Abstract Topic: 29. Iron metabolism, deficiency and overload
Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria are caused by pathogenic variants in the ferrochelatase (FECH) or 5’-aminolevulinate synthase 2 (ALAS2) genes, respectively, resulting in accumulation of photoreactive protoporphyrin IX (PPIX). In the protoporphyrias, PPIX is predominantly produced in erythroid cells in the bone marrow and subsequently delivered to the liver in red blood cells and plasma. Elevated levels of PPIX cause debilitating phototoxic skin reactions following exposure to sunlight, and may lead to 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.
Glycine transporter 1 (GlyT1) supplies extracellular glycine for the initial step of heme biosynthesis in erythroid cells. Bitopertin is an investigational small molecule inhibitor of GlyT1. It is hypothesized that GlyT1 inhibition leads to a decrease in heme pathway intermediates, including PPIX, and can improve light tolerance. In murine models of EPP and XLP, treatment with bitopertin lowered blood PPIX levels by >40% compared to controls. Bitopertin treatment in EPP mice also lowered liver PPIX levels and reduced histopathological evidence of liver cholestasis and fibrosis compared to controls.
Aims: Evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of bitopertin treatment in adults with EPP due to FECH or ALAS2 mutations. Efficacy assessments include changes in levels of metal-free PPIX, as well as measures of phototoxicity, sunlight tolerance, and pain.
Methods: BEACON is a Phase 2, randomized, open-label, parallel-arm trial (ACTRN12622000799752) of approximately 22 participants who will receive oral, once-daily administration of 20 mg or 60 mg of bitopertin for 24 weeks. The trial is being conducted at 2 sites in Australia and will enroll participants ≥18 years of age with a confirmed diagnosis of EPP by genetic testing or porphyrin analysis. Exclusion criteria include aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥2x upper limit of normal and hemoglobin <10 g/dL, as well as concurrent treatment with afamelanotide or dersimelagon. Randomization is stratified by baseline light tolerance (time to prodrome < or ≥30 minutes), as assessed over a 2-week screening period. The primary efficacy endpoint is percent change in whole-blood metal-free PPIX. Additional endpoints include patient-reported outcomes of light tolerance and quality of life, safety and tolerability, and PK parameters.
Results: Interim data on safety, changes from baseline in whole blood PPIX, measures of light tolerance, and patient reported outcomes will be presented.
Summary/Conclusion: Interim safety and efficacy data supporting the hypothesis that GlyT1 inhibition with bitopertin has the potential to be disease-modifying for EPP will be presented.
Keywords: Clinical trial