Well, good afternoon everyone, and welcome again to the fifth annual Guggenheim Genomic Medicines and Rare Disease Conference. My name is Ry Forseth, and here we have William Chou, part of Passage Bio. He's the chief executive officer, and he's going to give us an overview of the company. Thank you so much for joining us today.
Thanks for having me.
Let's start with a platform review and sort of key updates we can expect for 2023.
Sure. I'll start out with our GM1 program for GM1 gangliosidosis. We've treated 8 patients and shared data from the first 6. What we've seen from the first 6 patients is product has a favorable toxicity profile. We saw no SAEs due to the product. Second is we saw a good biologic response in all the patients treated, and we saw that patients who were earlier on treated before they had too much progression of their disease seemed to do better. Third, we saw a profound biomarker dose response effect. We will be doing later this year, we'll be sharing data from patients 7 and 8 midyear.
Those are patients who were treated with dose 2, the higher of the 2 doses we've used, and they're both early infantile patients, so they had less developmental delay at time of treatment. The other thing we'll be doing for the GM1 program is we have modified the protocol to go to an even higher 3rd dose because of the strong dose response that we saw, and we're also changing the inclusion criteria such that we don't treat patients who are more advanced in their disease. We catch them at an earlier stage. That's where we are for the GM1 program. For the FTD program, for patients with the GRN mutation, we are actively recruiting patients. We have great interest from GRN-positive patients who are at our available sites right now. We have 3 open sites now.
We are opening a fourth site next week, and we will be opening a fifth site, later on this spring. That is going well. We will be sharing data from cohort one, second half of this year.
Thanks for laying that out for us.
Mm-hmm.
Maybe thinking more philosophically.
Sure
... the FDA is positioning sort of on accelerated approval for gene therapies appears to be flexible in terms of trial design, but we believe there's an overall need from the agency to see a large clinical effect. What are your thoughts on regulatory flexibility as it relates to your pipeline?
Yeah. Sure. There's definitely been a lot of discussion from Peter Marks about flexibility. If you think about actual trial design, I think a lot of it depends on the specific population. If I look at our populations, GM1 patients have very rapidly progressive disease, so to do something like a randomized trial, it's just not gonna happen in GM1. It wouldn't be ethical. These patients are declining too fast. If they don't get treatment, they are definitely going to pass away. For something like that, a single-arm trial makes sense. For FTD, it progresses more rapidly than, say, Alzheimer's disease, but it's a slower progression. For an indication like that, in our base case, it's a randomized trial that we would have to do. In terms of biomarkers, there's been some great progress.
There's a lot of discussion from the FDA about accelerated approval. The ALS adcom, I think, was something that is very positive overall for the field. When I looked at that data, they showed a nice link between neurofilaments and future progression of disease. They also showed that a therapy that increased the neurofilament levels, patients do worse clinically. It was strong data. It wasn't necessarily a slam dunk for accelerated approval, but if the FDA moves forward with that adcom's recommendations, I think that'd be a strong overall message to the field. You can't read too much directly into for neurofilaments in particular from ALS to FTD. The link is just much stronger in ALS than it is for FTD, but I think big picture, it's very positive for the field.
Well, thanks. You actually stole my next question, which is good. We don't have to cover that, but maybe to get a little granular-
Sure
... about your thoughts, you know, sort of discussions amongst colleagues. There was some thought that there was a maybe discord between the statistician's approach and, say, more the clinical pharmacologist's. You know, sort of what did you see there between the dynamic that you think sort of allows you to use your narrative to, you know, help move through these regulatory?
Yeah
... mechanisms?
I don't wanna comment too much on somebody else's program. What I will say is when I look at, say, for GM1, we have a very nice potential biomarker and because we have the substrate. We have the gangliosides that have been known to correlate with disease severity, and we show a nice effect at dropping those substrates. We know that the FDA has recognized other programs' substrates as a great biomarker for accelerated approval. For something like GM1, we are more set up to have a nice biomarker. For FTD, it's gonna take some time.
Mm-hmm
... to establish that because nothing has been as strongly linked so far, for FTD.
Got it.
Yeah. Mm-hmm.
Thanks for that color. In your opinion, what's been holding back the gene therapy sector, and sort of what is Passage doing to come out of this perceived rut?
Sure. Sure. Well, obviously there's strong macro effects in this environment where, being able to raise funds through the public market has been particularly difficult. What we've heard is that there is more of a focus on later stage and less of a focus on riskier earlier stage programs. That did drive what we did at the end of last year, which was paring down our portfolio to focus on just the most advanced programs. Like I mentioned before, we have data, clinical data coming out from both of those programs this year. From our standpoint, we needed to extend our runway as much as possible so we could continue to generate strong clinical data. Right now we're looking to execute on that clinical data to deliver what we've promised.
We also continue to look for ways to save money as much as possible to extend our runway. It's something that every company is doing right now.
Thanks for that.
Mm-hmm.
At the WORLDSymposium, your company highlighted MRI data.
Sure
... indicating signals of stabilization for up to six months. If you were to plot this versus natural history over a comparable timeframe, you know, what would be the outcome? Because I believe the natural history sort of came from a longer timeframe.
Correct. Correct. For those of you who aren't familiar with our data at World, we showed from a published journal, it was late infantile patients followed for anywhere from 6 to 50 months. What we showed was their MRI severity score, with higher scores, meaning a worsening of clinical conditions on MRI. Those patients all got worse over time between month 6 and month 50. Our patients have been followed. We have 6 patients who've been followed from 6 to 12 months, and their MRI severity scores were all stable. A couple points that you mentioned. First, the comparator group was late infantile patients only. Yes, they were studied for much longer, up to 50 months. Ours were only 6 to 12 months.
Of course, we're going to have to watch that data for a longer period of time. I will note, though, that those late infantile patients, at none of the stages was there any flatness. Like, even early on, there was an upward slope, meaning a worsening of MRI scores, and we saw completely flat MRI scores in our treated patients. We have to watch that over time to see if it continues, but at least so far, it's a good sign. The other thing I will notice is that the comparator was late infantile patients, and those patients have a much slower course of disease than early infantile patients. Our data was both late and early infantile patients.
Got it.
Yeah.
Thanks for working through that with us.
Mm-hmm.
You covered it earlier, but maybe just to recap, you have an update on GM1 program mid-2023.
Mm-hmm.
Could you frame the scope of those data for us?
Sure. We will be sharing data from patients 7 and 8. These are patients who were treated in the 4th quarter of last year. They were both given the 2nd dose level, the higher dose of the 2 doses we've used to date. These are both early infantile patients who have less developmental delay at time of treatment. We'll be sharing 6-month biomarker and clinical data from patients 7 and 8, as well as refreshing the data from the 1st 6 patients.
Got it. Is the plan to finish dosing cohort 4 in the first half of 2023 and then engage the agency on the scope of future studies?
The plans in terms of regulatory are, as I mentioned, we are moving to a 3rd higher dose, so we will start dosing those patients the second half of this year. Once we dose those patients, we would go to the FDA to have a phase 2 discussion.
Okay. disease stabilization versus turning back the clock-
Mm-hmm
is the latter broadly feasible, especially as you move into early infantile patients?
Yeah. Well, certainly our goal is to make as much of a clinical impact as possible. That's why we're going to these earlier patients. Turning back the clock, I think by that you mean getting a continued improvement in developmental milestones. That's certainly something that is our goal and what we would like to achieve. I will say that for families with GM1, what is meaningful for them is maybe very different than what is meaningful to you and I. If you look at, for instance, the Zolgensma approval, the big changes were in EFS. That was survival plus not being on a ventilator, so an element of functional survival as well as achievement of binary milestones, either yes or no, you achieve those milestones that patients would otherwise not get.
For us, the important thing is to get the input of GM1 families, bring that input in discussions with the FDA for what is a meaningful quality of life for these patients.
Got it. Walk us through where you are with manufacturing and what additional investments you'd need prior to registrational studies.
Sure. Prior to registrational studies, we are fine. We actually have plenty of supply to get us into our registrational studies for both GM1 and FTD. We have supply on hand to get to registrational studies. In terms of eventual approval and commercialization, the platform we're using right now is an iCELLis platform, and that is scalable, that we believe can address the needs of for both indications commercially.
Great. Turning to FTD GRN program.
Mm-hmm.
The NHP experience suggests that low dose could establish proof of concept. Is that still the working hypothesis?
Yes, that is still the working hypothesis. Based on our NHP data, we would expect that the first dose that we're using for cohort one would, at a minimum, achieve physiologic levels of CSF progranulin. Yes, we do think it would achieve proof of our concept.
Great. Based on animal data, we would expect rapid expression increase of CSF progranulin with 30 days to peak level. Do you plan on sharing these on sentinel subjects, or would you wait for multiple patients and dosed cohorts?
Yeah. We're gonna wait for multiple patients, from cohort 1 and share the data, en masse, so by cohort.
Got it.
Mm-hmm.
For FTD, would you need a broad distribution? Is this achievable with a low-dose ICM route, or do you expect the highest planned dose to be?
Sure
the efficacy dose?
We, in our preclinical studies, at all doses, we have seen broad distribution of the vector throughout the brain. Given the way the vector works, you don't necessarily need to have the vector in all the cells in the brain, even though we do see it, because we get cross-correction. All of the transduced cells are creating progranulin. It goes out into the CSF. That is in equilibrium with the interstitial fluid, and then the interstitial fluid is really around all the cells. You have a higher level of progranulin in that interstitial fluid outside the cells, and that's how you can get cross-correction transducing any cells in the brain.
Got it.
Mm-hmm.
Passage exited full year 2022 with $190 million in cash.
Sure
Current market cap is $54 million.
Mm-hmm.
How confident are you that the preliminary FTD-GRN data will be compelling enough to change the outlook?
Sure, sure. There's a few pieces of context before I answer, and I am convinced it's going to change the outlook. The, the context is this. First, it's pretty broadly accepted that in FTD with the granulin mutation, if you replace the missing enzyme, that's going to have a downstream clinical effect. In fact, there are multiple other programs, as we all know, testing the same hypothesis and attacking it the same way. What we've also seen is when we look at our preclinical data and compare it to what we've seen in other programs' preclinical data, we are the only program that can test the hypothesis of getting super physiologic levels of CSF progranulin is going to have a better downstream clinical effect.
We've actually seen that improved downstream clinical effect from higher levels of CSF progranulin in our preclinical models. With that as the context, I do think just showing that our preclinical data is translating into the clinic, even at a lower dose, is going to help make that proof point that, yes, what we saw before is translating in the clinic. There is a large potential market. There's multiple people going after it. We've already shown that preclinically, our levels are higher than any other program can get clinically. We've also seen that other preclinical programs, what they showed preclinically is exactly what they're showing clinically as well. I do believe that with us showing with our early patients that we can get that translation of at least physiologic CSF progranulin, I think that will make an impact.
Great. Maybe to end, are there any particular questions that you think the street needs to be asking you that you're not hearing?
I would say the one other thing to think about is that GM1, I get some questions about GM1, but I get a lot about FTD. GM1 is a smaller indication, but it's our lead program. Thinking about some of the things that we just mentioned about the translation of preclinical data to the clinic, what we are seeing from GM1 is that the preclinical data that we saw, that came out of GTP at Penn, it is really translating into the clinic. We're seeing a nice dose response effect, just like we saw preclinically. We're using a different capsid for FTD.
It's not a one-to-one correlation, but what it does give us conviction on is the methods used to make that jump and to file that IND were sound for GM1, and we believe they're gonna be sound for FTD as well.
Wonderful. Well, William, thank you so much for your time. We appreciate you being here.
Okay, thanks for having me.
Thanks.
Take care.