FDA Approves Copper Histidinate Treatment for Pediatric Menkes Disease
Key Clinical Summary
- US FDA approved copper histidinate (Zycubo; Sentynl) based on 2 open-label, single-arm, single-site studies in pediatric Menkes disease (n=129), including patients with severe ATP7A loss-of-function mutations and historical untreated controls.
- Key outcomes: Early treatment (≤4 weeks of birth; CuHis-ET) reduced mortality vs historical controls (HR 0.208; 95% CI, 0.094–0.463; P < .0001); median overall survival 177.1 vs 16.1 months. Late treatment also reduced mortality (HR 0.253; 95% CI, 0.119–0.537; P < .0001).
- Subcutaneous copper histidinate was generally well tolerated; common adverse events included infections and seizures. FDA recommends monitoring for copper-related renal or hepatic toxicity. Not indicated for Occipital Horn Syndrome.
On Monday, January 12, 2026, the United States Food and Drug Administration (FDA) approved a copper histidinate (Zycubo) injection as the first treatment for Menkes disease in pediatric patients. The application received several designations, including Priority Review, Fast Track, Breakthrough Therapy, and Orphan Drug.
What Is Menkes Disease?
Menkes disease is a rare neurodegenerative disorder that impedes a child’s ability to absorb copper. It affects 1 in every 100,000-250,000 live births globally and is more common in males. Many patients who go untreated die between 2 to 3 years of age. According to Sentynl, treatment with copper histidinate achieves a nearly 80% reduction in risk of death.
“Menkes disease presents significant challenges for patients and their families. With no known cure, most untreated patients do not survive beyond 3 years of age,” said Matt Heck, CEO of Sentynl. “[The] FDA’s approval serves as compelling affirmation that a safe and effective therapy is now available for patients living with this devastating disease.”
Clinical Trial Evidence Supports Approval
The approval was supported by clinical data from 2 completed open-label, single-arm, single-site studies involving 129 patients with Menkes disease. Participants were treated twice daily with subcutaneous copper histidinate (1450 mg) until 12 months of age, and then once daily for up to 3 years.
Pooled analysis included 66 patients with severe loss-of-function ATP7A mutations who were categorized into an early treatment cohort (CuHis-ET; treatment begun within 4 weeks of birth; n=31) and a late treatment cohort (CuHis-LT; treatment begun after 4 weeks of birth; n=35). A historical control cohort of untreated patients (n=18) was also included, with patients stratified by early and late diagnosis. A total of 18 were included in the historical control-early treatment group (HC-ET) and 17 were included in the historical control-late treatment (HC-LT) group.
The primary endpoint in evaluating efficacy of copper histidinate was comparison of overall survival between early treated patients (CuHis-ET) and untreated HC-ET patients. The secondary endpoint was comparison of overall survival between late-treated patients (CuHis-LT) and untreated HC-LT patients.
Survival Outcomes With Early versus Late Treatment
Sentynl reported fulfilment of both primary and secondary endpoints. Treatment with CuHis-ET was associated with a lower risk of death compared with HC-ET (hazard ratio [HR] 0.208, 95% CI, 0.094-0.463; P < .0001) and a median overall survival of 177.1 months versus 16.1 months. Results also showed that CuHis-LT was associated with a reduced risk of death compared with HC-LT (HR, 0.253; 95% CI, 0.119-0.537; P < .0001), with a median overall survival of 62.4 months versus 17.6 months.
Safety and Monitoring Considerations
Copper histidinate was generally well-tolerated, with the most common side effects including infections, respiratory problems, seizures, vomiting, fever, anemia, and injection side reactions. Because copper can accumulate in the body, the FDA recommends close monitoring for potential toxicity in patients that could cause renal and/or liver dysfunction.
Subcutaneous copper histidinate is not indicated for the treatment of Occipital Horn Syndrome.
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