Expanding Frontotemporal Dementia Gene Therapy to Both GRN and C9orf72 Mutations
William Chou, MD, president and chief executive officer of Passage Bio, discussed feedback from a recent Type C meeting with the FDA.
William Chou, MD
Passage Bio, which is currently evaluating its investigational gene therapy PBFT02 in patients with frontotemporal dementia with GRN mutations (FTD-GRN), recently received positive feedback from the FDA in a Type C meeting regarding the company’s plans to expand eligibility for the study to patients with FTD with mutations in the C9orf72 gene (FTD-C9orf72). Following the meeting, CGTLive® reached out to William Chou, MD, president and chief executive officer of Passage Bio, to learn more.
Chou discussed the background and rationale behind the company's decision to seek alignment with the FDA on this move. He also highlighted some of the data supporting the discussion.
CGTLive: Can you discuss the Type C Meeting with the FDA and how Passage will use that feedback going forward?
William Chou, MD: This was a fantastic meeting from a lot of different perspectives. The goal of the meeting was to expand our current trial from just FTD-GRN patients to also include FTD patients who have a different mutation, a mutation called the C9orf72 mutation, and this would be the first time that we've seen that a development program has used a gene therapy beyond just the population that is deficient in that 1 gene. The reason that we feel very excited about this approach is there is good preclinical evidence that raising progranulin can ameliorate a pathology called TDP-43 pathology. It's a cellular pathology. It happens in certain neurodegenerative diseases such as FTD with the C9orf72 mutation, such as sporadic amyotrophic lateral sclerosis. If you can get to very high levels of progranulin in preclinical models, you can ameliorate TDP-43 pathology, and thereby ameliorate the neurodegeneration. We haven't seen before gene therapies raising a protein or an enzyme level and using that approach beyond just the genetically affected patient. In that sense, this type of approach is more like an oncology product, where you have a target, you start out within a certain cancer, and then you approach other tumor types where that mechanism might be beneficial.
We shared with the FDA the preclinical evidence that raising progranulin could help in C9orf72, and then we also shared with them our ongoing safety data, as well as our target engagement or efficacy data. We were very pleased that the FDA was completely aligned with our approach. I will be honest, the data that we shared with them was progranulin levels at 6 months that are up to a level of 27. The normal range in patients is about 3 to 8. We shared with them levels that were very high. FTD patients with the C9orf72 mutation actually start out at a slightly higher level of progranulin because they're not deficient in it like the GRN patients are. So we expect that we'll get to even higher levels in FTD-C9orf72 patients. There's no literature on any toxicity from getting to high levels of progranulin and we came to agreement with the FDA that we are going to start FTD-C9orf72 patients at the exact same dose that we're using for FTD-GRN patients. What that tells us is that, like us, the FDA was not concerned about even getting to slightly higher levels than 27 of progranulin. For us, this was a very important signal not just for the potential efficacy of the program, but it also validated our study of the effects of progranulin and whether there could be any toxicity from higher levels. It really validated that as well.
This transcript has been edited for clarity.
