William Chou, MD, strives to bring more hope to patients with neurodegenerative diseases. And Passage Bio, where Chou is president and CEO, may now have the green light to test their lead gene therapy asset more broadly than the initial focus of frontotemporal dementia (FTD) caused by mutations in one specific gene.
Passage Bio’s adeno-associated virus (AAV) gene therapy to rescue granulin (GRN) gene expression in the nervous system may also help people with FTD caused by genes other than GRN. The company has announced that the FDA has approved expanding the testing of PBFT02 in FTD patients beyond those with GRN mutations to those with mutations in C9orf72.
The FDA recently received preclinical evidence from Passage Bio that increasing progranulin levels, which are encoded by GRN, with PBFT02 improves outcomes in FTD models for GRN haploinsufficiency as well as mutations in C9orf72. The data also included safety and robust progranulin expression data from the first group of FTD-GRN patients treated with PBFT02.
“About a third of genetic FTD patients are FTD-GRN, and slightly more than a third are FTD-C9orf72,” Chou told Inside Precision Medicine. “We saw the preclinical promise of increased progranulin levels and realized we could safely administer PBFT02 to patients. We presented all of that data to the FDA, who agreed with our assessment that we could proceed and test it on [FTD-C9orf72] patients.”
The company intends to amend the protocol for the ongoing upliFT-D Phase I/II global study for FTD-GRN to introduce a new population of FTD-C9orf72 patients, who are expected to initiate dosing in the first half of 2025.
Double dipping
Since there are only some minor differences between FTD-GRN and FTD-C9orf27—FTD-GRN patients have the most rapid and aggressive form of the disease—the protocol will hardly change for the two additional cohorts of FTD-C9orf27 patients. The primary endpoint will still be safety, but Passage Bio will also look at pharmacokinetics as well as efficacy endpoints, including the clinical dementia rating scale, the levels of neurofilaments, and biomarkers of lysosomal dysfunction. So, while they differ in some ways, Chou said they will test all of the same types of biomarker endpoints.
But what may be one of the biggest boons to Passage Bio is that the marginal investment to get some clinical data for FTD-C9orf72 will be relatively small. Chou said that the overall cost of investing in PBFT02 is pretty small for a potentially more than double market. Chou noted that Passage Bio already has the internal analytical and process development capabilities to handle all of that work and that Passage Bio already has supplies for these two cohorts of FTD-C9orf27 patients. Additionally, the data generated for FTD-C9orf72 can potentially assist in any regulatory discussions for FTD-GRN.
“We do not need to increase supply or invest any money—we’ve got plenty on hand,” said Chou. “The previous investment in PBFT02 has been significant, not limited to manufacturing. The preclinical work is complete. It’s all of the tech transfer work. It’s all the tech development. If you look at the cost and time, it’s far less expensive to do an add-on indication like FTD-C9orf72 than a de novo program. But the cost itself should not be the driver of it. We 100% believe in the potential efficacy of this program, and I would say that we’re not the only ones.”
The TDP-43 umbrella of neurodegenerative diseases
While it is very exciting to Chou and Passage Bio that PBFT02 may work for multiple FTD genotypes, there are potentially even bigger fish to fry as it could be effective in other neurodegenerative diseases.
A specific cellular phenotype known as TDP-43 deficiency distinguishes FTD from other neurodegenerative diseases. TDP-43 is a protein that should be found inside a cell’s nucleus for various reasons, many of which are unknown. In some cases, it is mislocalized to the cytoplasm, causing inclusion bodies in neurodegeneration. According to Chou, FTD with the GRN or the C9orf72 mutations has TDP-43 pathology, as do almost all patients with sporadic Amyotrophic lateral sclerosis (ALS).
ALS and FTD are very similar diseases on a cellular level; they affect different parts of the nervous system—FTD is a central nervous system disease, whereas ALS is a motor neuron disease.
“The preclinical evidence supporting FTD-C9orf72 is very similar to that supporting ALS; it all revolves around TDP-43 pathology,” said Chou. “We believe we have enough preclinical data to have a strong case for ALS and go directly to the clinic. It was already clear enough to the FDA for FTD-C9orf27. So, we are in a unique position with PBFT02 to try to use progranulin to combat TDP-43 pathologies because of the extremely high levels we can obtain, which is why we are excited about the scientific potential of PBFT02. If we believe in the science, which we do, it is an excellent business opportunity.”
Indeed, ALS represents an even bigger opportunity. There are approximately 72,600 sporadic ALS patients in the United States and Europe (compared to 18,000 and 21,000 for FTD-GRN and FTD-C9orf72).
“There is a much larger market for ALS, so, from a business standpoint, it is very appealing to look into that,” said Chou.
Taking on Alzheimer’s
Passage Bio is also investigating whether PBFT02 could be efficacious in Alzheimer’s disease. According to Chou, approximately 30% of Alzheimer’s patients have a single nucleotide polymorphism in the GRN gene, resulting in slightly lower progranulin levels on average. That has been linked to an earlier onset of dementia and pathologic changes. Further, Chou said there is some preclinical evidence that lowering progranulin can exacerbate Alzheimer’s phenotypes in preclinical models, whereas increasing it can improve those phenotypes.
“What I will say about Alzheimer’s disease is that it is a much larger endeavor, with promising preclinical evidence,” said Chou. “We are doing some additional preclinical work on Alzheimer’s disease to gain more confidence in our decision to invest in this area. However, we have sufficient conviction to carry out the preclinical work.”
But Passage Bio will have to move quickly and efficiently, as other companies with a gene therapy candidate for raising progranulin levels are also studying neurodegenerative diseases. Notably, Alector is running a Phase III study of AL001, which aims to bring low progranulin protein levels back to normal in people with FTD. That differs slightly from PBFT02, which Chou said can raise progranulin levels two- to three-fold.
“There have been other programs that have looked at raising progranulin,” said Chou. “The trick is, can you get progranulin high enough to have an effect?”
Tailwinds for gene therapy in the nervous system
Ultimately, while it is great that Passage Bio may benefit as a business from the widespread applicability of PBFT02, the most critical thing to Chou is still the patient.
“There are not many trials right now for FTD-C9orf27 patients, so I hope this brings more hope to the patients,” said Chou. “We need to get the patient community excited, and we cannot guarantee what we will find, but we are in the business of bringing hope to patients. We have already heard from the American FTD Association, which is pretty excited about this because it will provide their patients with new opportunities who do not currently have access to new trials.
Chou said that perhaps the most important question for both patients and providers is whether PBFT02 will lead to a durable, long-term response. He said that the team at Passage Bio is excited to share more data on the FTD-GRN program this fall.
“I believe the main question people may have is whether this is a potential one-time therapy,” said Chou. “We have now shown data for six months.”
Chou pointed to data released by UniQure less than a week ago on their gene therapy for Huntington’s disease. “That program has had its ups and downs, but they showed two-year clinical results that appeared very strong,” said Chou. “As a fellow gene therapy company in CNS disease, it is very encouraging to know that if you have good science and keep pursuing it, it will eventually pay off. Sometimes, it takes time to see results, but you can make a difference for patients, and it appears that their product is helping patients. So we believe this is a positive tailwind for us in gene therapy and CNS disease.”
