Design of a Phase 1/2 Open-Label, Dose-Escalation Study of the Safety and Efficacy of Gene Therapy in Adults With Classic Congenital Adrenal Hyperplasia (CAH) Due to 21-hydroxylase Deficiency Through Administration of an Adeno-Associated Virus (AAV) Serotype 5-Based Recombinant Vector Encoding the Human CYP21A2 Gene

Abstract The CYP21A2 gene, which encodes the 21-hydroxylase enzyme, plays a critical role in glucocorticoid (GC) and mineralocorticoid synthesis by the adrenal cortex. CYP21A2 pathogenic variants cause 21-hydroxylase deficiency (21OHD), the most common type of CAH, characterized by variable degrees of adrenal insufficiency and androgen excess. Standard treatment of classic 21OHD consists of daily doses of GC and mineralocorticoid. However, suppressive GC doses are often required to reduce androgen excess, and it is often not possible to dose exogenous GC in a manner that provides adequate disease control while avoiding overtreatment. Disease-related and treatment-related comorbidities are common and include life-threatening adrenal crises, impaired growth and development during childhood, adult short stature, virilization in females, subfertility in both sexes, obesity and cardiovascular risk factors, and decreased bone mineral density. Novel treatment approaches are needed to address these challenges and a treatment that restores the ability of the adrenals to produce cortisol and aldosterone in a physiologically-regulated manner would be particularly helpful. Here we present the design and rationale of a clinical trial using BBP-631, an AAV5 gene replacement therapy for adults with classic CAH due to 21-OHD. This treatment approach is based on the demonstration that a single intravenous administration of BBP-631 corrects the enzyme deficiency in the H2-aw18 CYP21-/- CAH mouse model of 21OHD, including response to stress. This correction was robust, dose-dependent and durable. BBP-631 treatment also resulted in robust and durable expression of the human CYP21A2 transgene in the non-human primate adrenal cortex. BBP-631 appears to be safe and well-tolerated in mice with 21-OHD, healthy mice and non-human primates. Taken together, these data support initiating clinical trials in adults with classic CAH due to 21-OHD. The trial will sequentially enroll individuals in up to 3 successive dose-escalation cohorts. Each subject will receive a single dose of BBP-631 and safety will be assessed prior to dose escalation. Endogenous production rates of adrenal steroids (cortisol, 17-hydroxyprogesterone, androstenedione) will be determined pre- and post- dose, and their concentrations assessed over a 1-year period after which subjects will roll over into an extension study for at least 4 years. The Phase 1 study will determine the tolerability of a single dose of BBP-631. The magnitude and durability of BBP-631 and effects on adrenal steroids, ACTH and, where relevant, aldosterone levels will be monitored. The ability of BBP-631 to allow tapering of GC doses will also be explored. This first in human study of gene therapy for CAH represents a milestone in the development of novel and improved treatment approaches for patients with classic CAH.