Passage Bio Gets Positive Feedback From FDA on Plans to Test Gene Therapy PBFT02 in New Frontotemporal Dementia Indication

Passage Bio has received positive feedback from the FDA regarding its plans to expand eligibility for its phase 1/2 upliFT-D clinical trial (NCT04747431), which is currently evaluating investigational gene therapy PBFT02 in patients with frontotemporal dementia (FTD) with GRN mutations (FTD-GRN), to patients with FTD with mutations in the C9orf72 gene (FTD-C9orf72).¹

Passage Bio received the feedback on the proposal to ammend the upliFT-D protocol in the context of a Type C meeting process with the FDA. The company stated that attainment of the agency’s alignment on the matter was supported by preclinical evidence, along with efficacy and safety data from patients with FTD-GRN who were treated in the first cohort of upliFT-D. In light of the FDA’s feedback, Passage Bio intends to submit a revised trial protocol to relevant regulatory bodies and ethics committees shortly. Pending clearance, the company anticipates that it may begin dosing patients with FTD-C9orf72 in upliFT-D within the first half of next year.

Notably, both FTD-GRN and FTD-C9orf72 are associated with a pathological accumulation of transactive response DNA binding protein 43 in neuron cytoplasm. PBFT02, which utilizes an adeno-associated virus 1 vector, is intended to deliver a functional copy of the GRN gene, which encodes for the protein progranulin (PGRN). The gene therapy is administered via intracisterna magna injection with the intention of increasing levels of PGRN in the central nervous system.

"Securing FDA alignment on amending our upliFT-D protocol to include FTD-C9orf72 patients is a critical milestone in expanding access to those who could benefit from PBFT02,” William Chou, MD, the president and chief executive officer of Passage Bio, said in a statement.¹ “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. 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.”

Initial clinical data from upliFT-D was announced by Passage Bio in December of last year.² Among 3 patients treated with PBFT02 in the study’s first cohort, a 3.6 to 6.6-fold increase in cerebrospinal fluid (CSF) PGRN over baseline was observed at 30 days posttreatment. Furthermore, at 30 days posttreatment, CSF PGRN had reached 10.7 to 17.3 ng/mL in these patients, which was greater than the levels seen in a population of 61 healthy adults used as a control, whose CSF PRGN was measured at 3.3 to 8.2 ng/mL. It was additionally noted that the patients treated in upliFT-D had sustained their supraphysiologic PGRN levels in the CSF at 6 months after receiving the gene therapy.

"We are proud to announce initial clinical data from our upliFT-D clinical trial, which showcases the ability of PBFT02 to elevate CSF progranulin to supraphysiologic levels at the lowest tested dose, Dose 1, up to 6 months post-treatment,” Mark Forman, MD, PhD, the chief medical officer at Passage Bio, said in a December 2023 statement.¹ “We believe these data, surpassing our expectations based on preclinical nonhuman primate models, validate the compelling potential of PBFT02 to address PGRN deficiency—a key driver of disease progression in individuals with FTD-GRN.”

Passage Bio is not the first company to seek to treat FTD-C9orf72 with a genomic medicine approach. Notably, Wave Life Sciences had previously been evaluating the RNA therapy WVE-004 in an early clinical trial (NCT04931862) for C9orf72-associated FTD.³ Although, the trial was discontinued by the company in July 2023 after WVE-004 showed no clinical benefit for FTD or its other investigational indication, amyotrophic lateral sclerosis.

REFERENCES
1. Passage Bio announces positive feedback from FDA on expansion of upliFT-D trial of PBFT02 to include FTD-C9orf72 patients. News release. Passage Bio, Inc. July 16, 2024. Accessed July 19, 2024. https://www.passagebio.com/investors-and-news/press-releases-and-statements/news-details/2024/Passage-Bio-Announces-Positive-Feedback-from-FDA-on-Expansion-of-upliFT-D-Trial-of-PBFT02-to-Include-FTD-C9orf72-Patients/default.aspx
2. Passage Bio announces promising initial data from phase 1/2 clinical trial of PBFT02 in FTD-GRN and updated strategic priorities. News release. Passage Bio, Inc. December 20, 2023. Accessed July 19, 2024. https://www.passagebio.com/investors-and-news/press-releases-and-statements/news-details/2023/Passage-Bio-Announces-Promising-Initial-Data-From-Phase-12-Clinical-Trial-of-PBFT02-in-FTD-GRN-and-Updated-Strategic-Priorities/default.aspx
3. Wave Life Sciences announces topline results from phase 1b/2a FOCUS-C9 study of WVE-004 for C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia. News release. Wave Life Sciences. May 23, 2023. Accessed July 19, 2024. https://finance.yahoo.com/news/wave-life-sciences-announces-topline-113000549.html