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spk01: Thank you for holding. Good morning and welcome to the Passage Bio first quarter 2022 financial and operating results conference call. All participants are in a listen-only mode. Following the formal remarks, we will open the call for your questions. Please be advised this call is being recorded at the company's request. At this time, I'd like to turn the call over to Stuart Henderson, Vice President of Corporate Development and Investor Relations. Stuart, please proceed.
spk00: Thank you, Operator. This morning, we issued a press release that outlines the topics we plan to discuss today. This release is available on the Passage Bio website under the Press Releases and Statements section of Investors & News. On today's call, Bruce Goldsmith, President and Chief Executive Officer, will review our first quarter 2022 and recent business highlights, and Simona King, our Chief Financial Officer, will review our first quarter 2022 financial results. Before we begin, please note that today's call may include a number of forward-looking statements, including but not limited to comments on our expectations about timing and execution of anticipated milestones, including the initiation of clinical trials and the availability of clinical data from such trials, our expectation about our collaborators' and partners' ability to execute key initiatives, the ability of our lead product candidates to treat their respective target CNS disorder, manufacturing plans and strategies, trends with respect to financial performance and cash flows, the company's ability to fund research and development programs, impact of the COVID-19 pandemic on the company's operations, and its ability to manage costs along with the uses of cash and other matters. These forward-looking statements are based on assumptions that are subject to risks and uncertainties that could cause the company's actual results to differ significantly from those suggested by these statements. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements. Please refer to the company's filings with the SEC for information concerning risk factors that could cause its actual results to differ materially from expectations, including any forward-looking statements made on this call. Except as required by law, the company disclaims any obligation to publicly update or revise any forward-looking statements to account for or reflect events or circumstances that occur after this call. It is now my pleasure to pass the call over to CEO, Bruce Goldsmith. Bruce?
spk03: Thanks, Stuart, and thank you all for joining us this morning. We continue to make considerable progress across our programs as we remain committed to our mission of developing transformative therapies for devastating CNS disorders with limited or no approved treatment options. Recent examples of this progress include positive interim safety, biomarker, and clinical efficacy data from cohort one of our IMAGINE-1 trial for GM1 gangliosidosis. Dosing of the first patient in cohort two and completion of dosing of cohort three in this IMAGINE-1 trial. Dosing of the first patient in cohort one of the GALAXY clinical trial for early infantile Crab A disease. Opening of additional clinical trial sites in the U.S. and Brazil for our UPLIFT-D trial for frontal temporal dementia, bringing our total current active sites to three. We have established a global network of trial sites across our three clinical programs with active sites in the United States, Brazil, Canada, UK, Israel, and the Netherlands. We are also thrilled to announce that we recently submitted an IND for a phase one trial of PBM-L04 in metachromatic leukodystrophy, a rare pediatric lysosomal storage disorder. This marks the achievement of another of our corporate goals and brings us closer to having a fourth program in clinical development. As we continue to advance our programs and mission, we have continued to evaluate our business needs and adapt accordingly. In March, we announced the strategic decision to focus our organizational priorities, reduce our operating expenses, and invest in programs that support our forward-looking plans by aligning our organization and foundational partnership with Penn's GTP, or gene therapy program, around a more focused R&D strategy. Key elements of this strategic prioritization include continued commitment to the advancement of our three ongoing clinical programs for GM1 gangliosidosis, Krabbe disease, and FTD. focusing of our preclinical pipeline with continued investment in our programs for MLD, ALS, and Huntington's disease, as well as our exploratory research programs for Alzheimer's disease and temporal lobe epilepsy. As a result, rights to our programs for Canavan disease, Charcot-Marie-Tooth type 2a, and Parkinson's disease have been returned to the University of Pennsylvania for future development by GTP or external parties. Through this prioritization, we have retained balance in our CNS portfolio with three rare pediatric programs, three rare adult programs, and two exploratory research programs in large adult indications. We also continue to retain eight additional license options for future CNS indications through our productive partnership with Penn's GTP. Operationally, we streamlined our organization via a 13% workforce reduction and have slowed investment in our pilot manufacturing suite. This strategic prioritization and associated reductions to our operating expenses extends our cash runway into the second quarter of 2024, and we believe we are well positioned to deliver on multiple value-creating clinical milestones over the next two years. I will now review the progress made across each of our three ongoing clinical programs. First, let me discuss our lead program, PBGMO1 for GM1 gangliosidosis. GM1 is a fatal neurological lysosomal storage disease caused by a GLB1 gene mutation that results in low activity of the beta-galactosidase enzyme. This leads to rapid neurological decline and in the most severe forms, unfortunately, to mortality within several years. Our IMAGINE 1 clinical trial focuses on the early and late infantile forms of GM1, which are the most severe forms of the disease. This global phase 1-2 trial is an open-label dose escalation study with PBGMO1 enrolling four distinct cohorts divided by age and dose level. As a reminder, our approach uses a next-generation proprietary AAVHU68 capsid administered via the cisterna magna to deliver a codon-optimized GLB1 transgene to increase beta-galactosidase enzyme activity in the brain and peripheral tissues. We were pleased to report positive interim safety biomarker and clinical efficacy data from cohort one at the World Symposium in February. These data showed that PVGMO1 was well-tolerated and had a positive safety profile with no serious adverse events and no complications related to ICM delivery. We demonstrated no evidence of DRG toxicity based on nerve conduction studies and substantially increased beta-galactositis enzyme activity in both CSF and serum after ICM delivery. As we have previously discussed, we believe improvement in milestones is a very important clinical outcome for children with lysosomal storage diseases. We are extremely pleased to see meaningful improvement in developmental milestones for these children, including the regaining of lost milestones. Our IMAGINE 1 trial has experienced strong momentum. We have now dosed the first patient in the high-dose late infantile cohort 2 and have completed dosing of both patients in the low-dose early infantile cohort 3. We remain on track to report initial safety and biomarker data from each of these cohorts in the second half of 2022. We also look forward to sharing additional clinical data from Cohort 1 during a late-breaker oral presentation on Wednesday this week during the American Society of Gene and Cell Therapy 25th Annual Meeting. Moving on to our global PDKRF3 program in Krabbe disease called Galaxy, Krabbe disease is a condition that progresses rapidly, damaging both the brain and the peripheral nervous system and resulting in a life expectancy of only two years in the severe cases. Krabbe disease is a fatal neurological lysosomal storage disease caused by a GALC gene mutation that results in a decreased enzyme activity of galactosylcirimidase. Preclinical data supporting this program were recently published by our GTP colleagues in the journal Human Gene Therapy. These robust preclinical results reported marked improvements in both disease progression and key biomarkers in large and small animal models of Krabbe disease following a single administration of PBKR3 with no observed dose-limiting toxicities. Like GM1, this is also a pediatric leukodystrophy and lysosomal storage disease with an underserved population with a very devastating disease progression. Our approach is also similar, utilizing the same proprietary capsid and ICM delivery to potentially address both CNS and peripheral disease manifestations. GALX-C is an open-label dose escalation study of PBKR3 in patients with early infantile Krav-A disease. We have now opened four sites for recruiting globally, including in the United States, Canada, the Netherlands, and Israel. In March, we announced the dosing of the first patient in cohort one of our Galaxy clinical trial. As with all our trials, we are committed to patient safety and transparency, and in this spirit, we want to share that the first patient experienced a grade four adverse event. Following review of the safety data by the Independent Data Monitoring Committee, or IDMC, we are proceeding with the study. To review in a little detail, 26 days after dosing, the patient experienced a grade 4 adverse event of acute hydrocephalus, which is a buildup of the CSF in the brain. The patient underwent a procedure to manage this condition and has been stable post-procedure. Following an investigation, this adverse event was assessed to be possibly related to either study treatment or study procedures due to the temporal proximity of the adverse event to the administration of treatment. At the time of the event, there was no evidence of an inflammatory reaction to the AAV vector or transgene in blood or cerebral spinal fluid. However, the role of disease progression may also be a factor. Hydrocephalus has been reported in the literature in association with Krabbe disease, and baseline imaging showed evidence of changes in the ventricles of the brain that did progress following dosing in this patient. We have also noted that preliminary biomarker data showed rapid normalization of GALC activity and reduction of psychosine in both serum and CSF within 30 days. As I mentioned, patient safety is of the highest importance to us. We have been working closely with IDMC and external experts to gather further information and to advance the development of PBK-R03. We also notified health authorities and study investigators of this event. The IDMC has reviewed all available information and has recommended continuation of the clinical trial with specific modifications. These modifications include changes to the inclusion and exclusion criteria to limit potential risk of hydrocephalus and additional safety monitoring following administration of PBKR3. We are implementing these modifications expeditiously. In addition, we are increasing the number of subjects in cohort one from three to four per study protocol following this adverse event. We are actively recruiting patients for cohort one and look forward to reporting initial safety and biomarker data by the end of 2022. Our third clinical program, PBFTO2, is for frontal temporal dementia with granular mutations. FTD is a devastating form of early onset dementia affecting patients between the ages of 40 to 65. The form of the disease we are seeking to treat with our therapy is caused by a granulin or GRN gene mutation, which results in a deficiency of progranulin. It is estimated that about 5 to 10% of FTD is caused by a GRN mutation. We are utilizing the AAV1 capsid to deliver the GRN gene via ICM to the CSF. The goal of this treatment and delivery approach is to potentially provide higher than normal levels of progranulin protein to the CNS to overcome the progranulin deficiency in GRN gene mutation carriers. We plan to enroll two cohorts of three patients each, receiving two different ascending doses of PBFTO2, with an optional third cohort treated with a higher dose, depending on safety and biomarker results observed in the first two cohorts. We now have three active clinical trial sites, including two in the United States and one in Brazil, and activation efforts at additional sites continue. Patient identification also remains a key area of focus and continues to be a challenge to enrolling the initial patient on our study. We have been and continue to be working closely with referral centers and are employing strategies to improve the rate of the genetic testing among FTD patients. including sending testing kits free of charge to clinical sites and offering education on genetic testing. We believe these efforts, in addition to opening additional clinical trial sites, will improve patient recruitment, and we expect to dose the first patient in our FTD trial by mid-2022. Turning lastly to our program for metachromatic leukodystrophy, or MLD. Infantile MLD is a fatal inherited disease caused by mutations in the ARSA, or the aryl sulfatase A gene, which reduces enzyme activity. MLD is characterized by muscle weakness, rigidity, gait disorder, and developmental delays, and unfortunately, children typically die by the age of five. Worldwide incidence is approximately 1 in 100,000 live births. We are excited to have recently submitted an IND to FDA for a Phase 1-2 clinical trial of PBM-L04 in MLD, which we set out to accomplish by mid-2022. Following FDA review, we plan to provide more information about our clinical program. The study will utilize ICM administration to deliver an AAV HE68 capsid to express ARSA and hopefully address both the central nervous system and peripheral manifestations of this devastating disease. Preclinical data supporting this program will be presented in a poster from our GTP colleagues at the ASGCT meeting this week. We also look forward to sharing more about our clinical plans for this program in the future. Our clinical focus and mission are highlighted by the similarities across our GM1, CRABA, and MLD programs. All three indications are lysosomal storage disorders affecting children, and our approach to developing novel therapies for each of these programs utilizes a proprietary HU68 capsid and ICM delivery. With that, I will now turn the call over to Simona to review our financials.
spk09: Thank you, Bruce. Before reviewing our expenses for the quarter, I want to reiterate our strong cash position. As we reported in our press release this morning, we ended the quarter with approximately $267.1 million in cash, cash equivalents, and marketable securities, compared to $315.8 million as of December 31, 2021. Following our recent strategic prioritization and associated reduction in operating expenses, we expect these existing cash resources to fund operations into Q2 2024. R&D expenses were $26.2 million for the quarter ended March 31, 2022, compared to $25 million for the same quarter in 2021. The increase for the quarter was primarily due to a $5.1 million increase in clinical manufacturing expenses, a $1.6 million increase in clinical development and professional services expense, and a $1.1 million increase in facility and other expenses. These increases were partially offset by a $5.2 million decrease in research and development expenses associated with the PEN agreement, in a $1.4 million decrease in personnel-related expenses due to shared-based compensation modification expense incurred in the three months ended March 31, 2021, which was partially offset by an increase in headcount and severance-related expense. Acquired and processed R&D expenses for $1.5 million for the quarter ended March 31, 2022, in the same quarter in 2021. GMA expenses were $15.1 million for the quarter ended March 31, 2022, compared to $12.5 million for the same quarter in 2021. The increase for the quarter was primarily due to a $3.1 million increase in personnel-related and shared compensation expense due to an increase in employee headcount, as well as severance expenses incurred related to our workforce reduction. This was partially offset by a $0.5 million decrease in professional fees and other expenses. Net loss was $42.8 million for the quarter ended March 31, 2022, compared to $38.9 million for the same quarter in 2021. Let me now turn it back to Bruce for closing remarks.
spk03: Thank you, Simona. We are pleased with the work we have done in the first quarter of 2022 to kick off the year and we look forward to continued execution and clinical data readouts over the next several quarters. We expect to report initial data from cohorts two and three in our IMAGINE ONE clinical trial in the second half of 2022, and we expect to report initial safety and biomarker data from our GALAXY trial by the end of 2022. We expect to dose the first patient in our UPLIFT-D trial in mid-2022. Prior to taking your questions, I would like to thank the employees at Passage Bio for their dedication to our mission, as well as the talented group at the Gene Therapy Program for continued partnership and support. Additionally, the executive team at Passage Bio would like to sincerely thank the key stakeholders that share and support us to develop and bring transformative therapies to patients with devastating CNS disorders. With that, I would like to open the call for your questions. Operator?
spk01: We will now take any questions that you have. If you have a question, please press star 1 on your phone. If you would like to cancel your question, please press the pound key. Our first question comes from Madhu Kumar with Goldman Sachs.
spk05: Hey, everyone. Thanks for taking our questions. So I guess first on the Crab A hydrocephalus event, how should we think about kind of the distinction between drug versus procedure-related on the procedure-related piece? How much of that could relate to kind of the other clinical programs that rely upon ICM injection? And I'll have a follow-up.
spk03: Yeah. Thanks very much for the question. And it is a great one. You know, we did see on imaging prior to dosing when we went to further review this, we did see some imaging evidence of changes in the ventricles of the brain prior to dosing, and that may be related to the disease progression, and those changes did get progressively worse after dosing. So that's one link that suggests that it might be disease-related, although the root cause is extremely difficult to tease out, which is why we're continuing to assess all of this and talking to imaging experts, which we've done, and we've consulted with the IDMC. We've also gone back and obviously looked at the totality of the reported data around ICM. We found, I think we've said this before, but at the World Lysosomal Conference, there were 21 patients in other programs that had been treated with ICM with no reported events, and certainly in our program with GM1 in the first cohort, we had not seen these events So, you know, it's going to be very difficult to tell, but we wanted to make sure that we were very transparent because the adverse event, because of the temporal proximity to the administration, was thought to be possibly related either to study treatment or study procedures. And, again, we're not aware of any reports of hydrocephalus following ICM in the literature or any public presentations. So, you know, we basically... have gone back and looked. There's also no evidence of inflammation in the blood or CSF, for example. So we just want to be extremely cautious going forward, and so what we're going to do is implement additional screening such as this imaging, as well as follow-up monitoring. By protocol, the patient stays locally for 30 days, and we'll just be implementing additional monitoring in that 30-day period, especially, to make sure that there's no evidence of this repeating. So, again, it's difficult to ascribe the causality, as you probably know, in some of these circumstances, but we're just going to be continually be extremely cautious. And we don't think right now it has any relation to the other studies, but we're obviously monitoring this carefully.
spk05: Okay, and then kind of following up on GM1, I guess, obviously, the presentation at ASGCT on Wednesday, what are kind of the key kind of outcomes measures you would say people should be kind of looking out for in that presentation on Wednesday? Kind of anything you can speak to about what we should be looking for from Wednesday's morning's presentation.
spk03: Yeah, absolutely. And thanks. We're really excited about the late-breaker presentation on Wednesday that is going to be delivered by Dr. David Weinstein, who is the clinical leader for the program. So we will be presenting essentially updated data. So when we look back at the timelines for the first patient, it was dosed in March of last year, and the second patient was dosed in September. So we'll have the follow-ups that are aligned with those dates, so 12 months and six months, and we look forward to looking at biomarkers as well as obviously the more important is the clinical data and obviously any updates on safety.
spk05: And I can squeeze in one last one. How do you think about the kind of recruiting dynamics for the GM1 program given the recent discontinuation of the competitor program in this space? Is there the chance to kind of accelerate development by going after sites that they were pursuing previously?
spk03: Yes, and it's obviously unfortunate to see any potential therapeutic for this unmet medical need leave the developmental universe. It's a very, very challenging thing for the community. But to that point, I think we're certainly open to collaborate. It was a single center, which obviously is not a trivial center. It's Dr. Cynthia Tift at the NIH. And we're certainly happy to coordinate with her on any future patients that might be enrolled. The rate-limiting step right now is that the FDA has asked us to have an interval of 60 days in between patients, and what we said previously is as we gather enough information, we'll try to go back to the agency and decrease that interval, and that would certainly help accelerate the accrual. So we now have, I think, seven or eight sites that are open globally, We're obviously in touch with, you know, various sites around the world, including Dr. Tift, you know, if there are patients identified to bring them into our study and certainly happy to do that.
spk05: Excellent. Thanks so much, everybody.
spk01: Thank you. Our next question comes from Tessa Romero with JP Morgan.
spk06: Hey, guys. Good morning. So just on the crab A disease update on the A reported, Just to clarify, has the IDMC given you the go-ahead to proceed with dosing here? And then how is the inclusion-exclusion criteria changing? And are you able to identify patients that are more at risk for hydrocephalus? And if so, how do you do that? And then I have one follow-up.
spk03: Sure, Tessa. Thanks very much for the question. So one of the things that we have gone through in the last several weeks is had a number of conversations with with the IDMC, which culminated in a data review just last week, and they did agree that we should move forward with recruiting. So to answer the question, yes, we are moving forward in that. I also note that we did notify the health authorities within seven days, and we've shared other information as as it became available and that has to do with subsequent reports after the initial submission. So we've been extremely engaged with the IDMC and the health authorities. I just want to be clear that we do need to revise our clinical trial protocol and the informed consent to incorporate the IDMC's recommendation and we expect this to be completed soon because obviously we've been working on this as we've interacted with the IDMC. And what we need to do then is submit the revisions to the RRBs and regulatory authorities and ask them to work as expeditiously as possible given that, you know, patients with crab A disease progress rapidly. we're recruiting and we will enroll as quickly as possible. And it is possible, of course, to go, you know, if there's a patient waiting to try to use that information to expedite enrollment. And so we'll update you as we move forward. I think that's the answer to your first question. The second question, so I mentioned in my previous answer that there were baseline imaging showing changes in the ventricles of the brain of this child that retrospectively, when we went back and asked imaging experts and experts in the disease, could have been a signal, for example, of a potential CSF distribution and clearing. which is, of course, the buildup of CSF and the pressures is the acute hydrocephalus. So that's one of the things that we're going to be looking for is those types of imaging studies and careful analysis as a way of screening out patients that may have an increased risk of developing hydrocephalus. And obviously, we have to watch that going forward to see if that's indeed the result. It is The other thing we've discussed is this is a little bit tricky because we have an N of 1 and we don't fully understand the possible linkage to either disease or to study treatment or procedures, so we just have to look at the totality of the data going forward. But hopefully this is a very rare if a singular event that this screening implementation will remove.
spk06: Okay. All right. Given that you guys are reiterating kind of the guidance to have data by the end of the year, it sounds like you still think that you can meet kind of dosing of those four patients and kind of getting data by the end of the year.
spk03: Yeah, it's a great question, and I think the way we thought about this is we're certainly hopeful to have the full cohort of four patients, but what we've committed to is reporting initial biomarker and safety data from the cohort. Now, We want to be transparent that the number of patients included in that interim readout will obviously depend on the cadence of patient recruitment and enrollment throughout the year. So we do want to put data out, as we promised, and we don't want to change that guidance. So we will commit to that, but now that we're moving from three to four, we'll have to see the totality of the patients that we can put out and, of course, the duration of the follow-up we can include in that update.
spk06: Okay, got it. Thanks so much for taking our questions.
spk01: Thanks, Tessa. Our next question comes from Nina Berrito, Gargoyle City.
spk02: Hey, guys. Thanks for taking the question. I'm just curious on PBFT 02, you know, at this point, I guess, if you're thinking about making any changes to the inclusion criteria, maybe to be a little bit broader, just to help accelerate enrollment there. And then I'm also just curious about whether you're hearing anything from the investigators at the sites that you have opened about, you know, maybe other clinical trials and kind of how they're thinking about allocating patients to other trials versus your study. Thanks.
spk03: Thanks, Nina. So, yes, we actually did change the inclusion criteria late last year, and then it was updated at the sites, I think, either in the fourth quarter or into the first quarter of this year for exactly that purpose. And our clinical leader, in consultation with external experts, had thought about both the CDR score as well as other potential entry criteria that we could broaden And we did do that, and we're hoping that that will follow through with potential impacts of enrollment. But I think you've highlighted the single most challenging issue, which is not necessarily competitive studies that are ongoing now, although that is certainly part of it, because I think the other studies that have been opened previously essentially found the pre-identified patients with GRN mutations that were available and had enrolled those patients, not only at our study sites, but other study sites. So the challenge that our investigators are reporting is that very few of the patients, in the order of 1 in 10 or thereabouts, are pre-genotyped. And we've heard this from other companies as well, that the genotyping in adult disorders, in particular these disorders, with FDD has been challenging. And so what we've done is really focusing on patient ID in terms of genetic testing as well as consultation. And we're, for example, sending free kits, et cetera, to those clinical sites. So it has been a challenge because I think the The investigators are reporting that the number of patients that are, quote, in the queue are quite low, and that's what we need to continue to increase.
spk02: Okay, got it. So you're not having, like, a high screen scale rate or anything like that. It's essentially just that, yeah, there's not enough patients in the queue.
spk03: Yeah, that and also, you know, the formal term of screen failure, and we've talked about this a little bit in the GM1 and Krabbe disease setting as well, is that patients aren't even getting to screening because they, you know, the formal screening is that they've enrolled and then they've somehow failed. And we have a very low screen failure rate because essentially physicians are not bringing them into the study or they're not pre-identified with having the appropriate genetic mutation. So that's the issue, is that there aren't even enough patients that are being identified to fill the queue.
spk02: Got it. That's helpful. Thank you.
spk01: Our next question comes from Jan Werber with Cowan.
spk07: Hi, this is Brendan on For Your Own. Thanks, guys, for taking the questions. First, I have another one actually on Krabbe. So, I mean, given the updated screening criteria, and honestly, thanks for all the color here. It's super helpful. But do you really have any sense maybe from historical CRABE data or what you know so far as to maybe how common some of the symptomatology is in terms of hydrocephalus and the risk for it? And, you know, maybe how it might potentially narrow the field of patients you could enroll? And I guess in that same vein, is it something that you're, are these protocol updates something that you're potentially considering as applying to the other pediatric liquid dystrophy studies, and is that something that you think is necessary?
spk03: Thanks, Brendan. They're great questions, as they all are. So there are case reports of acute hydrocephaly in patients with Crab A disease. I don't think that there's a universal consensus on what the potential incidence is. I do think You know, this goes to catching patients early in the disease course before any of these kind of issues, you know, potentially arise. So that's one of the things that we're trying to do is obviously think about having patients come in that are early in the disease course, and that's one of the reasons we're moving to patients that are one to four months old at some point when we get past this first cohort, as well as in GM1 going into early diagnosis. So, you know, it's not a, it doesn't appear to be a prevalent finding because there are only small studies of case reports. And certainly we're going to, you know, look at any case reports and any other leukodystrophies such as metachromatic leukodystrophy or GM1, but so far it does not appear to to have the same issues, but obviously we'll be looking at that and adjusting the protocol if medically indicated. At this time, we do not have any reason to do that as far as we can tell from the discussions internally, but I will say that all of these reports are basically shared across the organization, obviously, and as appropriate with the IDMC to make sure that we're being as careful as possible.
spk07: Okay, great. I actually just have one quick follow-up on MLD actually there. You know, I'm assuming this is something that would potentially get up and running either later this year or maybe next year, but wanted to see what you might be able to share with us in terms of, you know, trial design, if you'll be stratifying by age group here as well, really just anything you can tell us about the clinical plan. Thanks.
spk03: Yeah, Brandon, thanks very much. So what we've done in the past is once we go through the IND process and get regulatory agreement on the final trial design, then we will talk further about this. And we've done this before where, in fact, the FDA has asked for small adjustments, and we'd rather not go out there and then have to change the trial design and re-explain things based on regulatory feedback, which is completely appropriate. So what we've committed to is essentially after we get through the IND process, coming back to the external group, not only yourselves, but also our partners in the advocacy organizations and share the complete trial design, not only in terms of the entry criteria, but also, you know, potentially the timelines which we hope to initiate the study.
spk07: All right, great. Super helpful, guys. Thank you.
spk01: Thank you. Our next question comes from Laura Chico with Woodbush Securities.
spk04: Good morning. This is Sam on for Laura. Thanks for taking the question. We have one on GM1. Could you remind us about the criteria for expanding the dosing cohorts in IMAGINE1? I believe the current protocol allows you to expand cohorts two and four by six subjects each. Just wondering what the gating factors are for cohort expansion. Thanks.
spk03: Hi, Sam. Thanks very much. So, yeah, those cohorts, after we finish the dose escalation cohorts and get to a high dose in both the early infantile and separately, I should say, the late-onset infantile. We plan to use those expansion cohorts as potential registration strategies in terms of a cohort that will meet the requirements for a potential biological license application or BLA in the U.S. and application in Europe. So, the way we're thinking about this is once we complete the high-dose cohorts and gather enough information, we'd like to go back to the regulatory authorities and get a consensus on what those expansion cohorts would look like and what the endpoints are, et cetera, in order to support a BLA. We have not put down a timeline for that at this point. but certainly will update along the way this year and give a better sense of when we expect to go to the FDA in a measured way. What we want to do is not jump the gun and we want to gather enough information based on our dose escalation cohorts to have a solid view of what a expansion cohort and therefore be a pathway to BLA would be. And we're certainly excited about the increase in clinical milestones et cetera, that we've seen as a basis for those conversations, but we're not quite ready to lay out the timelines yet.
spk04: Okay, thanks very much.
spk01: Our next question comes from Danielle Krill of Raymond James.
spk10: Hi, guys. Good morning. Thanks so much for the questions. I guess first, I'm curious how many patients have been screened with the genetic tests that you've been providing, and if any of those had GRN mutations. Just kind of wondering if it's possible that the prevalence of FTD-GRN is lower than previously thought. And then, also curious if there's anything gating to adding more sites or activating more sites. Thank you.
spk03: Male Speaker 1 Yeah, thanks very much for the question. So, we haven't gone into the details of testing and GRN positivity at this point. We are just continuing to move forward on both of those criteria as well as I will say expanding in two different ways. One is we've reached out to a number of centers that we have tracked using claims data in which we know that there are patients with FTD that have been diagnosed, and we're trying to create referral patterns for those centers that may not be involved in clinical studies but certainly have a group of patients. Now, the issue there, again, is that those patients are typically not genotypes because if you're not looking for a clinical study, there's really no reason. So it's a two- or three-step process there to build that market and dynamic for clinical studies. One is identifying those sites and interest. The second is getting sites, test kits, and testing. And the third is then getting those patients potentially referred to treatment centers. So it's a heavier lift, but that's certainly something that we've committed to and are working on. And then the last part is, yeah, we are looking to open more sites, and the gating items really are just logistics and operational. It's not any idiosyncratic issues. It's basically getting the sites, contracts, and off the ground. We are focusing on the primary three sites that we now have open. We opened two in the last quarter or so, and now we're looking at the second wave of opening sites. So just to wrap it together, you know, we don't know the point estimate of prevalence or incidence right now of GRN positivity. And I don't think, you know, I think that the quoted number of 3,000 to 6,000 patients of prevalence in the United States living with GRN positivity, FTD, is an estimate based on some papers that were published, but I don't think we know exactly what the number is, and that's certainly something as we get more testing, as we gather more information, we'll certainly revisit. It's a great question, and I guess we'll have to say stay tuned as the market develops.
spk10: Great. Thanks so much for the clarity.
spk01: Our next question comes from Yoon Zong with BTIG.
spk08: Hi, good morning. This is Shu for Wing. Thank you very much for taking our question. Just to follow up from the GM1 registration study, just have a set of questions. So if you continue to see very strong positive data in high-dose cohort from GM1, so for Then you go back to the FDA. So you think the expense in cold form might serve as a people to study. Is that correct?
spk03: Thanks, Xu. We're certainly hopeful that that's the case, and we base that on the precedent, for example, for Zolgensma in an SMA, which did get a full approval with post-marketing commitments based on clinical data which is the ability to lift and control a head unassisted, you know, a single clinical value, for example, with supportive data. There are examples of biochemical pathways getting approved, but we think, given your reference of the clinical signs that we've seen, that's the pathway that we're certainly interested in pursuing.
spk08: Thank you. So I have another question about the data readout timeline for the cohort 2-3 for GM1. So you mentioned you're going to report safety and biomarker data this year, but should we also expect functional data? Because you dose your first, you dose the patient in both high-dose cohort, late infantile and early infantile, low-dose cohort in February. So we should probably have six-month or nine-month data by year-end. And if we follow the progress in timeline, the low-dose cohort for late infantile, it seems like we might see some functional improvement after three or six months, and particularly for, like, the early infantile patients who have pretty aggressive disease progression. Do you think it should allow us to find earlier detection of efficacy signals?
spk03: Sure, that's a fantastic question, and it actually follows what we did last year. So last year when we presented the initial data, we wanted a minimum follow-up of the last patient of 60 days, but we did have longer data for the first patient dose because of the time difference of first and second dosing. So what we always have committed to is a minimal amount of data of the 60-day biomarker and safety information. But you're absolutely right that, you know, we're certainly looking at the timing of all of the data releases and longer follow-up perhaps on the patients that are initially dosed. So we're not committing to any specific data release. But once we actually put out the first data, what we've also said is we will update the rest of the data incrementally. So even if we start with biochemical and safety data, then we'll update again later in the year. So just like we're doing that with GM1 Cohort 1. So it's a great question. We have not mapped out every data release, but we certainly know that clinical milestones and developmental progression is really key to fitting not only what the therapeutic can do for patients, but also your first question, which is how do we approach the FDA? So great question, and stay tuned, but we're very excited about that possibility. Thank you very much. Thank you.
spk01: And I'm showing no further questions at this time. Ladies and gentlemen, thank you for participating in today's conference. This does conclude your program, and you may now disconnect. Everyone have a great day.
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