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spk04: Good morning and welcome to the Passage Bio Board Quarter and Full Year 2022 Financial and Operating Results Conference Call. At this time, all participants are in listen-only mode. Following the formal remarks, we will open the call-out for your questions. Please be advised that this call is being recorded at the company's request. Now, I'd like to turn it over to Stuart Henderson, Vice President of Corporate Development and Investor Relations. Stuart, please proceed.
spk01: 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, Chief Executive Officer Will Chu will review our fourth quarter 2022 and recent business highlights. Mark Foreman, our Chief Medical Officer, will review our clinical programs, and Simona King, our Chief Financial Officer, will review our fourth quarter and full year 2022 financial results. Before we begin, please note that today's call may include a number of forward-looking statements. 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 Will.
spk03: Thanks, Stuart, and thank you all for joining us this morning. I want to begin today's call by briefly reflecting on this past year. By honing our strategy and operational focus, we ended 2022 in a strong position, and I'm proud of the work the team did to lay the groundwork and build the momentum needed to ensure we can deliver meaningful clinical data from our two lead programs in 2023. I'm excited by what 2023 has in store for Passage Bio, and I'm pleased to report that the year is already off to a strong start with the presentation of additional data from cohorts one through three of our IMAGINE 1 clinical trial for GM1 gangliosidosis at the World Symposium last month. The data shared at World continue to demonstrate that PBGMO1 administration is well tolerated, has a positive safety profile, and exerts a biological effect across all treated infantile GM1 patients. Mark will review these results in more detail shortly, but this data builds upon the information we presented in December and adds to our confidence of the potential benefit that PB-GMO1 may offer the GM1 patient community. To date, we've completed dosing of the first four cohorts in our IMAGINE ONE study for a total of eight patients. and look forward to reporting initial data from cohort four, which is early infantile patients treated with a high dose, by mid-year. Based on the encouraging data we have generated thus far and our supporting preclinical data, we are moving forward with plans to treat additional patients with a higher dose than doses administered in cohorts one through four. We also plan to revise our study inclusion criteria to maximize the benefit-risk profile of PB-GMO1. By treating additional patients at a higher dose, we will generate important clinical data to further inform dose and patient selection, as well as discussions with regulatory authorities on the design of a confirmatory study. For our uplifted trial for frontotemporal dementia, or FTD, we remain focused on driving patient identification and recruitment initiatives and expanding our global footprint of clinical trial sites. Based on the momentum we are experiencing, we expect to report initial safety and biomarker data from cohort one in the second half of the year. While our primary focus is on generating meaningful clinical data for our GM1 and FTD programs, We also continue to advance our promising preclinical programs in amyotrophic lateral sclerosis, Huntington's disease, and temporal lobe epilepsy through our ongoing innovative research partnership with Penn's gene therapy program. Moreover, following the prioritization of our research and development efforts announced last November, we remain committed to exploring strategic alternatives to advance our two clinical stage programs for Krabbe disease and metachromatic leukodystrophy. In addition, we continue to leverage our strong in-house analytical capabilities at our CMC lab at Princeton West, as these capabilities provide a competitive advantage and are critical to support ongoing and future clinical development of our programs. Lastly, we are supported by a strong balance sheet, providing us with the necessary runway to generate meaningful clinical data for our GM1 and FTD programs. Simona will describe our financials in more detail, but we expect existing cash resources to fund operations into the first half of 2025. With that, I will now turn it over to Mark to review our two lead clinical programs and the recent GM1 data.
spk05: Thank you, Will. Let me begin with a brief overview of our lead program, PBGMO1 for GM1 gangliosidosis, and then I will review key findings from the interim data shared in December of last year. and more recently at the 19th Annual World Symposium. GM1 is a fatal pediatric neurological lysosomal storage disorder 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. Patients with GM1 are a rare and underserved population, and there are currently no disease-modifying therapies for this disorder. Our IMAGINE 1 clinical trial focuses on the early and late infantile forms of GM1, which are the most severe forms of the disease. The dose escalation portion of this global Phase 1-2 trial is an open-label study with PB-GMO1 enrolling four distinct cohorts divided by age and dose level. Our approach uses a next-generation proprietary AAV-HU68 capsid administered by the Cisterna Magnus to deliver a codon-optimized GLB1 transgene to increase beta-galactosidase enzyme activity in the brain and peripheral tissues. We've experienced strong momentum in our IMAGINE 1 trial. To date, we've completed dosing of the first four cohorts in the dose escalation portion of the study, representing a total of eight patients. In December of last year, and more recently at the World Symposium, we were excited to share promising interim results from the first three cohorts in the study. These cohorts represent the low-dose cohorts in both early and late infantile patients and the high-dose late infantile cohort for a total of six patients. Key findings from these interim data are as follows. First, we're excited to see that PBGMO1 continues to be well-tolerated and has a favorable safety profile. There have been no treatment-related serious adverse events, no evidence of dorsal root ganglion or DRG toxicity, no immune response requiring adjustment to the immunosuppression, and no complications related to the ICM procedure. Second, we observed dose-dependent increases in CSF beta-galactosidase enzyme activity, the enzyme of interest, and dose-dependent decreases in CSF GM1 ganglioside levels, a key substrate of beta-galactosidase. Biomarker data also demonstrate that ICM delivery of PBGMO1 leads to beta-gal enzyme activity in both the CNS and the periphery. Third, turning to clinical results, we observed that patients with a lower developmental delay of dosing experienced a better response to treatment on the Vineland and Bailey developmental scales, regardless of dosage level. We also reported imaging data from the MRI severity score, which can be used to assess treatment effects on brain volume and white matter integrity based on baseline and follow-up MRIs. At this interim analysis, PBGMO1 administration was associated with stabilization of MRI severity scores in all treated patients at a follow-up period of 6 to 12 months. In contrast, published natural history data from late infantile GM1 patients showed MRI severity scores increased in the majority of children at a follow-up period of 6 months to 4 years. Overall, the data generated to date give us confidence that PBGMO1 is exerting a biological effect in all treated patients with infantile GM1. Based on the favorable safety profile of PBGMO1 to date, the observed dose response and key biomarkers, and supporting preclinical data, we plan to treat additional patients at a higher dose than has currently been evaluated in the first four cohorts. Additionally, we are revising study inclusion criteria to maximize the benefit-risk profile of PBGMO1. These modifications to the study design will provide us with valuable clinical data to inform dose and patient selection as we seek to optimize the therapeutic benefit of PBGMO1. Moreover, these additional data will also allow us to have productive interactions with regulatory authorities on confirmatory study design and the pathway towards a biologics license application. We are excited to continue to advance our IMAGINE 1 program and expect to dose the first patient at the higher dose in the second half of 2023, following regulatory review. Let me discuss PBFTO2 for frontal temporal dementia with granulin 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 a functional copy of the granulin gene via ICM delivery to the CSF. The goal of this treatment and delivery approach is to potentially provide higher than normal levels of the progranulin protein to the CNF to overcome the deficiency in granulin gene mutation carriers. Our uplifted clinical trial is investigating two dose levels of PBFTO2 and is sequentially enrolling two cohorts. Based on the results of the first two cohorts, we have the optionality for a third dose level. The primary endpoint of the study is to evaluate the safety and tolerability of PBST02. Secondary endpoints include disease biomarkers and clinical outcome measures. We continue to focus on activating additional clinical sites, trial sites around the globe, and on driving a variety of initiatives to support patient identification and recruit Based on the momentum in these efforts, we expect to share initial safety and biomarker data from cohort one patients in the second half of 2023. These data will focus on safety and CSF levels of prognosis. With that, I will now turn the call over to Simona to review our financials.
spk06: Thank you, Mark. As we reported in our press release this morning, cash equivalents and marketable securities were $189.6 million as of December 31st, 2022, as compared to $315.8 million as of December 31st, 2021. Following the streamlining of our operations and prioritization of our research and development efforts announced last quarter, we expect these existing cash resources to fund operations into the first half of 2025. We will continue to manage our cash firm judiciously as we focus on program execution. R&D expenses were $17.7 million for the quarter ended December 31, 2022, and $86.1 million for the year ended December 31, 2022, compared to $33 million and $117.7 million for the same quarter and year in 2021. G&A expenses were $10.6 million for the quarter ended December 31st, 2022, and $49.3 million for the year ended December 31st, 2022, compared to $17.2 million and $60.1 million for the same quarter and year in 2021. Net loss was $27.1 million for the quarter and $136.1 million for the year ended December 31st, 2022, compared to $51.2 million for the quarter and $185.4 million for the year ended December 31st, 2021. Let me now turn it back to Will for closing remarks. Thank you, Simona.
spk03: The primary focus for 2023 is on strong execution and continuing to generate meaningful clinical data from our lead programs in GM1 and FTD. We expect to achieve several program milestones this year. By mid-2023, from our IMAGINE ONE study, we plan to report initial safety and biomarker data from cohort four, which is early infantile patients treated with a high dose. In the second half of 2023, We look forward to dosing the first GM1 patient at a higher dose than those previously evaluated and to reporting initial safety and biomarker data from cohort one of our uplifted study. Prior to taking your questions, I would like to thank my colleagues at Passage Bio who've shown their commitment to the pursuit of our ambitious mission. We also continue to be grateful for the support of the patients, families, and clinical trial investigators who have chosen to participate in our studies, as well as the support of our partners at the gene therapy program. With that, I would like to open the call for your questions. Operator?
spk04: Thank you. We will now take any questions you may have. Ladies and gentlemen, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, press star 11 again. Please stand by while we compile the Q&A roster. And our first question coming from the line of Yaron Webber with Cowan-Yelenis Alpen.
spk09: Hi, great. This is Brendan. I'm for Yaron. Thanks for taking the question. Congrats on all the progress. Maybe just a couple quick ones from us. In terms of the dose escalation plan, can you actually – can you confirm whether you've already identified additional patients? It looks like you're going to go both into early and late infantile for this higher dose. And then – Really, can you give us a sense, is there like a particular threshold you're trying to hit in terms of biomarker response or functional improvement, or are you really just looking to see how much you can maximize efficacy before transitioning to a pivotal study? And then just really quickly, on a potential pivotal study, based on what you know so far with these neurodevelopmental endpoints, can you maybe give us a sense of how long you think you would need to follow patients to support approval in GM1? Thanks very much.
spk03: Hey, thanks for the question, Brendan. I'm going to turn that over to Mark. Do you want to answer?
spk05: Yeah, thanks. So for the dose escalation cohorts that are currently being considered, I mean, over the course of the past few years, we've received a great deal of interest in our trial and inquiries from dozens of families interested, including both early infantile and late infantile. We've been reviewing these profiles as assessed by the adjudicator, and the majority of these children would meet the revised trial eligibility that we're planning on. Thus, we're confident that we're able to quickly recruit the study, even with the narrowing of the inclusion criteria. With regards to the second question with how much beta-galactosidase activity that we need, The amount of beta-galactosidase that is needed to correct the deficits in these patients is not known. What we do know is that in animal models, even modest reductions, and I'm specifically talking about the transgenic mouse knockout model that we used in our preclinical program, even modest increases in beta-galactosidase activity were associated with clinical improvement. That being said, we're really using the pharmacodynamic marker, the CSF levels of GM1 gangliosides to drive our program. And in the data that we've shared most recently at World, we've shown that at six months at the high dose, we've been able to reduce those levels to 75%. And the goal is to really normalize those levels. And so that is really what we'll be looking for going forward is looking at the levels of reduction of the ganglia side, GM1 ganglia side levels, in conjunction with the clinical outcomes, which we believe will be a lagging indicator.
spk03: I think the last question was on follow-up. And so, in terms of clinical follow-up, there is a long lead time for seeing developmental changes At a minimum, we would at least need to have follow-up of six months.
spk09: I got it. Thanks very much, guys.
spk04: Thank you. And our next question coming from the line of Madhu Kumar with Goldman Sachs. Your line is now open.
spk10: Hi, this is Omari. I'm from Madhu. So we have two questions. First, what are the specific outputs that you're looking for in early infantile high-dose cohort for GM1 to pursue registrational studies? And then second, do you have any visibility or registrational endpoints in GM1?
spk03: Okay, I'll take the first one and then I'll turn the second question over to Mark. So in terms of specific outputs that we're looking for, it's really two. We're looking for durable decreases in GM1 gangliosides, as Mark referenced previously, and we're looking for improvements in developmental age.
spk05: Mark? And the second question was regarding the registrational output. And we will be having ongoing discussions with the health authorities to define the endpoints that will that will be used for these studies, and we'll certainly provide updates on what those are as they become defined following our discussions with health authorities.
spk10: All right, thank you so much.
spk04: Thank you. And our next question, coming from the lineup, Laura Chico with Wetbush Illini-Selfin.
spk08: Good morning. Thanks very much for taking the question. The first one on GM1. How do the inclusion criteria changes impact potential labeling? I guess what I'm asking is, would this still be something that would be applied more broadly to GM1? And then in terms of perhaps a preclinical question, we're hearing about more constraints on NHP supply chain issues. I'm just curious how that might impact some of the preclinical efforts that you've got going on right now. Thank you.
spk03: Okay, sure. In terms of inclusion criteria, as you know, any protocol amendments we make are subject to regulatory review. So we will be happy to share the details of the inclusion criteria changes after that review is complete. And what we have said previously is we're looking to treat patients who are earlier on. And as you know, all GM1 patients pass through earlier stages. And our goal is to identify and find these patients at an earlier stage so we can maximize the risk benefit of the product. In terms of patient identification, what we do know is from the patients who have been suggested for the trial, who have been given to our adjudicator, we know that there are many patients who fit our new recommended inclusion criteria for the protocol. And so we feel confident in our ability to recruit these patients. Mark?
spk05: So the second question is around impacts to our preclinical programs in terms of non-human primate availability. And our preclinical programs are done in collaboration with the gene therapy program at the University of Pennsylvania. And to date, the the availability of primates has not impacted any of the ability of any of our preclinical pipeline to advance. So not an issue right now, but certainly something that we're carefully monitoring and we'll be working closely with our colleagues there to ensure that that doesn't hold things up.
spk08: Thanks very much.
spk04: Thank you. One moment please for our next question. And our next question coming from the line of Nina of Retreat of Cards with CD Group. Your line is open.
spk11: Hi, good morning, guys. This is Jarway on for Nina. Two questions from us. First being on PDGM-01, can you disclose what the higher dose is, and if not, perhaps how much higher in relation to the current doses you're looking at? And second, in relation to PBST-02, we recall that you guys had patients in the Q last quarter. Any reason why these patients do not get dosed? And, you know, have you guys dosed a second patient yet? Thanks.
spk03: Sure. So let me answer the first question. So for GMO1, as we mentioned before, the protocol changes are subject to regulatory review. So as soon as that review is complete, we would be happy to share the new dose. In terms of PBFTO2, we indeed have patients in the queue. We have GRN-positive patients who are at sites who are being queued up for future treatment. In terms of dosing, We are not providing specific details on patient-to-patient dosing within each cohort.
spk11: Got it. Thank you.
spk04: Thank you. One moment, please, for our next question. And our next question, coming from the line of Yoon Sung with BTIG. Your line is open.
spk00: Hi, good morning. Thank you very much for taking the question. So a follow-up question on dose escalation. Have you got approval on dose escalation itself, or would that still be dependent on data from COHO4? And on patient selection, sorry if I missed this, but is the next patient going to be late-onset or early-onset, or are you going to explore both early-onset and late-onset patient with the high dose? And finally, the I think you talked before about the developmental delay as a very critical factor affecting treatment outcome. But the two patients in cohort four seem to have very short delay, but not by design. So are you going to look for those patients specifically with the short delay?
spk03: Yeah, thanks for the question. So in terms of dependency on cohort four, no, we are increasing the dose significantly. right now. We are moving to do that regardless of any results for cohort four. For the additional patients that we will treat at dose three, the higher dose, we are going to be treating both early and late infantile patients. And then I'll turn it over to Mark for the last question.
spk05: Right. So can you just remind me again of the last question? Make sure I understand it.
spk00: Yeah. It's about developmental delay. And you talked in the past that it seems to be a very critical factor affecting treatment outcome. And both cohorts for patients, they have very short delay, but not really the intention, so not really by design that it looks like it was accidentally they had short delay. So are you going to, going forward, look for specifically patients with short delay to improve potential treatment outcomes, please?
spk05: Yes, so the goal moving forward is, as we're actively working to revise the inclusion criteria, is to shift the focus to earlier stages of disease, as Will mentioned earlier, with the goal of identifying patients who have the highest benefit-risk profile. So the current inclusion criteria would certainly not exclude those patients, as you pointed out in your comments, But the goal will be to try to enroll more patients with that profile with the shorter delay going forward.
spk00: Okay, great. Thank you very much.
spk04: Thank you. One moment, please, for our next question. Our next question coming from the line-up, Danielle Brill with Graham and James. Your line is now open.
spk02: Hey, guys. This is Alex. I'm for Danielle. Just looking at past notes, I believe that for the GM1 program, that the expectation was to have the end of phase two meeting with the agency somewhere in 2023, but with the added cohorts, when do you expect that conversation to take place? Are we looking more like a 2024 event? What we plan is to go discuss
spk03: the registrational pathway with regulatory authorities with data from the additional patients who are being treated at a higher dose. So, indeed, that will not be in 2023, as we plan on treating the first patients at this higher dose in the second half of this year.
spk09: Great. Thanks for the color.
spk04: Thank you. One moment before our next question. And our next question coming from the line up, with me, from . Hey, guys.
spk07: Excuse me. Thanks for taking the question. I guess on STD, so you mentioned the update later this year will be, will include safety and biomarker data. Can you remind us for the biomarkers, is that NFL levels or are there others that we should be thinking about? And how are you thinking about target levels or what would be good in terms of this first dosing cohort in your view?
spk03: sure so let me take that one mark so our initial data from cohort one is going to focus on safety and csf progranular levels so we plan to report progranular levels at baseline and after 30 days in the in the csf um what was the second part of your question uh so i guess as it relates to csf progranulin then what are
spk07: Is there a target level that you're aiming for, and are you expecting, or I guess what are your expectations given this is the first dose cohort relative to that potential target?
spk03: Sure, of course. So based on our preclinical data, what we saw at this current dose level is physiologic levels of CSF programming. So our expectations would be to at least see physiologic levels of CSF programming. I would like to say that before we discuss the patient recruitment, and because of all the patients we have who are identified at sites who are GRN positive, we are confident and looking forward to sharing data from the first cohort of patients in the second half of this year.
spk07: Got it. And then second part of the question, I guess, is I believe there's targeting enrollment of three patients. in this first cohort, correct me if I'm wrong, but is the expectation to provide data on a complete cohort, or will you provide data on if it ends up not being a complete cohort dose in the second half, you'll provide data on whatever patients you have treated?
spk03: We'll be providing data on multiple patients from the first cohort, and we will be able to give more specific guidance to that later this year.
spk07: Okay, great. Thanks for taking the question.
spk04: And I'm showing off for the questions in the queue 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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