Dear CAH Community,

In 2018, Adrenas Therapeutics, a BridgeBio company, began engaging with the CAH community to learn more about the challenges, unmet needs, and experiences of people and families living with CAH. The wisdom shared by the community, coupled with Adrenas’ desire to pursue an innovative therapy to treat CAH at its source, ultimately led to initiating a gene therapy clinical trial for BBP-631.

BBP-631 was designed to deliver a functional copy of the 21-hydroxylase gene through a single intravenous (IV) infusion with the goal of enabling people with CAH to produce their own cortisol and aldosterone, potentially eliminating, or significantly reducing the need for daily glucocorticoid and mineralocorticoid doses.

In 2021, the first participant was dosed in Adrenas’ ADventure investigational gene therapy clinical trial for adults with classic CAH. Over three years, eight participants received BBP-631 at four different dose levels, with two participants at each dose level. The primary objectives were to evaluate the safety and tolerability of BBP-631, and to select a dose for future studies with BBP-631. Selecting a BBP-631 dose would be based on a number of key hormonal variables including but not limited to cortisol, androstenedione (A4) and 17-OHP (17-hydroxyprogesterone).

Key results from the trial:

• BBP-631 has been well tolerated with no notable safety concerns.
• Participants at higher doses of BBP-631 were able to produce more cortisol. ACTH-stimulated cortisol levels up to 11µg/dL were observed at the highest dose, an important achievement as cortisol levels in classic CAH typically do not exceed 5µg/dL and are typically far lower. This marks the first instance of any therapeutic, experimental or otherwise, increasing the endogenous cortisol production in people living with classic CAH.
• Despite the acceptable safety profile and production of cortisol to notable levels, the overall trial results were not as transformative as we had hoped.

Implications of results:

• The trial has demonstrated that gene therapy for CAH can be done with appropriate safety profile, and that people living with CAH can make their own cortisol.
• However, given that the results were not enough for the gene therapy to be transformative in the lives of people living with CAH, Adrenas and parent company BridgeBio will not be moving the program forward. No additional participants will be dosed in the study. The eight dosed participants in the ADventure trial will continue to be monitored.
• We will continue trying to understand the data and will seek partners for the program.
• We currently have no plans to pursue a pediatric gene therapy trial, as there is no clear evidence that young people with CAH would be more likely to benefit from BBP-631 than adults. Further research is needed to explore the potential benefits and the potential risks of a gene therapy for this age group.
• We plan to publish our learnings from the ADventure trial as sharing the data may guide further development for the CAH community.

The Adrenas Therapeutics team acknowledges that this is disappointing news. While the clinical trial did not meet the high expectations we set for ourselves or for the CAH community we serve, we are assured that our combined efforts during the past six years have contributed to improved understanding and greater hope for what is possible for people living with CAH.

We extend our heartfelt thanks to the clinical trial and prescreening study participants as well as the clinical site physicians and their staff, all who led this innovative effort. We are also deeply grateful to the CAH patient advocacy leaders and the communities of the CARES Foundation, Adrenal Insufficiency United, and the MAGIC Foundation, who continue to be our partners in serving the CAH community. Thank you to all members of the CAH community for your curiosity, willingness, support, and hope for improving the lives of those with CAH.

With respect and gratitude,

The Adrenas Therapeutics Team