Bitopertin for Erythropoietic Protoporphyria: A New Paradigm — and New Hope — for a Rare, Devastating Disease

STUDY TITLE: (AURORA) A Randomized, Double-blind, Placebo-controlled Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in Participants with Erythropoietic Protoporphyria (EPP)

ClinicalTrials.gov Identifier: NCT05308472

PARTICIPATING CENTERS: 10 centers across the U.S.

ACCRUAL GOAL: 75 participants

STUDY DESIGN: This randomized clinical trial sponsored by Disc Medicine, Inc., is a multicenter phase II, double-blind, placebo-controlled, parallel-group study of bitopertin (DISC-1459) for erythropoietic protoporphyria (EPP). Participants are randomized to receive placebo, oral DISC-1459 at dose level 1, or oral DISC-1459 at dose level 2 for 120 days. Participants may then enter an open-label extension period during which they will continue to receive DISC-1459 at dose level 1 for up to eight months.

The primary outcome measure is the percent change in whole-blood, metal-free protoporphyrin IX (PPIX) levels from baseline. Secondary outcome measures include total hours of skin exposure to sunlight on pain-free days from 10:00 a.m. to 6:00 p.m., time from sunlight exposure (minutes) to the first associated prodromal symptom between one hour post-sunrise and one hour pre-sunset, intensity of pain associated with phototoxic reactions on a Likert scale (0 to 10), incidence of treatment-emergent adverse events, total PPIX concentrations in erythrocytes, total plasma PPIX concentrations, total whole-blood PPIX concentrations, and plasma bitopertin concentrations. Other outcome measures include the maximum measured drug concentration (Cmax) in plasma, time of maximum concentration (Tmax), and the area under the concentration–time curve (AUC).

Eligibility criteria include an age of 18 years or older and an established diagnosis of EPP based on the results of ferrochelatase (FECH) genotyping or biochemical porphyrin analysis. Among the additional inclusion criteria are a body weight greater than 50 kg, a washout period of at least two months from afamelanotide or dersimelagon (if applicable), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels less than twice the upper limit of normal (ULN), total bilirubin levels below the ULN, and albumin levels greater than the lower limit of normal (LLN). Exclusion criteria include major surgery within eight weeks before screening, an inherited or acquired red cell disease associated with anemia, history of known allergic reaction to any investigational product or history of anaphylaxis to any food or drug, history of liver transplant, history of alcohol dependence or excessive consumption, HIV/active hepatitis B/active hepatitis C, concurrent or planned treatment with afamelanotide or dersimelagon, treatment with opioids for any period longer than 7 days in the two months prior to screening or anticipated opioid use for more than 7 days at any point during the study, new treatment for anemia (including iron supplementation) in the two months prior to screening, use of inhibitors or inducers of CYP3A4 enzymes for 28 days prior to the first dose and throughout the study, and a hemoglobin level under 10 g/dL at screening.

RATIONALE: EPP, a rare hereditary disease caused by reduced expression of ferrochelatase, is characterized by painful non-blistering photosensitivity, hepatotoxicity, and anemia.^1,2  As with many rare diseases, there are few effective, evidence-based therapeutics available for EPP. Afamelanotide, an analogue of a-melanocyte-stimulating hormone administered via a subcutaneous implant, has been shown to increase the duration of pain-free sun exposure and improve quality of life in patients with EPP. Although afamelanotide has been approved for this indication in both the U.S. and E.U.,^1-3  its impact has been attenuated by difficulties in access given its high cost and mode of administration. More recently, dersimelagon — an orally administered selective melanocortin 1 receptor agonist — demonstrated similar results in a phase II trial among patients with EPP and X-linked protoporphyria.⁴ 

While these drugs represent a welcome advancement, both only address the photosensitivity associated with EPP, and hepatotoxicity remains a significant clinical concern, with elevation of liver enzymes and liver failure observed in up to 33% and 5% of patients, respectively.^1,2  Aside from liver or hematopoietic stem cell transplantation, which are associated with risks of morbidity and mortality, treatment options for these patients are very limited.²  Bitopertin is a selective inhibitor of glycine transporter 1 (GlyT1), a crucial substrate for the first step of heme biosynthesis.⁵ 

In reducing the availability of GlyT1, bitopertin in turn reduces the downstream accumulation of PPIX, which is thought to be the cause of both photosensitivity and hepatotoxicity in patients with EPP. Encouragingly, bitopertin has been shown to reduce the development and severity of liver fibrosis in a mouse model of EPP.⁵  As bitopertin has previously been studied for the treatment of neuropsychiatric disorders, investigators were able to move directly to phase II studies of this drug for the treatment of EPP — the impetus for both the AURORA study in the U.S. and another phase II study (BEACON) underway in Australia.⁶ 

COMMENT: With still only one approved pharmacologic treatment available for EPP (afamelanotide), any clinical trial of a new agent for this disease is welcome and exciting. If effective, bitopertin would aid in establishing a new paradigm for the treatment of EPP and provide a welcome oral alternative to afamelanotide for the treatment of photosensitivity. Moreover, by reducing the accumulation of toxic heme biosynthesis intermediates, this drug has the potential to address the multisystem manifestations of EPP, especially the risk of potentially devastating hepatotoxicity. Longer-term follow-up studies and future trials should examine these outcomes. Nonetheless, clinicians and patients alike await the results of the AURORA (and BEACON) trials with great anticipation.