Zycubo (copper histidinate): FDA approval, pivotal trial and safety
Approved
Type
New molecular entity · Subcutaneous
FDA-approved use
To treat Menkes diseaseWording from FDA's list of novel approvals.
FDA review
Priority reviewOrphan drug
Company
Sentynl Therapeutics
Application
NDA 211241
Specialty
Genetics
At a glance
Zycubo (copper histidinate) is a copper replacement product approved by the FDA on January 12, 2026 for Menkes disease in pediatric patients. In the pooled analysis compared with an untreated external control group, early treatment was linked to a hazard ratio for death of 0.22 (95% CI 0.10 to 0.49). The main safety concern is copper accumulation, with possible kidney, liver and blood toxicity.
What it is and how it works
Menkes disease results from ATP7A variants that impair copper absorption from the gut, copper transport into the brain, and the function of copper-dependent enzymes. Zycubo supplies bioavailable copper by subcutaneous injection, which bypasses the impaired gut absorption. It is a replacement of the missing nutrient. The label does not describe it as a gene therapy, and it is not indicated for Occipital Horn Syndrome.
Pivotal trials
Pooled analysis of Trial 1 and Trial 2 versus external control (overall survival)
Design
Two open-label, single-arm trials of copper histidinate for up to 3 years, with treated patients compared against an untreated contemporaneous external control cohort collected under a protocol amendment of Trial 2.
Patients
83 children in the pooled efficacy population (66 treated, 17 external control). All had Menkes disease with a severe ATP7A variant and were born after 1999. The primary analysis compared 31 early-treatment patients (started within 4 weeks of birth) with 17 early-treatment external controls. Of the 83 patients, 98% were male.
Compared with
Untreated external control cohort.
Primary endpoint
Overall survival in the early-treatment cohort compared with the early-treatment external control cohort.
Result
Early treatment lowered the risk of death, with a hazard ratio of 0.22 (95% CI 0.10 to 0.49), a 78% reduction. Median survival was 177.1 months (95% CI 33 to not estimable) versus 17.6 months (95% CI 11.5 to 28.6). At analysis, 16 treated patients (52%) and 2 controls (12%) were alive.
Other results
In the late-treatment comparison (started after 4 weeks of birth), treated patients also had better survival, with a 73% reduction in the risk of death. In the early-treatment cohort, 15 patients (48%) survived more than 6 years, including 7 (23%) who survived more than 12 years. No early-treatment external control survived more than 6 years.
Safety in the trial
The pooled safety set had 129 treated patients with median exposure of 24 months. Common reactions were pneumonia, viral infection, respiratory failure, seizure, bacterial infection and hemorrhage. Elevated transaminases and local administration reactions also occurred.
Neonatal diagnosis and treatment of Menkes disease (Kaler 2008) NCT00001262
Design
Prospective study of plasma neurochemical screening in infants at risk, with longitudinal follow-up of newborns who began copper replacement early.
Patients
81 infants at risk were screened. Twelve newborns who met eligibility criteria began copper treatment within 22 days after birth and were followed for 1.5 to 8 years.
Compared with
Historical control group of 15 patients with late diagnosis and late treatment.
Primary endpoint
Survival and neurodevelopment after early copper treatment, along with the diagnostic value of plasma neurochemical levels.
Result
Survival was 92% at a median follow-up of 4.6 years in the early-treated newborns, versus 13% at a median follow-up of 1.8 years in historical controls.
Other results
Two of the 12 treated patients had normal neurodevelopment and brain myelination. Both carried mutations that retained some ATP7A function. Neurochemical profiles had high sensitivity and specificity for detecting disease.
Safety in the trial
The abstract does not report specific adverse events.
How does Zycubo (copper histidinate) compare with the alternatives (Supportive care, Anticonvulsants, Unapproved copper histidine (expanded access or trials)) for Menkes disease? Summarize head-to-head and indirect evidence, efficacy, safety and where each fits, with citations.
Ask in EvidencePulseOpens in a new tab. Nothing is sent until you press Ask. Free to try, more with 2MM+.
Deep research is a core feature of 2MM Max.
Safety signals
There is no boxed warning. The main warning is copper accumulation and toxicity, which may cause drug-induced kidney injury (including renal tubular toxicity and glomerular injury), liver dysfunction and hematological abnormalities. Risk is highest in the first two years of life because the kidneys and liver are immature. The label calls for baseline and scheduled laboratory monitoring of copper, ceruloplasmin, electrolytes, kidney and liver function and a CBC, and for reducing, withholding or stopping treatment if abnormalities appear. In the pooled safety set of 129 children, the most common adverse reactions were pneumonia (30%), viral infection (27%), respiratory failure (23%), seizure (23%), bacterial infection (20%) and hemorrhage (18%). Serious reactions in at least 5% included pneumonia, dehydration, seizure and respiratory failure. These events occur often in Menkes disease itself, so attribution is difficult in single-arm data.
What it competes with
Before this approval, no FDA-approved disease-specific treatment existed for Menkes disease, and care was largely supportive. Copper histidine was given through expanded access or trials, and management focused on symptoms and complications.
Supportive careNutritional support, seizure control and management of infections and other complications remain the foundation of care.
AnticonvulsantsUsed to treat the seizures that commonly develop in affected children.
Unapproved copper histidine (expanded access or trials)The same therapy was previously available only through research or compassionate-use programs.
Bottom line for clinicians
Zycubo is for pediatric patients with Menkes disease, with the strongest evidence for treatment started within the first weeks of life in children with severe ATP7A variants. The efficacy data rest on open-label single-arm trials compared with an external untreated cohort, so confounding is possible. Plan the laboratory monitoring schedule carefully, since copper toxicity is the key risk, and keep expectations realistic about neurologic outcomes.
Dosing, contraindications and full warnings are in the prescribing information.
New FDA approvals in your inbox
The free 2 Minute Medicine Daily Brief: new approvals, landmark trials and the day's top studies, written by physicians.
Your subscription opens securely in a new tab.
Last updated October 28, 2026 by 2 Minute Medicine.
For healthcare professionals. A summary of public FDA documents and published trials, not medical advice. Check the full prescribing information before prescribing.
Get the app