Phase 2 Trial Suggests Disease-Modifying Role for Bitopertin in EPP

A recently published phase 2 clinical trial provides evidence that bitopertin, an oral glycine transporter 1 (GlyT1) inhibitor, may represent a disease-modifying therapeutic approach for erythropoietic protoporphyria (EPP). Results from the randomized, double-blind, placebo-controlled AURORA trial showed significant reductions in protoporphyrin-IX (PPIX) levels, improvements in sunlight tolerance measures, and a favorable safety profile in adults with EPP.¹

"Advances in therapeutics for rare genetic diseases are so crucial to giving patients hope. These phase 2 trial results for bitopertin are highly encouraging. The results signal bitopertin can be an effective and safe oral small molecule therapy to help treat patients with erythropoietic protoporphyria by reducing levels of toxic protoporphyrin-IX accumulation,” Christopher Bunick, MD, PhD, Dermatology Times editor-in-chief and associate professor of dermatology at Yale School of Medicine, said in an exclusive statement. “Bitopertin is a game-changer for reducing skin phototoxicity, pain, and other symptoms and I anticipate it will empower dermatology providers to be more comfortable identifying and treating EPP patients in their clinics."

Unmet Need in EPP

EPP is a rare inherited disorder of heme biosynthesis characterized by accumulation of metal-free PPIX, primarily within erythroid cells. Upon exposure to visible light, particularly in the blue-violet spectrum, PPIX generates reactive oxygen species that lead to acute phototoxic reactions. Patients typically experience severe pain, erythema, and swelling that are often disproportionate to visible skin findings. Beyond cutaneous symptoms, chronic PPIX accumulation poses a risk for progressive hepatobiliary disease.²

Current management largely centers on strict sunlight avoidance and protective strategies, which significantly impair quality of life. Afamelanotide, an α-melanocyte–stimulating hormone analog administered via subcutaneous implant, is the only approved therapy for adults with EPP. While it improves sunlight tolerance by increasing eumelanin, it does not reduce PPIX levels and therefore does not address the underlying biochemical driver of disease.

Rationale for Bitopertin

Bitopertin is a selective, orally bioavailable GlyT1 inhibitor. By limiting cellular glycine uptake, bitopertin reduces downstream production of heme intermediates, including PPIX. Preclinical studies and earlier clinical experience suggested that this mechanism could lower erythrocyte PPIX levels and potentially mitigate both cutaneous and hepatic manifestations of EPP.

AURORA Trial Design

The AURORA trial enrolled 75 adults with genetically or biochemically confirmed EPP across 9 US centers. Participants were randomized 1:1:1 to receive once-daily oral bitopertin 20 mg, bitopertin 60 mg, or placebo for 17 weeks. Randomization was stratified by baseline light tolerance.

The primary endpoint was percent change from baseline in whole-blood metal-free PPIX levels at day 121. Key secondary and exploratory endpoints included sunlight exposure on pain-free days, time to prodromal symptoms, frequency of phototoxic reactions, patient-reported outcomes, and safety.

Primary and Secondary Outcomes

Bitopertin met the primary endpoint in a dose-dependent manner. At day 121, whole-blood metal-free PPIX levels were reduced by 29.6% in the 20-mg group and 49.8% in the 60-mg group compared with placebo, with both reductions reaching statistical significance. Reductions were consistent across demographic and baseline disease subgroups and were observed in erythrocyte, plasma, and whole-blood PPIX measures.

The key secondary endpoint—total cumulative hours of sunlight exposure on pain-free days over the 17-week period—did not differ significantly between treatment and placebo groups. Investigators noted that expectation bias, seasonal variation, and limited statistical power may have influenced this outcome. However, a post hoc longitudinal analysis demonstrated that pain-free sunlight exposure increased over time in both bitopertin groups relative to placebo, particularly after week 7, corresponding with maximal PPIX reductions.

Phototoxicity and Patient-Reported Outcomes

Exploratory analyses suggested clinically meaningful benefits. Participants receiving bitopertin experienced fewer phototoxic reactions than those receiving placebo, with the greatest reduction observed in the 60-mg group. During the final 60 days of treatment, no phototoxic reactions were reported in the 60-mg group, compared with multiple events in the placebo arm.

Patient Global Impression of Change scores also favored bitopertin, particularly at the higher dose, with a greater proportion of patients reporting improvement in overall condition.

Safety and Tolerability

Bitopertin was generally well tolerated. Most adverse events were mild to moderate, with dizziness reported most frequently, particularly at the 60-mg dose. Dizziness typically occurred early in treatment and was transient. No serious adverse events were reported in bitopertin-treated participants, and there were no clinically meaningful changes in hemoglobin levels or liver function tests.

Clinical Implications

AURORA is among the largest placebo-controlled trials conducted in EPP and is the first to demonstrate significant reductions in PPIX levels in a randomized setting. These findings suggest that targeting glycine transport may address the underlying pathophysiology of EPP rather than solely mitigating photosensitivity.

While longer-term data are needed to assess durability of response and effects on hepatobiliary outcomes, the results support continued clinical development of bitopertin. If confirmed in larger and longer studies, bitopertin could represent a shift toward disease-modifying therapy in EPP, expanding treatment options for a patient population with historically limited choices.

References

1. Yeung AK, Bonkovsky HL, Balwani M, et al. Bitopertin shows efficacy in patients with erythropoietic protoporphyria: Results from the randomized, double-blind, placebo-controlled AURORA trial. J Am Acad Dermatol. Published online December 11, 2025. doi:10.1016/j.jaad.2025.12.024
2. Minder AE, Kluijver LG, Barman-Aksözen J, Minder EI, Langendonk JG. Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management. Liver Int. 2025;45(1):e16027. doi:10.1111/liv.16027