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

TL;DR

Treating MoCD Type A with cPMP improves survival and developmental outcomes, especially when started early in newborns.

Contribution

Demonstrates that early treatment with fosdenopterin/rcPMP significantly increases survival and developmental milestones in MoCD Type A patients.

Findings

Treated patients had a 5.1-fold lower risk of early death compared to untreated patients.

Biomarkers like urinary S-sulfocysteine and xanthine normalized in treated patients.

Early treatment within 14 days of birth led to better clinical outcomes.

Abstract

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.

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