BridgeBio Pharma Drops Development of Congenital Adrenal Hyperplasia Gene Therapy BBP-631

BridgeBio Pharma has made the decision to discontinue development of BBP-631, an investigational adeno-associated virus (AAV) 5 vector-based gene therapy that was being evaluated in the phase 1/2ADventure clinical trial (NCT04783181) for the treatment of congenital adrenal hyperplasia (CAH).¹

The company made the decision to axe the program in light of newly reported topline results from the clinical study. The findings showed that all patients treated at higher doses in the study showed increased endogenous cortisol production and that at the second to highest dose level a maximum change from baseline after ACTH stimulation test of 4.7 μg/dL was seen and at the highest dose levela maximum change from baseline of 6.6 μg/dL was seen. Cortisol levels as high as 11 μg/dL were recorded. Furthermore, activity of 21-hydroxylase, the transgene for which is encoded by BBP-63, was indicated by substantial and durable increases in its product 11-deoxycortisol and decreasesin its substrate 17-hydroxyprogesterone. BridgeBio pointed out that sustained 11-deoxycortisol averaged a 55-fold increase from baseline at the highest dose levels with a maximum of 99-fold increase from baseline, constituting an average maximum of 23-fold the upper-limit of normal. In addition, the majority of patients achieved a decrease in 17-hydroxyprogesterone of at least 50%; a maximum decrease of 95% was recorded.

In terms of safety, the gene therapy product was characterized as “well-tolerated.” Treatment-emergent adverse events (AEs) were noted to be mild to moderate. There were no serious AEs deemed related to the treatment in the study.

Although BBP-631 effected several noteworthy changes in the treated patients, BridgeBio does not consider the results substantial enough for further investment in the development of the product at this time. Although, the company stated that it is looking for a potential partner to continue the CAH program in its stead.

“While the data to date are not yet transformational, the study showed for the first time that people living with CAH can indeed make their own cortisol, and that gene therapy can be safely administered in this patient population,” Neil Kumar, PhD, the chief executive officer and the founder of BridgeBio, said in a statement.¹ “We remain committed to finding the right partner for those in the CAH community and are grateful to the participants and those who expressed interest in both the prescreening study (NCT04783181) and the ADventure study. We also want to thank the ADventure study investigators and staff, the CAH patient advocacy organizations, and the broader CAH community.”

Although BridgeBio’s pipeline seems to mostly consist of small molecule drugs, the company will continue to invest in the development of BBP-812, its other clinical-stage gene therapy program.^2,3 BBP-812, an AAV9 gene therapy intended to treat Canavan disease, is currently being evaluated in the phase 1/2 CANaspire clinical trial (NCT04998396). On September 10, 2024, BridgeBio announced that the FDA had granted BBP-812 regenerative medicine advanced therapy designation based on data from CANaspire. In particular, the data constituted 12 months of safety and efficacy findings that pertained to the first 8 patients treated in the trial. According to BridgeBio, improvements in functional outcomes were observed in all patients who had 1 or more follow-up examinations.

“Given that the results of the [ADventure trial for BBP-631] did not meet the threshold to warrant additional capital investment at this time, BridgeBio will be reducing the gene therapy budget more than $50 million, consistent with our capital allocation principles, and reserving gene therapy for priority targets that we cannot treat any other way,” Brian Stephenson, PhD, CFA, the chief financial officer of BridgeBio, added to Kumar’s statement.¹ “We believe that gene therapies have the potential to fulfill a significant unmet need and are eager to work closely with the FDA and the Canavan community with the goal of bringing our therapy to families living with Canavan disease as fast as possible.”

REFERENCES
1. BridgeBio Pharma reports topline results from phase 1/2 trial of investigational gene therapy for congenital adrenal hyperplasia (CAH). News release. BridgeBio Pharma, Inc. September 10, 2024. Accessed September 16, 2024. https://bridgebio.com/news/bridgebio-pharma-reports-topline-results-from-phase-1-2-trial-of-investigational-gene-therapy-for-congenital-adrenal-hyperplasia-cah/
2. The Pipeline. BridgeBio Pharma, Inc. Website. Accessed September 16, 2024. https://bridgebio.com/pipeline/#pipeline
3. BridgeBio receives FDA’s regenerative medicine advanced therapy (RMAT) designation for BBP-812 Canavan disease gene therapy program. News release. BridgeBio Pharma, Inc. September 10, 2024. Accessed September 16, 2024. https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-receives-fdas-regenerative-medicine-advanced-therapy