The current treatment of Wilson disease relies on copper chelators, zinc salts, and liver transplantation, with chelating agents considered the standard of care (SoC) for disease management.1

New experimental therapies have been developed that are designed to deliver a functional ATP7B gene into the patients’ cells, aiming to address the underlying cause of the disease.1,2 Different clinical trials are currently ongoing to determine the safety and efficacy of these new gene therapies as well as new decoppering strategies. 

ALXN1840 Clinical Trial

A pivotal phase 3 clinical trial, FoCus (NCT03403205), is currently ongoing to determine the safety and efficacy of the investigational drug ALXN1840 (bis-choline tetrathiomolybdate) compared to those of SoC when administered for 48 weeks.3 ALXN1840 is an oral investigational drug developed to bind selectively to copper to allow its efficient removal from the tissues and the blood.4

FoCus is a randomized, controlled, rater-blinded, multicenter clinical trial that includes patients with Wilson disease who are at least 12 years of age, and it has an estimated completion date of February 2026.3 SoC includes chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both.4 The primary endpoint assessment of FoCus is copper mobilization over 48 weeks, measured by the daily mean area under the effect curve for non-ceruloplasmin-bound copper.3,4 Secondary endpoints include changes in neurological function. The study enrolled 214 patients, who were randomized 3:1 into one of two cohorts (treatment-experienced:treatment-naïve). Patients from each cohort were then randomized 2:1 to receive the investigational drug or SoC, respectively.3,4

Recent results from this trial have shown that ALXN1840 met its primary endpoint, with a copper mobilization that was 3 times higher than that of SoC. Copper mobilization was rapid, with a response observed at 4 weeks and sustained until 48 weeks. An extension study period of up to 60 months is currently undergoing for the evaluation of the safety and efficacy of ALXN1840.3,4

A phase 1 clinical trial that aims to determine the effect of a supratherapeutic dose of ALXN1840 on the heart rate-corrected QT interval in healthy adults is currently enrolling participants by invitation (NCT04560816).5 ALXN1840 will also be investigated in two phase 2 clinical trials designed to explore the effects of the experimental treatment on copper balance (NCT04573309) and copper concentration in the liver (NCT04422431), as well as in a phase 3 clinical trial involving pediatric patients (NCT05047523).6-8

Read more about ALXN1840

Clinical Trials With Gene Therapies

VTX-801 is a potential gene therapy developed to deliver normal and functional copies of the ATP7B gene into the cells of patients with Wilson disease.9 The clinical trial, GATEWAY (Gene Therapy for Wilson Disease; NCT04537377), is currently recruiting and aims to determine the safety, tolerability, and efficacy of single-ascending doses of the investigational treatment in adult patients with Wilson disease, prior to and following background Wilson disease therapy withdrawal.10

GATEWAY is a phase 1/2, multicenter, nonrandomized, open-label trial that aims to enroll 16 participants. The trial will be conducted for up to 5 years and will allow the study of 3 different doses of VTX-801.11 The primary outcome of this study is the safety and tolerability profile of the experimental treatment, while second outcomes include free and total serum copper level determination, 24-hour urinary copper levels, serum ceruloplasmin activity, and responder status.10

Read more about VTX-801

UX701 is another potential gene therapy that delivers the normal ATP7B gene into Wilson disease patients’ cells.12,13 A seamless randomized, double-blind, placebo-controlled phase 1/2/3 clinical trial, Cyprus2+ (NCT04884815), has been designed to assess the safety and efficacy of this new investigational treatment.14 In February 2022, the first patient received a single infusion of UX701.15 

Cyprus2+ has been designed to include patients with Wilson disease who have received SoC for at least 12 months and who have maintained medication for at least 6 months before the start of the study. Baseline values of 24-hour copper concentration, blood cell count, and liver function will be determined over 4 to 12 weeks.13

Cyprus2+ includes 3 stages in which the safety, efficacy, and optimal dose of the investigational treatment will be determined. Then, the optimal dose will be assessed and compared to a placebo for up to 52 weeks. Finally, patients will be monitored beyond 52 weeks to allow the evaluation of the long-term safety, clinical benefits, and duration of response of the potential therapy.13

Read more about UX701


1. Dev S, Kruse RL, Hamilton JP, Lutsenko S. Wilson disease: update on pathophysiology and treatment. Front Cell Dev Biol. 2022;10:871877. doi:10.3389/fcell.2022.871877

2. 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

3. Efficacy and safety of ALXN1840 (administered for 48 weeks versus standard of care in participants with Wilson disease. January 18, 2018. Updated May 9, 2022. Accessed September 21, 2022.

4. ALXN1840 shows rapid and sustained improvement in copper mobilisation from tissues, potentially closing treatment gaps for Wilson disease community. News release. AstraZeneca; June 23, 2022.

5. A study of the cardiac effects of ALXN1840 in healthy adults. September 23, 2020. Updated February 15, 2021. Accessed September 21, 2022.

6. Copper and molybdenum balance in participants with Wilson disease treated with ALXN1840. October 5, 2020. Updated May 18, 2022. Accessed September 21, 2022.

7. Copper concentration & histopathologic changes in liver biopsy in participants with Wilson disease treated with ALXN1840. June 9, 2020. Updated July 12, 2022. Accessed September 21, 2022.

8. Study of ALXN1840 versus standard of care in pediatric participants with Wilson disease. September 17, 2021. Updated June 6, 2022. Accessed September 21, 2022.

9. VTX-801 receives U.S. FDA Fast Track designation for the treatment of Wilson disease. News release. Vivet Therapeutics and Pfizer Inc; August 12, 2021.

10. A phase I/II study of VTX-801 in adult patients with Wilson’s disease (GATEWAY). September 3, 2020. Updated August 5, 2022. Accessed September 21, 2022.

11. Introducing GATEWAY, a clinical trial for Wilson disease. Vivet Therapeutics. Accessed September 21, 2022.

12. UX701: gene therapy for the potential treatment of Wilson disease. Ultragenyx Pharmaceutical. Accessed September 21, 2022.

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

14. Clinical study of UX701 AAV-mediated gene transfer for the treatment of Wilson disease. May 13, 2021. Updated August 23, 2022. Accessed September 21, 2022.

15. Smith K. Ultragenyx Wilson disease update Feb 2022. Ultragenyx Pharmaceutical Inc. February 17, 2022. Accessed September 21, 2022.

Reviewed by Kyle Habet, MD, on 9/27/2022.