Thank you for joining the Guggenheim Securities Healthcare team at our Sixth Annual Conference. I am Debjit, and joining us from Passage Bio is its President and CEO, William Chou. Thank you for your time, Will.
Thanks for having me here.
Before we get to the Q&A, maybe a very quick introduction on Passage?
Sure, fantastic. So we are an AAV gene therapy company focused on neurodegenerative diseases, and our lead indication is in FTD patients with the GRN mutation.
Got it. And you had some preliminary data in December, looked really interesting. Supraphysiologic levels with a single dose. Clinical implications of supraphysiologic levels versus the mAb, mAb-based approach, we just got a breakthrough therapy designation-
Sure
- a couple of days ago.
Yeah, that was fantastic, that breakthrough designation. Great for FTD patients. So, I wanna focus on two things here. Focus on levels and also mechanism of action, and I wanna delineate between what is known and what is just hypothesis. So in terms of levels, what we do know is that this program, PBFT02, has been able to generate the highest levels of CSF progranulin, so 2x-3 x the normal levels. Highest levels of any program that is treating FTD-GRN patients. So we know that. We also have some preclinical evidence that getting to supraphysiologic levels can have an incremental benefit. We have our preclinical data in GRN knockout mice that shows getting to levels in the teens, shows incremental benefits in pathogenic inflammation.
We also have third-party research done in TDP-43 mouse models, and TDP-43 is the pathway, the cellular pathway for all patients with FTD-GRN, that if you can raise progranulin levels 2x-3x times the normal levels, it can ameliorate TDP-43 pathology. So that's what we know. What we don't know is will that translate into the clinic, into incremental benefits? But that's why we're doing the experiment, and we're really excited to be able to do that experiment because we can reach these levels. The other thing I wanna point out is mechanistic. So you mentioned the antibody approach. What we do know is that sortilin mediates bringing progranulin into the cell, and yes, does shuttle progranulin for destruction. But...
And we do know that progranulin has other ways of getting into the cell, but pro sortilin also mediates positive effects of progranulin on the lysosome. Progranulin also is a method by which other proteins get into the cell, such as prosaposin. So prosaposin binds the progranulin and is brought into the cell via sortilin. So what we don't know is, if by blocking sortilin, are you doing more than just preventing the destruction of progranulin? So that is an unknown out there.
So you mentioned getting it-
Mm-hmm.
2x- 3x fold higher.
Yeah.
So you're already there with Cohort 2.
Mm-hmm.
Why pursue Cohort 2?
Yeah.
What are you trying to achieve at the second Cohort?
Sure, sure. So Cohort 2, per the protocol, would be a 3x higher dose. It doesn't have to be a 3x higher dose. We have flexibility in the protocol to dose at the same dose level. And while our data is very encouraging so far, it is still early. So if we were able to consistently see these very high levels, 2x-3x higher of CSF progranulin than normal, then we would potentially not have to raise the dose for Cohort 2.
The Cohort 2 is expected to start in the first half of this year?
Correct.
What's that? Why the gap between when the Cohort 1 was dosed and Cohort 2? What are you try-
Yes, so we-
What are you trying to collect?
Right. We are dosing two more patients at the current dose as part of Cohort 1. So each Cohort can be three to five patients. Together with our IDMC, we've elected to dose two more patients at the current dose, and if the effect that we see is consistent with what we've seen in the first three patients, and if we continue to see durable high levels, then we will make a decision on Cohort 2 dose based on that.
Got it. These two patients who are gonna be dosed or are getting dosed, from a prophy steroid perspective, they'll be prophylactically dosed as, unlike the first patient?
Yes, they are going to get the modified higher dose of steroids, around treatment. Yes.
Does that impact expression levels, or that's more of a inflammation safety?
It does not impact expression levels. As you can see, we've continued to have very high expression levels in patients who've received this product. But it does affect the immediate immune response and also the late-stage immune response, based on what we've seen so far.
Are you planning to update the Street on the progress from the first five patients before you elect to move to Cohort 2?
So what we have shared is that in the second half of this year, we will be sharing more long-term data, so additional 6-month data. We should have some 12-month data then as well, and we'll have data from the newly dosed patients. And if at that time we have made a decision on what we're doing with Cohort 2, then, of course, we would disclose that then as well.
And for the patients who are being followed for, let's say, up to 12 months-
Mm-hmm
... what would be the clinical endpoints beyond expression that you can possibly capture?
Sure. Well, the one clinical endpoint that we're capturing is the CDR that has been, so the Clinical Dementia Rating scale modified for FTD, and that is the endpoint that everyone is using in this field. What I will say is that this endpoint takes some time to see a difference, and there's a lot of variability. So there's been published data in FTD-GRN looking at patients versus natural history, and what you see is you look at-
Mm-hmm
... individual patients, there's a lot of up/down in those patients, and some have a very large effect, and some have a smaller effect. So you need an appropriate end to really see something from a clinical standpoint. So it does require some patience and some volume of patients as well.
You touched upon natural history.
Mm-hmm.
Can you just walk us through what's typical time course for progression is in FTD-GRN?
Yeah. So FTD-GRN progression is very fast, so five to six years between diagnosis and death. The FTD-GRN patients are the most rapidly progressing of all the different forms of FTD. That's one of the reasons why it is a good first population to study. Because your likelihood of seeing a difference versus natural history is going to be highest in the most rapidly progressing disease.
So when these patients present-
Mm-hmm
... with a diagnosis-
Yeah
... do they have the last brain mass, brain volume, et cetera, like in Huntington's, or they still have preserved function?
It depends on when they present, and the later they present, the more changes in MRI that they are going to have.
So when you select your patients for the-
Mm-hmm
... ongoing study.
Yep
... what kind of patients are you sort of picking on?
Yeah. So our patients have to be symptomatic, and they have to be living in the community. So there is gonna be a range of severity of those patients. We've already seen that. If you look at our first three patients treated, they were moderate to severely affected. Our goal is to treat patients as early as possible, but we want to make this trial open to as many patients as possible. The ultimate goal is to get to treat patients who, before they are symptomatic. Eventually, we will get there, but obviously, that's a difficult place to start a study, a first-in-human study.
Got it. And from a platform perspective-
Mm-hmm
... you are sort of tethered to the, ICM route?
Mm-hmm.
Can you help us understand the time it takes for every patient for the entire procedure to be completed?
Sure.
Because let's say if you have your product approved and the mAb-based approach-
Yeah
... approved-
Yeah
... procedure times could also-
Sure, of course, of course. So, let me tell you a little bit about the ICM procedure. So, something I didn't know this, but I was taught this, is that they used to do ICM procedures without any imaging at all in medicine because it is a pretty big space. Now we do it under CT guidance. The procedure itself only takes about a half an hour, and so patient goes in, you insert the needle, get a CT scan, look for the placement of the needle, move the needle in a little bit more, get another CT scan. When you're in the right spot, then the product is administered. The actual administration of the product only takes a couple of minutes, just a quick push. But overall, the procedure is only about a half hour.
We ultimately envision this being a same-day surgery procedure. You wanna get patients in and out of the hospital. In terms of the invasiveness, remember, we're not going through brain parenchyma here. This is an open space that is outside of the brain. Interventional radiologists definitely hit much, much, much smaller spaces than this. From our own track record, we have treated now 11 GM1 patients who are infants with no adverse event from the ICM procedure. So this is not going to be a procedure, ultimately, that is gonna require a neurosurgeon, general anesthesia, a stay in the hospital. It is not going to require that. This needs to be a same-day procedure, and we do believe it can be a same-day procedure.
So the patients are not under general anesthesia, just local?
Well, eventually they will be.
But right now they are-
Right, right now they are. Some of this is a holdover. I ask, "Why? Why are we doing this now with these patients?" Some of it is a holdover because our original studies were in pediatrics trials, and so it just held over. For our pivotal study, we will move to something more like conscious sedation.
Got it. And then to effectively-
Mm-hmm
... say, compete versus the monoclonal-
Mm-hmm
... antibody approach-
Yeah
What do you need to demonstrate? You know, the reason I ask that is-
Yeah
... it takes, like you said, five years from a progression perspective.
Mm-hmm. Right.
You can't possibly run a five year study. You can't possibly run a randomized study.
Right. I'd say what we need to demonstrate to compete effectively is, at a minimum, at a minimum, show similar clinical efficacy, right? I think that is the bare minimum. We have seen many products who have had great uptake from patients because they are a one-time therapy versus something that is repetitive. If I look at patients and family members who are taking care of patients who have a behavioral dementia... Coming in every month for an IV for essentially the rest of your life, it's a pretty big commitment, and we do think at a bare minimum, if we show equivalent efficacy, that'll be a great option for patients. Based on everything I talked about from the preclinical data, we do think we're going to be better than that.
At a minimum, I do think equivalent efficacy would be meaningful, it'd be a meaningful option for patients and their families.
The one difference-
Mm-hmm.
From monoclonal antibodies to date is plasma progranulin levels?
Yeah.
What's the clinical significance of that? Because you don't-
Yeah
-raise.
Right. So we don't raise plasma progranulin levels. At the, the simplest way to explain this is, you know, we're trying to get on target effects in the CNS. This is a CNS disease. It is not a disease in the periphery, and so that is consistent. We are raising it in the CNS, but not in the periphery. Now, the more in-depth answer that I want to talk through is around safety. So we are asked sometimes, "Well, what do we know about the safety of getting high levels of progranulin?" And I want to share what we do know and what we don't know about high levels of progranulin. What we don't know, there is no level of progranulin that is too high. That's just not known. But, there's no literature on that at all.
What we do know is that we haven't seen any toxicity from our preclinical studies of... We've gotten up to a level of about 70, and we know that others are getting to high levels, both preclinically and in the clinic, and we have not heard of any toxicity from high levels of progranulin in the CSF. What is known, if you look up progranulin and toxicity, is in the oncology literature, in the solid tumor microenvironment, progranulin can be pro-growth. It can drive cell proliferation. So in theory, if you had a tumor, you would not want to have extra progranulin around, driving cell proliferation. The important thing to note here is that progranulin itself is not oncogenic. So you know, you know how tumors work. You have a mutation, and it causes constitutive secretion of a growth factor.
It's not the other way around, where the growth factor causes the mutation. This is getting back to your question about the plasma levels. So because our plasma levels are low and they remain low, we are not worried about if the patient happened to have a pre-existing tumor peripherally, because we don't affect peripheral progranulin. And in terms of CNS, all of our patients now and commercially, they are all gonna need imaging. So nobody is going to have a pre-existing tumor, if you're concerned about that, and be getting our product. So I wanted to use this as an opportunity to talk about what we do know about progranulin levels.
Yeah, that was helpful context.
Sure, yeah.
So the pipeline right now is, PBFT02-
Right.
spread across multiple diseases.
Mm-hmm.
Giving consideration to the balance sheet and the current environment where the stock is-
Yeah.
How quickly can you sort of generate proof of concept data from the other-
Yeah
-indications?
Yeah. So, we're very excited. Because we're excited by what we've seen so far from PBFT02, it's even more exciting that there is good reason to believe that we can be successful in other TDP-43 pathologies. The fact that we've invested so much in the preclinical, in generating safety data, and in understanding that we can actually get successful target engagement, being able to manufacture the product, advancing the process of how we're manufacturing the product to a more efficient way, this is all investment that we can now amortize other, across other large shots on goal, where we think there is a good reason to believe. Now, to answer your question, for ALS, there's obviously a better biomarker. So neurofilaments are a better biomarker. You can see neurofilament changes more quickly than you can see clinical changes, and there is a sound link in ALS.
So it is definitely faster once you treat patients to get to neurofilament levels. FTD-C9, we are gonna test a lot of exploratory biomarkers, similar to what we're doing in FTD-GRN. None of them are as strong as, say, neurofilament. So I do think you'll ultimately need to wait for clinical outcomes to see what happens, to see an effect. That being said, because we have an existing trial ongoing in FTD, opening that to FTD-C9 patients is a much lower bar. It, in terms of cost, in terms of time, we can get to treating patients with FTD-C9 faster.
So, to step back.
Mm-hmm.
You think there's gonna be a homology between dose that you use in FTD-GRN versus ALS or C9?
That's a great question. I will say that we are considering dose selection for FTD-C9 right now. It'll be a discussion that we have with regulators. I mean, I can tell you what our—what you—we know from looking at the data. So the baseline levels of progranulin in patients with FTD-GRN, so our patients have been just a little below three. If you look at some of the patients who've been treated with FTD-C9, they look like their baselines are slightly higher, but not that much higher, so in the five range. So, I would expect whatever we're seeing in FTD-GRN, you can imagine you just tack on two or three in progranulin level because they're starting at a higher baseline.
So it's not a significant difference in baseline, especially given the levels that we're getting to in the teens and the 20s. These are much higher increases than that small baseline difference.
How much would you need to increase in those indications?
So, based on the TDP-43 data, and that's the best analog I can give you from preclinically, we would be shooting to get to 2x-3x normal levels, 'cause that's what really ameliorated the TDP-43 pathology. If you're just getting a little bit above normal, that's not what those preclinical studies did.
Earlier, you mentioned-
Mm-hmm
... the potential noise in the harder clinical endpoints.
Mm-hmm. Sure.
As this data set matures, what are you gonna compare this with to conclusively say, "This is making a clinical impact?
Yeah. So the good thing about FTD is there are really readily available natural history data sets. So ALLFTD and GENFI are very strong, large data sets that have many FTD GRN patients in them. So ultimately, we'll be comparing to those natural history data sets as a first approach. And the question is just: how much of an N do you need to have to really see a meaningful difference?
Yeah, I mean, this is a vexing question because we've seen another company-
Mm-hmm
... trying to develop a Huntington disease gene therapy, and, you know, even with extended follow-up, it's really not separating from natural history.
Right.
But Huntington's is probably a slower progressing disease-
Sure
... and they had a healthier baseline. So, you know, tying it back to where the stock is currently and what you actually can show-
Mm-hmm
... to positively impact valuation-
Yeah
... is sort of an unknown question right now.
Yeah, I do think we have the advantage of there has been a nice groundwork laid connecting in FTD-GRN patients. Even a modest increase in progranulin levels to the normal range has shown benefits from both a biomarker perspective and also a clinical perspective. And so because that link has already been made, and because that is the basis of the, these patients' disease, is they're haploinsufficient in progranulin, that is what is causing their disease. Because of that, the important thing for us is to show, one, that we can safely administer the product, because we wanna, we've had two patients who've been safely given the product with the higher steroid regimen. We wanna build on that data set, and also that we can consistently get durable, high, supra physiologic levels of progranulin.
Those are the things that we think will really help us, because a lot of the, a lot of the other data set, the connecting data set, has already been generated.
So on the regulatory side-
Mm-hmm
... are you gonna be primarily dealing with CBER or the neurology division?
We'll be dealing with CBER. Mm-hmm.
So CBER has shown enormous flexibility in DMD, but somehow it has not translated into the neurodegenerative diseases. What needs to change from your side?
Yeah, I would say our goal is to show that we can make a good clinical effect. And if biomarkers are established such that there is a sound link between the biomarker and clinical outcome, then that is something that we can use to our advantage. I think it is very important for regulators to have a high bar like that, that we should not be approving programs that don't have a good potential clinical outcome. And so seeing that link between biomarker and clinical outcome, I think is an important bar to have. And we would certainly look to have that discussion with regulators.
We might not be there right now in FTD-GRN, where there is that clear link between biomarker X and clinical outcomes, but we may be in a short period of time, in a couple of years.
For the last few minutes, just wanted to touch on GM1, Krabbe, et cetera.
Sure.
You sort of are now with, sort of shelved, right? Waiting for a partner.
Yeah.
Given how small those indications are commercially-
Right
... do you think you'd be able to partner those and bring in some non-dilutive capital?
So I feel very positive about our prospects of outlicensing these. In fact, there is real interest in these programs. I think you have to think about them as a package, right? Any one of them, it's going to be hard to have that scale. But if you have a partner who is interested in multiple pediatric programs and having the scale to advance all of them, and also being able to do that, you need the scale both on a manufacturing standpoint and commercially. So the answer is yes, there are interested parties in that, and we feel very good about our ability to outlicense these.
So to wrap it up, from a cash runway perspective, where are you currently? And if you were to just prioritize FTD-GRN versus the-
Yeah
... ALS and the other indications, where does it take you?
Sure, sure. So our runway right now is out to the end of 2025, and of course, the FTD-GRN is the clear priority. So including that runway is this ongoing study for FTD-GRN, all the CMC process development and potency assay development that we're making great progress on, that is all part of it. Also included in that runway is the initial clinical work in FTD-C9. But ALS clinical, Alzheimer's clinical, those are not included in that runway. The preclinical work is included in that.
Got it. Appreciate the time, Will.
Okay.
Thank you so much, and good luck into the second half of the day.
All right, thanks very much.
Thanks so much.
Appreciate it.