Regulatory news: Nulibry (fosdenopterin) approved to reduce the risk of mortality in patients with molybdenum cofactor deficiency type A: <scp>FDA</scp> approval summary

Abstract

Molybdenum cofactor deficiency (MoCD) type A is a very rare, fatal, autosomal recessive disease with an estimated U.S. prevalence of approximately 50 patients, primarily under 10 years of age. It is caused by pathogenic variants in the MOCS1 gene that lead to deficiency of cyclic pyranopterin monophosphate (cPMP), an intermediate in the biosynthetic pathway of molybdenum cofactor (MoCo), an essential cofactor of certain enzymes.1, 2 cPMP deficiency causes accumulation of toxic metabolites including sulfites, taurine, thiosulfate, and S-sulfocysteine (SSC).3 Patients experience intractable seizures, failure to thrive, feeding difficulties, axial hypotonia, limb hypertonia, and significantly delayed neurocognitive and motor skills.2, 3 Most patients die in the first years of life with a median survival of 36 months.2, 3 Treatment thus far has focused on managing symptoms. Fosdenopterin is a chemically synthesized form of endogenous cPMP. It treats MoCD type A by replacing the deficient cPMP substrate and permitting the biosynthesis of MoCo, enabling activation of MoCo-dependent enzymes and the reduction of accumulated sulfites. Fosdenopterin is administered as an intravenous infusion once daily based on body weight. Improved survival with fosdenopterin was demonstrated in a cohort of 13 treated patients from two clinical studies and a retrospective observational study compared with a genotype-matched observational cohort of 18 untreated patients; these studies together constitute an adequate and well-controlled clinical investigation (see Figure 1). The mean survival time at 3 years was 32 months for fosdenopterin-treated patients and 24 months for the untreated patients. At 3 years, the Kaplan-Meier survival probability (95% confidence interval [CI]) was 84% (49, 96) for fosdenopterin-treated patients and 55% (30, 74) for untreated patients. The hazard ratio for risk of death (95% CI) was 0.18 (0.04, 0.72). Source: Nulibry Review Because there was only one adequate and well-controlled clinical investigation, confirmatory evidence of effectiveness was necessary to meet the substantial evidence of effectiveness requirement for FDA approval. This confirmatory evidence was derived from clinical pharmacodynamic biomarker data (urinary SSC) and an animal model of MoCD type A. Elevated urinary SSC is a characteristic finding of MoCD type A, resulting from a deficiency of MoCo for the proper functioning of sulfite oxidase. Without normal sulfite oxidase activity, SSC accumulates throughout the body and elevated concentrations are detected in the urine. Treatment with fosdenopterin reduced urinary SSC (normalized to creatinine) in patients with MoCD type A and the reduction was sustained with long-term treatment over 48 months. Additionally, higher systemic exposures to fosdenopterin were associated with lower urinary SSC concentrations. In a knockout MOCS1 mouse model of MoCD type A, fosdenopterin improved survival and body weight, and decreased plasma and brain SSC concentrations compared with placebo-treated mice.4 The safety of fosdenopterin was evaluated in the 13 patients with MoCD type A who received intravenous doses (administered via a central venous line) up to 1300 μg/kg daily (when received as cPMP, a hydrobromide salt form) or 980 μg/kg daily (when received as cPMP, a free base form). [Correction added on 21 August 2021 after first online publication: The preceding sentence has been updated to reflect the correct details for when intravenous doses are received as a free base form.]. The median total duration of exposure to fosdenopterin/rcPMP was 5.4 years. Eight of the 13 treated patients initially received rcPMP prior to transitioning to fosdenopterin, 4 of the patients received only rcPMP, and 1 patient received only fosdenopterin. Most adverse reactions were related to infections or the central venous catheter used to infuse the drug. Adverse reactions reported in three or more of the nine fosdenopterin-treated patients in the open-label studies included catheter-related complications (89%), fever (78%), viral infection (56%), pneumonia (44%), otitis media (44%), vomiting (44%), cough and sneezing (44%), bacteremia (33%), upper respiratory infection (33%), gastroenteritis (33%), and diarrhea (33%). The safety of fosdenopterin was also evaluated in chronic juvenile rat and dog studies. No adverse effects were observed in juvenile rats up to 18-fold the maximum recommended human dose nor in juvenile dogs up to sixfold the maximum recommended human dose. In a dedicated phototoxicity study in rats, fosdenopterin caused phototoxicity at doses more than fourfold the maximum recommended human dose. The clinical relevance of this finding is unknown. There were no reported cases of phototoxicity in the clinical studies, but those studies were underway before this risk was identified and were not designed to assess this risk. The approved labeling for fosdenopterin warns of this potential risk and recommends minimizing exposure to sunlight and using protective measures (eg, broad spectrum sunscreen). FDA will also monitor this risk postapproval. For drug approval, FDA requires substantial evidence of effectiveness, with benefits that outweigh the risks. Substantial evidence of effectiveness of fosdenopterin for the treatment of MoCD type A was established based on a survival benefit in one adequate and well-controlled clinical investigation together with confirmatory evidence. This confirmatory evidence was derived from rich, longitudinal sampling of urinary SSC, a pharmacodynamic biomarker related to the canonical pathophysiologic pathway of this disease and measured using validated bioanalytical methods, as well as from an animal knockout model of MoCD showing improved survival with fosdenopterin. The use of survival data from two pooled studies plus a retrospective observational study and the comparison to a matched observational cohort of untreated patients is one example of FDA's flexibility and innovative approaches to rare diseases like MoCD type A, while still meeting the regulatory standard for approval. This approach yielded interpretable data for MoCD type A because of the strengths of the collected data, which included the use of a reliable and objective endpoint of mortality, the demonstration of a large treatment effect size, the robustness of the data to various sensitivity analyses and assumptions, and the comparability of the treated and untreated groups. With FDA's approval of fosdenopterin, patients, caregivers, and healthcare providers can be confident that fosdenopterin has compelling evidence of a survival benefit that outweighs the risks when the drug is used according to the approved labeling.

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