ODP046 Initial Lessons from a Prescreening Protocol to Identify Participants with Classic CAH Potentially Eligible for Gene Therapy Treatment with BBP-631, an Adeno-associated Virus (AAV) Serotype 5-Based Recombinant Vector Encoding the Human CYP21A2 Gene
Authors: Bharucha Kamal , Weinstein Debra , Kirby Kathleen , Auchus Richard , Geffner Mitchell , Kim Mimi , Sarafoglou Kyriakie , Williams Rachel , Shaywitz Adam 
Published: November 2022

Abstract
Here we present the design and early findings from CAH-300 /NCT05101902, a prescreening protocol to identify participants who are potentially eligible for the CAH-301 Phase 1/2 treatment trial with BBP-631, an AAV5-based gene therapy for classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). The CYP21A2 gene encodes the 21-hydroxylase enzyme that plays a critical role in glucocorticoid and mineralocorticoid synthesis by the adrenal cortex. CYP21A2pathogenic variants cause 21OHD, the most common form of CAH, characterized by variable degrees of adrenal insufficiency and androgen excess. Standard treatment of classic CAH due to 21OHD usually consists of daily replacement doses of glucocorticoid (GC) and mineralocorticoid. However, supraphysiologic GC doses are often required to mitigate the androgen excess and it is difficult to dose exogenous GCs in a manner that provides adequate disease control while avoiding overtreatment. A gene therapy approach offers the potential to restore cortisol and aldosterone production from the adrenal glands in a physiologically regulated manner. To assess potential eligibility for the gene therapy trial CAH-301, participants in the prescreening protocol CAH-300 undergo initial assessments for the presence of exclusionary anti-21OH antibodies and anti-AAV5 antibodies, as well as for characterization of CYP21A2 genotype. After the participant meets initial eligibility criteria, referral to a treatment trial center may be arranged. To address the challenges in recruiting participants with this rare disorder, prescreening assessments are performed at the participant's home allowing for recruitment from broad geographic areas including those without proximity to a tertiary care center. Home assessments have also provided flexibility for participants during the COVID pandemic. Additional assessments during prescreening that further impact eligibility for the gene therapy trial include review of participant medical history and collection of hormonal biomarkers including 17-hydroxyprogestone, androstenedione, cortisol, and ACTH. Preliminary laboratory data show the expected presence of low cortisol (measured by both gas chromatography-mass spectrometry and immunoassay) with concomitant elevated ACTH, confirming the potential to detect meaningful changes in endogenous cortisol production after BBP-631 dosing. In summary, our prescreening approach with home assessments has enabled the efficient identification of participants potentially eligible for the CAH-301 gene therapy trial. Preliminary data have confirmed the presence of low cortisol and thus potential for detecting meaningful increases in endogenous cortisol production after gene therapy with BBP-631.
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