FDA Lifts Clinical Hold on Trial for 4D Molecular Therapeutics’ Fabry Disease Gene Therapy 4D-310

The FDA has lifted a clinical hold on the phase 1/2 INGLAXA (NCT04519749) clinical trial for 4D Molecular Therapeutics (4DMT)’s 4D-310, an investigational adeno-associated virus (AAV) vector-based gene therapy being evaluated for the treatment of Fabry disease.¹

In light of the FDA’s decision, 4DMT plans to continue enrolling patients in INGLAXA before the end of 2024, according to an announcement from the company. Furthermore, 4DMT anticipates that it will provide an update on the program at some point in 2025.

The FDA originally placed the hold on INGLAXA in early 2023, according to a United States Securities and Exchange Commission (SEC) FORM 8-K from February of that year.² The hold came weeks after 4DMT announced it was halting enrollment in the phase 1/2 clinical trial of 4D-310 (NCT04519749) after 3 instances of treatment-related serious adverse events (AEs) of atypical hemolytic uremic syndrome (aHUS) that had resolved within 2 to 4 weeks.³ In 1 participant, a 69-year-old man with underlying kidney dysfunction, the AE was classified as a grade 4 dose-limiting toxicity and required temporary hemodialysis; the other 2 patients did not receive dialysis.

“Consistent with the Company’s plans for the program as noted above and as communicated to the FDA, the FDA subsequently notified the Company of a Clinical Hold pursuant to CFR §312.42 (b)(iv),” 4DMT wrote in the SEC filing.² “In its notification, the FDA acknowledged the Company’s paused enrollment worldwide, directed the Company to continue long term follow up of treated patients under the current investigational new drug application (IND), and noted that it would provide feedback regarding the 4D-310 trials within 30 days. The IND for 4D-310 remains open and active.”

Updated data from INGLAXA was presented at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.⁴ In 5 evaluable patients who had been treated with the gene therapy, clinically meaningful improvements through 12-24 months posttreatment were reported in contractility as measured by echocardiography, in peak VO2 as measured by cardiopulmonary exercise testing, and/or cardiac quality of life as measured by the Kansas City Cardiomyopathy Questionnaire. In terms of safety, there were no clinically significant cardiac or liver toxicities reported. Furthermore, no new AEs assessed as greater than grade 1 in severity and deemed related to the gene therapy had occurred since the previous interim data update given from INGLAXA in February 2023.

“We are pleased to see 4D-310 continue to consistently demonstrate clinical activity across multiple important cardiac end points including cardiac function, exercise capacity, and quality of life,” said Robert Kim, MD, the chief medical officer of 4DMT, said in a February 12, 2024, statement.⁴ “Current therapies do not adequately address Fabry-related cardiovascular manifestations, and cardiovascular disease is the most common cause of death in these patients. 4D-310 continues to be well tolerated, with the previously reported cases of aHUS having fully resolved and no new drug-related adverse events over Grade 1 reported.”

In addition to 4D-310, 4DMT is developing other gene therapy products, including 4D-150, an investigational dual-mechanism gene therapy being evaluated for the treatment of wet age-related macular degeneration (AMD) in the phase 1/2 PRISM clinical trial (NCT05197270).⁵ Notably, just last month, the company reported new data from PRISM. As of the June 24, 2024, data cutoff, 30 patients in the phase 2 PRISM population extension cohort who received the planned phase 3 dose showed a mean decrease of 89% in annualized injection rate of standard of care antivascular endothelial growth factor (VEGF) injections. Furthermore, 93% of these patients received 0 or only 1 antiVEGF injection after treatment with the gene therapy and 77% were entirely free of antiVEGF injections.

REFERENCES
1. 4DMT Reports Second Quarter 2024 Financial Results and Operational Highlights. News release. 4D Molecular Therapeutics. August 8, 2024. Accessed August 12, 2024. https://4dmt.gcs-web.com/news-releases/news-release-details/4dmt-reports-second-quarter-2024-financial-results-and
2. US SEC Form 8K. 4D Molecular Therapeutics. February 3, 2023. Accessed August 12, 2024. https://ir.4dmoleculartherapeutics.com/node/7801/html
3. 4D Molecular Therapeutics announces updates on clinical pipeline and additional preclinical programs. 4D Molecular Therapeutics. January 9, 2023. Accessed August 12, 2024. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-updates-clinical-pipeline
4. 4DMT presents interim data from 4D-310 INGLAXA phase 1/2 clinical trials for Fabry disease cardiomyopathy at WorldSymposium™ 2024. 4D Molecular Therapeutics. February 12, 2024. Accessed August 12, 2024. https://4dmt.gcs-web.com/news-releases/news-release-details/4dmt-presents-interim-data-4d-310-inglaxa-phase-12-clinical
5. 4DMT Announces Positive Phase 2 PRISM Interim Results for Intravitreal 4D-150 in a Broad Wet AMD Population Affirming Favorable Safety Profile and Robust Clinical Activity. News release. 4D Molecular Therapeutics. July 17, 2024. Accessed August 12, 2024. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-positive-phase-2-prism-interim-results