Passage Bio, Inc.

Good morning, and welcome to the Passage Bio fourth quarter and full year 2021 financial and operating results conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open up the call for your questions. Please be advised that this call is being recorded at the company's request. At this time, I'd like to turn the conference over to Stuart Henderson, Vice President of Investor Relations and Strategic Finance. Stuart, please proceed. Thank you.

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 PassageBio website under the Press Releases and Statements section of Investors and News. On today's call, Bruce Goldsmith, President and Chief Executive Officer, will review our recent and 2021 business highlights. Eliseo Salinas, our Chief Research and Development Officer, will review our pipeline programs, including the GM1 data recently presented at the World Symposium and and Simona King, our Chief Financial Officer, will review our fourth quarter and full year 2021 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 data from such trials, our expectations 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, impacts of the COVID-19 pandemic on the company's operations, and its ability to manage costs along with uses of cash and other matters. These forward-looking statements are based in 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. Accept 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?

Thanks, Stuart, and thank you all for joining us this morning. I would like to first reflect on the significant evolution of our company over the last year. During 2021, we advanced three programs into the clinic, reported our first inhuman data, and substantially grew our pipeline, enhanced our executive leadership team and board, and scaled our organization to support clinical and commercial success. We continue to be guided by our three strategic pillars, which are our strong partnership with the University of Pennsylvania's renowned gene therapy program, our broad and robust pipeline, and our dedicated manufacturing and analytics, Through our partnership with GTP, we are creating sustained value for our company as well as the patients we serve by employing a diversified pipeline strategy. As a result, we now have a robust and differentiated CNS pipeline that spans pediatric and adult as well as rare and large disorders. Today, we have a total of nine pipeline programs and two additional exploratory research programs. That leaves us with the option to license eight additional CNS programs from GTP. As our pipeline advances, our primary focus continues to be on the execution of our three lead programs. For our lead program, IMAGINE-1 for GM1 gangliosidosis, we were excited to recently share positive safety, biomarker, and clinical efficacy data from cohort one. Eliseo will review this interim data in more detail shortly, but in summary, For the low-dose late infantile cohort, we have observed a positive safety profile with no serious adverse events and no complications related to intercisterna magna or ICM delivery. There was also no evidence of dorsal root ganglia or DRG toxicity. The data showed functional transgene expression and meaningful gains in developmental milestones for both patients, including regaining lost milestones. With these early results, we are experiencing strong interest and momentum in our GM1 program. So much so, we recently reported that we have already achieved one of our key 2022 goals, which is the dosing of the first patients in cohorts two and three for the IMAGINE ONE trial. We expect to report interim safety and biomarker data for each cohort in the second half of 2022. Our focus for each of our clinical programs is selecting, in partnership with GTP, an optimal AAV Capsid expression cassette and delivery method, which is ICM for our first three clinical trials. The positive interim data reinforces our confidence as we advance our additional global trials for Crab A disease and frontal temporal dementia with granular mutations. We are also pleased with our progress in activating multiple clinical trial sites in multiple countries. Thus far, we have activated sites for our three clinical programs in the United States, Brazil, Canada, UK, and the Netherlands. We accomplished this despite the challenges we have faced related to COVID-19, and we continue to bring remaining sites for those programs online. In addition to advancing our clinical programs, we are also excited about progressing our robust and differentiated pipeline. As I mentioned, we have exercised options for nine programs from GTP, most recently adding programs for Canavan and Huntington's disease. We also have two ongoing exploratory research programs in Alzheimer's disease and temporal lobe epilepsy that we continue to advance. We also plan to submit an IND application for our MLD program in mid-2022. And we look forward to sharing additional data on our pipeline throughout the year, including its scientific meetings. In addition to our robust pipeline and strategic partnership with GTP, our third key strategic focus is manufacturing and analytics. We continue to invest in our manufacturing and CMC capabilities to ensure product supply from clinical development through commercialization in a capital-efficient manner. We currently have a dedicated GMP suite at Catalan for clinical product manufacturing. In mid-2021, we opened a PassageBio CMC research and development lab focused on analytics, process development, and clinical product testing. Since then, our team has made significant progress in developing and advancing differentiated analytics using the latest technologies and methodologies. At this time, we are now investing in a pilot manufacturing suite to add scale-up capabilities to support our R&D pipeline as well as future development plans. We expect that our pilot suite will be operational by year-end. Lastly, we ended the year in a strong cash position, which allows us to deliver on multiple value drivers throughout 2022 and 2023. We are pleased with our progress over the last year, and we look forward to an execution-focused and data-rich 2022 on our path to developing transformative therapies for patients with devastating CNS disorders with significant unmet need. With that, I will now turn it over to LSAO, who will discuss our clinical programs, including our recently presented data for GM1.

Thank you, Bruce. I will start by discussing our GM1 program. 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, a relative rapid death. Life expectancy for children with infantile GM1 ranges from 2 to 10 years. Also, after initially gaining milestones, children with late infantile onset typically plateau at 12 to 13 months of age, meaning that they stop gaining normal milestones before they regress. Patients with GM1 are a rare and underserved population. Currently, there are no disease-modifying treatments for the disorder. A more imagined one trial focuses on the early and late infantile forms of GM1, which are the most severe forms of the disease. The global Phase I-II trial is an open-label dose escalation study with PB-GMO1, enrolling four distinct cohorts divided by age and dose level. As a reminder, our approach uses a next-generation proprietary AVHU68 capsid administered via the cisterna magna to deliver a COVAM-optimized GLB1 transgene to increase beta-galactosidase enzyme activity in the brain and peripheral tissues. We recently shared positive interim safety, biomarker, and clinical efficacy data from Cohort 1. consisting of two late infantile patients treated with a low dose of PBGM-01. This interim data showed that PBGM-01 was well-treated and had a positive safety profile with no serious adverse events and no complications related to ICM delivery. Demonstrated also no evidence of DRG toxicity based on nerve conduction status, and substantially increased beta-galenzyme activity in both the CSF and serum after ICM delivery. In terms of clinical efficacy, we presented developmental milestone data using two standardized norm-referenced scales, the Bayley-3, a formal assessment tool used by trained healthcare providers, and the Vineland-2, a scale for caregiver assessment. Today, I will review assessment results for each patient. Patient one had a chronological age of 14 months and a developmental age of 12 months at baseline. It's important to know that for the Vineline, we were able to share up to nine-month assessment for this patient after dosing conducted by the healthcare provider. But that was not the case for the Bayley 3 assessment as the patient was not able to be scored due to a potential COVID-19 exposure. Let's review the Bayley assessment for patient 1 first. There was improvement in all developmental areas through the six months observed following administration of PBGMO1 gene therapy. Overall development age progressed consistently and tracked closely to chronological age. Divine line scale assessments at nine months documented that following PGM-01 administration, there was also improvement in all developmental areas for this patient, with notable progress in the domains of fine motor skills, receptive language, and interpersonal relationships. Overall, The development age for patient one progressed from 12 months at study start to 23 months at the nine-month interim assessment, approaching the patient's chronological age of 24 months. Turning to patient two, he got a severe developmental delay at baseline with a chronological age of 31 months and a developmental age of 13 months on the Vineland scale, and 7 months on the Bayley. For this patient, there was a single follow-up available at 3 months. Improvements in the Bayley assessment were documented in patient 2 in motor, receptive language, and cognitive domains. The overall development age progressed during the 3 months following administration of the product from 7 months at baseline to 9 months. For the Vineland assessment, significant improvements were also observed, notably in expressive language and interpersonal relationships, despite a severe developmental delay. The overall development age progressed from 13 months at baseline to 16 months at the three-month assessment following administration of PBGMO1. Importantly, patients who not only acquired new milestones, but also regained previously lost milestones, in particular, the ability to walk and to use specific words. In summary, we believe the increase in beta-galenzyme activity observed in both CSF and serum after ICM delivery are positive indicators that PBGMO1 is exerting a biological effect. We were also pleased to see meaningful improvements in development milestones for these children, including the regaining of those milestones. While we remain cautious in the context of an open-label study and a small number of patients, we are very encouraged by these initial reports of clinical improvement and about the potential of PBGMO1 for patients. We look forward to further follow up and continue with additional cohorts in the IMAGINE 1 study. As Bruce said, following this positive interim safety and biomarker data for Cohort 1, the IMAGINE 1 study has progressed to enroll additional cohorts. We are enrolling Cohort 2 with two late infantile GM1 patients receiving the high dose of PVGM1, and Cohort 3 with two early infantile GM1 patients receiving the low dose of PBGM01. Thus far, the first patient in each of these cohorts has been dosed. We look forward to being able to share initial safety and biomarker data for these two cohorts in the second half of 2022. Moving on now to our global PBKRO3 program in crabby disease called GALAX-C. 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 results from decreased enzyme activity of galactosylceramidase, or GALC. Like GM1, This is also a pediatric leukodystrophy and lysosomal storage disease with an underserved population with a very devastating disease progression. GALAXY is an open-label dose escalation study of PVK-RO3 in patients with early infantile Krabbe disease. PVK-RO3 uses the same proprietary AAVHU68 viral vector to deliver a functional GALC gene that codes for GALC. PBKRO3 will be delivered directly to the CSF by ICM delivery with the goal of increasing activity of the GALC enzyme in both the CNS and the peripheral nervous system. The study will run similarly to our IMAGINE1 trial, with the first cohort evaluating an initial dose of PBKRO3 in late-onset patients and then progress into early onset and high dose cohorts after an assessment of cohort one. Additionally, there will be a confirmatory expansion cohort for both age groups once the dose escalation phase of the study is completed. The main goal of the initial part of the study is to assess the safety and durability of ascending doses of PDKI or three in patients with early infantile crabby disease, as well to assess the impact on GAL-C in CSF and serum. We had the privilege of having the clinical trial designed for GAL-C as well as IMAGINE ONE presented at the World Symposium last month. We are grateful for the interest and support we are seeing from both the research and the patient advocacy community for our programs, and we look forward to soon those in the first patient in our GALAXY trial. Turning to our third clinical program, PVFTO2 for frontotemporal dementia with granuline mutation. 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 granuline, or GRN, gene mutation, which results in a deficiency of progranulin. It is estimated that five to 10% of all FTD is caused by a GRN mutation. In the most typical forms of FTD with GRN mutation, patients experience significant speech alterations and severe behavioral changes culminating in dementia. This is an underserved population with no disease-modifying therapies approved and an average survival of eight years after the onset of neurocognitive deterioration. Our global Phase I-II clinical trial, APLIFT-D, is an open-label dose escalation study of PVFTO2 in FTD-GRN patients. PVFTO2 uses an AAV1 viral vector to deliver a modified DNA encoding the granular gene to a patient's cell. Based on proclinical data, PVF-T02 has the potential to increase progranular levels to more than 50 times normal human levels. In the clinical study, the construct will be administered into the CSF by ICM delivery. The goal of this treatment and delivery approach is to potentially provide higher than normal levels of the 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 PVFTO2, with an optional third cohort treated with a higher dose, depending on safety and biomarker results observed in the first two cohorts. Like our other lead programs, our two key goals are to assess the safety and durability of ascending doses of PVF-T02, as well as its impact on progranular levels. We anticipate that we will be dosing our first patient soon. Turning now to our preclinical program for MLD or metachromatic leukodystrophy. Infantile MLD is a fatal inherited disease characterized by muscle weakness, rigidity, case disorder, and developmental delays. It is caused by a mutation in the ARSA, or the aryl sulfatase A gene, which reduces the enzyme activity. Children typically die by the age of five, and the worldwide prevalence is one in about 100,000 live births. As Bruce noted earlier, we plan to submit an IND for our MLD program by mid-year. Our approach here is very similar to our GM1 and Krav-E programs, where we are using a next-generation proprietary AAVHU68 capsid to deliver a functional ARSA gene via cistern amygdala injection. Advancing programs for CNS diseases requires tremendous support from a variety of stakeholders. I would like to conclude by recognizing and thanking the caregivers healthcare providers, advocacy organizations, and patients in these communities. With that, I will now turn the call over to Simona to review our financials.

Thank you, Eliseo. As we reported in our press release this morning, we ended the year with approximately $315.8 million in cash, cash equivalents, and marketable securities, compared to $304.8 million as of December 31st 2020. R&D expenses were $33 million and $117.7 million for the quarter and year ended December 31st, 2021, compared to $27.9 million and $81.8 million for the same quarter and year in 2020. The increase for the year was primarily due to a $19.7 million increase in personnel-related expenses including share-based compensation due to a higher employee headcount, an $18.7 million increase in clinical manufacturing expenses, a $10.9 million increase in clinical operations expenses to support the clinical trials for our clinical product candidates, and a $3.7 million increase in facility and other expenses. These increases were partially offset by a $2.5 million decrease in professional services and consulting expenses, and a $14.6 million decrease in research and development expenses with Penn, which relates to expenses incurred for preclinical work performed in preparation for IND filings for our clinical programs. Acquired and processed R&D expenses were $1 million and $8 million for the quarter and year ended December 31st, 2021, compared to $1 million for the quarter and year ended in 2020. The increase for the year was primarily due to an extension of the research collaboration and license agreement with Penn, additional option exercises, and the achievement of certain clinical milestones occurring in 2021. GNA expenses were $17.2 million and $60.1 million for the quarter and year ended December 31st, 2021. compared to $10.1 million and $30.1 million for the quarter and year ended in 2020. The increase for the year was primarily due to a $21.8 million increase in personnel related expenses, including share based compensation, resulting from an increase in employee headcount. Professional fees and other expenses also increased $8.2 million as we expanded our operations to support our research and development efforts and incurred expenses operating as a public company. Net loss was $51.2 million and $185.4 million for the quarter and year ended December 31st, 2021. compared to $38.9 million and $112.2 million for the quarter and year-ended in 2020. As we continue to advance our pipeline and invest in our capabilities, we are supported by the strength of our balance sheet. We expect our cash, cash equivalents, and marketable securities to fund our operations to year-end 2023. Let me now turn it back to Bruce for closing remarks.

Thank you, Simona. We look forward to continuing to deliver on multiple clinical and corporate milestones, including enrolling additional patients across our clinical studies and providing more data throughout 2022. Now with the first patient's dose in cohorts two and three for the GM1 trial, we expect to report interim data in the second half of 2022. Our patient engagement team also has built productive partnerships with the advocacy community, which has helped tremendously in raising awareness of our clinical trial programs. Our clinical operations team is executing well as we continue to open clinical trial sites around the globe. Our clinical pipeline is also expanding as we plan to file an IND in mid-2022 for MLD. We continue to invest in our in-house CMC capabilities, and we expect our pilot plan suite to be operational by year end. Before taking your questions, I'd like to thank the incredible Passage Bio team and Jim Wilson and his team at GTP for our many accomplishments over the last year. I'd also like to echo Eliseo by personally thanking the patients as well as the caregivers, healthcare professionals, scientists, and advocacy groups who share and support our mission of developing transformative therapies for devastating CNS disorders. With that, I would like to open the call up for questions. Operator?

Thank you. We will now take any questions you may have. If you have a question, please press star 1, and you'll be placed into the queue. If you would like to cancel your question, please press the pound key. Our first question comes from Tessa Romero with J.P. Morgan. Your line is now open.

Hey, guys. I hope everyone's doing well. Thanks for taking the question. I wanted to ask about the CRABE and SEB GRN studies. You've reiterated the guide now to dose the first patients in early 2022. Just curious, what underscores the conviction here of achieving this milestone for both trials? And have these patients been identified, screened, and or enrolled yet? And is there any queue of patients in either of the indications that's building? Thanks so much.

Hi, Tessa. Thanks so much for the question this morning. So we continue to do several things that are leading indicators of our progress. One is to continue to work through the site openings. We've obviously had challenges in the past doing that, and we are pleased that the CRABE study sites are continuing to open, and we believe that additional FTD sites will open in the coming weeks to months. So that's certainly areas of progress that we're very happy with, but we definitely recognize the challenge that we've had in moving the patients from identification into the studies. So we have not announced and we don't typically announce enrollment status, because for all of these programs, there is a significant amount of work for each patient, not only pre-identification, but once patients are enrolled, they have to go through a several-week screening process, which is typical for gene therapy programs, as well as for neurology programs, CNS programs. So what we will do is once a patient is dosed, make that first patient dose announcement. And we certainly hope to do that in the early part of this year. We do have an ongoing effort to identify patients across all of our studies. One of the things that we've pointed out in the frontal temporal dementia space is that while there are patients that are identified with FTD, because there have been no traditional treatments, the genetic genotyping to identify patients with GRN mutations hasn't traditionally been done. With the start of multiple studies, including our own, that is increasing. And we've also gone to sites where there are patient populations identified through various programs, such as the GENFE program and the AFTD database. So those are some of the areas that we're focused on. And then for CRAB-A, We're also replicating what we've done in the initial stages of the GM1 study for reaching out for both patient advocacy as well as patients that may be at those sites. The difference there is that, obviously, similar to GM1, the patients with Crab A disease do progress very, very quickly. So we have to move fast once we identify those patients and get them into the centers. So those are all the initiatives that we're working on. And we continue to make progress, and we certainly look forward to not only enrolling but dosing our first patients in both of those studies.

Okay. Thanks, Bruce, so much. And, yeah, thanks for the call. I appreciate it.

Thank you. Thank you. Our next question comes from Madhu Kumar with Goldman Sachs. Your line is open.

Good morning. This is Omari Ong from Madhu. So, for our first question, we're wondering how do you think about quantifying the clinical improvements observed in month four, the last patient described at world? And also, like, do you think these improvements could translate over into the early infantile cohort?

Thanks. I'm going to make an introductory comment and then turn it over to Eliseo. So, to your point, we're extremely happy for these two patients for the initial data. one with three-month follow-up and one with longer follow-up, up to nine months, that we've actually not only seen improvements in the milestones, but for patient two, for example, we saw restoration of previously gained milestones that had been lost. So really exciting. This is obviously early data and two patients. So maybe Alisao can add some comments about what what we interpret that to be and also how that may translate into the early infantile population.

Right. Regarding the first part of your question, the quantification, fortunately the Bayley in particular gives you a very precise quantification of the patient status. The Bayley has more than 300 items. and on the motor is more than 140. So very specific items that are assessed during the interview. Patient number one, at the Bailey, had a developmental age of 12 months and chronological age of 14. It was at the beginning of his plateauing. And that patient grew from 12 to 17 months. on the six months of observation period. So significant and quantifiable benefit. Patient two also on the Bayley, the clinician rated scale, was much more severely delayed with an overall developmental age of seven months for a baby with a chronological age of 31 months. And that patient also gained two months of developmental age in the three months of the treatment. And as I said, these are very specific. This is not an overall assessment, gestalt type of assessment. These are specific things that the child does or doesn't do during the interview. So, yeah, we are confident that those developmental milestones have been documented very clearly. Regarding extrapolation to early infantile, well, it's the same enzyme It's the same disease, and it's a more aggressive disease on the earlier infantile. So we can make promises, but we think that what we observe in these first two patients is a very reasonable basis to be cautiously optimistic about the rest of the study.

All right, thanks. And for the second question, what are the gating events for starting the FTD CREB-A trials?

So we have, yeah, thanks for the question. So we have the sites that can enroll in dose patients open. It's really getting those patients into the centers that have both the appropriate mutations as well as entry criteria and then enrolling them in screening. And the screening, as I said, does take, you know, quite some time to both establish the – there's a pre-screening when patients are initially identified at various centers. When they get actually to the site, then there is an on-site screening as well to confirm final eligibility. And then once they're there, all of the baseline assessments occur. So the real gating item is identifying those patients and getting them enrolled in the study. They're slightly different considerations for both. For the patients with Krabbe disease, similar to patients with GM1, it is a rapidly progressing disease. We're actually focusing on an earlier population than initial for GM1, and these patients, the Krabbe children, are four to nine months old. In the second part of the study, that will even go down to one month to four months because this is a very rapidly progressing disease. And some patients, with Krabbe disease and their families do opt for the potential for going for a stem cell transplant that's appropriate for patients that are not symptomatic and have a donor and are qualified for stem cell. So that is all of the considerations that go into the Krabbe disease patient population and moving those patients into the study. For frontal dementia, really it is having the patients identified and moving to the sites We have identified patients previously, and there unfortunately have been considerations that have precluded them from moving on to the study, such as comorbidities or, unfortunately, side effects that have occurred for their current interventions prior to actually enrolling in the study. So that's just a really challenging time for us to identify the patients and move them on to the study. So back to your earlier point, The real gating item is simply moving those patients to identification and enrollment.

All right. Thanks for answering our questions and the update. Thank you.

Thank you. Our next question comes from Nina Petrito. Garb, with Citi, your line is open.

Hey, guys. Thanks for taking my question. Just kind of a follow-up to some of the questions that were already asked around the FTD study. I know some of the sites that you're using, like you said, are associated with some of the major registries for FTD, and so I'm just curious, are some of the challenges that you're seeing with getting the patients actually into the study, do you think that those are kind of similar challenges that are being seen by other studies in FTD that are being run, or is there something unique here, I guess, in terms of the screening process that's maybe making it more difficult for patients to get enrolled in the study. Thanks.

Thank you for the question. Thanks for joining us this morning. It's a great question. What we've done over the last six to 12 months is really look at our protocol, other protocols, as well as feedback from our investigators. And we have adjusted the protocol, to your point, to make sure that we're as appropriately broad as possible while ensuring that we both the patients that we're treating as well as the therapeutic PBFTO2 has an opportunity to provide therapeutic benefit. And that's always the challenge, I think, for all studies, nothing unique to what we're trying to do. And so that is certainly one consideration. I think the other consideration that we've certainly seen is that as we've entered the program, we obviously have come on to the clinical development with two other companies enrolling, one gene therapy and obviously one of a much larger patient population looking at a phase three study for this sirtulin antibody. And what, you know, the challenge that presented is that the immediately available patients maybe 12 months ago were obviously, if possible, that is a viable alternative because there are no treatment opportunities. So what we're focusing on is really the patient population that was not addressed by those opportunities, or identifying new patients. I don't think there's anything idiosyncratic about our enrollment criteria or our process that we've seen or, in fact, gotten feedback from our various sites, but it is just the challenge, I think, of enrolling patients in this patient population where there is not typically a screening from a genetics perspective. That's why we, and just to go back one further step, that's why we and others are investing quite a bit of time and funding for genetic testing and for FTD awareness.

Got it. So just to clarify, when you say that you're looking kind of for a population that's not addressed by some of the other programs, that's not something necessarily built into the actual inclusion criteria, right? It's just patients that haven't been identified yet. So you have to do a little bit more work to kind of identify them first.

Correct. And just to clarify, it's not that we have entry criteria that's different or a different patient population. We wanted to make sure that we had as broad a population as feasible and appropriate for studying the therapeutics. So we looked at the other protocols and we discussed with investigators to make sure that we were as aligned as possible taking into consideration our own goals as well. But also the timing, I think, has just made it so that the population has changed because the available previously identified patients may have gone to other studies. So that's why we and others are focusing on the genotyping and identifying additional patients and moving those patients into therapy.

Okay, got it. Thank you.

Thank you.

Thank you. Our next question comes from Yaron Werber with Cowan. Your line is open.

Great. Thanks for taking my question. Bruce, I actually wanted to shift to MLB. You're going to be following the IMD public mid-year. I assume you're targeting the aerosulfapase A enzyme. Can you comment a little bit? What kind of an AV vector are you planning on using? I assume it's obviously going to be ICM. Are you going to be doing late infantile or early juvenile ICM? What kind of endpoint and how is the approval of MLD in Europe, admittedly sales and so far fairly small, impact enrollment? Thank you.

Thank you, Yaron. Yeah, great question and I appreciate it. And we're really excited about the potential of moving forward with MLD because of the synergy we have across the GM1 CRABE experience as well as the alignment with MLD. To your point, we are using the exact same capsid, which is HU68. Obviously, the synergy is with GM1 that is a lysosomal storage disease. In addition, it is ICM as well. So, you know, one of the things that we are certainly interested in is the GM1 program continues to develop as well as the Krav-A disease is that there's a lot of synergy both between the research and development ideas, and also, you know, the potential market to your second question. The way we're thinking about this is actually quite similar to the approach for Crab A disease. Lemeldi has had absolutely remarkable effects on patients with MLD. Obviously, that's a patient population there that takes stem cells ex vivo has gene therapy and then re-infused, and with myeloablation as well. So it has similarities to a stem cell approach for Krabbe disease in that there is a focus on patient population which are largely asymptomatic in MLD as well as Krabbe disease. So the way we're thinking about this is potentially moving earlier in the disease treatment for a pre-symptomatic or asymptomatic as well as potentially initial signs of those diseases, the disease for MLD. And most likely, we will also, we haven't gone into a lot of detail about MLD, but what we're thinking about is also going after an infantile population first, similar to GM1 and CRAV8, for initial clinical proof of concept. So, it's been some time since we brought forward the initial programs, but what we, prefer to do is have the discussions with FDA as we file the IND and then go into more details about the actual clinical protocol because, as you know, based on feedback from FDA, that can change over time. So that's the way we're thinking about it, is really just an alignment with where a lamellity may have benefit or may have benefit, obviously in Europe and in the U.S., and then treating patients that that doesn't quite meet or earlier in the patient population. Really excited about the IND and, again, the synergy between the various programs.

Thank you.

Thank you. Our next question comes from Devjit Chattopadhyay with Guggenheim. Your line is open.

Hey, good morning, and thank you for taking my question. So just to follow up on the MLD program, How should we think about reconstitution of glial cells and its implication for disease reversal versus the busulfan conditioning that's used for antiviral gene therapy?

Yeah, no, that's a great question. I'm going to ask Aliseo to jump in.

Okay, so, yeah, so we have a decent knowledge of the mechanism of action of LipMLD and how it achieves the clinical result that that we have seen. As you know, the approach with the transgene in our construct is completely different. It's orthogonal to that. And we believe it's more fundamental. So it's early. Soon we're going to have the publications, the proclinical publications showing a little bit more detail about your specific question in terms of glial intervention and participation on the mechanism of action. At this stage, what we can say is that it's a completely different approach that we believe is closer to the core of the side of the action and the disease.

Got it. That's helpful. And just a follow-up question on the FTD-GRN program. Could you help us think through where the starting dose could line up versus the GM1 program, given that you'll be treating adults? versus, you know, infantile patients?

Yeah, absolutely. So, in all of the programs, we dose based on anticipated or expected or projected brain weight in terms of genome copies per gram. So, the starting dose for FTD is 3.3E10 per estimated gram weight. For adults, the estimated gram weight of an adult brain is approximately 1.6 kilograms. Approximately, sorry. Yeah, okay. And pediatric patients, it depends on the age, but it's approximately between 800 grams and 1 kilogram, depending on the age. So in absolute genocopies, it may be double, but in the genocopy per gram, it's basically the same as the GM1 starting dose.

Appreciate it. Thank you so much, and good luck. Thank you.

Thank you. Our next question comes from Laura Chica with Redbush. Your line is open.

Good morning. Thank you for taking the question. I actually have two. So first, obviously, early days here for FTD and CREBA, but wondering how much should we read into whether screening complexities inform on a future addressable market? And then a question on capital allocation, R&D prioritization. What levers do you have available to extend cash runway beyond 23? And I guess kind of related to that, any comments you might be able to provide directly on how spend could change over that period? Thanks.

Yeah, Laura, thanks very much. I'm going to make a comment and then turn it over to Eliseo. So I think the entire field for frontal temporal dementia is actually increasing the amount of screening that's going on with the recognition that genotype is actually important in interventions. But up until Recently, there really haven't been a lot of studies involved in doing that. So there's certainly a lot of interest. And, for example, we attended the All-FTD study group meeting last fall, and there is an increase in the need for genotyping for C9R, for GRN, et cetera. It's really getting that message out there, and I think there are a number of companies trying to do that. So it's really just the, I think the, it's like a pediatric disease where there's not newborn screening. There's just a lot of efforts then in terms of getting those patients screened and the subtype identified. So it's really, it's not a, I think, read-through on the field. I think it's just that it's early days. So with that as introductory comments, LSAO, do you want to jump in as well? Yes, Laura.

So first, a statement of facts. We are very happy with the momentum on GM1, and we are disappointed with Cravea and FTD. But that shouldn't cloud the analysis of the facts. The INDs were approved in January and February last year. That's 14 months ago. In a trial like this one, you need two things, identify patients and open in size. But those are sequential. Before you open the size, identifying patients cannot result in enrollment. In the first seven months of those 14, we opened one site. In the second seven months, we opened 10 sites. Now we have six sites open in GM1, and the momentum is great. As you know, there are fewer GM1 patients than granuline FTD patients, and yet we're finding it very easily because those sites are open. In the FTD, we have one site, and soon, as Bruce said, there will be more open sites that will open up the gates to that funnel that we already initiated. So that's what we are now 100% focused on executing the opening of the site and continuing the patient identification that Bruce summarized. So that's why we are confident that both for CREP-A and FTD. For CREP-A, we have four sites open now. That's enough to open the gates to the patients available. So that's why we are confident that soon we'll have patients in both two studies.

And Laura, on your second question, yes, go ahead, please.

Great, thanks, Laura, for the question. Yeah, so let me start off addressing, I think, the first part of your question on capital allocation. So I think what's important to note, and you can see that in our historical financials as we broke down the program-specific expenses, by our three clinical programs spent, as well as MLD and the rest being other programs and discovery, so the other pen expenses. So when you look across those investments, it's very clear that a lot of our investment, about 85% of that, is really targeted towards the three clinical programs plus MLD. And within that, we don't break it down specifically around manufacturing and clinical operations, but that's inclusive of spend behind these two areas. And we expect that essentially to continue in terms of the focus from an overall investment on those lead programs. And then in terms of the other question on the cash runway, as we stated, we feel very confident that we can fund our operations until the end of 2023, but of course we can continue to focus on cash management and refine how we're investing behind not only our key programs, but there are other expenses that support the company's infrastructure and so forth. Generally, we do expect our cash burn to be relatively consistent with prior orders and continue to be within the range, as you've seen there, about $35 to $45 million per quarter.

Thanks very much.

Thank you. Our next question comes from Daniel Brillo with Raymond James. Your line is open.

Hey guys, this is Alex on for Danielle. Thanks for taking our question. Forgive me if you've already stated, I've got a granular question and then a zoomed out one. Has UPenn, with respect to the FDD program, has UPenn permitting, are they permitting elective procedures now as well as in-person screenings? And if so, could you comment on the cadence of the screening process if COVID is permitting an increased cadence in in-person screenings. And then to zoom out, have you seen any, you know, translating the GM1 world results, the increased patient enthusiasm for those results? Do you see, have you seen those translate to recruitment enthusiasm for your other FTD and CRAVE programs? Thanks so much.

Thanks very much for the question. So, In general, what we have seen is that the interrupt, and I'll go to your Penn question in particular, but in general, what we've seen is that most of the sites that we have been interacting with, the COVID restrictions are starting to lift. The elective surgery, you know, interruptions that we saw really intensely last summer and somewhat over the fall have also started to lift. So Penn, for example, was going through a hybrid on-site visit throughout the winter that is starting to lift as well. So to your point, we have had difficulty, especially patients with frontal temporal dementia, you know, that have both severe speech aphasia and emotional disturbances. Just on-site visits have been challenging, not particularly for us, but just we've heard from sites. So we do hope that that's going to help alleviate things and can has allowed, to our knowledge, elective procedures as well as freed up now on-site visits, those two things being very important for final assessments and moving forward with the ICM procedures. So great question and certainly been interrupted throughout the year. For the other question on GM1 and CRAVA, yes. So it's a great and important question. There hasn't been, I think, so much read-through necessarily on the frontal temporal dementia, although we've certainly talked to our physicians about this. And one of the pieces of feedback we've heard is certainly very positive that ICM is safe in the pediatric patients. We've also seen at World, I think, up to around 20 or just over 20 procedures using ICM across various studies have been reported with no safety effects. We've been communicating that message as well. And that helps, I think, from the frontal temporal dementia perspective, just knowing that ICM is gaining in traction, not only in the adult populations, but also pediatric. But the real read-through, I think, has been in the Krabbe population. We've certainly been in touch with our investigators, but also at the world meeting, spoke to a variety of groups that support, from an advocacy perspective, the Krabbe community. And, again, the ICM, the HE68, it's a lysosomal storage disease. We're treating children. And, of course, the developmental gains are all perceived as extremely promising. So we actually have seen quite a lot of positive feedback from the Crabbe community and hope that reads through to accelerating the study and getting patients on the therapy.

Great. Thanks so much for the call. Thank you.

Thank you. Our next question comes from Yun Zong with BTIG. Your line is open.

Hi. Good morning. Thank you for taking the question. So on the GM1 data readout in the second half of 2022, is it reasonable to expect that the data readout will only be coming from one patient, from the high-dose cohort and the early infantile patient? And sorry for asking the same question, although it's on GM1 program. Have you identified the second patient for each cohort, and just wanted to confirm that the dosing of the second patient, it's not dependent on data from the first patient, is that correct?

Great, thanks for the question. So first, what we expect to report by the end of the year is cohort-level data on cohorts two and three, which would be, again, two patients in those cohorts each. And the anticipation is that we are going to be able to enroll the second patient in both cohort as quickly as possible. And to your point, each patient right now under the FDA guidance has a 60-day interval in between dosing. That allows for the biomarkers at 30 days, similar to cohort one, as well as the safety follow-up through the end of day 60. So that would be That's required before we dose our second patient in each of these cohorts. And then any subsequent cohort, cohort four, for example, would require an IDMC and then move it forward. So what we're expecting to report out is two patients from the high-dose late infantile and two patients from the low-dose early infantile. And your last question is the quote-unquote identification of patients. So we are... I think as we mentioned at some point, we are having a significant interest in the study, which is fantastic. And we're trying to get patients identified, adjudicated for the potential of enrolling and then enrolling as quickly as possible after that 60-day interval.

Okay. So the press release had safety and biomarker, but given the fast disease progression maybe in the early infantile patients, Do you think, for example, the six-month data could allow you to report some efficacy signal as well by year-end?

It's a great question. So similar to what we did in cohort one, we will make that decision kind of when we see what the data is and the data maturity. You know, similar to what we said in December, we had six-month follow-up on one patient and only two-month follow-up 60 days on the second patient. Then we reported clinical efficacy data on both when we actually got to that three-month time point, which was the first evaluation of both the Bailey and Vineland. So we don't want to commit to that, but we're certainly, you know, we just have to let the data mature. It is possible that we would have data by the end of the year that is longer-term follow-up. It really just depends on when those visits are scheduled, when those databases, you know, come in-house, and when we can get enough comfort that we understand the data. So we're committing only to 30-day biomarker, and 60-day safety. Stay tuned, and we'll update you as we go through the year. Great. Thank you very much.

Thank you. And I'm currently showing no further questions at this time. Ladies and gentlemen, thank you for participating in today's conference. You may now disconnect. Everyone have a great day.

Thank you.