Maintenance of disease-relevant biomarker improvement in patients with Molybdenum Cofactor Deficiency (MoCD) Type A administered ALXN1101, a synthetic form of cyclic pyranopterin monophosphate

Abstract

Objective: To evaluate molybdenum cofactor deficiency (MoCD) disease biomarkers in urine and plasma in patients with MoCD Type A treated with synthetic cyclic pyranopterin monophosphate (cPMP). MoCD Type A is an ultra-rare autosomal recessive disease caused by mutations in molybdenum cofactor synthase 1 (MOCS1) resulting in sulfite toxicity with severe, irreversible neurological damage and infant mortality. MOCS1 catalyzes the conversion of guanosine triphosphate (GTP) to cPMP, the first step in the synthesis of molybdenum cofactor (MoCo). Deficient MoCo biosynthesis results in the loss of activity in MoCo-dependent enzymes, including sulfite oxidase (SO) and xanthine oxidoreductase (XOR), resulting in elevated concentrations of S-sulfocysteine (SSC) and xanthine and low concentrations of uric acid in urine and plasma. E. coli-derived recombinant cPMP has been administered to 11 patients with MoCD Type A with improvement in disease biomarkers (Schwahn 2015) and a method for chemical synthesis of cPMP (ALXN1101) has been developed (Clinch 2013). Methods: Patients with MoCD Type A receiving daily recombinant cPMP were transitioned to a matching dose of ALXN1101 (synthetic cPMP) and dose-escalated to a maximum daily dose of 1200 ug/kg IV of ALXN1101. Measured biomarkers included SSC, xanthine, and uric acid. Tandem LC/MS methods were developed to evaluate urine and plasma. Results: Normalization of MoCD biomarkers associated with treatment with recombinant cPMP was maintained after transition to ALXN1101. Dose escalation of ALXN1101 to 1200 ug/kg/day was associated with minimal additional changes in concentrations of SSC, xanthine, and uric acid over ≥12 months. Conclusion: Observed normalization of MoCD biomarker concentrations in urine and plasma associated with treatment with recombinant cPMP is maintained after transition to ALXN1101 as well as during subsequent dose-escalation and maintenance treatment.