AUTHORS
Amy Yeung, MD, Mark Amster, MD, MBA2, Karl E. Anderson, MD3, Manisha Balwani, MD, MS4, Herbert L. Bonkovsky, MD5, Edward Cordasco, MD6, Manuchehr Darani, MD7, Laurent Gouya, MD8, Sioban Keel, MD9, Janneke Langendonk, MD, PhD10, Cynthia Levy, MD11, Tasneem F. Mohammad, MD12, Bruce Wang, MD13, Will Savage, MD, PhD14, Gayle Ross, MD15
AFFILIATIONS
1 Harvard Medical School, Boston, Massachusetts, United States, Massachusetts General Hospital, Boston, Massachusetts, United States
2 MetroBoston Clinical Partners, Boston, Massachusetts, United States
3 University of Texas Medical Branch, Galveston, Texas, United States
4 Icahn School of Medicine at Mount Sinai, New York, New York, United States
5 Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, United States, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
6 Remington-Davis Clinical Research, Columbus, Ohio, United States
7 Marvel Clinical Research, Huntington Beach, California, United States
8 University of Paris Diderot, Paris, France
9 University of Washington/Fred Hutch Cancer Institute, Seattle, Washington, United States
10 Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
11 University of Miami Miller School of Medicine, Miami, Florida, United States
12 Henry Ford Health System, Detroit, Michigan, United States
13 University of California San Francisco Porphyria Center, San Francisco, California, United States
14 Disc Medicine, Watertown, Massachusetts, United States
15 Royal Melbourne Hospital, Melbourne, Australia
ABSTRACT
Background:
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare, genetic, metabolic disorders that result in protoporphyrin IX (PPIX) accumulation in the skin. When PPIX accumulates, it causes painful phototoxic reactions with cellular injury and inflammation, and potentially, hepatobiliary disease. Glycine transporter 1 (GlyT1) imports extracellular glycine for heme biosynthesis. Bitopertin is an investigational oral GlyT1 inhibitor shown to significantly reduce PPIX in Phase 2 EPP studies (AURORA [NCT05308472], BEACON [ACTRN12622000799752]). Improvement in sunlight tolerance and prevention of hepatobiliary dysfunction through PPIX reductions lead to meaningful improvement in quality of life in patients with EPP or XLP. APOLLO (NCT06910358) is a global Phase 3 safety, tolerability, and efficacy study of bitopertin in adults and adolescents with EPP or XLP.
Methods:
APOLLO is a randomized, double-blind, placebo-controlled study of bitopertin 60 mg versus placebo once daily for 6 months. Eligible participants had EPP or XLP confirmed by genotyping and were ≥12?years old.
Primary endpoints are percent change in whole blood metal-free PPIX and average monthly total time in sunlight without pain from a phototoxic reaction between 10:00 and 18:00 after 6 months of treatment. Secondary endpoints are occurrence of phototoxic reactions, cumulative sunlight exposure without pain, and change from baseline in time to first prodromal symptoms. Patient-reported outcomes and quality-of-life measures, such as Patient-Reported Outcomes Measurement Information System (PROMIS), Patient Global Impression of Change, Patient Global Impression of Severity, and healthcare utilization, will also be assessed. Participants who complete treatment may continue into the long-term open-label extension study (HELIOS [NCT05883748]).
Results:
One hundred ninety-nine patients were screened at 28 study sites from April 2025 to March 2026 in the US, Canada, Europe, United Kingdom, and Australia; 183 participants were randomized to bitopertin 60 mg or placebo. Mean (SD) age was 37 (17) years; 59% were female, and 91% were White. Most participants (93%) had EPP, and 7% had XLP. Biochemical testing (52%) or genetic testing (48%) of participants confirmed diagnosis. Overall, 28% of participants previously received afamelanotide and 18% previously received dersimelagon; most participants (60%) had not received prior EPP treatment. Sunlight tolerance at baseline was similar among participants with <30 versus ≥30 minutes of tolerance. Adolescents (12 to <18 years) represented 19% of enrolled participants, and most adolescents (85%) had not previously received afamelanotide or dersimelagon. Other baseline characteristics were generally similar across adolescent and adult subpopulations. Additional data, including baseline PPIX levels and measures of light tolerance, will be presented.
Conclusion:
APOLLO is designed to evaluate bitopertin as a potential disease-modifying treatment for EPP and XLP. Baseline demographic and disease characteristics were generally consistent with prior EPP/XLP studies and reflective of the broader patient population, supporting the relevance and generalizability of the study results.
DISCLOSURES
Amy Yeung, MD: Disc Medicine - Research Funding; Disc Medicine - Consultancy (Includes expert testimony)