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spk02: Good morning, and welcome to the Selecta Biosciences fourth quarter and full year 2021 financial results and corporate update conference call. Currently, all participants are in a listen-only mode. This call is being webcast live on the investors and media section of Selecta's website at www.selectabio.com, and it is being recorded. For opening remarks, I would like to introduce Kevin Tan, Chief Financial Officer of Selecta. Please go ahead.
spk05: Thank you and good morning. Welcome to our fourth quarter and full year 2021 financial results and corporate update conference call. The press release reporting our financial results is available in the investors and media section of Selective's website, worldwidewebselectivebio.com, and our annual report on Form 10-K for the year to end at December 31st, 2021, which will be filed today with the Securities and Exchange Commission, or SEC. Joining me today are Carson Bruhn, President and Chief Executive Officer, and Peter Traver, Chief Medical Officer. During today's call, we will be making certain forward-looking statements, including without limitation statements about the potential safety, efficacy, and regulatory and clinical progress of our product candidates, financial projections, and our future expectations, plans, partnerships, and prospects. These statements are subject to various risks that are described in the filings made with the SEC, including the most recent annual report on Form 10-K. Your company should not place undue reliance on these forward-looking statements, which speak to the urgency of March 10, 2022, to select and disclaim any obligations of these such statements, even if management's views change. I would now like to turn the call over to Karsten Bruhn. Karsten?
spk10: Thank you, Kevin. Good morning. I appreciate everyone joining us today. Before we begin, I'm thrilled to announce that on March 9th, the FDA cleared the Investigational New Drug, or IMD, application for a Phase I Genotherapy Clinical Trial of SGL302 to treat metabolic acidemia, or MMA, a serious and life-threatening metabolic disorder. This clinical trial is a critical step in our efforts to treat MMA and enable redosing of AUV-mediated gene therapies. We expect to initiate the phase one trial in the second half of 2022, and we look forward to bringing hope to all those patients and families affected by this terrible disease. 2021 was a very busy and transformational year. and we're extremely pleased with the significant progress to propel our business forward. Over the past year, we advanced our pipeline of wholly owned and partnered programs. We entered a number of key strategic partnerships and are close to catalyzing an evolution of our precision immune tolerance platform. By combining mTOR with a Treg-selective IL-2 molecule, we've observed synergistic effects in the induction and expansion of antigen-specific regular T cells for Tregs. We believe this transformative combination, which we call mTOR-IL, has the potential to enhance the induction and durability of antigen-specific immune tolerance, a substantial leap forward for our mTOR platform. I would now like to walk you through key updates and recent strategic partnerships pertaining to the three pillars of our pipeline. Reimagining immunotherapy for autoimmune disease, unlocking the potential of adeno-associated virus or AAV gene therapy, and amplifying the efficacy of biologics. The current standard of care for autoimmune diseases is broad immune suppression, which is associated with side effects that often leave patients vulnerable to serious infection and malignancies. By reimagining immunotherapy for autoimmune diseases, we have taken important steps to address the significant need for antigen-specific therapies without chronic and systemic immune suppression. I want to start out with our most exciting finding from the last 12 months. In recent preclinical data generated by our scientific teams, we observed that IMTOR showed profound synergistic activity when combined with engineered IL-2 molecules that are selected for T-REX. Mice harboring transgenic antigen-specific T-cells were dosed with a target antigen and then treated with IMTOR-IL, a combination of IMTOR and a T-rex-selective IL-2. We observed IMTOR alone to induce antigen-specific T-rex. and from my extensive clinical experience with mTOR, find this level of Treg induction to be clinically meaningful. Interestingly, the administration of mTOR-IL combined with the target antigen led to a substantially greater increase in antigen-specific Tregs. In contrast, mice dosed with the engineered IL-2 plus antigen showed only an expansion of total Tregs, but little or no expansion of any specific T-Rex. We believe mTOR-IL is a transformative evolution of our precision immune tolerance platform with implications across our entire pipeline. Importantly, mTOR-IL has the potential to unlock treatments for patients with a variety of autoimmune diseases. We also tested IMTO-IL in an annual model for the ability to induce durable immune tolerance to a co-administered AAV gene therapy. In this study, IMTO-IL was co-administered with two doses of an AAV vector. we observed complete inhibition of anti-AV antibody formation after multiple vector doses through 117 days. And most excitingly, this synergistic effect was observed at doses that are considered sub-therapeutic for mTOR alone. These results suggest that the addition of a Treg-selective IL-2 to mTOR has the potential to increase the potency, durability, and potentially allow for dose sparing of mTOR. Current programs of engineered IL-2 molecules in development for autoimmune diseases focus on non-selective expansion of total existing T-Rex, but not T-Rex-specific for the autoenogens that drive the pathogenesis of the disease. IMTR-IL has the potential to be a truly differentiated, first-in-class, antigen-specific immunotherapy that restores balance in vivo to the millions of patients suffering from autoimmune disease today. On September 8, 2021, we entered into a collaboration with Cyrus Biotechnology, a world-leading protein engineering company, to design a next-generation proprietary key retroactive IL-2 molecule. A key priority for 2022 will be to identify target indications and accelerate the development of IMTOR-IL into the clinic. In parallel, we are continuing IND-enabling studies for our primary blood cholangitis, or PBC, program. Moving on to our work in gene therapy. In 2021, we reported with our partner, Aspio, on a clinical proof-of-concept study of mTOR combined with an AAV empty capsid in healthy volunteers, which I'll expand on later. We also published preclinical studies in Science Advances describing the first-dose benefits of mTOR on enhancing transient expression when co-administered with the initial dose of an A-B vector. In addition, we published a paper in Frontiers in Immunology describing the potential hepatoprotective properties of mTOR. These findings build on the growing body of evidence demonstrating the potentially multifaceted benefits of mTOR for enhancing the efficacy and safety of AV genes therapy. On October 4, 2021, we entered a strategic license agreement with Takeda, a global pharmaceutical leader with expertise in rare diseases, to combine mTOR with their targeted next-generation gene therapies for two lysosomal storage disorders. We are encouraged by the strong endorsement from one of the leaders in the lysosomal storage disorder landscape. as a validation of our approach and precision immune tolerance platform. We look forward to working closely with and supporting Takeda. We also continue to seek partnerships to expand our platform with technologies that can be applied to mitigating immunogenicity of AAV gene therapies. On October 21st, 2021, we announced an exclusive license agreement with Genovese to advance Zork, a differentiated IgG protease to enable the dosing of transformative gene therapies in patients with preexisting anti-AAV immunity. Currently, up to 50% of the potential patient population for gene therapy trials are ineligible for inclusion due to preexisting neutralizing anti-AEV antibodies that are a result of natural infection with wild-type AAV. Thus, many patients in need are unable to access potentially life-altering treatments for their genetic diseases, for which there may be few or no treatment alternatives. Zork is a bacterial protease that is designed to specifically cleave human IgG and is being developed as a pretreatment in advance of an AV gene therapy with a goal of transiently clearing preexisting neutralizing antibodies to create a treatment window during which gene therapy can be administered. Zork is differentiated from some other I2G proteases in that Zork is derived from a non-human pathogen and therefore has demonstrated very low cross-reactivity to pre-existing anti-I2G protease antibodies. The combination of Zork and IMTOR has the potential to address two of the biggest issues currently limiting AAV gene therapy. Zork to bring the power of gene therapies to those patients who would be otherwise ineligible for treatment due to preexisting antibodies, and IMTOR to mitigate the normal immune responses to AAV gene therapy and enable redosing. We believe that the combination of Zork and mTOR has the potential to provide safer and more effective gene therapies to more patients. We also announced a collaboration with Ginkgo Bioworks on January 10, 2022, to design novel AV capsids with a goal of improving transduction efficiency, liver tropism, and immunogenicity profile. Ginkgo will design and engineer the capsids, and Selector will conduct all nonclinical and clinical studies thereafter. This partnership leverages skin-co-cell engineering and high-throughput screening capabilities and Selecta's mTOR precision immune tolerance platform to advance gene therapy delivery. A major hurdle for the gene therapy field has been the toxicity associated with high AAV doses. In many cases, the toxicity is inextricably linked to immunogenicity. Our vision is to change the treatment paradigm to dose low and slow by combining mTOR with more efficient capsids to enable administration of multiple smaller doses rather than a single high AAV dose, which is often associated with serious adverse events. As mentioned earlier, in 2021, we announced top-line results from the first in-human phase one dose escalation trial of SEL399, which we conducted jointly with our partner, ASBio. SEL399 is an AV8 empty vector capsid containing no DNA combined with mTOR at doses of 0.15 mcg per kg and 0.3 mcg per kg. The randomized, placebo-controlled, double-blind dose escalation study conducted in Healthy Volunteers was designed to determine the dose regimen of mTOR to mitigate the formation of lutealizing antibodies, or NAPs, against AV8 serotype capsid used in chinotherapies. We observed a strong immune response in humans administered AAV anti-capsids alone. The addition of mTOR to the administration of anti-capsids reduced the formation of anti-AAV8 NAVs in a dose-dependent manner at day 30. Consistent with preclinical data, we observed that the single dose of intro cohorts saw delayed formation of NAFs, eventually reaching similar median levels of NAFs to the control group by day 90. Based on prior animal studies, we believe that if NAFs are inhibited at day 30, Administration of two additional monthly doses of mTOR has the potential to inhibit the formation of NAVs with improved durability. We expect that the learnings from the empty capsules clinical trials and our nonclinical studies employing three monthly doses of mTOR will guide the clinical development of our proprietary gene therapy program, SEL302. SEL302 is a combination of mTOR with MMA101, an AV gene therapy being delivered for the treatment of MMA, a rare metabolic disease in which the body cannot break down certain proteins and fats. As previously mentioned, on March 9th, the FDA cleared the IND application for our Phase I clinical trial of SEL302 to treat MMA, I want to thank our dedicated clinical, regulatory, and CMC teams here at Selecta and our external partners for all their hard work in addressing the clinical hold. The trial is expected to initiate in the second half of 2022 and will evaluate the safety and efficacy of SEL302 and the prevention of formation of utilizing antibodies against the MMA101AEV capsid. Our second wholly-owned proprietary gene therapy product candidate is SEL313 for the treatment of ornithine transcarbamylase deficiency. While we had originally anticipated a clinical trial application and IMD filing in 2022, we have decided to prioritize our resources on the MMA program for the time being. Overall, we're seeing excellent progress across our gene therapy programs and look forward to continuing to progress Intour, both in our wholly-owned gene therapies as well as in partnership with our leading gene therapy partners. We believe that the platform technologies of Intour and Zork position Selector as a leader in unlocking the true potential of AAV gene therapy. Lastly, a few key updates on our biologics programs, our most mature pipeline pillar. Many biologics can be highly immunogenic, resulting in suboptimal responses due to the development of anti-drug antibodies after multiple treatments. Patients that develop an immune response may be forced to discontinue treatment or experience adverse reactions. We believe the use of mTOR as an adjunct to biologics offers a promising approach to minimize the healthcare and economic burden of anti-drug antibodies. SEL212 is comprised of IMTOR, co-administered with our proprietary EU case, the GATRI case, for the treatment of chronic refractory gout and was licensed to SOBI in 2020. As a reminder, our Phase III dissolved clinical program kicked off in the third quarter of 2020 and consists of two double-blind, placebo-controlled trials of SEL212. In both trials, SEL212 will be evaluated at two doses of mTOR, 0.15 mgs per kg and 0.15 mgs per kg, and one dose of Pegatricase, 0.2 mgs per kg. Each trial aims to enroll up to 120 patients with up to 40 subjects in each of the two treatment arms and up to 40 on placebo. On December 1, 2021, we announced full enrollment of DISSOLVE-1, which is being conducted in the United States. Enrollment into the DISSOLVE-2 trial is ongoing, and the study is being conducted in the United States and four countries across Eastern Europe. We are closely monitoring the evolving geopolitical situation in Ukraine and Russia and have proactively undertaken mitigation steps to prioritize the safety of our patients and investigators first and foremost, as well as address any potential disruptions. While we have some temporarily closed screening and randomization at sites in both Russia and Ukraine due to shipping constraints, We have proactively added 11 additional sites in the United States to offset and speed enrollment in Resolve 2. Of these additional enrollment sites, nine have already been activated and two are pending initiation and activation. We will continue to work closely with our licensing partners SOBI, our clinical trial providers, and regulatory authorities to assess the potential impact on the program. Before turning back to our pipeline and program updates, we want to emphasize that our hearts are with the people of Ukraine during this unprecedented humanitarian crisis. With extensive clinical data and an asset currently in Phase III, we believe our biologics pipeline is well positioned to leverage these learnings into our second biologic indication in IgA nephropathy, a kidney disease that occurs when immune complexes of an antibody called immunoglobulin A1 or IgA1 accumulate in the kidneys. Current treatments fail to address the underlying pathophysiology of the disease, which are the IgA immune deposits. We believe our novel approach, which combines INTOR with an IgA1 protease, has the potential to remove injurious IgA from the kidneys and improve markers of renal dysfunction. We're currently working with IGaN Biosciences on a first-generation IgA protease derived from the Haemophilus influenzae bacteria. On October 26, 2021, we entered a collaboration with Ginkgo Bioworks to discover next-generation enzyme therapies. Today, we're announcing that the first program will focus on generating a second-generation IgA protease with lower immunogenicity and potentially transformative therapy potential when combined with mTORP. We're extremely excited about these advancements and the value-driving milestones ahead. With that, I'll turn the call over to Kevin to run through our financial results for the fourth quarter and fiscal year ended December 31st, 2021. Kevin? Thank you, Karsten.
spk05: We remain well capitalized with $129.4 million in liquidity as of December 31st, 2021, which compares to $140.1 million in liquidity as of December 31st, 2020. We believe our liquidity will be sufficient to meet our operating requirements into the third quarter of 2023. It is important to note that this is the most conservative forecast of our cash runway, as it considers none of the potential incoming milestones and royalties from our numerous partnerships. Net cash used is $60.4 million for the 12 months and fiscal year ended December 31, 2021, as compared with $34.9 million net cash provided by operating activities for the same period in 2020. Collaboration and license revenue recognized for the fourth quarter and fiscal year 2021 was $29.9 million and $85.1 million, compared to $12 million and $16.6 million for the same periods in 2020. Revenue was primarily driven by the license agreement with SOBI, resulting from the shipment of clinical supply and the reimbursement of costs incurred for the Phase III Dissolve Clinical Program. Additionally, during the fourth quarter, Selecta recognized $1 million for shipments of clinical supply under the license agreement with Takeda and $0.4 million for shipments under the license agreement with SRAPTA. Research and development expenses for the fourth quarter and fiscal year 2021 were $20.3 million and $68.7 million respectively, which compares with $15.1 million and $54.5 million for the same periods in 2020. The quarterly and annual increases were primarily driven by expenses incurred for preclinical programs, payroll costs, and ASK-BIO collaboration costs. General and administrative expenses for the fourth quarter and fiscal year 2021 were $5.5 million and $20.9 million, respectively, which compares with $4.8 million and $18.9 million for the same periods in 2020. The quarterly and annual increases were primarily driven by increases in stock compensation expenses and consulting fees, offset by a reduction in professional fees. For the full year 2021, Selecta recognized an income tax expense of $16 million. The expense was the result of our decision to opt out of the installment sales method that would have been applied to the sale of the SOE license for income tax purposes. By electing out of the installment method, the company was taxed on an estimated fair value of the current and future proceeds from the SOBI license as part of our 2020 income tax return filing. As a reminder, the SOBI agreement provides for up to $630 million in development, regulatory, and sales milestones, as well as royalty payments based on tractual sales tiers. As a result of this election, any revenues resulting from these future milestones and royalties will be excluded from selectors taxable income. For the fourth quarter and fiscal year 2021, we reported net income of 12.2 million or basic net income per share of 10 cents per share. The net loss is 25.7 million or basic net loss per share of 22 cents. For the fourth quarter and full year 2020, we reported net losses of $15.4 million or a net loss of $0.14 per share and $68.9 million or a net loss of $0.68 per share. I will now turn it back to Carson for closing remarks. Carson?
spk10: Thank you, Kevin. In summary, 2021 was an incredibly productive year for Selecta. We're excited to enter the clinic with SAL302 about the continued growth of our pipeline, our multiple shots on goal, and numerous validating partnerships. Furthermore, we remain confident in the broad applicability of our precision immune-tolerance platform to potentially restore self-tolerance in autoimmune disease and overcome immunogenicity in gene therapies and biologics. We believe InterIL, an evolution of the Inter platform, potentially represents a generational leap forward. The strong synergistic effects we have seen in our preclinical work demonstrates mTOR-RL has the potential to unlock antigen-specific immunotherapies for autoimmune diseases, as well as improve the efficacy and safety profile of therapies across our entire pipeline. With multiple anticipated catalysts in 2022, we look forward to providing additional updates on our progress as we explore gene therapy-enabling opportunities, advance SAL302, complete the dissolved phase III trial of SAL212 in chronic defector gout, and continue to expand our diversified pipeline to autoimmune diseases. Looking ahead, we believe we're well-positioned to deliver on our sharpened clinical development strategy with a focus on autoimmune disease indications, explore gene therapy and aping applications, and realize the full potential of our evolving intro platform. Before we conclude today's call, I would also like to thank the entire selector team, our investors, and the many people who have been supportive along the way, including our patients and their families. With that, we're happy to take questions.
spk02: We will now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. Our first question will come from Kristen Kluska with Cantor Fitzgerald. Please go ahead.
spk00: Hi, good morning. Thanks for taking my questions and congrats on addressing this hold and getting it lifted in under four months. So I wanted to ask at a high level if you could talk about some of the CMC-related items for this hold, and by addressing these now, do you think that running future studies, whether in MMA or other indications, it could be more seamless from making some of these changes now, but then also understanding what the agency is looking for in IMD packages on CMC?
spk10: Yeah, good question, Kristen. So we haven't disclosed the exact nature of the questions, but I think I've been clear in the past. They were all around the AEV capsid, MMA 101. They had questions around additional analytics, which usually have been asked more in a phase three setting. But, you know, as you said, I think it's great we got this out of the way early to before we even started the trial. And, you know, just to give you one specific example, the FDA is looking at the ratio of empty to full capsules, for example. I mean, that's one very specific question. So we completed all the analytical work and then, you know, supplied the answers, provided the answers on February 9th, and then got the wonderful news yesterday to move forward into the clinic. And there's definitely learnings for us, but also for our partners as well. I think it's important that we have a clear clinical path with three monthly doses, you know, in kids actually. So I think that provides a lot of certainty for our partners as well. There's a clear regulatory path for in-tour and in-gene therapy.
spk00: Got it, thanks. And recently the FDA published a draft guidance on immunogenicity information for therapeutics, including a focus on anti-drug antibody formation and thoughts about how this should be labeled and communicated. So obviously this phenomenon isn't new across biologics, but curious to hear your thoughts on how some of these criteria across labeling might impact physician behavior, especially if alternatives come to the market, including with your mTOR technology.
spk10: Yeah, it's not a great question. And, you know, obviously the FDA has been focused on ADA mitigation for quite a while. And I think the most recent guidance even puts, you know, more emphasis on the importance of ADA mitigation. And I think, you know, to our knowledge, we're the only company actually with clinical stage assets that specifically address ADAs. And I think we have demonstrated now across a number of modalities, you know, and obviously most advanced with our gout asset where we recently published a phase one data where we clearly, you know, address ADAs and with a very immunogenic enzyme, the get-to case, you pretty much have ADAs in 100% of patients if you don't add Intor. So we're extremely encouraged by this, and I think this will foster even more interest in our platform because it can help overcome the challenge of many of the biologics who all have, to some degree, induced ADAs, which impacts efficacy and, more importantly, maybe patient safety.
spk00: Thank you. And you're clearly very excited about the data you've seen for mTOR IL and the potential broad applicability. So how are you thinking about integrating this into your current pipeline, including some of these earlier stage programs versus looking at newer indications and targets?
spk10: Yeah, we're definitely very excited about Intel IL. We really think that's a generational leap for us. And, you know, there's excitement around the T-Rex selective IL-2s alone already. You know, the IL-2s basically... expand pre-existing T-Rex, but don't address the antigen-specific T-Rex, versus IMTOR alone induces antigen-specific T-Rex, but not necessarily expand. And the combination, really, we saw highly genetic effects where we both induce and expand antigen-specific T-Rex, which is really an amazing evolution of the platform We see the application really across all three pillars of the pipeline. We've shown some data In a preclinical model of AV gene therapy, we saw, you know, very good control of losing antibodies actually at a quarter of the dose of mTOR, which is, I think, very encouraging as well. So that's potential for this combination to be dose-bearing. But we're extremely excited about the application in autoimmune disease as, you know, anti-immune tolerance is kind of the holy grail, if you like. And with our approach, you know, we're trying to reimagine immunotherapy for autoimmune disease. Obviously, we've just released this exciting data around JP Morgan conference, and we're in the process to identify target indications. But you see us, you know, focus a lot more on the autoimmune disease space, you know, based on this exciting data.
spk00: Thank you again.
spk02: Thanks, Kristen. Our next question will come from John Newman with Canaccord. Please go ahead.
spk03: Hi, gentlemen. Thanks for taking my question, and congrats on the progress. I have a specific question regarding the potential design for the SEL302 study in MMA. I know that that study will be initiated later this about some of the potential aspects of that design regarding things like frequency of mTOR dosing, et cetera, just whatever you might be able to share. Thank you.
spk10: Yeah, thanks for the question. I'll hand this to Peter, our CMO.
spk09: Yeah, hi, this is Peter Traber, and thanks, John, for that question. You know, with the agreement of the FDA that the clinical trial proceed, I think we can now provide some details regarding the MMA clinical trial. Just as background, as we've stated previously, the trial will be conducted at the NIH by Dr. Chuck Venditti, a leading investigator with the largest MMA population in the United States. The trial will be conducted in cohorts of patients starting with adolescents age 12 through 18 and then progressing to children ages 2 through 12. The AV8 gene vector carrying the mute gene replacement designated MMA101 will be administered at a dose of 1E13 viral genomes per kilogram. This is a dose which has been shown to have excellent efficacy in non-clinical animal models, and we expect this dose to have therapeutic efficacy in humans. The dose of MMA-101 will be given with three doses of mTOR to potentially prevent the development of antibodies, which might allow future redosing to mitigate hepatic toxicity associated with gene therapy and enhance the first-dose effect of gene therapy, as Karsten had mentioned. The first dose of mTOR will be administered at the time of the gene therapy administration, And then doses two and three will be given on day 28 and day 56 following the MMA 101 administration. There are provisions in the protocol for dose escalation of mTOR depending on the effect on anti-AV8 antibody production. And there will be an adolescent subject treated without mTOR for comparison with that patient will get steroid prophylaxis, whereas those treated with mTOR will not have steroid prophylaxis as that's not a relative contraindication in subjects with MMA. Each subject will be treated sequentially with the assessment of safety and efficacy by a data safety monitoring board at three months following the infusion of the gene therapy before progressing to the next patient. The three adolescents will be treated, followed by three children with a dose of 1E13. The primary efficacy measures will be done at three months, and they'll be serum methylmalonic acid levels, C13 propionic breath test, which is a direct measurement of enzymatic activity, as well as clinical status, including episodes of decompensation and dietary prescription. In addition, the primary immunologic endpoint will be the development of neutralizing antibodies to AAV8 to assess the effect of mTOR. Following enrollment and assessment of the six treated subjects, three adolescents and three children, we will hold discussions with the FDA to determine whether to continue the program with the 1E13 dose of MMA-101 or to consider dose escalation or even potentially de-escalation. And as Karsten mentioned, now with the program off clinical hold, we anticipate infusing the first subject in the trial in the second half of this year. So, John, those are some details of the trial. Happy to answer any questions regarding that.
spk03: Great. Thank you. That's a lot of detail. It's really helpful. The only follow-up I had was just curious how long you'll be able to follow patients in the study.
spk09: Yeah, so the initial assessment of efficacy and safety will be, as I mentioned, at three months. But the study will follow closely the subjects for a full year and then intermittent follow-up over the next four years. So we will follow the subjects for at least five years following the dosing.
spk02: Excellent. Thank you. Our next question will come from Raju Prasad with William Blair. Please go ahead.
spk06: Thanks for taking the question. On the Phase 1 trial for 399, did you mention the potential to redose and how will that determination be made?
spk09: Yeah, Carson, I can answer that if you like. It's a very good question. Redosing of gene therapy or dosing of gene therapy is – primarily related to whether there are neutralizing antibodies present. So anywhere from 20 to 50% of people have neutralizing antibodies to AAV, and they are generally not eligible for gene therapy. So we have a guidance. So redosing, the eligibility for redosing would be based on the level of neutralizing antibodies at the time when redosing was going to be done. And we think that that's a regulatory endpoint which will be defensible. In the 399 study, with the 0.3 mg per kg dose, we had antibodies at 30 days that were at the level that would allow redosing. By 90 days, as you'll recall, the neutralizing antibody levels rose. And that's the same thing we have found in animal studies. In animal studies, when we gave three doses of mTOR, we were able to suppress antibody production at 90 days and beyond. And so that's why we think that giving three doses of mTOR will allow us to suppress antibodies long-term. And it's why the FDA agreed that we should give three doses of mTOR in the MMA trial. I don't know if that answers your question, Roger, if you have a follow-up.
spk06: Yeah, no, that's helpful. Is there a plan to go to ages below two years in the trial at any point? Obviously, another MMA program is put on clinical hold for two cases of TMA in younger patients, but I'm just kind of curious to hear your thoughts there as well.
spk09: Yes, that's also a very good observation. We know that As the adverse effect profile gets filled out both for gene therapies as well as particular indications. So each gene therapy is not just related to the vector that's given, it's also the underlying disease. And, of course, given the two cases that LogicBio announced of TMA and That's very concerning, and it's why we're taking the approach of treating first adolescents, then children. And then, of course, in the future, the goal would be to extend therapy to children less than two years old. But by that time, we'll have a lot more data on the efficacy and safety of our dosing. The other thing is, you know, our dose of AV8 is lower than Logic Bio. And what we've seen so far with both hepatotoxicity as well as TMA, that it's the higher doses of gene therapy, you know, approaching or going over 1E14, which is a log higher than where we're starting, is where most of the problems have been, the major problems have been seen.
spk06: Great. Thanks, Peter. And then you mentioned, Carson, in the prepared comments and the press release on the DISSOLVE-2 trial being kind of impacted by the conflict in Russia, or sorry, in Ukraine. But how many patients in the DISSOLVE-1 trial were enrolled at those sites? And are there any potential complications on follow-up there. Just kind of curious to hear the, the impact kind of to the program overall. Thanks.
spk10: Yeah, that's a great question. And I'm going to give that to Peter. He's going to get all the difficult questions today.
spk09: Yeah. Thank you. Yeah. That's a very good question. And just to review, um, The Dissolve 1 and 2 trials are identical Phase 3 trials with a primary endpoint at six months. The only difference between the two is that Dissolve 1 has a six-month treatment extension period, so the total treatment period is 12 months. The Dissolve 1 study is U.S. only. and enrolled, already completed enrollment, as Karsten mentioned, of 112 subjects by last November. and we will have top-line data by the end of the year. So there's nothing in the Russia-Ukraine situation that will affect the completion of subjects in the DISSOLVE-1 trial. The DISSOLVE-2 trial, which has not yet completed enrollment but still has a six-month endpoint, has several European sites, including Russia and Ukraine. The disruption of our clinical programs, of course, due to the Russian invasion, is an industry-wide problem. Our main issues have been operations disruptions, such as the resupply of drugs and other supplies, the lack of in-country personnel, limited communication, payment uncertainty, and interruption of patient visits. And we're closely working with our CRO Paracel to address and while maintaining the safety of the personnel and patients. We have four active sites in Russia and three active sites in Ukraine, representing about 12% of the total number of sites in our study. And that's kind of representative of many other companies' clinical trials. We've temporarily closed the Russian and Ukrainian sites to patient screening and enrollment of new patients so that we can focus on conserving resources and supplies to complete the already enrolled subjects. And given the very fluid situation, at this time we don't have an estimate of what percentages or numbers of subjects we'll be able to complete. We have undertaken a couple of really key mitigation measures. As Karsten mentioned, we've added 11 study sites to the DISSOLVE trial, all in the United States, and nine of those have already been activated, and the final two will be activated this month. And second, we've requested a meeting with the FDA to discuss the statistical handling of subjects enrolled in Russia and Ukraine. should they not be able to complete the study due to the war. This will be important to our understanding whether additional subjects need to be enrolled in the trial to maintain study power and so forth. While our guidance right now is top line data for Dissolve 2 in addition to Dissolve 1 by the end of the year, we continue to assess our continued assessment of the status of the enrolled subjects in Russia and Ukraine, our consultation with the FDA. And the performance of our newly added sites will be monitored and we'll update guidance as the situation is clarified. At the present time, it's a little hard to project while we have all these different moving parts. Thanks.
spk02: Our next question will come from Gail Bloom with Needham. Please go ahead.
spk11: Hey, this is Chen for Gail. Thank you for taking our question. I just want to ask if you have observed any developed immunity against the Pabchin and or previously? Generated immunity to what? I'm sorry. Oh, generated immunity against the pack chain in mTOR. The packaging? The pack chain, P-E-G chain in the particles.
spk09: I'm not sure.
spk11: Sorry, polyethylene particle chains in the particles. Yeah. Yeah, because there is percolation in a particle. So is there any developed immunity against that?
spk09: Yes, OK. Yeah, that's a good question because there is PEG attached to the mTOR particle. And no, we have not identified specific antibody generation against the nanoparticle-associated PEG. Now, there is the enzyme, Pegadricase, is also heavily pegylated. But the antibodies that we've seen that have been generated to agaricase is more to the protein epitope rather than the pegylation. With Cristexa pegyloticase, that uricase, the antibodies have been generated to the pegylated portion, but that's not what we've seen with pegagricase. Thank you.
spk02: Sure. Our next question will come from Yan Zhang with BTIG. Please go ahead.
spk04: Hi. Thank you for taking the question. So the first one is on MMA program. Can you remind us the origin of the MMA 101 capsid? Was it derived from some type of wild type capsid, please?
spk09: Yes, it's an ABA vaccine.
spk04: A vaccine, okay. So, yeah, just to kind of follow up on the TMA observation from another study, I know that you're in combination with mTOR to deal with the immunogenicity, but any lessons that you can potentially learn from that observation, and do you think you have – sufficient medication already incorporated in the study to prevent any potential immunogenicity-related side effects?
spk10: Yeah, obviously, we were building on the learnings that we have with mTOR, and one of the Potential benefits is that, you know, we're addressing the immunogenicity of the AV capsid. But, you know, we have extensive experience within TOR in the GAU trial where we've demonstrated we prevent the formation of ADAs. And then we have, you know, indication from TOR. the 399 trial, the empty capsid, that we prevent the formation of NAPs, and that's really what we're building on our assumption, and that's how we discussed with the FDA, and they were comfortable that this is a very interesting approach, which could be actually transformational for the field if we're able to prevent the formation of NAPs. Ultimately, we dose and address many of the secondary issues, such as the high doses and toxicity associated with the high doses. We've also demonstrated, at least in animal models, that IMTA also has hepatoprotective properties as well, probably related to autophagy, but obviously we'll have to see in the actual trial. But we feel comfortable that we, and the FDA, most importantly, is comfortable that we have a safe setup here.
spk04: Okay. So with the decision to deprioritize OTC deficiency program, does that mean that in the long term, enzymatic therapy and also autoimmune diseases could potentially be more interesting or more promising direction for the company? And did you say that the combination of mTOR and IO2, and the combination also has activity or potential use in gene therapy as well?
spk10: Yeah, so I think pausing the OTC program is really giving the market backdrop. We're very cautious on how we spend our money. We're not saying we're discontinuing the program. We're pausing it for now, which leads to obviously cost savings, and we put our efforts behind the MMA program. This is not an indication that we're less excited about gene therapy, but we think the deployment of capital is the most efficient in focusing on the MMA program for now. We obviously also have a number of partnerships, growing partnerships, most recently with Takeda. So we see a lot of potential use of mTOR in gene therapy, not only mTOR but also with SORG. And you're right, we have generated very compelling data with mTOR-IL, so the combination of mTOR with an IL-2 receptor agonist in a mouse model of AV gene therapy where we demonstrated Basically, complete control of NAVs after two AV doses at a quarter of the dose of mTOR, which would usually be a subtherapeutic dose. So we definitely see application also in gene therapy down the line.
spk04: Okay, great. Thank you very much.
spk02: Thank you, Ian. Our next question comes from Uyir with Mizuho. Please go ahead.
spk01: Hey, guys. Thanks for taking my question. Just going back to the trial design for SEL302, I wasn't sure if I heard correctly. In the protocol, is there anything for redosing, I guess, at the end of the first three months if you don't see efficacy in the patients?
spk09: Yes, no. In this protocol, there's no provision for redosing. during the first three months or within a year. Redosing is going to depend on the level of efficacy of the gene therapy and how long it lasts and so forth. The FDA was very interested in that possibility and opened the door for us coming back to them at any point in time if we see results that would allow redosing, but there's nothing in the protocol.
spk01: Okay. So even after three months, after the assessment, I guess what you seem to be saying is that you could go back to the FDA and retreat the patients. Is that correct?
spk09: Yes. So in our discussions with the FDA, they left that open for us to return to talk to them about that. They didn't want to approve that a priori, but they were very open for us to come back and discuss that.
spk01: Okay, thanks. And I guess the second question I have is on Dissolve2. I'm just wondering, like, what was the targeted number of patients that were expected to enroll in Ukraine and Russia? And how many patients have been, I guess, treated and have completed treatment? If you can share that.
spk09: Yeah, we haven't disclosed exact numbers of patients per country or how many were enrolled and so forth. And the situation is quite fluid. We've enrolled a certain number of subjects in Ukraine and Russia. And we're not certain at this point. We will over the next month or so. understand how many of those are going to be complete and valuable. So we haven't disclosed the exact number. What I will say is that the total number of projected payments for Russia and Ukraine was nearing the capacity that we had initially set up. So we did have a targeted number for those countries as well as other countries, and it was reaching that target. So now the key thing is where are each of those subjects in the six-month treatment, and can we complete them? And that's a very fluid situation.
spk01: With, do you think that, I mean, it's kind of hard to assess now, I guess, as you indicated, but based on the number of patients, I guess, that have completed, do you think that you would need to enroll additional patients? in order to not have it meaningfully change your, I guess, your statistics?
spk09: Yeah, that's what we're in the process of assessing. And, you know, the study was highly powered already. And as you know, it's a comparison of treatment versus placebo. And the treatment and placebo has basically a zero response rate. So it was high powered for a straightforward endpoint. But nevertheless, that's one of the reasons why we'll be talking to the FDA and trying to see how they would have us consider any subjects that do not complete in Ukraine and Russia and assess whether we change the The target for enrollment was already increased from 105 to 120 some time ago, and our target right now is still approximately 120.
spk01: Okay. Last question for, I guess, for Kevin. Kevin, yeah, could you sort of help us think about the quarterly cadence for the R&D spend? I guess the last two quarters have sort of been in the 20 millions and 20s. Would it be something similar, or do you sort of expect it to grow modestly over the year on a quarterly basis?
spk05: That's a great question. With the reprioritization of our spend, I wouldn't expect it to be markedly different going forward. Obviously, you know, we have paused one program, so we're reprioritizing our spend. and trying to optimize our cash resources for the highest value assets that we have. And, you know, I think that's probably a fair support.
spk01: Okay. All right. Thank you so much.
spk02: Again, if you have a question, please press star then 1. Our next question will come from Bubulan Pachiyapan. Please go ahead.
spk07: Hi. Can you hear me okay? Yes, thank you. Okay, great. A couple of questions from our end. So firstly, how do you envision the Ginkgo partnership to evolve over the next three to five years, and what would be the key indicators for success in this partnership?
spk10: Yeah, that's a great question. We have, as you know, two partnerships for two of our pillars. One is around the biologics where they're working on a second generation IgA protease. And there's obviously, you know, predefined milestones, you know, where they have to deliver certain advancements of the enzyme over time. The same is true for the AEV capsid as well. And obviously, the goal is to have clinical candidates as quickly as possible. But overall, as you can tell, the cadence of deals, we're quite excited about the partnership. We're in close collaboration with them on both programs.
spk07: Okay, helpful. And secondly, do you think there might be opportunities for mTOR to be combined with existing approved gene therapy drugs to make the safety profiles better? If so, which drugs would be most appropriate to assess from a combination regimen perspective?
spk10: Yeah, I mean, it's a great question. And obviously, with our portfolio with both Intor and Zork, we have the opportunity to address some of the unmet needs or some of the key unmet needs out of the marketplace. Obviously, right now, there are a limited number of gene therapies. But I mean, that's definitely a potential approach to leverage both Zork and Intor in the future.
spk02: All right. Thank you. Thank you. This concludes our question and answer portion of the call. I will now turn the call back to Selecto CEO, Carson Bruhn, for closing remarks. Carson?
spk10: Yeah, thank you, Operator, and thank you to everyone who joined us this morning for the numerous questions. Please stay safe and healthy, and this concludes today's call. Thank you.
spk02: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
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