The Research Associate at HC Wainwright. Please introduce Dr. William (Will) Cho, who is the President and Chief Executive Officer of Passage Bio.
Great, thanks for the introduction, Joseph, and for having us here today. Will Cho, CEO of Passage Bio. We are a clinical stage genetic medicines company focused on neurodegenerative disease. I'm going to be talking today primarily about our lead clinical program in frontotemporal dementia. It is called PBFT02. A summary of what I'm going to be saying today is on this slide. There is a huge unmet need in FTD with the GRN mutation. It's a particular genetic form of FTD, as there are no approved disease-modifying therapies. I'm going to share with you our clinical data from our ongoing phase I-2 study. I'm also going to share with you why we believe this product is differentiated and potentially best in class in a therapeutic category that is rather crowded because of its attractiveness. One of the reasons it's attractive is because of the population.
This is a rare disease, but not an ultra-rare disease. Patients with frontotemporal dementia with the GRN mutation number about 18,000 across the U.S. and Europe, and FTD with the C9orf72 mutation number about 21,000 across the U.S. and Europe. These are the two indications where we are pursuing PBFT02, our current gene therapy program. Milestones coming up. I'll just start at the end. In two week s 2025, we will be seeking regulatory feedback on comparability of our suspension-based manufacturing. In the first half of 2026, we'll be reporting on dose two data, as well as seeking regulatory feedback on registrational trial design. First, an overview of PBFT02 and this clinical program. We are studying this product in frontotemporal dementia, which is one of the most common early-onset dementias. The hallmark of this is changes in personality and behavior. Patients get loss of inhibition, apathy, and often their personality completely changes.
There's currently no treatment at all for a disease that after about eight years, people usually succumb to. In patients with frontotemporal dementia with the GRN mutation, this one specific type of FTD, patients who have a dysfunctional GRN gene are haploinsufficient. They have decreased levels of the protein progranulin. Progranulin is very important for CNS cell homeostasis. When you have overly low levels of progranulin, it results in lysosomal dysfunction, neuronal dysfunction, TDP-43 pathology, pathogenic inflammation, and ultimately widespread neurodegeneration. The important thing to remember is that in this type of frontotemporal dementia, low levels of progranulin are the defining characteristics. They are the proximal cause. That's why there are so many entrants in this area, because replacing progranulin is a logical way to prevent neurodegeneration in these patients. The normal functioning of progranulin lends itself very well to AAV gene therapy.
Progranulin in its normal physiology is a secreted protein that is secreted into the extracellular fluid. From the extracellular fluid, it is endocytosed by a variety of cell membrane receptors on neurons and microglia. It is then brought inside the cell where it exerts a positive effect on the lysosomes. Because it is normally an extracellular protein, AAVs can leverage cross-correction. When we administer our AAV, it can transduce cells that are not the at-risk neurons and microglia. It can transduce other cells. Those other cells can then secrete progranulin into the extracellular space, thereby increasing the amount of substrate for potentially at-risk cells to take up. That's why this mechanism of action of progranulin lends itself to AAV gene therapy and cross-correction. This is some data from our preclinical studies. As you know, AAVs can have multiple different types of serotypes. We tested multiple capsids.
This data is showing three capsids, AAV1 versus AAV5 versus an AAV9 variant called AAVHU68. The y-axis is target engagement, which is progranulin levels. The gray area is the healthy adult range. You can see in non-human primates, AAV1 dramatically outperformed both AAV5 and AAV9 in target engagement. That is, levels of CSF progranulin. Because of this reason, we selected AAV1 as the capsid for PBFT02. The route of administration for PBFT02 is intracisterna magna. This is a direct injection to the CSF at the base of the brain. ICM administration of PBFT02 led to a broad distribution of vector throughout the brain and spinal cord. You can see PBFT02 was administered at low, medium, and high doses. There was a dose-dependent large distribution of vector in all sampled areas of the brain and the spinal cord at 90 days after ICM injection of PBFT02.
The other thing we've shown is that in preclinical GRN knockout mice, raising progranulin levels was able to prevent lysosomal dysfunction. We've shown that in multiple different models. You can see most importantly here in the thalamus of these affected mice, only at the highest doses and the highest levels of progranulin did we see incremental improvement in CD68 levels, which is a marker of pathogenic inflammation. This is one of the reasons why we believe that higher levels of progranulin can have incremental positive effects on pathogenic inflammation. This is a schematic, but as an overview of our ongoing phase I-2 trial of PBFT02. This is a multicenter international open-label dose exploration study. We are currently open in the U.S., Canada, Portugal, and Brazil. We have seven sites open, and we will shortly be opening three to four additional sites in the next few months.
We have completed the first two cohorts, so cohorts one and two. We will be holding an IDMC to close cohort two and then opening cohort three. Interestingly, the first dose we used, dose one, was quite effective. I will be sharing some of that information with you. Because of the effectiveness of this dose, and also to optimize the safety profile of the product, we elected to lower the dose for dose two to half the level. Dose two is 2.2E13 genome copies per patient. Dose one is twice that, 4.5E13 genome copies per patient. To date, we have dosed two patients with dose two. Subsequently, all of cohort three patients will also be treated with dose two. The primary endpoints are safety and tolerability. The key biomarkers that we will be looking at are CSF progranulin level.
That is the important level of target engagement. We are trying to increase progranulin in the CSF. The other key biomarker that we will be looking at is plasma levels of neurofilaments. I will share some data from both of these biomarkers with you. Of course, we are also collecting measures of clinical response. The clinical dementia rating scale is a commonly used rating scale in multiple dementia studies. The scale we are using is modified for patients with frontotemporal dementia. The method of administration, as I mentioned before, is intracisterna magna. The reason we chose intracisterna magna is first, it allows for broad CNS biodistribution, as I shared with you previously from our NHP studies. You can give lower doses compared to IV systemic delivery. As shown in the previous slide, we are only delivering levels of vector in the E13 total range. That is markedly lower.
That's two logs lower than the doses being administered with systemic AAVs. There's also a reduced impact of neutralizing antibodies. This procedure is done under CT guidance by an interventional radiologist and does not require a neurosurgeon because the needle does not penetrate brain parenchyma. It's pretty quick. Patients are in and out of the CT scanner in less than an hour-long procedure with actual needle-in time of only about 10 minutes. Some key baseline characteristics for the first eight patients who have been treated in the study: of note, we have treated nine patients, but we are only sharing data from the first eight patients in this presentation. Key things to note here are disease duration at baseline was about three years, so these patients had been progressing. Remember, they only progressed for about eight years. They only lived for about eight years after diagnosis.
The clinical dementia rating scale, sum of boxes score, was 10. Let me put that in perspective. This scale goes from zero, which is unaffected, to 24, which is the worst score, which is the most severe score you could have. Our patients were actually quite impaired on average at the time of treatment. First, a look at the interim safety profile. This is again from the first eight treated patients. Five of eight patients had no SAEs. Three patients did experience SAEs. At dose one, two patients experienced the asymptomatic SAE of a venous sinus thrombus. This is a blood clot in the venous sinus, which is a vein in the brain. It was completely asymptomatic, and both were picked up by routine MRI. Both have completely resolved with anticoagulation and no symptoms to the patient.
At dose two, patient eight had a pulmonary embolism in the setting of a concurrent systemic infection. Even though patient eight, this SAE was deemed to be possibly related to the therapy because of a concurrent systemic infection, because three of eight patients have had a venous thromboembolic event, although they were asymptomatic and were easily treated, because it was three of eight, we have decided to add a prophylactic anticoagulation regimen to all future treated patients. The regimen we will be using is low-dose apixaban, which is a factor Xa inhibitor. We will be using doses that are half of a therapeutic dose. For context, this is a regimen that has been very, very well studied in older patients who are receiving hip replacement and knee replacement therapy.
It is currently the standard of care for prophylactic anticoagulation for several weeks for all older patients receiving hip and knee replacement. It was studied in more than 3,000 patients, and the product has been on the market for this indication for more than 10 years. There is an ample amount of data. This is a very safe and effective method of prophylactic anticoagulation. We're looking forward to introducing that to the study. One of the reasons we're really excited by this program is the level of progranulin that PBFT02 has been able to generate. What you are looking at here is the y-axis shows CSF progranulin levels, the x-axis shows time since treatment. The first thing I'll orient you to is the healthy adult range, which is about 3- 8 ng per ml. That is the gray shaded area.
Note at time point zero at baseline, all of the affected patients were lower than that normal range. As one would expect, they're haploinsufficient in the GRN gene, therefore they have low levels of progranulin. Let's look at dose one first, the higher dose. All of these patients had an immediate robust increase in progranulin levels, and by month 12, their progranulin levels were more than 25 ng per ml on average. This was durable out to 18 months. As I mentioned, we've started dosing patients with the lower dose, dose two. There is only one data point available for dose two at this time, but that data point is very encouraging. The first dose two patient at 30 days has already reached a level of 7.6 ng per ml, which is already at the high end of the normal range.
If you look at the pattern of increase that we've seen with dose one, we fully expect these dose two patients to plateau at a level above the healthy adult range, which is what we are targeting with this therapy. We're pleased so far by the robust and durable responses we've seen at dose one, which is another reason we felt very comfortable with moving to a lower dose, which is dose two. The other biomarker that I mentioned before is plasma neurofilament levels. Neurofilaments are a sign of degenerating neurons, and they go up over time as patients have more neurodegeneration. Plasma levels, or blood levels, of neurofilaments are the only biomarker that are available in a longitudinal way in natural history of untreated patients with frontotemporal dementia.
This is really the only biomarker of disease progression that we can track over time and know what it looks like in untreated patients. In those untreated patients, in both published research and in our own analysis of available natural history data, the annual rate of change of blood neurofilaments is about a 29% increase per year. In our four patients who were treated with PBFT02, who have reached one year of follow-up, the average rate of change was 3.7%. Clearly, it appears that the product is having an effect on slowing neurodegeneration. While it's still early, this is a good early signal. I mentioned before that we believe this product to be differentiated. What I'm showing here on this slide is PBFT02 next to other therapies for FTD GRN that have shared clinical data to date. As mentioned, PBFT02 is an AAV1 delivered ICM and is a one-time therapy.
At month 12, it's achieved progranulin levels on average of 26 ng per ml, and it's shown durability out to 18 months. There is an antisortillin antibody that has completed enrollment of its phase three study and will be reading out data later this year, which we are all looking forward to. This product is delivered IV monthly. It has achieved, in past data disclosed, phase two data, levels of 4-5 nanograms per milliliter, so markedly lower than PBFT02. Durability is not really an issue here because this is a monthly administration. Imagine these patients who have a behavioral dementia, their family needs to take them to the hospital once a month indefinitely. We believe that a one-time therapy is going to be preferred. From our market research, we believe that it will be preferred by families as well as physicians.
Finally, there is one other one-time AAV therapy, an AAV9 that is delivered ICM. It has shown CSF progranulin levels at 12 months of four to eight nanograms per ml, so lower than PBFT02, and has also showed a declining profile of CSF progranulin from month two to month 12. We believe PBFT02 is uniquely positioned to offer a one-time therapy capable of achieving the highest durable progranulin levels. In summary, from our GRN patients treated, three of eight patients experienced a total of four SAEs. There's been no evidence of any clinically significant immune response in any of our eight patients who have been treated with a combined IV and p.o. steroid immunosuppression regimen. Our immunosuppression is only steroids. It's three days of IV steroids followed by 57 days of oral steroids. There have been no complications during the ICM administration.
This product has the potential to have best-in-class progranulin levels that are durable. Plasma neurofilaments have shown early evidence of improvement versus natural history. The anticipated next steps for the program are we are holding a cohort two IDMC and also implementing a protocol then to introduce this short course of prophylactic anticoagulation and also revise the inclusion criteria to include earlier patients and also exclude the more severely progressed patients. We will continue to enroll both FTD GRN and FTD C9 patients. Before I end, I want to briefly mention FTD C9. PBFT02 has the opportunity to treat a multitude of diseases because progranulin raising has been shown to improve TDP-43 pathology. FTD GRN, FTD C9, and ALS all have TDP-43 pathology. Several preclinical models have shown that raising progranulin can improve and ameliorate TDP-43 pathology.
That is why we will be opening up a clinical study to FTD C9 patients later this year. We have already achieved, aligned with the FDA, on a functional potency assay. We have already completed developing a suspension-based manufacturing process where a single lot is estimated to yield greater than 1,000 doses at dose two and has shown greater than 70% full capsid rates. This is a very robust commercial-ready manufacturing process. In conclusion, our upcoming milestones: second half of 2025, we will seek regulatory feedback on the suspension-based manufacturing process. In the first half of 2026, we will report updated interim safety and biomarker data from dose two and seek regulatory feedback on registrational design. We are advancing a Huntington's disease preclinical program that we're very excited about. We're looking forward to disclosing more data on later this year or earlier next year.
We have cash balance of $58 million as of the end of the second quarter and cash runway into the first quarter of 2027. Ample time for us to continue to treat patients and see continued response in prevention of neurodegeneration. Thank you very much for your time. I look forward to any other questions in one-on-ones.
Thank you again, everyone, for joining us. A replay of today's presentation will be available on your conference portal. Thank you.