Background Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are 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.^1–3

Glycine transporter 1 (GlyT1) supplies extracellular glycine for the initial step of heme biosynthesis in erythroid cells.⁴ 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.⁵

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 ≥12 years of age with a confirmed diagnosis of EPP or XLP.

Results As of data cutoff (20 October 2023), a total of 22 adults had been enrolled. For the primary endpoint, treatment with bitopertin resulted in significant, sustained, dose-dependent reductions in PPIX levels; mean reduction >40% (p<0.001 versus baseline). For the key secondary endpoint, the mean (± SD) cumulative total time in light observed over the 6-month treatment period on days without pain was 222.6 ± 129.3 hours, which represents approximately a 3-fold increase with bitopertin treatment relative to historical control.⁶

Other aggregate measures of light tolerance also improved over time. The proportion of days without symptoms (with sun exposure) increased from 33% during screening to 78% while on treatment, and patient-reported phototoxic reactions decreased by 92% with bitopertin compared to baseline (n=22). This functional benefit was also associated with improvements in quality of life; in the Patient Global Impression of Change, nearly all participants who completed treatment (12/13) reported their EPP was much better or a little better at the end of the study.

Bitopertin was generally well tolerated at both dose levels with no serious adverse events (AEs), stable mean hemoglobin levels, and no anemia AEs reported. The most common AEs (reported in >1 participant) were dizziness, lightheadedness, headache, and nausea.

Conclusion By reducing PPIX levels, bitopertin targets the underlying pathophysiology of EPP, resulting in consistent improvements in multiple measures of light tolerance and quality of life. Bitopertin has been well tolerated to date. Final adult results from the study will be presented at the meeting.