Increased Survival in Patients With Molybdenum Cofactor Deficiency Type A Treated With Cyclic Pyranopterin Monophosphate

Molybdenum cofactor deficiency (MoCD) Type A is an ultrarare disorder causing neurodegeneration and early death. Cyclic pyranopterin monophosphate (cPMP), a molybdenum cofactor precursor, is a therapeutic option for patients with MoCD Type A. In this study, efficacy in patients with MoCD Type A treated with recombinant cPMP (rcPMP) and/or fosdenopterin, a synthetic form of cPMP, from one retrospective and two prospective open-label studies (N = 14), was compared with a retrospective/prospective natural history study (untreated; N = 37). Safety was evaluated in treated patients. Patients treated with fosdenopterin/rcPMP had significantly reduced risk of premature/early death versus untreated patients (Cox proportional hazards 5.1; 95% CI 1.32–19.36; p = 0.01). MoCD disease biomarkers of urinary S-sulfocysteine and xanthine returned to near-normal from baseline to last visit in treated patients but remained abnormal in untreated patients. At 12 months, in treated patients, 43% could sit unassisted, 44% were ambulatory, and 57% could feed orally. Initiating fosdenopterin/rcPMP treatment ≤ 14 days after birth appeared to result in better clinical outcomes than initiating > 14 days after birth. Most patients (13/14) had a treatment-emergent adverse event; most were unrelated to fosdenopterin/rcPMP, were mild to moderate in severity, and none led to treatment discontinuation. These results demonstrate that patients with MoCD Type A who received fosdenopterin/rcPMP versus untreated patients were more likely to survive. Some treated patients were able to feed orally and achieve developmental milestones including walking. Fosdenopterin/rcPMP was generally well-tolerated. Improved outcomes in patients treated early support the importance of identifying MoCD in neonates and initiating treatment as soon as possible.