FDA Approves Sentynl’s Menkes Disease Therapy

Rare Daily Staff

The U.S. Food and Drug Administration approved Sentynl Therapeutics’ Zycubo, the first treatment in the United States for Menkes disease, a rare and often fatal genetic disorder that affects copper metabolism in infants.

Zycubo is approved for the treatment of Menkes disease in pediatric patients and is not indicated for Occipital Horn Syndrome, a related but distinct condition, the company said.

Menkes disease is caused by mutations in the ATP7A gene, which encodes a copper transporter. Affected infants cannot properly absorb dietary copper or move copper across the blood-brain barrier, leading to severe neurological impairment and other systemic complications. The condition is marked by sparse, depigmented “kinky” hair, connective tissue problems, and severe neurological symptoms such as seizures, low muscle tone, failure to thrive and developmental delay. Many untreated children die by age 2 to 3, according to published estimates.

Zycubo is a subcutaneous injectable formulation of copper histidinate designed to restore copper balance and maintain copper levels in patients with Menkes disease. In pooled data from two open-label, single-arm clinical trials, early treatment with Zycubo was associated with a nearly 80 percent reduction in the risk of death compared with an untreated contemporaneous external control group. Median overall survival was 177.1 months in the early-treatment cohort versus 17.6 months in the control group, according to the prescribing information.

Sentynl acquired Zycubo from Cyprium Therapeutics in 2023 and advanced it through late-stage development and regulatory review. The program received multiple FDA designations, including Breakthrough Therapy, Fast Track, Rare Pediatric Disease and Orphan Drug designations. Copper histidinate has also been granted orphan designation by the European Medicines Agency.

The most common adverse reactions, occurring in at least 7 percent of patients, included pneumonia, viral infection, respiratory failure, seizures, bacterial infections, hemorrhage, hypotension, vomiting, tachycardia, fever, volume depletion, fractures, shortness of breath, elevated liver enzymes, diarrhea, fungal infections, anemia and local injection-site reactions, the label says.

Copper accumulation and toxicity remain key safety concerns. Because impaired copper transport can already cause copper buildup in the kidneys, liver and blood-forming system, treatment with Zycubo may increase the risk of organ dysfunction, particularly in the first two years of life. The label recommends regular monitoring of kidney and liver function and blood counts, with dose adjustments based on lab results.

“Menkes disease presents significant challenges for patients and their families. With no known cure, most untreated patients do not survive beyond three years of age,” Matt Heck, Sentynl’s CEO, said. “FDA’s approval serves as compelling affirmation that a safe and effective therapy is now available for patients living with this devastating disease.”