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

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, and there remains an unmet need for therapies that can reduce PPIX.

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 study (ACTRN12622000799752) in participants with a confirmed diagnosis of EPP or Xlinked protoporphyria (XLP). Participants received oral, once-daily administration of 20 mg or 60 mg of bitopertin for 24 weeks. The study was conducted at 2 sites in Australia. The primary efficacy endpoint was percent change in whole-blood metal-free PPIX. Additional endpoints included daily patient-reported outcomes (PROs) of light tolerance and quality of life, as well as safety and tolerability. Final results from adult participants (n=22) are presented herein.

Results: For the primary endpoint, treatment with bitopertin resulted in significant and sustained reductions in PPIX levels compared to baseline levels at both the 20-mg and 60-mg dose levels. The reductions were dose dependent with more pronounced decreases observed with 60 mg (61.1±7.0% [p<0.001 vs baseline]) compared to the decrease observed with 20 mg (34.3±7.1% [p<0.001 vs baseline]). For the key secondary endpoint, there was a dose-dependent increase in the cumulative total time in light without pain observed over a 6-month treatment period, with LS mean (±SE) of 212.1±37.6 hours in the 60-mg dose group compared to 180.0±38.2 hours in the 20mg dose group. Bitopertin improved other measures of life tolerance; the proportion of prodrome-free sunlight challenges increased from 7% at screening to 55% while receiving bitopertin (n=22), and the proportion of days without symptoms (with sun exposure) increased from 33% at screening to 79% while receiving bitopertin (n=22). Patient-reported phototoxic reactions decreased by 92% while on treatment compared to the number of phototoxic reactions at screening (n=22).

No serious adverse events were reported. One participant randomized to 20 mg of bitopertin discontinued treatment early due to a treatment-emergent adverse event (TEAE) of cluster headache, which was the only Grade 3 TEAE reported in the study. All other TEAEs (98%) were mild to moderate in intensity. Dizziness was the most commonly reported TEAE with bitopertin, with a similar number of events occurring across the 20-mg (6 [55%]) and 60-mg dose (7 [64%]) groups.

Conclusion: By reducing whole-blood 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 with no changes in hemoglobin, and its safety profile in EPP is consistent with prior studies that enrolled more than 4000 participants. Additional analyses will be presented at the meeting.

Ross:Disc Medicine: Other: Principal Investigator on clinical trial. Stewart:Disc Medicine: Other: Principal Investigator on clinical trial. Mensing:Disc Medicine: Current Employment, Current equity holder in publicly-traded company. Chin:Disc Medicine: Current Employment, Current equity holder in publicly-traded company. Howell:Disc Medicine: Current Employment, Current equity holder in publicly-traded company. Mangus:Disc Medicine: Current Employment, Current equity holder in publicly-traded company. Savage:Disc Medicine: Current Employment, Current equity holder in publicly-traded company.