UX701 is an investigational adeno-associated viral vector serotype 9 (AAV9) gene therapy. Developed by Ultragenyx, it is currently being evaluated as a treatment for Wilson disease,1,2 a rare genetic disorder of copper metabolism.1 Wilson disease is caused by a mutation in the ATP7B gene, which encodes a protein involved in the transport of copper from the liver to other sites of the body.1 The excess copper can have toxic effects on the liver and nervous system, and the disease can be fatal if not treated.1

Mode of Action

UX701 is an innovative therapeutic approach for Wilson disease in that it is designed to treat the underlying cause of the disorder. The current management of Wilson disease is based on removing excess copper from the tissues with chelating drugs and preventing the absorption of copper in the gastrointestinal tract. Neither strategy addresses the faulty ATP7B gene.3 In addition, the treatments in current use can cause side effects that may be severe, and intolerance to treatment may develop.4

UX701 uses a virus to deliver copies of a normally functioning ATP7B gene into patients’ cells. With this strategy, normal ATP7B protein can be produced. The drug is administered as a single intravenous infusion.1,2

Clinical Studies

In preclinical studies, UX701 normalized copper metabolism and copper levels. This investigational drug has been granted Orphan Drug Designation in the United States and the European Union and Fast Track Designation in the United States.1 The US Food and Drug Administration approved the UX701 Investigational New Drug Application in January 2021, and a seamless phase 1/2/3 clinical trial, Cyprus2+ (NCT04884815), has been undertaken to evaluate the safety and efficacy of the new gene therapy.5,6 

The design of this pivotal clinical trial required agreement on the clinical endpoints and prior determination of the manufacturing requirements. Ultragenyx used a proprietary and commercial-scale manufacturing platform to produce and test a GMP-grade drug product, a HeLa producer cell line (PCL), for the trial.2,5

Read more about experimental therapies for Wilson disease

Cyprus2+ Clinical Trial

Cyprus2+ is designed to enroll patients with Wilson disease who have been receiving standard-of-care treatment with chelating agents and/or zinc for at least 12 months. No changes of medication and doses can be registered for at least 6 months before enrollment. Patients’ first screen includes an evaluation of AAV9 capsid antibodies. Following the screen, 24-hour copper concentration, blood cell count, and liver function are evaluated in a 4- to 12-week baseline monitoring period.2 In October 2021, Ultragenyx announced the successful screening and enrollment of multiple patients into the baseline monitoring period preceding dosing.2 In February 2022, the first patient had received a single infusion of UX701.7

Cyprus2+ is a randomized, double-blind, placebo-controlled, adaptive phase 1/2/3 clinical trial with 3 seamless stages.6 In stage 1, the safety and efficacy of 3 different doses of UX701 will be assessed in 27 patients randomized to receive the gene therapy or placebo. Biomarkers of copper metabolism, reductions in the use of standard-of-care treatment, and the safety profile observed in these patients will be used to determine the optimal dose.5

Stage 2 of the clinical trial will focus on evaluating the optimal dose determined in stage 1. A total of 63 patients will be enrolled and randomized to therapy or placebo. The 24-hour urinary copper concentration and reduction in the use of standard-of-care treatment at week 52 will be the primary efficacy endpoints. Additional biomarkers of copper metabolism will be also evaluated.2,5 

In the third and final stage of the clinical trial, the patients will be followed beyond the 52 weeks of the study period. The patients enrolled in stage 1 and stage 2 who received placebo can now receive UX701 at the dose determined in stage 2. The long-term safety, duration of response, and clinical benefit of UX701 will be evaluated.5,6


1. UX701 for Wilson disease. Ultragenyx. Accessed September 16, 2022.

2. Ultragenyx initiates Cyprus2+, a pivotal clinical trial evaluating UX701 gene therapy for the treatment of Wilson Disease. News release. GlobeNewswire; October 18, 2021.

3. Gilroy RK. Wilson disease medication. Medscape. Updated February 14, 2019. Accessed September 16, 2022.

4. Ranucci G, Polishchuck R, Iorio R. Wilson’s disease: prospective developments towards new therapies. World J Gastroenterol. 2017;23(30):5451-5456. doi:10.3748/wjg.v23.i30.5451

5. Ultragenyx announces FDA clearance of Investigational New Drug (IND) application for UX701, a new gene therapy for the treatment of Wilson Disease. News release. BioSpace; January 21, 2021.

6. Clinical study of UX701 AAV-mediated gene transfer for the treatment of Wilson disease. ClinicalTrials.gov. May 13, 2021. Updated August 23, 2022. Accessed September 15, 2022.

7. Cyprus2+ update. Ultragenyx. February 17, 2022. Accessed September 16, 2022.

Reviewed by Harshi Dhingra, MD, on 9/27/2022.