Biopharmaceutical company Passage Bio announced on July 16 that it has received positive feedback from the U.S. Food and Drug Administration (FDA) regarding a proposal to expand its clinical trial for a gene therapy for people with FTD caused by a variant in the GRN gene to also include people with FTD caused by the C9orf72 gene.

Inherited variants in the GRN and C9orf72 genes are common causes of genetic FTD. When such variants are present, the protein TDP-43 can accumulate abnormally in an affected person’s brain, while also suppressing production of a different protein called progranulin; both are linked to the onset of FTD. Passage Bio’s gene therapy PBFT02 seeks to remedy this by delivering healthy copies of GRN into the body via an engineered virus known as a vector.

In late 2023, Passage Bio released promising initial data from the trial, in which participants showed significant increases in progranulin in their cerebrospinal fluid after 30 days. In a 2024 update on the trial, Passage Bio noted that two participants showed continued elevation in progranulin levels six months after being dosed.

Progranulin plays key roles in multiple functions critical to the health and survival of brain cells, including autophagy, the process responsible for clearing damaged or abnormal proteins, and inflammation. Because both the pathological GRN variant and the disease-causing expansion of the C9orf72 gene have harmful effects on autophagy and cells known as microglia, which regulate inflammation, and both lead to the abnormal accumulation of TDP-43, increasing progranulin levels could be helpful in FTD-C9 as well as FTD-GRN. In addition, variants in the GRN gene that don’t cause FTD but do modify the impact of the C9orf72 variant cause reductions in progranulin that could be reversed by treatment with drugs such as PBFT02.

Now, in a significant step forward – thanks to the FDA’s positive feedback – Passage Bio will open its trial to people with C9orf72 variants. Passage Bio president and CEO Will Chou, MD, called this step “a critical milestone in expanding access to those who could benefit from PBFT02.

“Given the limited clinical trials for FTD-C9orf72 patients, we believe PBFT02 could fill a significant unmet need and bring new hope to this underserved patient community,” Dr. Chou continued. “We look forward to further advancing the clinical development of PBFT02 and building upon the encouraging data we’ve seen from the upliFT-D trial so far.”

Passage Bio is working on revising its trial protocol to include people with C9orf72 variants and will submit it for review soon. The company plans to begin enrolling people with C9orf72 variants in 2025; AFTD and the FTD Disorders Registry will provide updates on when enrollment will begin as more details emerge.

“AFTD congratulates Passage Bio on this breakthrough,” said AFTD Senior Director of Scientific Initiatives Penny Dacks, PhD. “Their achievement demonstrates how an FTD trial, including one with a limited scope of eligible participants, may sometimes expand its eligibility to bring hope to other families with FTD. We look forward to following Passage Bio’s next steps as this process unfolds.”

Are you or a loved one interested in participating in the upliFT-D trial? Learn more about trial site locations, inclusion criteria, and more by visiting the upliFT-D trial page and clinicaltrials.gov. And be sure to join the FTD Disorders Registry to learn about opportunities to participate in other FTD clinical trials as they emerge.

If you are uncertain about your genetic status, AFTD strongly recommends genetic counseling as a first step to consider if genetic testing is the right choice for you. If you have questions about genetic counseling or testing, contact AFTD’s HelpLine at 1-866-507-7222 or info@theaftd.org.