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spk05: Good morning, and welcome to the Selecta Biosciences first quarter 2022 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.
spk06: Thank you and good morning. Welcome to our first quarter 2022 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 quarterly report on form 10Q for the quarter ended March 31st, 2022, which will be filed today with the Securities and Exchange Commission or SEC. Joining me today are Carson Bruin, President and Chief Executive Officer, Peter Traber, Chief Medical Officer, and Kate Kishimoto, Chief Scientific 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 our quarterly report on Form 10Q. Your caution is not to place undue reliance on these forward-looking statements, which speak only as of today, May 5, 2022, and select a disclaims any obligation to update such statements, even if management's views change. I would now like to turn the call over to Carson. Carson?
spk03: Good morning. I appreciate everyone taking the time to join us today. Despite geopolitical turbulence, macroeconomic volatility, and sector-specific headwinds, we believe Selecta's proactive approach to managing risk, which included opening additional SEL212 clinical trial sites in the US in the face of heightened geopolitical instability, Prioritizing our product portfolio to manage our resources and raising additional capital ensures that Selecta can build on the exciting progress made in 2021 and realize the full potential of our leading precision tolerance platform. We continue to make steady progress across our proprietary pipeline, as well as deliver on several key strategic and financial milestones. Most notably, We recently announced that the clinical hold on SEL302, our wholly-owned gene therapy candidate for medic malonic acidemia, or MMA, was lifted on March 9th, and we successfully completed an underwritten offering in April, which raised approximately $38.7 million in cross proceeds. With our focused wholly-owned portfolio and financial runway into mid-2024, We believe Selecta is well-positioned to execute on our clinical stage assets in biologics and gene therapies, advance our proprietary I2G protease Zork into the clinic, complete our I2A protease clinical candidate selection for a program and accelerate the development of IMTO-IL, our next-generation antigen-specific precision immune tolerance platform. We're incredibly excited to advance our IMTO platform and bring hope to the over 24 million Americans suffering from autoimmune diseases daily. Our sharpened strategic approach has allowed us to support and accelerate the development of our wholly-owned pipeline with a focus on autogenic therapies for autoimmune diseases and therapeutic biologics, as well as provide transformative solutions for our gene therapy partners to unlock the true potential of adeno-associated virus or AV gene therapies. I would now like to walk you through key updates and recent strategic partnerships pertaining to the three pillars of our pipeline. The current standard of care for autoimmune diseases utilizes immunosuppressive drugs, which are associated with side effects that often leave patients vulnerable to serious infection and malignancies or treatments that provide only symptomatic relief. Our approach is to reimagine the treatment paradigm for autoimmune disease by using our precision immune tolerance platform to restore natural immune system balance by inducing and expanding Anderson-specific regulatory T cells, thus avoiding the need for systemic immune suppression or chronic symptom masking treatments. Recent preclinical data generated by our scientific team showed synergistic activity when mTOR was combined with engineered IL-2 molecules that are selective for Tregs. This combination, which we call IMTR-IL, shows a substantial increase in antigen-specific Tregs when co-administered with a target antigen well beyond what we see with IMTR alone, in which we already have observed clinically meaningful benefits. We tested IMTR-IL for the ability to induce durable immune tolerance to a co-administered AV gene therapy vector in mice. We observed complete inhibition of anti-ADB antibody formation after multiple doses of gene therapy through 117 days. Most excitingly, this effect was observed and will be considered subtherapeutic doses for mTOR alone. These results suggest that this combination of a T-REX selective IL-2 with mTOR has the potential to increase the potency durability, and efficacy of the antigen-specific immune tolerance that mTOR elicits. Current programs of engineered Treg-selective IL-2 molecules focus on a generalized expansion of total existing Tregs, but not Treg-specific for the autoantigens responsible for the pathogenesis of autoimmune diseases. Thus, we believe mTOR-IL has the potential to be a truly differentiated first-in-class antigen-specific immunotherapy for autoimmune disease that restores immune system balance in vivo. We believe that our ability to induce antigen-specific T-Rex in vivo is potentially the most elegant solution to the intractable problem of restoring balance to the immune system. Further, we believe mTOR-IL represents a transformative evolution of our precision immune tolerance platform with implications across all three pillars of our pipeline, in particular, the potential to create breakthrough therapies for the treatment of autoimmune disease. A key priority for Selecta in 2022 will be to accelerate the development of a proprietary engineered IL-2 molecule. We have partnered with Cyrus Biotechnology, a world-leading protein engineering company spun out of David Baker's lab, at the University of Washington to speed the development of a next generation, highly differentiated IL-2 mutine to combine with mTOR. We believe our mTOR platform is ideally suited to address primary bilayer cholangitis, or PBC, a T-cell liver disease driven by a well-defined antigen. In PBC, the immune system mistakenly attacks tissue in the liver and damages the small bile ducts. Treatments to help slow the progression and prevent complication of PBC are available. However, these medications ultimately fail to control PBC, and patients often require a liver transplant. As shown in animal models of liver injury and inflammation, the ability of mTOR to target the liver coupled with the expansion of antigen-specific Tregs when co-administered with IL-2 suggests that mTOR-IL may be beneficial in the treatment of patients with PBC. We are continuing IND and APN studies for this program. In parallel, we are evaluating additional targets and indications that be well-suited for our first-in-class antigen-specific immunotherapy, and we'll update the market as we add indications to our pipeline in autoimmune disease. Moving on to our work in gene therapy, we believe Selector, with a combination of Intor and our proprietary ITG protease Zork, has the potential to solve some of the most difficult challenges facing the AAV gene therapy field. Patients who have preexisting antibodies against the capsids due to prior natural exposure to the AAV virus are often ineligible for treatment. Additionally, the anti-capsid immune response prevents the ability to re-administer AAV vectors. As a result, gene therapies are considered one-time only treatments. Currently, 30 to 70% of the patient population for gene therapy trials are ineligible for inclusion due to preexisting utilizing anti-AEV antibodies, which are a result of natural infections. Thus, many patients in need are unable to access potentially life-altering therapies for which there may be few or no treatment alternatives. IgG proteases have shown promise as a pretreatment to translate clear preexisting neutralizing antibodies and create a window during which AV gene therapies could be administered. However, IgG proteases are derived from bacteria and are themselves highly immunogenic. Additionally, some IgG proteases are derived from a common human pathogen, and consequently, the vast majority of individuals have preexisting antibodies against these proteases. Zork, our proprietary ITG protease candidate that is designed to specifically cleave human ITG, is derived from non-human pathogen and will observe low cross-reactivity to pre-existing anti-ITG protease antibodies. We believe that the combination of Zork with mTOR could enable repeat dosing of this enzyme therapy. This combination of Zork and mTOR has the potential to simultaneously address two of the biggest issues currently limiting AAV gene therapy, XORC 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 novel immune responses to AAV gene therapy and enable redosing. We believe that the combination of XORC and IMTOR has the potential to provide safer and more effective gene therapies to more patients and truly unlock the potential of the gene therapy modality by transforming a treatment into a durable, long-term cure. Preclinical studies suggest multiple potential benefits of mTOR in AV gene therapy, including increased transient expression in the first dose, mitigation of hepatic inflammation, more durable transient expression, and inhibition of capsid-specific B and T cell responses. We are proud to have multiple presentations, both independently and in partnership with AskBio, at the upcoming annual meeting of the American Society of Gene and Cell Therapy, or ASGCT, this month. Our presentations will highlight the ability of mTOR and mTOR-IL to mitigate anti-AEV antibodies and enable repeat vector dosing. In a single-dose clinical study in Healthy Human Volunteers, conducted in partnership with AskBio, we observed the ability of mTOR to mitigate the formation of anti-AV neutralizing antibodies out to 30 days, and our preclinical data in mice and non-human primates suggest that control of antibodies can be maintained with two additional doses of mTOR. Another major challenge for the genotherapy field relates to the serious toxicities associated with vector doses of 1E14VG per kigs or higher. Solving this problem will likely require a multi-pronged approach, including engineering more efficient capsids. The ability to redose AV vectors could provide a complementary strategy by enabling the administration of multiple lower doses of capsids. We would like to see the dosing paradigm for AV gene therapy change from one and done to low and slow. By giving multiple lower doses of a gene therapy, we could potentially titrate up to the intended therapeutic level while avoiding the unfortunate adverse events that have been seen at high doses of gene therapies. Initial studies in mice suggested mTOR-L has the potential to mitigate anti-AV antibody responses at high vector doses up to 5E13 VG per kicks. We're also excited about our collaboration with Ginkgo Bioworks 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 Ginkgo's cell engineering and high throughput screening capabilities, and Selector's mTOR precision immune tolerance platform to advance gene therapy delivery. By combining mTOR with more efficient capsids, we could potentially reduce the dose of gene therapy needed to see therapeutic benefit and further mitigate the risk of serious adverse events associated with high vector doses. Moving on to our wholly owned gene therapy asset, SEL302. On March 9th, the FDA cleared the IND application for our phase one gene therapy clinical trial of SEL302, a combination of mTOR with MMA101 being developed for the treatment of MMA, a rare metabolic disease in which the body cannot break down certain proteins and fats. The trial is expected to initiate in the second half of 2022 and will evaluate the safety and efficacy of SEL302 and the mitigation of neutralizing antibodies against the MMA101 AV capsid. We are hopeful that the phase one trial of SEL302 will build on the growing body of evidence supporting the potentially multifaceted benefits of mTOR for enhancing the efficacy and safety of AV gene therapies and the learnings from our MTAV8 capsid study in healthy volunteers. We believe development of a wholly owned asset in MMA will provide an important regulatory and clinical blueprint for our leading gene therapy partners, including Takeda, Cerepsa, and Aspile. We are seeing excellent progress across our gene therapy platform, and we look forward to continuing to progress in TOR in our wholly owned gene therapy programs. To maximize the full potential of our platform, we plan to actively pursue business development and out licensing opportunities for both mTOR and ZORG for gene therapy applications. Lastly, I want to provide an update on our biologics pipeline, which houses our most mature program. SEL212 has served as an important clinical validation for a precision immune tolerance platform with over 450 patients' dose to date. 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 that 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 mTOR, co-administer with the proprietary urocase, Pegatocase, for the treatment of chronic refractory gout and was licensed to Swedish Orphan Bivitrum, or 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, 0.1 mgs per gig, and 0.15 mgs per gig, and one dose of the Gatricase, 0.2 mgs per gig. The original enrollment target for both studies was 105 subjects. On December 1st, 2021, we closed enrollment in 112 subjects for Dissolve-1, which is being conducted in the United States. Dissolve 2 enrollment is continuing at pace and is being conducted in four countries across Eastern Europe and the United States. We have proactively undertaken steps to prioritize the safety of our patients and investigators, as well as mitigate any potential disruptions due to the evolving geopolitical situation in Ukraine and Russia. Firstly, we have temporarily suspended screening and randomization for new patients in both Russia and Ukraine. and have reserved existing clinical trial supplies in these countries for those already involved in the study. Secondly, to mitigate the risk of any delays, we proactively added 11 additional sites in the United States to offset the potential loss of subjects in Ukraine and Russia and speed enrollment in DISSOLVE-2. We now have 55 active sites and are on track to complete the study in Q4 2022. Finally, in agreement with our partner SOBI, we have increased enrollment in DISSOLVE-2 to approximately 140 subjects in an effort to replace subjects enrolled in Russia and Ukraine who may be lost to operational issues. We anticipate that these mitigation efforts will see us complete both DISSOLVE studies in Q4 2022 with joint top-line data available in Q1 2023. We will continue to work closely with our partner SOBI our clinical trial providers, and regulatory authorities to ensure the successful completion of the DISSOLVE program. With extensive clinical data and SEL212 currently in phase three, we believe our biologics pipeline is mechanistically de-risked and Selecta 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 IgA protein deposits, the underlying pathophysiology of the disease. We believe our novel approach, which combines mTOR with an IgA1 protease, has the potential to remove injurious IgA from the kidneys, improve markers of renal dysfunction, and have a transformative impact on patients' lives. We're currently working with IGEN Biosciences on the first-generation IgA protease derived from the Haemophilus influenzae bacteria. Additionally, in October 2021, we entered a collaboration with Ginkgo Bioworks to generate a second-generation IgA protease designed to have lower immunogenicity and, when combined with mTOR, have a potentially transformative therapeutic profile. We plan to finalize clinical candidate selection by the end of the year. We're extremely excited about the advancements across all three pillars of our pipeline and the value driving milestones ahead. With that, I will turn the call over to Kevin to run through our financial results for the first quarter ended March 31st, 2022. Kevin.
spk06: Thank you, Karsten. During the first quarter, we proactively took several steps to further bolster our balance sheet. We prioritized our wholly owned portfolio to conserve resources restructured our loan agreement to defer principal payments for an additional 12 months. And most notably, on April 6th, we priced an underwritten equity offering, raising approximately 38.7 million before fees and expenses. As a result of these initiatives, we announced approximately 154 million in cash, cash equivalents, investments, and restricted cash on hand as of April 11th, 2022. We believe our current liquidity will be sufficient to meet our operating requirements into mid-2024. Selecta enters the second quarter of 2022 with a strengthened cash balance that we believe will allow us to execute on our priorities despite geopolitical uncertainty, macroeconomic volatility, and biotechnology specific headwinds. We have multiple clinical readouts and IND filings anticipated within our cash runway, and we will continue to be careful stewards of stockholders' capital and execute our strategic plans expeditiously. Reviewing our financial results in the quarter ended March 31st, 2022, net cash used in operating activities was $11.9 million for the first quarter of 2022 as compared to $12.1 million in the same period in 2021. Collaboration and license revenue recognized was $34 million for the first quarter of 2022 as compared to $11.1 million for the same period in 2021. Revenue was primarily driven by the shipment of clinical supply and the reimbursement of costs incurred for the Phase III dissolved clinical program under the license agreement with SOBE. Research and development expenses were $17.7 million for the first quarter of 2022 as compared to $13 million for the same period in 2021. The increase in cost was primarily the result of expenses incurred for the preclinical programs, salaries, contract license, and milestone payments. General administrative expenses were $5.5 million for the first quarter of 2022 as compared to $5.2 million for the same period in 2021. The increase in cost was primarily the result of an increase in stock compensation expense. For the first quarter of 2022, Selecta reported net income of $28.8 million for basic net income per share of 23 cents compared to net loss of 24.6 million or 22 cents per share for the same period in 2021. I will now turn it back to Carson for closing remarks. Carson.
spk03: Thank you, Kevin. In summary, we're pleased with their progress in Q1 2022. With the financial runway into mid 2024, We believe Selecta is positioned to reach potentially transformation inflection points across all three pillars of our pipeline. Most notably, we are excited by our plans to enter the clinic with SEL 302, complete the DISSOLVE program with our partner Sobe, advance IND labeling studies across our wholly-owned pipeline, support our numerous collaboration partners, and rapidly progress our next-generation precision immune tolerance technology, IMTO-IL, into the clinic. We believe IMTO-IL could represent a generation leap forward for the IMTO platform. The strong genetic effects we've seen in our preclinical work support our belief that IMTO-IL has the potential to unlock first-in-class antigen-specific immunotherapies for autoimmune disease, as well as improve the efficacy and safety profile of therapies in biologics and gene therapy. We will continue to deliver on our unrelenting commitment to solving the hardest challenges in autoimmune disease and help patients overcome autoimmunity and immunogenicity through our evolving mTOR precision tolerance platform. Before we conclude today's call, I would also like to thank the entire Selecta 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.
spk05: 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 2. At this time, we will pause momentarily to assemble our roster. Our first question will come from John Newman with Canaccord. Please go ahead.
spk09: Hi, gentlemen. Good morning, and thanks for taking my question. You know, I had a question about the work you're doing with IL-2. Really interesting here. What I'm wondering is you've got a proprietary IL-2 program running here with Cyrus. I'm wondering, when you take mTOR into the clinic in combination with IL-2, do you think you'll be taking it into the clinic with your proprietary IL-2, or might you investigate mTOR on its own first with unavailable formulation? Thanks.
spk03: Hey, John. It's a good question. So as you rightly said, we are working with Cyrus to develop a proprietary IL-2 mutine and plan to take it into the clinic with that IL-2. Having said that, I mean, there are other IL-2s in clinical development, and there's always a chance to look at those as well. But for now, the plan is to take the combination with the IL-2 from Cyrus into the clinic first. We believe that the data we have at least demonstrated so far combining mTOR with IL-2 in the mouse studies where we see really a profound increase both in induction and expansion of Tregs will be really meaningful in autoimmune disease. The other piece which we're excited about is that this not only limits us to autoimmune disease, but we're also really encouraged by the data we have seen in gene therapy, where the combination actually was dose sparing, which is very encouraging. We also see a potential application combining it with biologics as well.
spk09: Okay, great. I just had one additional question, if I may. You've also got some interesting work going on with your IgG protease. And I know that this is a bit early, but just curious as to how you might like to study that in the clinic once you get there. Just wondering if you'd look at antibodies against gene therapy vectors or if there are some other things that you'd like to evaluate that you think would be more meaningful. Thanks.
spk03: Yeah, that's a great question. Peter answer this, but just to kind of frame it up for everyone. So our proprietary ITG protease is from a non-human pathogen so that we haven't seen any cross-reactivity human sera, which we believe is a major advantage. And there are multiple applications, but the one we're most excited about is as a pretreatment for patients that had a prior AED infection are not eligible for gene therapy. And Peter, maybe you can elaborate. Well, we haven't really guided the detail, but, you know, how we might look at this from a proof of concept.
spk11: Yes. Thank you, Karsten. Hi, John. The ability to test the IgG protease in healthy volunteers, we think, is a real advantage because there is a an incidence of AAV antibodies in the population. So we think that we would start with a healthy volunteer study to look at the abrogation of AAV antibodies in that population. That would set up the potential for looking at multiple different gene therapies with pretreatment with Zork. So we think that the initial clinical development is relatively straightforward in that way. Of course, then we are looking for either with our proprietary MMA program or OTCD potentially, we're looking for, or other programs, looking for those programs where we could then test it clinically with a specific chemotherapy. But the first relatively straightforward approach is to look at antibodies.
spk09: Okay, great. Thank you.
spk05: Our next question will come from Rick Miller with Cantor Fitzgerald. Please go ahead.
spk00: Hi, good morning. This is actually Kristen. Sorry about that. Wanted to ask just based on the abstracts that were published for the ASGCT conference earlier this week, and I know the presentations are very near term here, but could you talk about from a high level the questions you're looking to really answer with some of these studies that you haven't reported on yet? And it looks like you had some promising effects on inhibiting AAVRH32 IgG antibodies versus methotrexate. And you're looking at different capsids and routes of administration. So essentially, how might some of these studies that you plan on presenting on help shape future directions of mTOR for gene therapy, either by you or a partner?
spk03: Yeah, hey, Chris, that's a great, great question. And actually, I let the man who actually conducted the studies speak to it, since we have Kay on the call. Kay.
spk10: Hi, Kristen. Yeah, we have a lot of really interesting presentations at ASGCT, both our own and also ones that we are presenting with our partner, AskBio. So the study you referred to with the AAVRH32.33 capsid was actually being presented by our colleagues at SBILE. And it's a very interesting study because although in humans it's often seen that you get this increase in capsid-specific CD8 T cells, That hasn't been so much noted in animal models. But with the exception of this one capsid, which has been previously published by the Wilson Group to induce capsid-specific CD8s. So, in this study, the Aspile Group used mTOR and also compared it to a multi-dose regimen of methotrexate. The results are really pretty impressive that mTOR inhibited capsid-specific CD8 T cells as well as the anti-AV antibodies as expected, whereas methotrexate really had pretty marginal effects. The other abstracts that we're presenting relate to kind of getting to being able to redose AV. So as you know, we had the humans healthy volunteer study that we also did with AskBio. And we have previously reported on that and the finding that we could inhibit neutralizing antibodies out through 30 days with mTOR, with a single dose of mTOR in healthy volunteers. Our preclinical studies in both mice and non-human primates indicate that by giving additional monthly doses of mTOR, we can sustain that inhibition. In addition, as Carson was alluding to earlier, I think one of the aspirations that we have, and I think really the whole field, is mitigation of these high dose vector toxicities. Of course, one aspect is to engineer more efficient capsids or transgene cassettes. And certainly, we're working with our partner, Ginkgo, on better capsids. But we also feel like by changing the paradigm from dosing one and done to being able to do multiple doses or slow and low would be a significant benefit. instead of giving one large vector dose, if we could give multiple smaller doses. So we present in two different posters, one combining mTOR with IL-2, so mTOR-IL, and the second combining mTOR with an anti-BAF agent. We show that we can inhibit antibody formation to capsid doses as high as five times 10 to the 13th VG per kg. And to our knowledge, no one has been able to mitigate antibody formation at such high vector doses.
spk00: Okay, thank you for that. Looking forward to the presentations in a couple weeks here. And then just on mTOR IL, I know, you know, you're doing a lot of work here and you're extremely excited about the potential, but could you maybe share for us some of the work you're doing to at least narrow down some of the potential indications you might look to start with here? Thanks again for taking the questions.
spk03: Yeah, that's a great question. So, we actually have started with an area we know really well, which is in gene therapy, and that's what Kate just referenced. We're extremely excited with the results we see there. We have guided to PBC as our lead indication, but we are working through a process right now to identify additional indications that are, you know, that have Treg mediated. We're looking at this, you know, both from a scientific perspective, you know, where do you have a high chance of technical success, looking at available data. I mean, there is some data available already from phase one and some phase two from other companies that pursue IL-2s in autoimmune disease. That definitely, you know, helps to guide as well. And we'll likely guide to another indication this year or a range of indications that we might potentially pursue. So it's really a combination of, you know, what's a good proof of concept where there's clear biomarkers. We think there's a high chance of technical success balanced with commercial potential, of course, as well. So I think that's kind of where we are right now. We're conducting additional studies right now in animal models in autoimmune disease, which are always a bit lengthier, and you can expect for us to share some of this data as they come in.
spk05: Our next question will come from Yun Zhang with BTIG. Please go ahead.
spk08: Hi. Thanks very much for taking the question. So it's a follow-up question about mTOR IL. It's very interesting data, and you showed there seems to be a big difference between the combination and mTOR alone. And also, you said you are going to explore potential use in gene therapy as well, not just the autoimmune disease. But I guess you're not going to use mTOR IL in the planned MMA study and at what point and in which way do you think you will be introducing mTOR IL into gene therapy programs and is that going to be more likely your own gene therapy program or more for potential partnership discussions?
spk03: That's a great question. As you know, mTOR alone induces antispecific T-Rex, whereas IL-2s alone only expand pre-existing T-Rex, and really the combination, you get the best of both worlds. You get an induction and expansion of antispecific T-Rex, which really is differentiated. We see really the main application in autoimmune disease where we want to you know, tip the balance between T-effector cells and Tregs, and that's what we're really excited about. But you're right, we're also, you know, seeing this being used in gene therapy, but we will not at least initially include this in MMA. I mean, in the MMA program, we're testing in TOR based on the, you know, pretty compelling data we've generated in the anti-capsid study. I mean, there's always a chance to amend this IND and add intra-L down the line, but at least for now, we're really focused on getting the study started in the second half of this year. But it's definitely something that we continue to explore further to really fine-tune the treatment paradigm in gene therapy.
spk08: Then a quick follow-up, if I may. So you mentioned the next generation IO2 in the press release, and with that next generation, are you able to comment what exactly are you trying to achieve or what kind of improvement as compared to the current version?
spk03: Yeah, so we haven't exactly guided to our approach, but I think we've been pretty clear we're working with a leading protein engineering company, Cyrus. They come out of David Baker's lab in Seattle. Obviously, we're trying to optimize the Treg specific component and not have any effects on T-effector cells. There are multiple approaches. If you look at the IL-2 field, from fusion proteins, mutines. There's various approaches, but we haven't guided the approach that we are taking for this program.
spk08: Okay, great.
spk05: Thank you very much. Our next question will come from Raju Prasad with William Blair. Please go ahead.
spk07: Thanks for taking the question. Just curious to know, kind of in your conversation with KOLs on the gene therapy side, with ASCT coming up, what the duration of effect is for gene therapy and the use of mTOR in the clinical setting. Thank you.
spk03: Yeah, that's a great question. And obviously, if you look at the data we have generated so far, is that in the human proof of concept study, with a single dose of mTOR, we're able to control NAP titers at day 30. We know from the animal studies that mTOR extends to half-life of AV capsids, so we see a rebound of the titers out to day 90, which is expected. We've seen this in non-group primates, but we've also shown that You know, once you control titers at day 30 to give two additional doses, actually, you are able to control the titers long-term. And we also believe that, you know, after day 90, there's no more capsid around, so no more antigen. So our hypothesis and speaking with KRLs but also the FDA, we believe that three-monthly doses actually is, you know, is a reasonable path to go, and that's how we approach it. in our MMA program where we plan to give three monthly doses of mTOR.
spk07: Great. And can you give us some color or context on the PBC model preclinically and how well that mimics the immune features of the disease and when we can expect data? Thank you.
spk03: Was it PBC?
spk07: Yeah.
spk03: Yeah, okay. Yeah, let Kay speak about the model. And Kay, you're on mute.
spk10: Sorry about that. Yeah, there's actually a couple of interesting models for PVC in that these are genetic models, so the disease is spontaneous. So you don't have to induce disease in these animals. So we think it's a more accurate reflection of natural disease. And certainly, they're pretty well established in this field.
spk05: Our next question will come from Mr. Oiir with Mizuho. Please go ahead.
spk01: Hi, guys, thanks for taking my questions. I guess my first question is on SEL212, just wondering if you need to consult with the FDA to increase the number of patients, and if that's the case, whether you have done so. And I guess my second question is sort of jumping ahead a little bit. Regarding the gene therapy phase one MMA study, Just wondering about how you will disclose the data. Will you do it either by patients, by cohort, or wait until the study completes? Thanks.
spk03: Thanks for your questions. I'll give the first question to Peter around how we have an increase of number of patients.
spk11: Yes, hi. Could you please repeat your question?
spk01: Sure. Just wanted to know whether you need to consult with the FDA to increase the number of patients in the Phase III gout study, and if you have, whether you have done so. And if I may, can I also add, you know, the top line data is now pushed out to first quarter of 2023 and just wondering if that's a result of the additional patients and additional clinical sites or is it something else as well? Thanks.
spk11: Yeah, sure. Yeah, we did consult with the FDA on the changes that we made to the protocol as well as we will handle the data from Russia and Ukraine. Some will be continuing discussion with the FDA. But the increase to 140 subjects is underway. The issue of the reporting in Q1 of both trials is related to the increase in the number of subjects to the trial. And as we report, we'll complete both trials this year, meaning last patient, last visit, will be completed this year. But because it'll be at the end of the year, it'll take a couple of months to lock the data
spk03: Thanks, Peter. And then your second question is around MMA. We will likely report patient by patient as we get results. We get the first results basically 90 days after we dose the first patient. So we'll likely report it patient by patient basis as the data comes
spk01: Okay, thank you.
spk05: Again, if you have a question, please press star then one. Our next question will come from Bubulan Pashiyappan with HC Wainwright. Please go ahead.
spk04: Hi, can you hear me okay?
spk09: Yes, thank you.
spk04: All right, great. So a couple of questions from our side. Firstly, with respect to MMA phase one trial, that's us. So do you plan to include patients with isolated MMA only or those with MMA plus high homocysteine levels and what would be a rationale for that?
spk11: I'll give this question to Peter. Yes, all the subjects in the trial will have null mutations and they have clinically severe disease.
spk04: Okay. So secondly, with respect to your dissolved data release, so your previous guidance for the top line was fourth quarter 2022. And per today's release, it's actually pushed to first quarter 2023. So just curious, is there an advantage of combining the data from both the trials and then releasing it in one first quarter 2023 versus, you know, releasing the dissolved one data in fourth quarter 2022, given that dissolved one enrollment was completed last year?
spk03: Yeah, it's a good question. I mean, as we have decided, so first of all, the good news is that we have clarity now on the timing. So And we've decided to increase the patient numbers to up to 140 in Dissolve 2. Both studies will read out by the end of this year in Q4. And we've decided to do a joint release, you know, because they're so close together, it is cleaner to report both pivotal studies at the same time.
spk04: Okay. Obviously, mTOR IL is pretty interesting. I think you have been hearing this a lot today. Just curious, can you comment on what kind of safety and tolerability characteristics you're looking for before initiation of your phase one?
spk03: Yeah, I think obviously we have a pretty good understanding of the safety and tolerability of mTOR. I mentioned it in the main call of over 450 patients' dose. We'll obviously do tox studies with our proprietary IL-2, but we see some indications from the phase one, phase two studies of the other IL-2 molecules, you know, which look pretty promising as well.
spk04: Okay, that's it from me. Thanks for taking my questions.
spk05: Our next question will come from Chang Lu with Neatham. Please go ahead.
spk02: Hey, this is your channel for Gail. Thank you for taking our questions. Our first question is, is there any near term update or potential milestone from select as partners?
spk03: Yeah, good question. We get a lot. We do have multiple partnerships. It's always difficult to guide but obviously, We've publicly disclosed that we are eligible to receive milestones of up to 80 million around clinical regulatory milestones from a partner SOBE. We haven't disclosed the exact timing, but obviously there's some important milestones coming up. We also have guided that Sarepsa, their option period, basically expires in June of this year. And there's basically three scenarios. One is they opt in. We have a fully negotiated commercial term sheet. The second is they discontinue the work, but there's also an option for them to extend the option period versus a pre-negotiated payment And there's potential other milestones and it's very difficult to guide as they come in. But I think what's important to note as well is that our cash guidance into MID24 doesn't include any of the milestone payments from any of the partnerships.
spk02: Thank you. So our second question is, So considering the higher activity of mTOR IL, so is there any logic of moving forward with mTOR in earlier programs such as autoimmune diseases like PBC or LGA nephropathy?
spk03: Yeah, that's a great question. I think what's important is that we see very good clinical activity with mTOR alone. I think that's very important. But we're clearly, especially in autoimmune disease, are especially excited about mTOR-L in the context where you have to, in autoimmune diseases, restore balance between T-effector and TREC. And we believe that mTOR-L is ideally suited to that. But we stay focused on the programs we use mTOR alone, such as SEL212 and MMA. But for autoimmune disease, specifically PBC, we will likely take mTOR-IL into the clinic in that indication. Great.
spk05: Thank you. This concludes our question and answer session. I would like to turn the conference back over to Carson Bruhn for any closing remarks.
spk03: Yeah, thank you, operator, and thank you to everyone who joined us this morning. Stay safe and healthy, and this concludes today's call. Thank you.
spk05: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
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