain ongoing clinical trials for Regenexx 314 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 a balance in cash equivalents and marketable securities of $682 million as of June 30th, 2022 to fund our operations into 2025. Call Ken, I will turn it over to you. Thanks, Vince.
spk06: Overall, I'm incredibly encouraged about how Regenexx BIO continues to perform at a very high level, and I'd like to take this time to thank our entire Regenexx BIO team, our investigators, and the patient communities for their commitment and involvement in the development of our innovative AAV therapeutics. To summarize what you've heard from us today, 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 are receiving treatment every quarter. We have an amazing team of scientists and engineers dedicated to expanding the understanding and applications of AAV vectors, applying differentiated capabilities of NAV technology platforms, and exploring the potential to generate new innovative AAV therapeutics for diseases that have the potential to significantly impact patients' lives. Our global eye care collaboration with AbbVie continues to advance and is on track for the first BLA filing in 2024. Progress in trial enrollment and emerging clinical trial data supports excellent progress in our suprachoroidal delivery programs. Preparation for the initiation of the first in-human trial for RGX202 continues. We're readying the clinical trial site and manufacturing additional clinical supply for the trial, including the first batches to be produced at our Manufacturing Innovation Center in Rockville. We continue to anticipate dosing the first patient in this trial in the first half of 2023. Our manufacturing innovation center and our GMP capability remains a key differentiator for Regenexx Bio and a key element of our strategy. Our in-house facility is cutting edge, allows us to move quickly from candidate selection to the production of clinical grade material, which supports accelerating the early development of AAV therapeutics. Additionally, we believe our approach focuses on early product quality and process control, which lessens the need for changes during clinical development to enable efficient transition from clinical trials to commercial readiness. We're excited to be advancing RGX121 into pivotal stage, making this our second active pivotal program and another opportunity for BLA filing by 2024. We feel that our intention to use the accelerated approval pathway for RGX121 has positive implications for the rare disease community. It signifies the ability to leverage FDA's regulatory tools to facilitate and expedite drug development and offers hope for rapid access to new therapies for patients living with the more than 7,000 rare diseases. Our plan for accelerated approval is supported by our NAVXpress process and our manufacturing innovation center designed for the high-yield manufacturing quality of AEB therapeutics at scales necessary to support clinical development and commercialization. And as required under the accelerated approval pathway, we are and will continue to be committed to conducting post-approval confirmatory trials to verify that RGX121 provides the expected clinical benefit. And lastly, as you heard from VIT, we have a foundation of capital, over $680 million to fund our mission and operations into 2025 and through multiple filings and other anticipated data milestones that leave us well positioned to execute our five by 25 strategy of advancing five AAV therapeutics to late stage development and commercialization by 2025. So with that, I will turn the call over operator for questions.
spk10: Thank you. Ladies and gentlemen, if you have a question or comment, star 1 1 on your telephone at this time, please star 1 1. Please stand by while we compile the Q&A roster. Our first question comes from Gina Wang from Barclays. Your line is open.
spk00: Thank you for taking our question. This is for Gina. I have two questions, one for RJX121 and the other for RJX314. So for the 121, since you announced the Pivotal program, have you fully aligned with FDA on the primary endpoint, like CSF GAGS? and follow-up duration and comparator arm for the phase three trial? And if not, what's your base case assumption? And for the 314, since you have dosed a few NAB patients plus positive patients, have you seen the toxus profile any different than what we have seen, like what has been reported so far? Thanks.
spk06: Hey, Tom. It's Ken. Thanks for the question. I'll take one, two, one, and maybe turn the 314 question over to Steve. So as we alluded to, the announcement this morning about moving into pivotal phase following the accelerated approval pathway was done in concert with communication with FDA. And the trial design that Steve outlined for campsite doesn't include a comparator arm. It involves the measurement of GAGs and CSS at four months. which we believe is an opportunity to represent a surrogate endpoint in the accelerated approval pathway. So we're really excited to make this announcement today and that the structure of the campsite study is not only an amendment to the existing IND, but also is active and we've been enrolling patients as part of our pivotal program.
spk09: Great, and thanks for the question on RGX314. regarding NABS or neutralizing antibody status and any impact in the two trials that we're running with supracoroidal delivery. As you know, with subretinal delivery, we already know that neutralizing antibody status of patients doesn't impact the safety and efficacy that we see. We are excited that we're able to characterize superchoroidal delivery of gene therapy with our NAB technology with RGX314, where we can answer the question that you've asked. And we've gone about this very methodically, both in terms of dose escalation, but also looking at both NAB negative and NAB positive cohorts of patients at dose level two and dose level three in the AVA wet AMD study, and at dose level two in the altitude DR study. And in the data releases that we've discussed previously, we've actually not seen any evidence of impact. We're not seeing, for example, any greater safety or inflammatory findings in patients who are NAP and in the data cuts where we can look at NAB negative and NAB positive, like in ABA, we're going to be able to assess this over time. But to date in the releases that we've had, we've been very pleased with the lack of any clear differentiation in terms of safety between NAB negative and NAB positive.
spk00: Thank you.
spk10: Thank you. Our next question or comment comes from Raymond James. Mr. Leon, your line is open.
spk08: Thank you for taking the questions and congrats on the progress. Just two kind of easy things to confirm for me. Can you just confirm that you'll have an update on aviate and altitude in the back half of this year? And then secondly, can you just slow walk us through the campsite requirements from the FDA in terms of the primary endpoint? I think I misheard, but I thought you said the requirement is 10 patients in the primary analysis set with a measurement of gag reduction in the CSF at month four. Again, I probably misheard that, but if you could just clarify, thank you.
spk06: Hey, Dane. It's Ken. I can take both of these, actually. You can expand that if you want. No, that's right. We announced that we'll have suprachoroidal data from the ongoing trials later this year. That would include avian and altitude updates. With respect to... one-to-one, no, you were being a great listener. I think you actually heard the information that we communicated that, you know, Campsite is a trial that is a pivotal phase expansion of what was the ongoing phase one-two trial where we continue to collect the number of endpoints across the entirety of the trial with boys that enroll. But with respect to the accelerated approval plan, we've been focused on and have alignment that GAGS At an end point of 4 months would have the opportunity to support an accelerated approval as a surrogate endpoint. And so that's what we're executing on now in order to achieve what we think is an exciting timeline for a in 2024. Okay, thank you.
spk08: I guess if I can ask the follow up to that, I mean. Can you rank your level of confidence here? I guess why you're getting this question is this doesn't seem to be in line, again, different mechanism, but this doesn't seem to be in line with what JCR did not only understand to be the requirements in Hunter for a regulatory approval.
spk06: obviously can't speak to other people's programs, Dane, and as you pointed out, you know, we don't know of another program that uses AAV therapeutic technology to focus on Hunter Syndrome delivered directly to the CNF. What we can communicate is what we, in terms of an understanding of the opportunity for accelerated approval for RGX121, And our degree of confidence is such that we announced this morning and follow up this afternoon that we're going to execute on this plan. And I think this is a really encouraging thing for patients.
spk08: Okay. Thank you very much.
spk06: Thanks.
spk10: Thank you. Our next question or comment comes from the line of Alex Stranahan from Bank of America. Mr. Stranahan, your line. Question or comment comes from the line of Alex Stranahan from Bank of America. Mr. Stranahan, your line is open.
spk11: Hey, guys. This is John. I'm up for Alex. Thanks for taking our question. Just a short one from us. In terms of manufacturing, what do the economics look like right now in terms of moving things in-house versus still going with a contractor? You know, if you can put, like, a specific percentage of cost savings in moving things in-house, that would be really helpful. And second part to that would be, what are we looking at in terms of expecting all the pipelines to fully and completely move in-house, and how long are we expecting the still-going partial external production to continue? Thanks.
spk06: Hey, John. Thanks for the question. As we've announced, we have opened the facility here in Rockville, and we've started to make the first batches to support program work here at Regenexx Bio, and we highlighted the fact that we've prioritized the first batches to support the clinical supply for RGX202. We continue to have material made at, bulk material in particular, made at the CDMO sites that we use, principally Fujifilm down in Texas. And I think that your question about kind of the future focus here, is a good one, but we're still in the early phases of kind of utilization of the new facility, and the planning overall is something that is, as you can expect, sort of multivariable. We've got clinical supply needs in the immediate for RGX202. I should point out that we actually have the inventory that we need in place made with the NavXpress bioreactor process to support the RGX121 pivotal phase. And we have a lot of inventory in place. Of course, we've been continuing to expand the inventory and then use it with respect to execution of atmosphere ascent as well as aviated in altitude. So when it comes to RJX 314, that's a very dynamic process and now one that's starting to include add to you with respect to that planning. So I don't know that we have a finite answer at this point, John, but what I can say is that the plan in terms of the investment was to rely more and more on ourselves to deliver material for all the needs that we have across the pipeline, as well as through commercialization. And we think that the capacity is there in Rockville to achieve that. The absolute timeline, you know, I rely on sort of the expertise of our highly capable technical operations team to work on those transitions of processes here to support our needs and balance that with continuing to have backup options in the CDMO space. In terms of the cost component of it, I don't know that we would project right now any material changes to our P&L and R&D expenses with respect to how we're thinking about use of our new facility in addition to the ongoing CDMO relationship use. What I would say is we're making a lot of material. We have a lot of programs. We have two programs that are now in pivotal phase, and so I think we probably have among the sort of highest use of any of the gene therapy companies that I can think of, particularly on a diversity of program basis. I feel really well positioned with where we are right now for our needs.
spk11: All right. Thank you, Ken. Thanks for the call.
spk10: Thank you. Our next question or comment comes from the line of Ellie Murrow from UBS. Stand by. Murrow, your line is up.
spk01: Hey, guys. Thanks for taking the question. Just on RGX111 and MPS1, you know, I guess after the update on the, you know, registrational study for MPS2, how are you thinking about the potential path in MPS1 and, you know, if the design would look, you know, relatively similar and any initial FDA feedback on that or any timeframe under which we can expect to learn more feedback And then just a follow-up question on the MPS II study. I guess in terms of the endpoints, any sort of magnitude of effect or effect size that was discussed on those endpoints with the regulators? And then just last question on 314. I know you haven't given sort of direct guidance in terms of the timing, but any kind of high level how we should think about, you know, certain medical meetings that could be good candidates for learning more just anything to help us think about when we could kind of learn more about some of these higher dose and NAB positive cohorts. Thanks.
spk06: Thanks, Allie. Good robust set of questions there, so I'll try to dig through a few of them and certainly going to involve Steve here as well. You know, the focus with respect to 121, you know, juxtaposed with 111 for MPS1 has certainly been affected by the fact that we've you know, accumulated more patients in the 1-2-1 phase 1-2 trial. We've gone through additional dose escalation, being able to go through additional longer-term, you know, safety assessments for certain of the patients with MPS-2. And so, you know, conversations around The concept of the accelerated approval pathway were, frankly, just supported by more data, particularly on the safety side, but also on kind of the dose responses that we saw with respect to the biochemical markers and, as we've reported, the emergence of kind of understanding of correlations in certain patients with respect to the clinical outcomes as well. And, you know, I think speaking to the point, you know, that Dane had raised, and I think, you know, you're bringing up again with respect to, you know, some of the robustness of that data and where we were, I mean, we were beginning to report, you know, as early as February of this year that with the dose level 3 in the Phase 1-2 study, which is the pivotal dose now, it's part of the pivotal program expansion Steve alluded to, the 2.9E11 dose. is one where we began to see normalization of certain gags in the CSF. And so I think, you know, as we're thinking about these diseases, thinking about surrogate biomarkers for approvable endpoints in things like the accelerated approval pathway and thinking about how to make not just the logical scientific arguments, but the scientific arguments connect with a biomarker argument that's going to connect with confirmatory studies that, you know, we also believe are part of the process of kind of dynamically engaging in an accelerated approval pathway program, we really saw the totality of that with respect to RGX121. We know and acknowledge that RGX111 and MPS1 is a closely related disease adjacent to MPS2. But we're not where we were with 121 or are with 121 with respect to the level of enrollment and the robustness of the data set at this time. So we'll continue to expand the 111 program, but absolutely right now the focus for us is on accelerating the 121 program against this new timeline, which we're really encouraged about. On 314, Steve?
spk09: So on your question about any more granularity on updates on ABA at altitude on the back end of this year and medical meetings are not, as you mentioned, we're not able to give any more specifics. And it's the type of thing that we work on planning with our strategic partner, AbbVie, as well. But we do share the view that it is good to be opportunistic and try to take advantage of the typical big meetings that happen on the usual cadence around the year. So that would be in the mix of what we're thinking about. But certainly we look forward to giving an update on both programs in the second half of the year.
spk01: Cool. Thanks.
spk10: Thank you. Our next question comes from the line of Lisa Walter from RBC Capital Markets.
spk04: Oh, perfect. Thanks for taking the question. This is Lisa for Luca. So three for me relating to this accelerated approval or potential accelerated approval path for RGX121. First, you know, we know the new FDA commissioner has been supportive of reforming the accelerated approval pathway, partially so that approvals can only occur once the confirmatory phase three is already ongoing. So, just wondering how confident are you that this will not apply to RGX121? And question number two, assuming you can file RGX121 early, How are you thinking about the actual primary endpoint for a confirmatory phase three trial later on? And one last question, just on campsite, just wondering if you could provide more color on the trial design. Will patients be allowed to be on background enzyme replacement therapy? Thanks.
spk09: I think one of the benefits here as Ken mentioned is right from the beginning we are committed to a confirmatory study for complying with the accelerated approval pathway and with the goal of 2024 BLA via the accelerated approval pathway We're now just approaching second half of 2022. I think that gives a lot of time in terms of fine-tuning the actual confirmatory aspect. I think the benefit is we believe in the reasonably likely to predict clinical benefit, particularly in this disease with replacement of the enzyme via gene therapy directly to the CNS. And that's really going to put us in a good position to, as rapidly as we can, get this product to patients in need. And in parallel plan for that confirmatory study, one of the realities we know with this disease and a lot of these rare diseases for which accelerated approval pathway is intended, that the actual demonstration of the clinical benefit Just takes up more patients and longer follow up given the inherent variability. In these different diseases, including MPS 2, but certainly we feel confident we can do a confirmatory study, but with more patients. and longer follow-up where we'll be able to look at neurocognitive outcome measures like the ones that we do include in our ongoing study. So we feel very good in terms of the first two parts of your three-part question. So I think we're in a really good place now that we have campsite ongoing and hitting the pivotal part of the program.
spk06: Yeah, and I think that as I addressed with respect to some of the earlier questions, this is an accelerated approval plan approach. We want to sort of accelerate the use of the biomarkers that we think have shown evidence of correlating to clinical outcomes that we've shown in our data. We also believe that those biomarkers have been things that have been strongly associated with good scientific understanding, including in animal models of the disease. And we think that, you know, at this stage, we have a really robust safety data set, not Frankly, in patients that are in extension of the Phase 1-2 into the campsite study, but we also have to acknowledge that we've, you know, over the last year or so, also stood up an additional Phase 1-2 study for boys 5 and older with respect to MPS-2 as well. So there was a lot to draw from in terms of the communications and the interactions that we had. with stakeholders both in the patient communities. We brought our investigators forward. We talked to physician experts who were not investigators in currently RGX121 studies to bear on conversations with the FDA and others about how to accelerate the development of RGX121. say, you know, one point, Lisa, I mean, I'm not sure that I have heard or hear, you know, the same thing that you're kind of representing about what the new commissioner of the FDA is saying about confirmatory studies. We certainly have a commitment to running confirmatory studies. We expect to bring confirmatory evidence forward, as Steve alluded to. I think it's pretty straightforward with respect to Hunter syndrome. We need to see the neurodevelopmental outcomes And we want to see a lot of important caregiver-reported outcomes as well. When you talk to the field, there's not just sort of a singular perspective on what are the outcomes, because there's so much heterogeneity in a small population. And I think those types of conversations falling on the years of leadership at FDA and regulators has a profound impact on sort of how they think about the need and the kind of interest behind accelerating a gene therapy for Hunter syndrome. So for us, It's more dynamic than saying we're going to run a confirmatory study and we have to figure out what that design is going to be. It's actually, in my view, built into the development plan and the program even through campsite. As Steve alluded to, we're still collecting all of these other measures. We're going to be relying most heavily on the surrogate biomarker to support the accelerated approval plan. But the boys that have already been enrolled, boys that are enrolled through this accelerated approval plan phase, and the trial is actually open to enrolling boys in addition to the 10 that we would associate with the accelerated approval plan to be able to continue to collect evidence and have that apply as part of the confirmatory evidence. I think there's no reason to put any of this into a box. My view is that what's been most encouraging about these discussions is that there's a lot of confidence in the data that we brought forward in terms of the safety, the correlation of the potential of surrogate biomarkers. in animals, in the human data we've shown, to the disease process, to the outcomes that we've shown with respect to things like the neurodevelopmental outcomes and the caregiver-reported outcomes already. And so it's just shepherding that to something that makes it accessible to patients in as efficient a way as possible. And I think that's been what we've seen over the last quarter or two emerge in conversations with all stakeholders.
spk04: Well, thank you. Thank you a lot for that very thorough answer, Ken. And then I guess just on the enzyme replacement therapy, are you going to be including or excluding patients?
spk06: Yeah, as we've done in the Phase I-II study, we've always continued to enroll patients on Eliprase. We acknowledge that the background of Eliprase doesn't affect and is known not to have any effect on the neurodegenerative pathology associated with MPS II. So we've shown that in the data that we presented to date in the Phase I-II study from Cohort I to Cohort III. Occasionally, we have had enzyme-naive patients enroll in the study from certain sites, but in general, especially in the U.S., Lisa, we see patients coming in on LFRase IV, and they get RGX121 on top of it, and that's been the expected continued approach on campsite.
spk04: Excellent. Thank you for taking our questions.
spk10: Thank you. Our next question or comment comes from the line of from . Mr. , your line is open.
spk03: Hi. Can you guys hear me? The operator cut out.
spk06: Yep, we got you.
spk03: Hey, okay, great. Yeah, thanks for taking the questions. Congrats on the progress as well. So, for the MPS II program, just a couple of follow-up questions here, and along the same lines of a previous question. And this has to do with the interactions with the FDA. I mean, how important did they consider this correlation between biomarkers and, I guess, the functional measures? I don't believe we saw the functional measures from cohort three in the February update, so when might we get that data? Has the FDA seen that data? And can you remind us, you know, what you've seen to date, you know, what's really informed the phase three dose? And then on 314 superchoroidal, just to clarify on... a press release. It says that no patients were previously treated or treated after a dosing. Is that from all of the remaining cohorts as well? Thank you.
spk06: I'm not sure I understood the last part of the question, Andre.
spk03: Did you? Yeah, I'll clarify. Sorry if I wasn't clear. So, the way it was worded is that, you know, is implied, at least from my reading of it, that you have not seen, none of the patients have received prophylactic steroids prior to or after being dosed in all of the cohorts.
spk09: Yeah, that's correct. So, as we've discussed previously for both studies, both AB8 and altitude in all the cohorts, we have not included prophylactic steroids either before or after the administration of RJX314.
spk03: Okay, and does that have, I mean, I'm trying to understand if that has anything to do with or any research to the, to any observations and information in these additional cohorts. You can speak to that.
spk09: Well, right from the initial cohorts in both studies, we did not have prophylactic steroids either before or after. And as we dose escalated in both studies, given excellent tolerability, we did not institute prophylactic steroids at the higher doses.
spk06: And so with respect to the 121 program question, I think just continuing to support the understanding here that the dynamic conversations with FDA have certainly included the data that we have presented on podium, as well as information that we've included in both the amendment with respect to the campsite study conversations that you know we have multiple of these you know designations including things like fast track that allow for a dynamic interaction with respect to FDA on this topic and you know it's Something that, you know, also has, you know, been part of multiple, I'd say, you know, interactions that we've had with stakeholders, including FDA, on the topic of accelerated approval for things like, you know, Hunter and Herler syndrome, I think I alluded to in my remarks. You know, our initiation with Solid Bioscience is in the formation of the Pathway Development Consortium. which is something that we announced late in 2021, actually started out with working group focus in Duchenne and talking about concepts of how to accelerate AAB therapeutics in the background of Duchenne. Later, that group came together and issued a white paper that was more broad spectrum, but identified categories of different types of diseases and how you would come forward and think about Acceleration of development based on the science or the pathology of the disease, or kind of the residency with respect to tissue type and some of that white paper work landed on diseases or neurodegenerative diseases, including MPS diseases. where evidence from those discussions, and I think validated through the announcement today, is that there's support for accelerated approval to rely on a justifiable endpoint, something like GAGS and CSF, based on the emergence of, I've seen FDA leadership allude to animal data as supportive. We've certainly seen them be supportive of human clinical data and the reconciliation of those things. In terms of the correlation to where the confirmatory evidence is going to come from, I think it's inherent in the biomarker, from my perspective, that when, especially in the case of GAGs and CSF, when you're talking about The substrate of the enzyme that's deficient in the disease that is going to correlate has correlated with changes in pathology in animal models and is going to correlate with changes in pathology in the humans and eventually be confirmed in things like the neurodevelopmental outcomes and the caregiver-reported outcomes. There's a unique space in my view for the MPS CNS diseases and their relationship with respect to AAV therapeutics that has been part of many discussions, including for diseases that are more rare than the MPS disease as well, of course, progenics. And many other companies are part of this other paradigm approach for bespoke AAV gene therapies where I've observed there have been similar conversations about how do we speed and accelerate the development of AAV therapeutics once we have safety and sort of stable manufacturing capabilities for patients. So for me, I think we've been talking with all of you about our involvement in a lot of those different consortiums and groups. We've been talking about the interest that we've had in sort of finding pathways for acceleration of rare disease. Obviously, we've announced work in Duchenne, but most of our clinical data, of course, in rare diseases in RGX121 and Hunter syndrome, and I think just based on a very mature kind of and sort of longitudinal set of conversations and regulatory interactions that have gotten us to this point from And really encouraged and pleased with this outcome because it sets us up to file the BLA and as fast a timeline as, you know, probably our team can handle. And we're up to the task for executing.
spk03: Great. Thanks for the call.
spk10: Thank you. Our next question or comment comes from the line of Mani Faruha from SBC Securities. Stand by.
spk02: Thanks for taking the question. A lot of the colleagues at other firms have dug in on clinical data, et cetera. I wanted to revisit another topic that's been discussed a little bit on this call around the wholly owned manufacturing and the value of manufacturing for AAV specifically. The specific question I have is how you see the expansion in capacity. Obviously, there's been tremendous investment amongst the CDMO community. into the face of blowing investment into AV development in venture and large-cap pharma. Give us a sense of where we are in terms of the available capacity and what that means about the value of investments in wholly owned manufacturing.
spk06: Mani, I don't know that, you know, we are the company that sort of may be best to kind of, you know, give the overview of what the entire CDMO landscape is like at this moment. I think, you know, and we've talked with you for a while, and I think others on this call about our journey. You know, it started four or five years ago when we had, you know, need for high-quality clinical material, and You know, we experience a lot of things with a lot of different CDMOs and up to and, you know, most recently including our experience with this final fill finish third party in the CDMO network. I think with respect to capacity. It may be there. It may not be. I don't know. It's a really hard thing to establish when I think about the CapEx investment in particular, because like you, I think we see a lot of announcements about new facilities being invested in and built perhaps But what I can say about our interest in our approach, and this really came from, you know, kind of the leadership team here and some of the most experienced people that we have in the company when it comes to manufacturing, is that, you know, really to be able to scale high-quality, you know, manufacturers, especially in a new area, you need real continuity with respect to the quality team. and with respect to the floor operations team. And that was something that I would say we certainly observed with respect to this dynamic change in demand for the CDMO space, is that there's been the potential for a lot of movement in people and in expertise. And that was something that I would say was a driver for, you know, our investment and something that was making us uncomfortable that now we are more comfortable with. And I think one that we are prideful about that we have an excellent quality team, an excellent operations team, and a team that, you know, we think is really connected to the mission of Regenexx Bio and one that's here in our building where the research labs are and you know, where I work and others work. And, you know, having that type of opportunity at this time and place, I think, establishes that, you know, it wasn't just about the CapEx investment, but it was about the people investment, making it something that was going to last in a sort of continuous way for us. And look, we've got designs on taking now, you know, two pivotal programs to BLA in 2024, and we've got the five by 25 strategy, we want to commercialize. So, you know, having that responsibility means having a stable, not just a, you know, set of equipment, but a set of people as possible as well. And I think that's been, if it's fair, you know, kind of the, one of the big priorities of our focus on investment.
spk02: Great. And if I could ask a separate question, I know it's been discussed earlier, but I'm not sure if the answer was complete or maybe I missed it because the quality of the audio is a little weak. Could you give us a little more detail on where you think exactly the requirement for milestones is on the Bayley score in a little bit of detail, I mean quantitatively?
spk06: We didn't address any sort of specific quantitation with respect to the neurodegenerative outcome requirements on a confirmatory study. I think the way that I addressed that is when we've engaged with the physician clinical experts in MPS when we talked with the patient family stakeholders and brought them together in circumstances where we're able to do so with the FDA and with our own data and own assessments, there is no absolute hard cutoff on any one measure or domain for any of that. So what we've seen and what we've continued to do in our clinical program is to collect all of that data, collect all the domains of things like, you know, Bailey and the sort of equivalent assessments on an age-adjusted basis, include caregiver-reported outcomes, include the, you know, biochemical measures and the other measures that are sort of evidence of the gene therapy turning on and the gene therapy having both biochemical and sort of cellular and morphological changes occurring. And that, you know, the confirmatory evidence is actually going to be something that's going to be, you know, I think a journey that is going to involve a lot more patients to sort of grow that understanding against the heterogeneity of the disease in general. And so, you know, what I can say is that we're really encouraged about everyone recognizing that and recognizing that there are sufficient changes occurring in the voice on the basis of our gene therapy approach for something like MPS II, that there's an interest and an opportunity in wanting to accelerate its access. to more families and boys, and that our commitment to continue to sort of grow that understanding, that understanding of, you know, what are the different types of neurological outcomes that we're going to see in different types of boys at different ages against the heterogeneity disease is going to be something that, you know, I think is also going to leave its mark. But that's not going to be something that can be achieved by 2024. That's something that is going to take many more years of confirmatory commitment to achieve. We'll be there to do that as well.
spk02: Okay, thanks.
spk10: Our next question or comment comes from the line of Caroline Polomique from BCM. Your line is open.
spk07: Hi, thanks for taking the question. I just had a quick question on if you could provide some guidance on the R&D and G&A expense. Just wondering if you Just expect them to keep trending up just in the near term. You can just get a little more color on that.
spk06: I mean, you know, I think we've seen R&D expense grow as we've expanded into, you know, pivotal phase of development and sort of increased, you know, manufacturing and supply requirements for things, including the Duchenne muscular dystrophy program, which obviously is larger quantities of AAV that we need on a per-patient basis. So, you know, moving into continuing, you know, first in human development of RGX 202, pivotal phase with RGX 121 is going to have some increased costs. We're going to have increased costs with respect to the expansion of all the work around RGX 314. Yes, we would continue to see that. R&D increase, although as Vin alluded to, there is going to be some continued offset as AbbVie continues to shoulder more and more of the clinical trial and development expense. However, you know, with a 2024 BLA filing to your GNA point, we'll also be transitioning into, you know, pre-commercial readiness modes with things like RGX314 subretinal. So, you know, I think that, you know, sort of added growth will be something that, you know, on a year-to-year basis, we'll continue to see increases in as we head towards these BLA filings for, you know, two pivotal phase programs. You know, we continue, though, to support the guidance that, you know, the cash on hand will afford us the opportunity to execute on all these milestones, the regulatory achievements as well as the clinical development milestones into 2025. And, you know, as part of our 2025 strategy, I think this is all rather consistent.
spk07: That's helpful. Thanks.
spk10: Thank you. I'm sure no additional questions in the queue at this time. I would like to turn the conference back over to Mr. Ken Mills for any closing comments.
spk06: Thanks, everyone, for listening today. Thanks for all the great questions. We really are excited about the advancement of all of the programs, particularly the event of the announcement of the Active Pivotal Program for RGX 121. We're looking forward to engaging with all of you more on updates throughout this year, and have a good rest of your summer.
spk10: Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.
spk05: The conference will begin shortly. To raise your hand during Q&A, you can dial star 1 1.
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