Interim Analyses from the Beacon Trial: A Phase 2, Randomized, Open-Label Trial of Bitopertin in Erythropoietic Protoporphyria

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.923-923
• Main Authors: Ross, Gayle, Stewart, Peter, Mensing, George, Chin, Melanie, Howell, Haley, Mangus, Heidi, Savage, William
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-175011

Introduction: Erythropoietic protoporphyria (EPP) is associated with accumulation of photoreactive protoporphyrin IX (PPIX) in the skin and other organs, causing debilitating phototoxic skin reactions following exposure to sunlight, and potentially life-threatening protoporphyric hepatopathy in some patients. Reduction of PPIX is associated with amelioration of disease in the settings of hematopoietic stem cell transplant, pregnancy, and extracorporeal photoinactivation. Glycine transporter 1 (GlyT1) supplies extracellular glycine for the initial step of heme biosynthesis in erythroid cells. Bitopertin is an investigational, orally-administered inhibitor of GlyT1. It is hypothesized that GlyT1 inhibition leads to a decrease in heme pathway intermediates, including PPIX, and can improve light tolerance. Methods: BEACON is a Phase 2, randomized, open-label, parallel-arm trial (ACTRN12622000799752) of 22 participants who will receive oral, once-daily administration of 20 mg or 60 mg of bitopertin for 24 weeks. The trial is being conducted at 2 sites in Australia and includes participants ≥18 years of age with a confirmed diagnosis of EPP. The primary efficacy endpoint is percent change in whole-blood metal-free PPIX. Additional endpoints include daily patient-reported outcomes (PRO) of light tolerance and quality of life, as well as safety and tolerability. Results: As of data cutoff (05 July 2023), a total of 17 subjects had been enrolled. Treatment with bitopertin resulted in mean (SD) decreases in PPIX of -39% ± 17% by Day 43 (n=12), with more pronounced decreases observed with 60 mg compared to 20 mg (Figure 1). Bitopertin also improved multiple measures of light tolerance. A participant randomized to 20 mg bitopertin reported a >80-fold increase in sunlight tolerance on Day 88 of treatment, increasing from 4.5 minutes at baseline to over 6 hours; no prodromes were reported during any sunlight challenge after Day 20. A participant randomized to 60 mg bitopertin reported a >200-fold increase in sunlight tolerance on Day 74 of treatment, increasing from 1.3 minutes at baseline to over 4 hours, and did not report a prodrome during any sunlight challenge after Day 120. Aggregate measures of light tolerance also improved over time, including time to prodrome averaged over a 2-week period and weekly averages of total time in sunlight. The proportion of prodrome-free sunlight challenges increased from 2% during screening to 49% while receiving bitopertin (n=17),