Results from the Aurora Study: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Bitopertin in Erythropoietic Protoporphyria

Background: 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 in a subset of patients, lifethreatening protoporphyric hepatopathy. 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. Through GlyT1 inhibition, bitopertin restricts glycine availability and decreases accumulation of the phototoxic heme pathway intermediate PPIX.

Methods: AURORA is a Phase 2, double-blind, placebo-controlled study (NCT05308472) that randomized 75 participants (1:1:1) to receive oral, once-daily administration of 20-mg or 60-mg bitopertin or placebo for 17 weeks. Participants ≥18 years of age with a confirmed diagnosis of EPP were enrolled. The primary endpoint was percent change from baseline in whole-blood metal-free PPIX in participants randomized to bitopertin compared to percent change from baseline for those randomized to placebo.

Results: Treatment with bitopertin resulted in significant and sustained reductions in PPIX levels compared to PPIX levels for treatment with placebo at both the 20-mg and 60-mg dose levels (least-squares [LS] mean difference relative to placebo: 29.7% [p=0.004] and 48.7% [p<0.001], respectively). The reductions in PPIX with bitopertin were observed across several prespecified subgroups, including age, sex, and disease severity. Treatment with bitopertin significantly reduced the rate of phototoxic reactions compared to the rate observed in treatment with placebo; the incidence rate ratios relative to those of placebo were 0.397 (p=0.11) in the 20mg bitopertin group and 0.247 (p=0.01) in the 60-mg bitopertin group, corresponding to 60% and 75% reductions in the phototoxic reaction rate compared to the rate in the placebo group. PPIX reductions were associated with improvements in multiple sunlight tolerance measures, including cumulative total pain-free time in sunlight, time to first prodromal symptom, occurrence of phototoxic reactions, and improvements in how participants reported feeling in the Patient Global Impression of Change. A post hoc longitudinal mixed model for repeated-measures analysis showed nominally statistically significant, time-dependent improvements in pain-free sunlight exposure with bitopertin compared to the improvements with placebo in both the 20mg and 60-mg dose groups (LS mean [±SE] difference relative to placebo: 7.1±3.2 hours [p=0.026] and 8.0±3.2 hours, [p=0.013], respectively), and participants randomized to bitopertin had a 2fold improvement in average daily sunlight exposure at the end of study relative to baseline.

Overall, nearly all treatment-emergent adverse events (TEAEs) were mild to moderate in intensity. One serious adverse event of obstructive pancreatitis was reported in a participant randomized to placebo. Two participants randomized to 60 mg of bitopertin discontinued treatment due to a TEAE (dizziness, rash). The most commonly reported TEAE was dizziness, which occurred in 17%, 15%, and 44% of participants randomized to placebo, 20mg bitopertin, and 60-mg bitopertin, respectively. No meaningful changes in hemoglobin were observed.

Summary/Conclusion: By reducing PPIX levels, bitopertin targets the underlying pathophysiology of EPP. PPIX reductions with bitopertin were consistently associated with improvements across multiple clinical outcome measures. Treatment with bitopertin resulted in time-dependent improvements in sunlight tolerance, with a 2-fold increase relative to baseline tolerance at the end of study. Bitopertin was well tolerated. Its safety profile in EPP is consistent with prior studies of bitopertin that enrolled more than 4000 participants in other non-EPP indications. Additional analyses will be presented at the meeting.

Dickey:Disc Medicine: Other: Principal Investigator on clinical trial. Keel:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Bonkovsky:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Anderson:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Balwani:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Levy:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Thapar:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Wang:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. McGuire:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial. Savage:Disc Medicine: Current Employment, Current equity holder in publicly-traded company.