Dear members of the Wilson disease community,

We are pleased to update you on the progress of GATEWAY, the first gene therapy clinical study evaluating the effects of Vivet’s investigational therapy VTX-801, which is intended to treat patients living with Wilson disease. The GATEWAY study is ongoing, actively enrolling, and is taking place across several locations across the US, UK, Germany and Denmark. Each participant receives a single intravenous infusion of VTX-801 and is then followed-up for 5 years to evaluate the safety and the efficacy of the product. Three consecutive groups of patients receive an increasing dose level of VTX-801, the first group receiving the lowest dose to be studied. Early April, we announced that dosing of the first group of patients (lower dose) has been completed, and that the first patient of the second group has been dosed (intermediate dose); dosing of the second group followed the favorable opinion of an independent Safety Committee composed of four Wilson disease experts who reviewed the promising data collected so far in the first patient group.

Dr. Michael Schilsky, Principal Investigator at the Yale clinical trial site for GATEWAY, commented, “Evaluation of VTX-801 as a treatment option for Wilson disease is making good progress with no detected serious adverse events in the first dose, Cohort 1 patients. Existing treatments for Wilson disease are lifelong and adherence to daily treatment often requiring multiple medication doses aimed at removing excess copper from the body is a serious problem. Additionally, current treatments are not universally effective and can cause adverse side effects in some patients. VTX-801 is designed to restore the normal copper metabolism by providing an engineered, fully functional version of the ATP7B copper transporter gene in the liver, and gives hope to the possibility of eliminating the need for additional medical therapy for this disorder. Early, encouraging data from Cohort 1 has shown detectable vector transduction and transgene expression with early signs of improvement in liver function and histology. We look forward to moving this groundbreaking program further through the GATEWAY study and future clinical trials as we seek to demonstrate its transformative potential for patients with Wilson disease.”

Please visit the GATEWAY clinical trial site for more information about the study. Additional questions can be sent to patients@vivet-therapeutics.com.

As Ultragenyx continues to advance its research for Wilson disease, please find a status update on the CYPRUS2+ study.

The CYPRUS2+ study is designed with three stages. We are currently in Stage 1 where we are evaluating the safety and efficacy of three dose levels of UX701, an investigational gene therapy for the treatment of Wilson disease. UX701 is delivered by a one-time infusion directly into the bloodstream through a vein (IV). All 15 patients in Stage 1 have received UX701 and are being followed over the course of 52 weeks. Once initial dose finding data are evaluated, a Stage 2 dose will be selected for further evaluation in the randomized, placebo-controlled portion of this study.

For Stage 2 of the CYPRUS2+ study, we plan to enroll an additional 63 patients randomized 2:1 to receive UX701 or placebo. Two thirds of the patients will be randomly selected to receive a single IV infusion of UX701 and one third will receive placebo, they will be carefully monitored by the study team over 52 weeks. Patients will then crossover to receive a second infusion of either study drug or placebo. After the initial 52-week period, all study participants will receive long-term follow up in Stage 3.

Ultragenyx is sponsoring this global study of UX701, which aims to correct the ATP7B gene with the goal of restoring the body’s ability to transport copper so that it does not collect inside the organs. We expect to have a better understanding of the associated benefits of UX701 on liver function and neurological symptoms as the study progresses. The safety and effectiveness of UX701 has yet to be established. This type of research takes time, so it will be a while before we know whether and when UX701 will receive regulatory approval.

As requested, we will continue to share updates as new information becomes available. For questions, please email PatientAdvocacy@Ultragenyx.com.

As requested, we are providing an update on Stage 1 of our Cyprus2+ study, assessing safety and efficacy of UX701, an investigational gene therapy for the treatment of Wilson disease.
The status update below is based on the first dosing group of 5 patients as of October 8, 2023:

• Four out of 5 patients have had reductions in urinary copper and are tapering off of chelators and/or zinc therapy, including 2 of 3 earlier treated patients in the group that are now completely off standard therapy
• Duration of time on the study for this group ranged from 16 to 82 weeks
• Tapering of chelators and/or zinc therapy began at 12 weeks following a single intravenous infusion of UX701
• While none of the patients have experienced treatment-related adverse events, we do not have sufficient data to reach any conclusions regarding the safety of UX701 or whether adverse events will occur as the study continues.

Additional information:

• The study is expected to complete dosing of all 15 patients in Stage 1 at the end of 2023
• Additional information on safety and efficacy is expected to be shared in the first half of 2024
• Ultragenyx is sponsoring this global study of UX701, an investigational gene therapy for which safety and effectiveness has not been established. This type of research takes time, so it will be a while before we know whether and when UX701 will receive regulatory approval.

Ultragenyx would like to express our gratitude to those individuals who are participating in our study. These experiences and insights help advance our understanding of Wilson disease and have the potential to move research forward for future generations. As requested, we will continue to share updates as new information becomes available. For questions, please email PatientAdvocacy@ultragenyx.com.

On behalf of the Vivet Therapeutics Wilson disease study team, we are happy to share updates about the ongoing and enrolling GATEWAY clinical trial.

GATEWAY is an international gene therapy clinical trial for people living with Wilson disease assessing the safety, efficacy and durability (how long-lasting) of study medication VTX-801.

What is VTX-801? In people living with Wilson disease, the ATP7B gene – normally active in the liver – is malfunctioning. VTX-801 is an investigational gene therapy containing a corrective version of the ATP7B gene; this gene is packaged within a vector, which is the empty (non-infectious) shell of a virus engineered to deliver the corrective gene into liver cells via the blood. The treatment is administered as a single intravenous infusion.

Where is this study taking place? There are now ten participating sites open across the United States and Europe: 6 sites in the U.S. (California, Connecticut, Florida, Michigan, Texas and North Carolina) and 4 sites in Europe (Denmark, Germany and the UK). For eligible patients, assistance with travel and study-related expenses will be available.

Who is sponsoring the study? Vivet Therapeutics is sponsoring the GATEWAY clinical trial. Vivet is dedicated to the development of innovative therapies for people affected by rare liver disorders such as Wilson disease.

Visit www.gatewaytrialwilsondisease.com/ for more information about eligibility and clinical trial sites.

Vivet Therapeutics, a biotechnology company researching a potential treatment for Wilson disease, is looking to speak with patients and caregivers in the Wilson disease community.