Passage Bio Inc (PASG) 2020 Q4 法說會逐字稿

Thank you for holding. Good morning, and welcome to the Passage Bio Fourth Quarter and Full Year 2020 Financial and Operating Results Conference call. (Operator Instructions) Please be advised that this call is being recorded at the company's request.

At this time, I'd like to turn it over to Stuart Henderson, Vice President of Investor Relations and strategic finance. Stuart, please proceed.

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 at investors.passage bio.com under the News and Events section.

On today's call, Bruce Goldsmith, President and Chief Executive Officer, and Rich Morris, Chief Financial Officer, will review our fourth quarter and full year 2020 financial results and discuss recent business highlights. Gary Romano, our Chief Medical Officer, and Jill Quigley, our Chief Operating Officer, will also be available for the Q&A portion of the call.

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 expectations about our collaborators and partners' ability to execute key initiatives; the ability of our lead product candidates to treat their respective target monogenic 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 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?

Thanks, Stuart, and thank you all for joining us this morning. Let me begin by remarking on the incredible year of accomplishments we had at Passage Bio in 2020 despite the COVID-19 pandemic and other challenges we all faced last year. Our company's work is grounded in the mission to develop life transforming therapies for patients with devastating CNS disorders.

We view 2020 as a foundational year in which we focused on preparing for a successful transition to a clinical-stage company in 2021. We began 2020 with a successful IPO, which gave us a strong financial position from which to build. We further strengthened our financial position earlier this year with a public offering that raised $166 million in net proceeds.

Our work over the past year focused on advancing 3 programs, all of which are set to begin clinical development in the first half of this year. PBGM01 for GM1 gangliosidosis, PBKR03 for crave disease and PBFT02 for frontotemporal dementia with granulin mutations.

We recently received regulatory clearance in the U.S., U.K. and Canada for the global PBGM01 Phase I/II clinical study in Imagine-1, for the treatment of patients with infantile GM1. We have also activated our first site in the U.S. and are currently recruiting patients. Other site activations are in progress, and we continue to expect to dose our first patient in the first quarter of 2021.

In early 2021, we also received FDA clearance for the IND applications for 2 additional programs in early infantile Krabbe disease and in frontotemporal dementia with granulin mutations. Other recent regulatory actions to take note of are orphan drug and rare pediatric disease designations from FDA for both the GM1 and Krabbe programs.

Adoption of a positive opinion by the European Medicines Agency for PBKR03 and Krabbe disease for an orphan drug designation, we expect the European Commission to endorse the positive opinion by the end of the quarter.

Just recently, FDA granted our FTD program Fast Track Designation, which is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill unmet medical need. Our FTD program also received orphan drug designation earlier this year from FDA.

We have also made important strides expanding our patient identification and engagement efforts, which are crucial to advancing successful gene therapy programs. For our GM1 program, in addition to our ongoing natural history study with the Penns Orphan Disease Center, we have collaborations with Invitae and New York ScreenPlus to help identify patients as early as possible who may be able to benefit from our investigational therapies.

We are also sponsoring genetic screening and counseling for patients with FTD, while also engaging FTD trial sites that are participating in the ongoing all FTD and genetic and natural history studies, which may be helpful to identify patients for enrollment in our clinical study.

On the manufacturing side, we are establishing internal and external manufacturing capabilities to meet the needs of our growing pipeline. This includes initiation of vector manufacturing in our dedicated CGMP suite at Catalent late last year as well as the planned opening of our owned CMC lab in the second quarter of this year to support analytical development, clinical product testing and assay validation. These, together with our supply chain partnerships will enable us to advance our growing pipeline and will provide us with increased control and flexibility across our global end-to-end clinical supply chain.

As I said at the outset, we have been able to support all these initiatives from advancing our pipeline programs to supporting various patient identification and engagement initiatives, to bolstering our manufacturing capabilities in large part because of our strong financial position and our experienced team.

In 2021, we continue to operate from a position of financial strength, and our priority will be progressing our 3 most advanced programs through clinical development as well as continuing to expand our pipeline and internal operations. The advancement of Passage Bio deliver 3 programs to the clinical stage as well as continued investment in our earlier pipeline demonstrates the extremely productive collaboration between Passage Bio and Jim Wilson and the Gene Therapy Program at Penn. We anticipate 2021 and beyond to continue that strong partnership with a shared goal of advancing programs to patients with rare CNS disorders.

I will spend the next portion of my remarks updating you on each of our planned clinical development programs. Let's start with our Imagine-1 study for infantile GM1. As I mentioned, we are extremely excited to have received regulatory clearance and be moving our first assay into clinical development. As a reminder, GM1 is a devastating rare monogenic recessive lysosomal storage disease that impacts patients worldwide. It is caused by mutations in the GLB1 gene encoding the enzyme beta galactosidase. We are targeting the infantile form of the disease, which is the most severe, with a very rapid disease course and no current treatment options beyond supportive care.

PBGM01 utilizes the next-generation AAVhu68 capsid administered through the intra-cisterna magna to deliver a functional GLB1 gene, including beta-gal to the brain and also to peripheral tissues. Published preclinical data from GTP in the peer reviewed journal, human gene therapy supports the potential of PBGM01 as a treatment for GM1.

Our Phase I/II trial, Imagine-1, is a global open-label dose escalation study of PBGM01, administered by a single injection into the cisterna Magna in subjects with early and lead onset infantile GM1. The study will enroll a total of 4 cohorts of 2 patients each with separate dose escalation cohorts for late onset infantile and early onset infantile GM1.

As I mentioned earlier, we have activated our first site and expect to dose our first patient in this quarter. We also expect to report 30-day initial safety and biomarker data, specifically the impact on beta-gal enzyme activity from our initial cohort in mid-2021. We are actively screening eligible patients for the trial and activations are underway for additional sites. We plan to open 10 sites globally and currently have clinical trial authorizations in the U.S., U.K. and Canada. We are also in discussion with regulatory agencies and key physicians in Brazil and Turkey, both countries in which there is a higher incidence of GM1 due to a founder's effect.

As we continue to bring on clinical sites, we are ramping up patient identification and education efforts. This includes our partnership with Invitae, a leading medical genetic testing company as well as our sponsorship of the New York ScreenPlus Pilot Program, which offers newborn screening for rare diseases. Additionally, we have strong relationships with the site coordinators and investigators that are driving the study forward.

Turning to Krabbe disease at FTD-GRN. We are very happy to receive IND clearance from FDA for both programs and preparations for the Phase I/II trials are continuing. We anticipate the start of both trials to occur in the first half of this year with initial 30-day safety and biomarker data readouts in late 2021 or early 2022.

As we seek to expand our reach to patients around the globe for these 2 indications, we are also filing for clinical trial authorizations in countries outside the U.S., and we'll provide further updates on those regulatory filings as appropriate.

Next, I will give you a brief overview of the programs for Krabbe disease and FTD-GRN, starting with Krabbe disease. PBKR03 is being developed for the treatment of early infantile Krabbe disease or globoid cell leukodystrophy, a rare lysosomal storage disease caused by mutations in the gene encoding the enzyme galactosylceramidase or GALC. This results in rapid progressive damage to both the brain and peripheral nervous system and if untreated, leads to mortality by 2 years of age. PBKR03 utilizes a next-generation AAVhu68 capsid to deliver DNA encoding galactosylceramidase enzyme to patient cells.

Our Phase I/II trial will be an open-label dose escalation study of PDKR03 administered by a single injection into the cisterna magna in pediatric subjects with early infantile Krabbe disease. Our first goal of the study is to demonstrate that PBKR03 is safe for patients with early infantile Krabbe disease. Our second goal is to demonstrate an increase in GALC. We hope to demonstrate this increase in the biomarker in both cerebral spinal fluid and serum of patients. The dose escalation portion of the trial will look very similar to the design for our GM1 program, separated by dosage and by age group. We will be enrolling a total of 4 cohorts of 3 subjects each with separate dose escalation cohorts based on age and enrollment.

We will initiate dosing with the low dose of PBKR03 in the first cohort of subjects who are between 4 and 9 months of age. If deems safe and tolerable, we will move into a high-dose cohort in subjects who are also between 4 and 9 months of age and a low-dose cohort in subjects who are between 1 and 4 months of age. Our final dose escalation cohort is planned to evaluate a high dose in subjects between 1 and 4 months of age. These dose escalation cohorts will be followed by a confirmatory expansion cohort for both age groups. The initial data readout from the first cohort will include 30-day biomarker and safety data.

As I've discussed for other programs and as the case with all rare diseases, patient identification is a main focus point, especially when considering the early and devastating impacts of a disease such as Krabbe. To support this, we are working with leading physicians and patient groups on initiatives to expand newborn screening.

Turning our attention to PBFT02 for FTD granulin, which is an adult condition generally affecting patients in their 50s but can impact adults as young as the 30s. FTD is one of the most common causes of early onset or mid-life dementia, causing impairment in behavior, language and executive function, and it occurs at a similar frequency to Alzheimer disease in patients younger than 65 years old. And approximately 5% to 10% of individuals with FTD, 3,000 to 6,000 patients in the United States, this disease occurs because of mutations in the GRN gene, causing a deficiency of progranulin. The mechanism by which progranulin deficiency results in FTD is uncertain, but increasing evidence points to progranulin's role in lysosomal function. The rapid progression of FTD results in an average survival of only 8 years after onset of symptoms.

As a reminder, PBFT02 is a gene therapy that utilizes an AAV1 vector to deliver to the brain a functional granulin gene encoding the progranulin protein.

In a preclinical study by GTP, published in the peer-reviewed scientific journal of Annals of Clinical and Translational Neurology, a single administration of PBFT02 via the optimized AAV1 GRN vector demonstrated CSF progranulin, reaching levels of more than 50 fold, supporting our advancement of PBFT02 and into clinical study.

The Phase I/II program will be an open-label dose escalation study of PBFT02 administered by a single injection into the cisterna magna in subjects with early symptomatic FTD and pathogenic mutations in the progranulin gene or FTD-GRN.

We have 2 key goals for the Phase I/II study. Our first goal is to demonstrate that PBFT02 is safe for patients with FTD-GRN, our second goal is to demonstrate increased progranulin levels in the CSF. We will enroll 2 cohorts of 3 patients each with an optional third cohort, and we'll initiate dosing with a low dose of PBFT02 in the first cohort as is typical for a dose escalation study. If the low dose is well tolerated, we will study a higher dose in the second cohort. The initial data readout for the first cohort will include safety data and 30-day biomarker data including change from baseline and CSF progranular levels.

As we have discussed, FTD is a devastating disease that impacts patients worldwide, and we are dedicated to serving patients in the U.S. and across geographies. We have continued to build relationships with patient groups to help increase the potential reach of our programs and are working to support genetic screening and counseling to patients with FTD free of charge. As we embark on all 3 clinical development programs, the safety of our patients is our top priority.

To address the current challenges associated with COVID-19, we have implemented approaches such as remote assessments where possible, and concierge services through third-party vendors to facilitate travel due to increased burdens and restrictions. We believe these measures will provide patient support while also maintaining the rigor of our clinical trials and our ability to provide these potentially life-altering therapies to patients. Again, we are very excited to have received regulatory clearance for all 3 of our lead programs and look forward to providing further updates as we begin dosing patients in the coming months.

Turning to manufacturing. As I mentioned earlier, we have made important progress this year towards establishing both our internal and external manufacturing capabilities. Manufacturing capacity has been a key tenet of our strategy since launching the company and securing control of our supply chain is an important part of our differentiated approach as we continue to advance and grow our pipeline.

Some recent accomplishments include: initiated vector manufacturing in our dedicated CGMP suite at the Catalent cell and gene therapy facility in Maryland, signed a lease for our manufacturing laboratories at the Princeton West Innovation Campus in Hopewell, New Jersey, which we plan to open in the second quarter of 2021 and which will support analytical development as well as clinical product testing and assay validation.

Established a flexible global end-to-end clinical supply chain by entering into a number of partnerships and supply agreements. These agreements span from plasma production for our vectors to clinical packaging and on-demand global distribution to our clinical sites based on patient need.

We are pleased to share that our clinical supply for PBGM01 for our Phase I/II Imagine-1 trial manufactured through our partnership with Catalent is already in place. We have also manufactured clinical supplies to support initiation of our clinical study for our next 2 of most advanced programs, for Krabbe disease and for FTD-GRN.

Finally, we want to note that in 2020, we invested to substantially expand our R&D and manufacturing internal expertise. In 2021, we are continuing to hire key talent to ensure superb execution of our clinical trial programs and our end-to-end manufacturing processes with the goal to be a leader in delivering transformational gene therapies to patients. And with that, I will turn the call over to Rich to give a financial update.

Thank you, Bruce. As Bruce mentioned, we have secured incredible financial security over the past year, which will enable important optionality as we continue to advance and grow our pipeline.

As we reported in our press release this morning, we ended the year with cash, cash equivalents and marketable securities of approximately $305 million as compared to $159 million as of December 31, 2019. In addition, we also have received $166 million in net proceeds from our recent public offering, which together, we expect to fund our operations for at least the next 24 months.

R&D expenses were $81.8 million for the year ended December 31 compared to $29.7 million for 2019. The increase was primarily due to an increase of $24.7 million in clinical manufacturing costs, an increase of $6.6 million in preclinical research and development costs incurred in preparation for IND filings, a $4.4 million increase in clinical development costs and a $3.4 million increase in consulting expense as we prepare for our clinical trials to begin in the first half of 2021.

We also had a $12.5 million increase in personnel-related costs, including share-based compensation, due to increased employee headcount in the R&D function.

G&A expenses were $30.1 million for the year ended December 31 compared to $7.0 million for 2019. The increase was primarily due to a $15.3 million increase in personnel-related and share-based compensation expense due to increases in employee headcount.

Our facility costs and professional fees also increased by $4.6 million and $3.3 million, respectively, as we expanded our operations to support our research and development efforts. Net loss was $112.2 million for the year ended December 31, 2020, compared to $45.6 million for 2019.

Now I'll turn the call back to Bruce for closing remarks.

Thanks, Rich. Looking ahead, we continue to establish Passage Bio as a leading clinical-stage company focused on developing life-changing therapies for patients with rare monogenic CNS disorders. As a reminder, our key anticipated milestones for the upcoming year are: To dose the first patient in a Phase I/II trial for the treatment of patients with infantile GM1 in the first quarter of 2021; report initial 30-day safety and biomarker data from that trial in midyear 2021; initiate Phase I/II trials for the treatment of FTD-GRN and for the treatment of early infantile Krabbe disease in the first half of 2021; open our CMC research and development site in the second quarter of 2021; and finally, to continue to advance preclinical programs from MLD ALS CMC 2A and our undisclosed program in adult CNS and bring additional candidates forward.

Before taking your questions, I'd like to take this opportunity to recognize and thank the team here at Passage Bio and our partners at Penn's GTP and for their hard work and diligence that set the stage forward is going to be a milestone filled year to come.

At this time, we'd like to open the call up for questions. Operator?

(Operator Instructions) Our first question comes from the line of Anupam Rama from JPMorgan.

Bruce, just wondering, what are the gating factors to dosing that first patient in GM1? And can you remind us -- I think you mentioned on the call, 10 sites that you're opening up for GM1, is it going to be site overlap with Krabbe and FTD?

Anupam, thanks very much for the question. So I'll talk a little bit and turn it over to Gary for additional remarks. So as we mentioned on the call, we do have the manufacturer -- the supply manufactured and ready to distribute. So that's certainly in place. As we, I think, highlighted also and is updated on clinicaltrials.gov for the trial listing, we have -- we are starting to recruit with one site open and we're continuing to advance the other sites as well.

And maybe, Gary, you can talk about just the -- what we're going through in terms of additional patient identification and then a comment on overlap between Krabbe and GM1.

Thanks, Bruce. Yes. So there's -- we've seen a lot of interest in the trial, as evidenced by the number of caregivers contacting us through our patient portal to inquire about eligibility and enrollment. And we -- as we've outlined before, we are -- have a number of engagement initiatives to help us enroll into trial, including engagement with the rare disease community, specific advocacy groups.

We have, of course, very strong relationships with sites and study coordinators, investigators. We're decreasing burden to trial participants by having a strategy for remote visits and video -- in-home video assessments as well as enhanced travel services. And we also have a vendor outreach program, working with Invitae to identify patients as rapidly and as early in disease as possible.

Regarding the sites, we're planning to open at least 7 sites globally, and we currently have, as Bruce mentioned, regulatory clearance in the U.S., Canada and the U.K. We're also looking to open sites in Brazil and Turkey, where there's a higher incidence due to the founder's effect. In Brazil, we're working with Dr. Roberto Giuliani, who is a world-renowned expert is just one example of our relationships.

Regarding overlap of sites, there is some overlap insights between the Krabbe and GM1 program. But the Krabbe is a leukodystrophy which is different from GM1. And so we have a concentration of sites that are well-known sites that we've received many referrals for leukodystrophy patients for the Krabbe program.

Our next question comes from the line of Salveen Richter from Goldman Sachs.

Hello?

Yes. Can you hear me?

Hello?

Yes. This is Bruce, I am just waiting to take your question.

I am so sorry about that (technical difficulty)

Operator, maybe we have lost Salveen Richter.

Our next question comes from the line of Yaron Werber from Cowen.

This is Brendan on for Yaron. Congrats to the team, on the solid progress. Just a couple of quick ones from us. First, just about the data readout in GM1, thanks for all the detail on the design. We're just kind of wondering maybe what your plans and maybe the threshold for that release are, kind of how many patients at which dose levels you're hoping to include, whether that would be kind of more of a press release or medical meeting kind of thing.

And then just quickly on the pipeline, wondering if you're planning to release any of the preclinical data from the MLD or ALS programs this year?

Brandon, thanks very much for the question. Yes. So the first question on the readout in midyear for GM1, which focuses on 30-day safety and biomarker data, in particular, beta-galactosidase enzyme activity. What we've said is that it'll be available in the middle of the year. I don't think there's a medical conference that's completely aligned with that. So we may release that via press release.

I think we have to determine the final form of that as we approach. But then the second part of that question was what -- basically what kind of patient data in terms of numbers. The way we've always positioned this is that we really desire to release data on a complete cohort. And in this particular trial design for GM1 in the late onset infantile patients accord is 2 patients. And so we would expect to report on those 2 patients.

And obviously, that would also be contingent on bringing that data to DSMB and then also thinking about expanding both to a higher dose for the late onset patients and then the lower dose for early onset patients later this year as well. So that's how we think about the release of the initial data. And on your -- can you repeat your second question? Apologies.

No, no problem. I was really just about if you're having any plans to release any of the preclinical data from the MLP or ALS program?

Yes. That will be dependent on both Congress availability and abstracts that were submitted, and that might be submitted as well as any papers that are written by Jim Wilson and his team at GTP, as you know they're responsible for the preclinical data. So until those become public in terms of any potential papers, et cetera, we're not commenting on when those data would be released.

Our next question comes from the line of Salveen Richter from Goldman Sachs.

I'm sorry about the technical difficulties earlier. Maybe you could just talk about the natural history work that you're doing for these indications and how that's playing out in cadence with running your clinical trials? And then also, as you look at the pipeline that's coming from Penn, how you're thinking about prioritization of that on the Ford?

Sure. So why don't I make a brief introductory comment and then I'll give it to Gary to talk about how we're approaching kind of natural history. And maybe we can focus on both GM1 and Krabbe disease. The basic idea that we're approaching -- how we're approaching this is looking at both studies that we're running, for example, in GM1, we're running study with the orphan disease center at Penn to create our own natural history data.

But we're also looking at sites that might have of data, and we could pull that information in. And the whole idea is to have this as a potential comparator once the study in terms of the expansion cohorts could read out. So we don't necessarily need that data anytime in the near term, but we certainly want to generate it and make sure that there's high-quality data for potential comparison. And maybe, Gary, you can talk a little bit about -- in more detail about how we're approaching this with GM1 and Krabbe.

Yes. Thanks, Bruce. So in GM1, we are we're conducting our own -- well, through the Orphan Disease Center at Penn, a prospective natural history study that matches our cohort very closely -- our interventional trial protocol very closely and is also being conducted at the same sites as the study as the interventional study. This is to ensure comparability of the data. That study is enrolling. And we've seen enrollment pick up recently. So we're very happy to see that.

We're also planning to access other sources of data, and we've had conversations with FDA about this strategy. What I mean by that is other data that exists either from academic cohorts or even publications. In Krabbe, we -- thanks to the fact that there are a number of academic go into 2 of observational studies in Krabbe infants and a wealth of natural history data as a result. There, we don't feel that it's necessary to initiate an independent prospective natural history study.

Instead, we're engaged with those centers who've collected that data and working with them to gain access to the data to use in comparison to our interventional trial.

Great. And then on prioritization, as we think about new potential indications, we essentially look at a number of different attributes. The one really critical driving factor that is underlying the foundation of the company is, can we produce a program that is highly differentiated. And the way we think about this in GM1, Krabbe and FTD is -- are there reasons to believe that this -- the capsid, the vector, the combination of those or the administration, for example, can lead to a highly differentiated and potentially best-in-class approach.

And that's certainly the driving factor behind selection of new potential additions to our pipeline through the 10 remaining options that we have. And then we look at things like feasibility, developability and obviously, also commercial potential at some level as well. And we put those together and when we think about developability and feasibility, we also think about other animal models that are somewhat predictive or highly predictive, can we overcome any technical challenges to reach the clinic. And we do this in very close collaboration with Jim Wilson and his group, ranging from the manufacturing and vector core group to the preclinical scientists as well.

And so it really is an integrated effort to think about which new indications we could bring in. And that's resulted, obviously, in one additional indication that we brought in last fall, which is an unnamed adult CNS, neurodegenerative disease that we're highly interested in, and Jim and his team are now progressing from a preclinical perspective.

And we're certainly interested in growing our pipeline more this year as well. That's very helpful.

Our next question comes from the line of Neena Bitritto-Garg from Citi.

So I just had a question about the Krabbe disease study. I saw in clinicaltrials.gov, some of the inclusion criteria. And I guess, can you just talk a little bit about how well the criteria that you're using to screen patients kind of correspond with what's generally screened for under some of the newborn screening programs in terms of like GALC activity and things like that. Since I noticed that I think you are allowing presymptomatic patients into the study as well?

Sure. Yes, thanks, Neena. Thanks for your question. And I'll probably turn it over to Gary to highlight several of the inclusion criteria that we think are important and kind of talk through those considerations. Gary?

Sorry, yes. Yes. So for the Krabbe study, we're going to enroll early infantile Krabbe disease. This is patients who have onset before 6 months of age, and we're enrolling patients who are ages 1 to 9 months of age. Your question was around what goes on in screening and there is enzyme activity screening for GALC. What we're -- our inclusion criteria include GALC activity. Also, importantly, whole blood psychosine levels. We have a threshold there.

That is because psychosine levels the threshold we're using 10 nanomolar has been shown to be predictive of the early infantile form of disease to rapidly progressive, really infantile form of the disease. They'll also have to have pathogenic GALC mutations or big gene variants as described.

And as you mentioned, we are enrolling both symptomatic and presymptomatic patients in this trial. So that's -- but they have to -- we'll have to have a minimum level of neurological and developmental exhibit -- a minimum level of neurological and developmental function. That is they can't be too far progressed to be in the trial.

We're going to be enrolling the study in 2 separate cohorts. We're going to start with cohorts that are -- the older age children who are 4 to 9 months of age. And then with acceptable safety initiate dosing in the younger infants, 1 to 4 months of age and also dose escalate in the older infants.

Thanks, Gary. And I think to bring it back to -- into -- to your -- to those screening criteria and how that links to newborn screening, it's a little bit variable because this is state-by-state on the 9 or 10 states that have newborn screening in place for Krabbe disease.

But all do start with, I believe, GALC enzyme tests. And then if there's a -- and it's also possible to look for mutations first. But those all would then precipitate a more quantitative look at either the mutations or the GALC enzyme levels and then also potentially psychosine. So it lines up fairly well, but obviously, the screening by any state level, new born screening would obviously be followed by our own screening criteria as well.

So it does line up at least at the beginning quite well. And obviously, it requires additional testing for entry into the study.

Our next question comes from the line of Gbola Amusa from Chardan.

Great. So you've shown that you can get 3 INDs cleared very recently. I'm curious about your sort of next cluster of indications in MLD, ALS, CMT2a the adult CNS indication. Question is whether there are any unique device-related issues on those programs or other issues that you're focused on to move them forward and get them clear?

Yes. Thanks, and thanks for the question. We're really not commenting on the other approaches. We haven't kind of talked about the -- even the vector selection or the potential target population at this point. So we'll have to wait to talk about this as we define the programs. I think the first 3 indications were a little bit different because they were far advanced at the time we went public and really had a lot more detail in those as we progress towards both filing and then, obviously, for the IND approvals.

And we're likely to follow that same pattern, which is as the program moves through, for example, IND-enabling studies as well as potentially showing activity in various models of -- disease models, we'll give more and more detail as those progress. But right now, we're not willing to kind of give that information publicly because it just hasn't been completely defined at this point until we have a candidate.

Sure. And I may get the same response for the next question, so forgive me. But in ALS, we've seen, for example, I think one preclinical program has been sitting there for 5 years elsewhere. Can you talk conceptually about what issues you're trying to overcome to ensure that your programs to clinic in a reasonable amount of time?

Yes. I think, without going into a lot of the details, I think what Jim and his team are looking at are both the expression of the particular enzyme as well as suppression of the mutation in C9orf and the balance of that as well as readouts in potential disease models as well as dynamic models. And those would kind of give us the clear pathway forward or the decisions that we have to make to revisit the constructs.

And I think that, that's what some of the other companies have also faced that you're alluding to. So we're being very, I think, careful and judicious in our preclinical work that, again, Jim is conducting to derisk this as much as possible before we move forward.

Great. And congrats on the progress. Look forward to biomarker data in the year ahead.

Our next question comes from the line of Laura Chico from Wedbush Securities.

I guess, first question, certainly looking forward to the safety biomarker data for GM1 in the middle of this year. But wondering if you could elaborate a little bit further on potential timing to clinical data and kind of given the size of the cohorts, just trying to understand what would you need to see at this stage from the clinical data to advance to further studies? And then I have one quick follow-up after that.

Yes. No, thanks very much for the question, and thanks for joining us. So well, the way we're thinking about this for GM1 and Krabbe and also for FTD are all trying to look at as much natural history disease -- of the disease as we can to think about what could trigger the expansion.

And obviously, the primary goal of all of the initial cohorts is clearly safety, but then we're going to look at either enzymatic activity or in the case of FTD, looking at progranulin levels. And then potentially -- at those early stages. We're only going to have 30 days of those samples, is really to move forward to the higher dose in order to then progress to potential expansion arms and looking at the longer-term follow-up for potential biomarkers of disease progression or disease modification.

So the early decisions, I think -- and I'll turn this over to Gary as well, if he has any additional comments, but I think the early decisions are really about safety and initial view of the enzymatic activity or protein levels that we're able to achieve. Gary, is that -- is it a fair summary? Or do you have any other?

Yes. Well, I think you covered that very nicely around the biomarker data. I think what part of the question was also around when we get to know it's clinically effective. And I'd just make a couple of comments here maybe. Overall, depending on the age of onset for these patients, therapeutic effect on developmental trajectories is what our clinical objectives or outcomes are, will take up to 24 months.

So the primary efficacy endpoint is, therefore, 24 months, although we'll certainly evaluate clinical changes throughout the study at defined point. I think it's important to remember that children with this GM1 show rapid developmental progression. They have lots of development milestones starting around 6 to 12 months of age.

And after we -- as Bruce mentioned, look at enzyme activity and disease progression markers, with longer-term follow-up and expansion of the cohort we'll then assess impact on patient developmental trajectories, demonstrating that the treatment has restored developmental potential and has positive effects on patients' quality of life.

That's really helpful, Gary. And then one quick follow-up. You mentioned the Invitae LSD collaboration. And wondering if you could talk a little bit how that complements or fits into your own in-house strategies to identify patients.

And I guess, if you could walk through the mechanics on how that information is conveyed from Invitae to passage, that would be helpful. I guess, basically just could there be ways to further extend this collaboration to the other disease settings outside of GM1 that passage is working on?

No. Great question. And yes, maybe I can turn it over to Jill to kind of highlight how the programs work together and how we're thinking about both distributing information and integrating that information into in-house. And again, to your point, how it works not only with GM1, but how we're thinking about the future as well. Jill?

Yes. So Invitae has -- is providing a great service for patients. So essentially, what we're sponsoring here in Invitae is free genetic screening. So when a patient is identified with GALC levels or other things and if there's temperature through genetic screening, that is paid for its free, and they get results through Invitae. The way that, that feeds into passage, we obviously do not get patient-specific information, but importantly, the patient now has a diagnosis and hopefully, earlier than they may have otherwise received it, and they receive clinical trial information through Invitae, through their physician. So they'll be notified about our study and about other studies.

And then we'll be able to funnel through the system in that way. So we're excited about Invitae coming on board. It's definitely important for early patient identification and a longer-term view towards identifying patients as you're moving into a commercial product.

Our next question comes from the line of Di Debjit Chattopadhyay from Guggenheim Securities.

This is Aaron on for Debjit. So I just had a question on how much should we read-through on the risk to the basal ganglia from the GM1 study to the FTD study since the -- you're using different vectors. And I know that AAV1 was selected for a transaction of the ependymal cells, but how well does it transduce neurons, especially relative to AAVhu68.

Yes. Thanks very much. So the GM1 and Krabbe program both use hu68. And if I was to interpret your question, you're talking about the DRG neurons, is that what your referring to?

Yes. Yes.

So yes, we -- and maybe I'll have Gary comment a little bit about the AAV1 both ependymal and other transduction as well. But let me first back up and say that we've reported and been very clear that all of the programs do see some DRG neuronal death and axonopathy. However, in all of our studies, we have not seen this result in any gross symptomology.

Obviously, you can't ask nonhuman primates, but we can assess the behavior and in the studies, there was not any clinical manifestations that we could see. We did see a decrease in the sensory neuron action potentials and conduction velocity. We're going to be monitoring that, and we'll continue to do that because we think it's important to investigate this in patients as well.

And it's also important to note that Jim put out a paper last summer that essentially across multiple different studies, routes of administration and also different AAVs that he did see the dorsal root ganglion toxicity in -- basically across different studies in nonhuman primates.

So it seems to be somewhat agnostic as to the -- both capsid as well as their de route of administration, although it certainly is influenced by the levels achieved in CNS. So we're going to monitor this, but we haven't seen anything clinically to date in terms of our 12 nonhuman primate studies. So maybe I'll turn it over to Gary to talk -- to give any more detail, but also to talk about the AAV1.

You mentioned the ependymal cells. That's not the only cell that gets transduced. So Gary, maybe you can talk about anything that I missed on DRG and the AAV as well.

Yes, I think you covered the DRG. I'm happy to take any follow-up questions here. Regarding the question about the -- I think you're asking about the biodistribution of those vectors. So we see broad brain biodistribution with both hu68, which is the variant of AAV9 and with AAV1 and it's really very, very comparable. The difference is with AAV1 is that we also see a very high transduction of ependymal cells, the cells align the CSF spaces and can secrete programming to the CSF. We see that with AAV1, whereas -- so -- with much less with the hu68. So with AAV1, we see about 50% of ependymal cells are transduced, where it's about 1% to 2% with hu68.

So in a disease like progranulin -- like FTD progranulin, where we believe that superphysiological levels of CSF progranulin are going to be required to correct the intracellular deficiency progranulin, we are using AAV1 because we really want to try progranulin levels up in the CNS. Of course, we don't know that we're going to require 50 fold normal levels, which is what we've achieved in nonhuman primates with that AV1 vector. But we're very happy to be able to dose escalate and determine empirically the levels of progranulin dose of our product that will need to modify the disease pathophysiology.

In contrast, in GM1, we expect that our doses there, which may achieve just -- so let me just put that into perspective. In GM1, we don't expect to need super physiological levels, but if we can bring levels back to the levels of heterozygous, which are 50%, they are completely -- they have no phenotype.

So -- and even patients with 20% of normal activity have a very mild adult form of the disease. So we feel like the bar is much lower there, and that's the rationale for the different vectors in those 2 different programs.

Our next question comes from the line of Yasmeen Rahimi from Piper Sandler.

I have a lot of very tedious questions around beta-gal measurements. It's a critically important data readout mid this year. So maybe we could spend some time talking about the beta-gal assay, how it works, variability associated with it. Is there a certain consideration and blood or CSF collection that we should be aware to contribute or reduce variability in the assay?

And then secondly, maybe also help us understand what are substrates for beta-gal that you're going to be measuring and hopefully sharing with us at day 30 the significance of those biomarkers as prove of concept?

Thanks very much for the question as well. Yes. In terms of the details of the beta-gal assay, certainly turn that over to Gary to talk through. And I think you were asking not only the details, but also are there idiosyncrasies in terms of blood and CNS kind of measurements. I guess, Gary, can you maybe address that too or I can jump back in and then ask you a question.

Happy to do that. Yes. So just first, as I think you understood, we're planning to measure safety and 30-day biomarker data in the program as our first data readout. And that will include levels -- beta-gal activity in both CSF and serum. And we certainly hope to see treatment-related increases in beta-gal activity in those fluids, and that will depend of course on the magnitude of the increase we have -- we observe and our ability to detect it.

To speak to some of your questions about the intricacies of the beta-gal assay, we're using a floor metric assay, and that's what's used across the field. One challenge is that in normal subjects, beta-gal activity in the spinal fluid is much lower. It's about 20-fold lower than it is in serum.

And another challenge to this assay is that beta-gal activity is very labile. So it requires very careful sample collection and storage. We've worked through a lot of the analytical methods to optimize this. So these factors can make detecting CSF -- levels in CSF, where it's much lower, a challenge. But as I said, we've developed the analytical methods to do so. And we're confident we're going to be able to measure activity in serum and hopefully CSF.

But we're not -- we're also planning to use not just beta-gal -- measure beta-gal directly, but also indirectly by looking at substrates, measuring various substrates in beta-gal. And also by looking at other indicators of lysosomal function. So hexosaminidase, which shows a compensatory increase in the presence of lysosomal storage. We'll be looking at that as well as another indicator. So we'll be looking at the totality of the data, the beta-gal activity, but also these other biomarkers to understand the impact of our treatment on beta-gal activity and lysosomal function.

Yes. Yes. And I would just add one thing. I think we've mentioned this before. This is obviously an ICM injection. And while there are specific technical challenges of measuring potential CSF levels, just because of the low endogenous levels of both patients with -- people without the disease and people with the disease, it's going to be very low. But since we're doing ICM injection, and we're measuring both CSF and serum, we'll be very happy to see increases in serum for beta-gal independently of CSF, just simply because we're injecting into the brain, we see blood levels increase, that would also be a very positive outcome.

And then as Gary said, we're also looking at the downstream hexosaminidase and I think keratan sulfate and some other downstream markers as well. So again, the way we're thinking about this is the totality of the data as well as the different compartments, both CSF as well as serum.

Maybe one follow-up question. Do we have a good understanding that day-to-day variability in beta-gal activity in blood in these patients? I guess what I'm trying to understand is there going to be a fluctuation between day 30 versus maybe day 60 or even day 30 versus day 31.

One of the things -- so I'm not sure day-to-day, but I know that Gary and I have talked about that we're going to try to account for any circadian rhythm changes by asking for collection at similar times during the day. I'm not sure if there are in these children, for example, monthly cycles. It's a great question. But I don't know, Gary, if you know the answer to that either.

There is -- there will certainly anticipate some biological variability, but I can just say -- tell you that from our preclinical studies, both in mice and in NHPs, we see durability of effect on beta-gal activity. And so we think that we'll be able to still measure a treatment effect over and above that biological variability.

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.