FDA Approves Sentynl's Zycubo, First US Treatment for Menkes Disease in Children

The US Food and Drug Administration on January 12 approved Zycubo (copper histidinate) injection as the first treatment for Menkes disease in pediatric patients, the agency announced. The approval went to Sentynl Therapeutics, a Solana Beach, California, company wholly owned by India's Zydus Lifesciences, which announced the decision on January 13.

Menkes disease is an inherited neurodegenerative disorder in which a genetic defect impairs a child's ability to absorb copper. The FDA said it causes seizures, failure to grow, developmental delays and intellectual disability, and that children with the classical form, about 90% of cases, begin to show symptoms in infancy and typically do not live past three years. The agency put its frequency at about one in every 100,000 to 250,000 live births worldwide.

Zycubo is a copper replacement therapy given daily by injection under the skin. The FDA said it delivers copper in a form that bypasses the defect in intestinal absorption.

The evidence behind the approval

The FDA said it evaluated Zycubo in two open-label, single-arm clinical trials, which Sentynl described as pivotal studies, in children treated for up to three years. Survival was assessed by comparing 66 treated patients with 17 untreated patients from contemporaneous external control groups, most of them in the United States.

Children who began treatment within four weeks of birth had a 78% reduction in the risk of death compared with untreated patients, according to the FDA. Nearly half of early-treated patients survived beyond six years, and some beyond 12 years, while no untreated patient survived beyond six years. Children who started later also had a substantial survival benefit, the agency said. Sentynl, citing the US prescribing information, said median overall survival was 177.1 months in the early-treatment cohort versus 17.6 months in the untreated control cohort.

"The company demonstrated a large improvement in overall survival compared with untreated patients, using an innovative trial design that addressed the challenges of studying an ultra-rare disease," said Tracy Beth Hoeg, acting director of the FDA's Center for Drug Evaluation and Research, in the agency's release.

The most common side effects included infections, respiratory problems, seizures, vomiting, fever, anemia and injection site reactions, the FDA said. Because copper can build up in the body, patients receiving the drug should be closely monitored for toxicity. Sentynl noted that Zycubo is not indicated for Occipital Horn Syndrome.

Path to approval

The application received Priority Review, Fast Track, Breakthrough Therapy and Orphan Drug designations, according to the FDA. Sentynl acquired the drug, formerly known as CUTX-101, from Cyprium Therapeutics in 2023, the company said.

The approval came after an earlier rejection. As reported by pharmaphorum, the FDA turned the application down in September over manufacturing concerns, and Sentynl resubmitted it in November. Pharmaphorum also reported that Sentynl had not announced a launch date or pricing, and that the drug, which holds orphan designation in Europe, had not yet been submitted for approval there.