FDA Approves Subcutaneous Copper Histidinate as First Treatment for Pediatric Menkes Disease

Months after the FDA issued a complete response letter (CRL) to the new drug application (NDA) for Sentynl Therapeutics’ copper histidinate, the agency has approved the agent as the first treatment for pediatric patients with Menkes disease, a rare genetic neurodegenerative disorder.¹ Marketed as Zycubo, the therapy is a subcutaneous copper replacement treatment that delivers copper in a form designed to bypass impaired intestinal absorption and support systemic utilization of the mineral.²

"This milestone represents the culmination of decades of research into better understanding and ultimately finding an effective treatment for Menkes disease," Stephen Kaler, MD, a clinical genetics and genomics specialist, and professor of pediatrics at the Columbia University Medical Center, said in a statement.² "Increased awareness of Menkes disease and rapid testing upon suspicion are critical, as beginning copper histidinate therapy in affected neonates has been shown to reduce symptoms and prolong life."

The company resubmitted a revised NDA for copper histidinate on November 14, 2025, following receipt of a CRL from the FDA on September 30, 2025.³ In the CRL, the agency cited observations related to current good manufacturing practice compliance at the manufacturing site. According to Sentynl, no additional approvability concerns were identified, and the FDA did not note deficiencies in the efficacy or safety data, which showed improved overall survival among patients with Menkes disease who received early treatment.⁴

The agency’s decision for approval was supported by data from 2 completed open-label, single-arm, single-site studies in which 129 patients with Menkes disease were treated with copper histidinate, formerly known as CUTX-101. In the studies, treatment consisted of subcutaneous administration of copper histidinate (1450-mcg, equivalent to 250-mcg elemental copper) twice daily until 12 months of age and once daily thereafter, for a total treatment duration of up to 3 years.⁵

Within these studies, 66 patients born after 1999 with severe loss-of-function ATP7A mutations were included in a pooled analysis. Coming into the analysis, patients were categorized into an early treatment cohort (CuHis-ET; treatment initiated in 4 weeks of birth, corrected for prematurity; n = 31) and a late treatment cohort (CuHis-LT; treatment initiated after 4 weeks of birth; n = 35).

A historical control cohort of 18 patients with Menkes disease who did not receive copper histidinate was included, comprising 18 patients in the historical control–early treatment (HC-ET) group, 17 of whom were also included in the historical control–late treatment (HC-LT) group. Efficacy of copper histidinate was evaluated by comparing early-treated patients (CuHis-ET) with untreated HC-ET patients using overall survival as the primary end point, and by comparing late-treated patients (CuHis-LT) with untreated HC-LT patients using overall survival as the secondary end point.

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The company reported that both the primary and secondary efficacy end points were met when comparing CuHis-ET with HC-E as well as CuHis-LT with HC-LT. Overall, findings showed that treatment with CuHis-ET was associated with a lower risk of death compared with HC-ET, with a hazard ratio of 0.208 (95% CI, 0.094–0.463; P <.0001) and median overall survival of 177.1 months versus 16.1 months, respectively. Similarly, results revealed 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 median overall survival of 62.4 months for CuHis-LT and 17.6 months for HC-LT.

Sentynl Therapeutics observed that clinical benefit was greater among patients who initiated treatment with copper histidinate within 4 weeks of birth, underscoring the importance of early identification and timely treatment initiation. The company noted that newborn screening for Menkes disease may facilitate earlier diagnosis, and a screening assay is currently under development.

In terms of safety, findings showed that treatment with copper histidinate among participants was generally well tolerated. In the both CuHis-ET and CuHis-LT cohorts, the company observed that the most frequently reported treatment-emergent adverse events were pneumonia (30.3%), seizures (21.2%), dehydration (18.2%), failure to thrive (16.7%), and respiratory distress (15.2%). Notably, no patients discontinued treatment because of adverse events considered related to the study drug.

“With today’s action, children with this devastating, degenerative disease will have an FDA-approved treatment option and the potential to live longer,” Christine Nguyen, MD, Deputy Director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine in the FDA’s Center for Drug Evaluation and Research, said statement.¹ “The FDA will continue to work with the rare disease community to advance drug development for patients with Menkes disease and other rare conditions.”

REFERENCES
1. FDA Approves First Treatment for Children With Menkes Disease. News release. U.S. Food and Drug Administration. January 12, 2026. Accessed January 13, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-menkes-disease?utm_medium=email&utm_source=govdelivery
2. Sentynl Therapeutics Inc. Announces FDA Approval of ZYCUBO® (copper histidinate). News release. Sentynl Therapeutics. January 13, 2026. Accessed January 13, 2026. https://sentynl.com/news/zycubo-fda-approval/
3. Sentynl Therapeutics Announces FDA Acceptance of CUTX-101 NDA Resubmission. News release. Sentynl Therapeutics. December 15, 2025. Accessed January 13, 2026. https://sentynl.com/news/sentynl-therapeutics-announces-fda-acceptance-of-cutx-101-nda-resubmission/
4. Sentynl Therapeutics updates on its NDA for CUTX-101. News release. Sentynl Therapeutics. October 1, 2025. Accessed January 13, 2026. https://sentynl.com/news/sentynl-therapeutics-updates-on-its-nda-for-cutx-101/
5. Fortress Biotech and Cyprium Therapeutics Announce Positive Clinical Data for CUTX-101, Copper Histidinate, Presented at 2021 American Academy of Pediatrics National Conference & Exhibition. News release. Sentynl Therapeutics. October 8, 2021. Accessed January 13, 2026. https://sentynl.com/news/fortress-biotech-and-cyprium-therapeutics-announce-positive-clinical-data-for-cutx-101-copper-histidinate-presented-at-2021-american-academy-of-pediatrics-national-conference-exhibition/