Targeting Progranulin With Gene Therapy for Frontotemporal Dementia
William Chou, MD, president and chief executive officer of Passage Bio, discussed feedback from a recent Type C meeting with the FDA.
This is the second part of an interview with William Chou, MD. For the first part, click here.
William Chou, MD
Passage Bio is currently evaluating its investigational gene therapy PBFT02 in patients with frontotemporal dementia with GRN mutations (FTD-GRN). Notably, the company also recently received positive feedback from the FDA in a Type C meeting regarding plans to expand eligibility for the study to patients with FTD with mutations in the C9orf72 gene.
Following the meeting, CGTLive® reached out to William Chou, MD, president and chief executive officer of Passage Bio, to get some more background information about PBFT02 and the promising early data it has generated so far in FTD-GRN. Chou also discussed remaining questions about the therapy's efficacy and safety that will require more long-term data collection.
CGTLive: Can you give some background info about PBFT02?
William Chou, MD: Our lead program is PBFT02. It is in AAV that is administered directly to the central nervous system (CNS). The first indication that we are attacking with PBFT02 FTD patients who have a mutation in the granulin gene. FTD is the most common early onset dementia. This one particular genetic form of FTD strikes about 10% overall of FTD patients. In the US, about 6000 patients in have FTD with the granulin mutation. When patients have this mutation, they're haploinsufficient in creating a protein called progranulin. Their levels of progranulin are too low, and that leads to neurodegeneration. In FTD-GRN, lack of progranulin is the definitive proximal cause of this disease. Our AAV replaces that progranulin. It gives them a functioning granulin gene, and then they make progranulin in the CNS.
Can you speak about the progress of assessing this gene therapy so far?
We're very excited. We are in the midst of a phase 1/2 study of PBFT02 in patients who have FTD with the granulin mutation. We have treated 5 patients. At this point, we have shared data from the first 3 patients, and what we've seen so far we have been very excited about. So far, the levels of progranulin that this product has been able to achieve in these patients is quite high. It's markedly higher than any of the other developmental programs that are also looking to replace progranulin in these patients. The reason getting to these high levels is important is no one knows how high we need to get progranulin to really save neurodegeneration from happening in these patients. The the field believes there is some threshold that you have to get across, but no one knows what that threshold is. Now, for every patient who gets any modality, there is going to be variability in how high their target engagement is and how high their progranulin gets. It's like if you're on a statin, it may work better for some people, not as well for other people. If, on average, we can get to much higher levels, the variability patient to patient is going to be around a much higher level. Therefore our odds of being over that threshold of clinical effectiveness go way up, and there is no known toxicity from having high levels of progranulin. Therefore we have a very good window. We're really pleased with the levels that we've gotten to. They're about 2 to 3 times higher than the normal level, and certainly higher than what we've seen from other programs in the clinic.
Is there anything else you want to share about the program?
I mentioned before we've shared data from 3 patients. There's a couple of remaining questions in the near-term about our data. The first is that our first patient who we treated had 2 serious adverse events (SAEs), and we had given that patient a very low dose of immunosuppression. We subsequently increased the immunosuppression, and patients 2 and 3 hadn't no SAEs at all. [So] we had 1 patient with 2 SAEs and 2 patients who did much better with the new immunosuppression, but people are waiting to see more safety data to really feel good that we can safely administer this product with the immunosuppression regimen. So that's 1 piece of data that will be coming. We'll be releasing that at the 4th International Conference on Frontotemporal Dementias, held September 19 to 22, 2024, in Amsterdam, the Netherlands.
The other big data that people are interested in is—we have seen other AAV programs in CNS that are looking to raise progranulin—we've seen progranulin levels in those other programs decline over time and not show durability out to 12 months. That's significant. If you're going to do a procedure, if you're going to get a gene therapy, you do want it to be a one-time therapy; that is the goal. We have to this date only shared data out to 6 months. In September, we'll be sharing our first 12 month data. I know many people are looking to see is this going to be durable, or is this going to show decline, like other programs have shown? Those are 2 big pieces of data that we will be sharing come September.
This transcript has been edited for clarity.
