Hey, everyone. Welcome. I think we're ready to start here. Yeah, I'm glad to see you've all survived and made it to the last day here at the TD Cowen Healthcare Conference. I'm Chad Wiatrowski, part of the Biotech and Tools/Dx team here. I'm looking forward to introduce Will Chou, CEO of Passage Bio, just to talk about the exciting things happening at the company today and sort of what we can look forward to in the next upcoming years.
OK, great. Thank you for the introduction. I'm going to be talking today primarily about PBFT02, which is our lead asset. The first indication that we are pursuing for PBFT02 is in frontotemporal dementia patients with a granulin mutation. I'm going to take us through a little bit about the background of progranulin and FTD, a bit about our preclinical data and why we chose this particular vector, and then finally into our updates on the clinical data. Frontotemporal dementia patients with the granulin mutation, they are a subset of FTD who have a mutation in the granulin gene. They are haploinsufficient in making the protein progranulin, and that's what drives the neurodegeneration in these patients. There are no approved disease-modifying therapies for any patients with FTD. Now, what is PBFT02? PBFT02 is an AAV1 that appears to have a differentiated, potentially best-in-class product profile.
With just a single non-surgical injection into the CSF, this product has demonstrated durable, sustained, elevated progranulin levels in the CSF that are really higher than what we've seen from other clinical programs. A little bit about the market size for FTD. FTD patients with the granulin mutation number about 18,000 across the U.S. and Europe. We are also expanding our current protocol to leverage PBFT02 in patients who have the FTD C9 mutation. That's a slightly larger population. That's 21,000 patients. We have also received approval from the FDA to pursue PBFT02 in ALS. We are currently executing some preclinical work to study the effects of raising progranulin in models of Alzheimer's disease. This is a product that raises progranulin levels. Because of the potential benefits of progranulin across multiple diseases, we do have the potential for a pipeline in a single product.
I'm going to get to our guidance and milestones at the end of the program. Let me take you first through a little bit of background about FTD. Frontotemporal dementia is one of the most common early-onset dementias. The constellation of symptoms you can see at the bottom of the slide. In summary, I would call this dementia a behavioral dementia. It's important to think of it as a behavioral dementia because when I get to some of the differentiation with other clinical programs, getting out into the world with patients with FTD is difficult. Going to the store, going to the doctor, going to the hospital, because of all the social irregularities from these patients, family members tell us it's hard to do. Patients live about eight years after the onset of symptoms. As mentioned before, there's no treatments.
For patients who have FTD with the granulin mutation, this mutation is the proximal cause of their neurodegeneration. These patients are haploinsufficient in this gene. Therefore, they have lower levels of the product, which is the protein progranulin. Progranulin is necessary for proper lysosomal function. When you have too little progranulin, you get lysosomal dysfunction, pathogenic inflammation, and ultimately neurodegeneration. Low progranulin levels are the defining cause of FTD in this subset of patients. The interesting thing about this vector that makes it a little bit different from other vectors, especially for neurodegenerative or neuromuscular disease, is because of the normal homeostasis of progranulin, this vector does not need to get into every affected or at-risk cell to have its effect. You may be familiar with DMD. The vector needs to get into every muscle cell to have an effect. Huntington's, same thing.
You need to get into every cell that could be affected. That vector needs to transduce each of those cells. It's a little bit different with progranulin because progranulin in the normal environment lives in the extracellular fluid. It is secreted into the extracellular fluid. Then it is endocytosed by a variety of cell membrane receptors. Then once inside the cell, it exerts its positive effect on lysosomal health. If you can drive elevated progranulin levels in the extracellular space, that increases the substrate for progranulin to be taken into the cell and exert a positive effect. Thus, we can leverage cross-correction. Yes, this vector transduces neurons that transduces glial cells that could be affected. It also transduces other cells that live forever. If those other cells create progranulin and put it into the extracellular space, the at-risk cells can also benefit.
What we have seen from some of our preclinical non-human primate data is that this capsid, in particular, the AAV1, has a particular tropism for ependymal cells, which are everlasting cells. They live just like neurons for as long as the patient does. AAV1 has dramatically more than 40x higher tropism than, say, AAV9 for ependymal cells. This unique tropism might be why we see such a difference between AAV1 and other capsids. This is some other non-human primate preclinical data that demonstrates this. The y-axis is human progranulin levels in non-human primates. The big spike line is AAV1. The other lines are AAV5. AAVhu68 is actually our proprietary AAV9. You can see from this non-human primate study, AAV1 dramatically outperformed AAV9 and AAV5, which is why we selected this capsid for PBFT02.
The one other piece of preclinical data I wanted to share is about vector distribution of our capsid via the ICM route of administration. This is in non-human primates. In our non-human primate studies, a single ICM administration demonstrated robust distribution of vector in every part of the brain that was sampled, so cortical and subcortical regions. We have seen other data from other places say that ICM is unable to get vector throughout the brain. Some of that data is actually in sheep, not in non-human primates. From what we have seen in non-human primates, you certainly can get vector throughout every part of the brain with a single ICM injection. Now on to our ongoing phase 1-2 study of PBFT02. This is a multi-center, multi-cohort open-label study. We currently have seven sites open across the U.S., Canada, Portugal, and Brazil.
We have dosed seven patients to date. The first seven patients have been dosed with dose 1, which is a higher dose. The subsequent patients in cohort 2 and likely in cohort 3 will be dosed with the lower dose, dose 2, which is 50% of dose 1. I'm going to explain both the safety and efficacy reasons of why we're actually moving down in dose instead of going up in dose. The primary endpoints are safety and tolerability. We are testing a host of biomarkers as well as clinical endpoints. The clinical endpoint in FTD is the Clinical Dementia Rating Scale that has been adjusted for patients with FTD. I would say the key endpoints we're looking at in this study from a biomarker standpoint are going to be target engagement, which is CSF progranulin.
Is the product doing what it's supposed to do in raising CSF progranulin. Also neurofilaments. Neurofilaments are a well-accepted signal of neurodegeneration. In the FTD natural history data, the only neurofilament data that exists is plasma neurofilaments in terms of natural history data. We'll share some of that in a moment. A bit about our route of administration. Intra-cisterna magna. The cisterna magna is a pocket of CSF at the base of the skull. This procedure takes about 45 minutes. It is done by an interventional radiologist or a neurosurgeon. Most of the time in our study, it's been interventional radiologists. The needle does not penetrate the brain parenchyma. It only goes into the cisterna magna. Therefore, we avoid any of the micro lesions that one might get from the needle penetrating brain parenchyma.
It allows for broad CNS distribution, as we showed in our non-human primate data, and lower doses compared to IV systemic delivery. As I mentioned, we've treated seven patients to date. In five of the seven patients, they had no SAEs. Two of the seven patients experienced a total of three SAEs. The first patient we treated got a very low level of immunosuppression. They were only getting 60 milligrams of oral prednisone daily as their immunosuppression. This patient had two SAEs. They had an asymptomatic venous sinus thrombus. They also had systemic hepatotoxicity, which responded to IV steroids. After that first patient, we modified the protocol. We added three days of pulse IV steroids around dosing, followed by a 57-day course of oral steroids. All the subsequent patients have had no LFT abnormalities at all and no signs of systemic immunosuppression.
Patient 7 did have an asymptomatic venous sinus thrombus. This is the second patient who's seen this SAE that had completely resolved with anticoagulation by the day 30 MRI. As mentioned, they had no evidence of any hepatotoxicity or any immune response. Our best hypothesis for why this patient also had a VST is while they didn't have any systemic inflammatory response, it is possible that there could be a local immune response that is occurring and causing a local hypercoagulable state. What we have done is we have decided to lower the dose to 50% of the original dose, dose 1. One of the reasons that we feel very comfortable lowering the dose is the robust target engagement that we've seen from dose 1. What you see here on the y-axis again is CSF levels of progranulin. This is the missing protein.
Let me just first guide you to the upper right. At baseline, patients with FTD GRN have levels of about 1.5-2.9. Our patients did. The normal range is 3-8 with an average of about 5. That would be an unaffected person. You can see all of our patients have had a marked increase in CSF progranulin. Anywhere at six months from 13-27, markedly higher than the normal range. Importantly, this effect has been durable. It has been durable to 12 months. In our longest treated patient, it has been durable out to 18 months. I will compare these levels to what we have seen from other clinical programs. The normal range is about 3-8.
There is a monthly IV antibody that raises progranulin levels that gets to an average of about 5-6 with a monthly IV administration. There is also an AAV9 that is delivered also one time via ICM that, oops, it gets to peak levels of about 13 or 14 at month 2, right around here on this chart, and then has shown a decline out to month 12 to about levels of 6-8. What we have seen so far in terms of a target engagement profile is an excellent area under the curve of progranulin at dose 1. Dose 2, we expect to also be consistently above the normal range. For plasma progranulin, FTD GRN patients all start below the gray normal range. As expected, nothing happens to their plasma progranulin with our product, which is by design. The deficiency is in the CNS.
We want to keep our progranulin increases in the CNS where it has the potential to have an effect on neurodegeneration. I had mentioned neurofilaments before. Plasma neurofilaments are the only biomarker where we have a natural history pattern for untreated patients with FTD GRN. In symptomatic FTD GRN patients, the annual rate of change for untreated patients is 29% a year. We have two patients only who have been followed out to two years. With this limited number of patients, we can see that on average, they have a rate of change of negative 13%. While this is a very low end, and clearly it is very early in our study, we are pleased with what we are seeing so far. There is definitely a separation on this biomarker that is a signal that the product is having an effect on neurodegeneration.
We do think that the profile that we have seen so far with PBFT02 does offer the potential to be best in class. PBFT02 is an AAV1 gene therapy delivered via the ICM route. It is a one-time therapy. It has achieved progranulin levels anywhere from 13-27 ng per mL at six months. It has shown to be durable out to 18 months. No decline at all in target engagement. There is an anti-sortilin antibody that is completing its phase III. There will be a readout later this year. It is delivered IV monthly. It achieves progranulin levels of about 4-5. Durability, it is really an NA because this is a monthly therapy. Now, OK, there is a difference in progranulin levels. I am asked all the time, do you know that a higher progranulin level will make a difference in clinical outcomes?
We absolutely do not know that. It has not been demonstrated yet. That is why we are doing the study. I can say that from just a pure drug development standpoint, our goal is to get target engagement as high as possible without having adverse side effects. The higher you can get the target engagement, the more likely you are to have a responder. It is not clear in the literature what level of progranulin is necessary to actually have a clinical response. It may, in fact, be different for every patient. In drug development, you try and get the target engagement as high as possible to maximize your probability of a response. The other thing I will say about this is, as I mentioned before, this is a behavioral dementia.
I do think there is a real place for a one-time therapy, even with the exact same efficacy as a monthly therapy, because many families do not want to go out again and again once a month for the rest of their family member's life to the doctor or the hospital. We do think there is a place even with equivalent efficacy. As I mentioned, there is an AAV9 gene therapy that is also delivered ICM as a one-time therapy. Peak levels are at about two months. Those progranulin levels have declined and are declining between months 2 and 12 from the data that we have seen to date. From this, we do think that the product profile continues to be differentiated.
Now looking ahead a bit, one of the big risks that we've seen from past AAVs really is around tech ops when you get to commercialization. The two big areas where past programs have tripped up are functional potency assay. I'm happy to say that we have aligned with the FDA on our methodology for a functional potency assay to release new batches of PBFT02. The other thing is moving from less efficient academic manufacturing processes to more efficient commercial-ready processes. I'm happy here also to say that we have completed development of a high productivity suspension-based process. At the end of last year, we completed our first 200 L batch of a suspension process. The productivity is extremely high, such that dose 2, we could potentially dose more than 1,000 patients with a single 200 L batch.
Really, really fantastic work by some really wonderful scientists from Passage Bio. The last thing I'll note is we will be seeking regulatory feedback on our registrational strategy in the first half of 2026. At the end of last year, there was a really exciting precedent in adult neurodegenerative disease for gene therapy and Huntington's disease, where CBER agreed to use a natural history comparator for this therapy. We think this is a wonderful precedent that CBER is setting. We think it means a lot for patients in terms of access to innovative therapies more quickly. We're in the process of analyzing the existing databases, natural history databases for FTD GRN. Similar to Huntington's disease, the FTD field also has well-structured prospective natural history databases. We're in the process of interrogating those now. Finally, I will come back to our corporate milestones.
Later this year, second half of this year, we will report additional 12-month data on dose 1 and also interim progranulin and safety data from dose 2. In the first half of 2026, we will seek regulatory feedback on a registrational path. We are also initiating dosing of patients with FTD C9 in the first half of this year. We are looking forward to using dose 2 for those patients. In our pipeline, we have a preclinical program for Huntington's disease. We have a cash balance of $77 million as of the end of last year, which takes our runway out into the first quarter of 2027, which is ample time for us to continue to be dosing patients and seeing this data play out. I believe that is my last slide. With that, I am going to pause and I have a few minutes to answer any questions.
Steroid regimen question. Steroid regimen question, sure.
It may be naive. It is early. I am entitled to naive questions.
Yeah.
Are others doing that? Can you kind of better characterize what AAV you think could be resolved? Oh, apologies. Sorry to repeat the question. Can you just better describe or give us a little bit more color commentary on the prophylactic regimen? My general sense is that we do not need to do as much prophylaxis if we are going specifically into the brain, cerebrospinal fluid, as opposed to systemic. Can you just kind of better update me or update me on what the industry sentiment is?
Sure. You are absolutely right. The CSF is a more immunoprotected space. Actually, the original protocol started with just 60 mg of prednisone, thinking that this was a very immunoprotective space.
That clearly was not enough because some vector, of course, spills out systemically. The first patient got an inflammatory response. I mentioned there is an AAV9 program. That program actually started with steroids. Some patients had rituximab. Some patients had additional T cell inhibitors. I think it was tacrolimus. That program scaled back to now steroids, just like us. We have kind of come in two different directions to the same endpoint, which is just steroids.
Maybe just shifting over to your Huntington's preclinical asset. I know that is early, obviously. Sorry. In a preclinical stage. When you are looking at entrance into the clinic, what are you looking for in regards to early efficacy signs, safety profile that would give you more confidence on that entrance?
Maybe what are the upcoming steps and expected timeline that you see for that asset?
Sure, sure. I'll answer the last one first. We have not given any guidance on timelines for that asset. Obviously, what we are looking for, there are good preclinical models of Huntington's disease. We are looking for good effectiveness in those preclinical models. I will say that this is a very competitive space. We do not want to be repeating what anyone else is doing. We want to offer something different to patients.
In January, you went through sort of a business model transition. There was a sort of a commercial reorganization and you extended your cash runway. Can you just give a high-level overview of what the genesis of that was and where we are at today?
Sure. The genesis of that is it takes time for this data to mature. We know it takes time for the data to mature. The longer we can get our runway, the better. The main component of our reorganization was we previously had our internal lab for analytical development and process development. As I mentioned, these are some incredible scientists. They achieved some amazing things with developing our in-house potency assay and developing our suspension process.
Those were both massive successes. Given our current portfolio and where it is, we were not going to have enough activity for that lab moving forward, at least for the next year. We have decided to close that lab down. We have moved to an outsourcing model for our analytical work. We do not have any more process development work for PBFT02. All of our GMP manufacturing is already outsourced.
We've never done any of our own GMP manufacturing. That was the big change.