Wilson disease, a genetic disorder with autosomal-recessive inheritance, is caused by alterations in the ATP7B gene, which encodes the copper-transporting ATPase 2 enzyme.1 ATPase 2 transports copper from the liver to different parts of the body while also removing excess copper.2 Mutations in the ATP7B gene result in a toxic accumulation of copper in the liver, brain, and other organs and tissues, and excessive amounts of copper can be harmful to the body.1,2 When untreated, Wilson disease can be fatal.2 

Wilson disease is treated by administering chelating agents and drugs that prevent the absorption of copper in the gastrointestinal tract.3 However, some patients become unable to tolerate the drugs, and/or side effects may develop that can be severe.4 Additionally, the treatments do not address the underlying cause of the disease.2 Novel therapeutic strategies are therefore being designed to overcome these limitations. These novel strategies has led to discovery of new compounds that circumvent ATP7B deficiency and comprise correction of ATP7B mutants.4


ALXN1840 is an oral investigational drug from Alexion, an AstraZeneca group that develops treatments for rare diseases. It binds selectively to copper and removes excess copper from the blood and tissues.5 ALXN1840 is a first-in-class copper-protein binding drug whose mode of action is distinct from that of drugs such as trientine and d-penicillamine; it forms a tripartite complex with copper and albumin to promote the elimination of copper via biliary excretion.6

Recently, the phase 3 clinical trial FoCus reported that when taken once daily, ALXN1840 met its primary endpoint, demonstrating mobilization of copper from the tissues 3 times greater than mobilization with standard of care (SoC0. Improvements in the neurological scores of patients who were symptomatic at baseline were greater in those treated with ALXN1840 than in those who received SoC. Overall, ALXN1840 was well tolerated, and its long-term safety and efficacy are currently being evaluated within a period of up to 60 months.5 

ALXN1840 has been granted Orphan Drug Designation in the United States as well as orphan designation in the European Union for the treatment of Wilson disease.5

Read more about Wilson disease therapies


Gene therapy in Wilson disease is focused on delivering normal ATP7B gene copies into cells via specific vectors.4 UX701, an investigational adeno-associated viral vector serotype 9 (AAV9) gene therapy that is being developed by Ultragenyx Pharmaceutical, delivers modified ATP7B genes to the cells of patients with Wilson disease in a single intravenous infusion. The ATP7B gene is often too large to be delivered through an AAV vector. In this therapy, a modified virus containing normal copies of the gene encoding ATP7B protein can be delivered into cells, so that normal ATP7B protein can be produced.2,7 

Preclinical studies have shown that UX701 normalizes copper trafficking and excretion, reducing the accumulation of copper in the liver and increasing ceruloplasmin levels. This investigational therapy has been granted Orphan Drug Designation in the United States and the European Union as well as Fast Track Designation in the United States.2 Ultragenyx plans to conduct a pivotal seamless adaptive phase 1/2/3 clinical trial of this drug, Cyprus2+, and recruitment for the phase 1/2 study is currently ongoing.7 The safety and efficacy of up to 3 dose levels will be addressed in the first stage of the study, and a dose will be selected for further evaluation in stage 2. Patients will undergo long-term follow-up in stage 3.8


VTX-801, a novel investigational gene therapy manufactured by Pfizer in collaboration with Vivet Therapeutics, is designed to deliver a miniaturized ATP7B transgene that encodes a normal and functional ATP7B protein. It has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Commission and Fast Track Designation by the FDA.9 

This recombinant AAV-based gene therapy vector has been shown to restore copper homeostasis, reducing copper accumulation in the brain in a mouse model of Wilson disease. The serotype of this therapy was chosen on the basis of its demonstrated tropism for transducing human liver cells.9 

A non-randomised, open label, 5-year follow-up multicenter phase 1/2 clinical trial, GATEWAY, is currently recruiting and will evaluate the safety, tolerability, and pharmacological activity of a single intravenous infusion of VTX-801 in adult patients before and after background Wilson disease therapy withdrawal. VTX-801 is a recombinant adeno-associated viral vector (rAAV) with a shortened version of ATP7B mini gene consisting of a single-stranded DNA genome in AAV liver tropic capsid.10 Enrollment of 16 adult patients with Wilson disease is planned, and up to 3 doses of VTX-801 are expected to be evaluated in this trial.9


1. Ott P, Ala A, Askari FK, et al. Designing clinical trials in Wilson’s disease. Hepatology. 2021;74(6):3460-3471. doi:10.1002/hep.32074

2. UX701: AAV9 gene therapy for Wilson disease. Ultragenyx. Accessed September 11, 2022.

3. Gilroy RK. Wilson disease medication. Medscape. Updated February 14, 2019. Accessed September 11, 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. LXN1840 shows rapid and sustained improvement in copper mobilisation from tissues, potentially closing treatment gaps for Wilson disease community. News release. AstraZeneca; June 23, 2022.

6. Kim P, Zhang CC, Thoröe-Boveleth S, et al. Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b-/- copper overload mouse model. Biomedicines. 2021;9(12):1861. doi:10.3390/biomedicines9121861

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

8. 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.

9. VTX-801 receives U.S. FDA Fast Track Designation for the treatment of Wilson disease. News release. GlobeNewswire; August 12, 2021

10. A phase I/II dtudy of VTX-801 in adult patients with Wilson’s disease (GATEWAY). ClinicalTrials.gov. September 3, 2020. Updated August 5, 2022. Accessed September 11, 2022.

Reviewed by Debjyoti Talukdar, MD, on 9/27/2022.