Ultragenyx Completes Dosing of UX701 Gene Therapy in Patients With Wilson Disease


The ongoing, multistage phase 1/2/3 Cyprus2+ study (NCT04884815) expects to read out initial safety and efficacy data in the first half of 2024.

Eric Crombez, MD, the chief medical officer at Ultragenyx

Eric Crombez, MD

Ultragenyx has completed the dosing of patients with Wilson disease with its investigational adeno-associated virus 9 (AAV9) gene therapy, UX701, in the first stage of the ongoing phase 1/2/3 Cyprus2+ study (NCT04884815), according to a recent announcement.1 These 15 patients include all of those enrolled across 3 dose-escalation cohorts, assessing varying levels of genome copy (GC) delivery: 5.0 x 1012 GC/kg, 1.0 x 1013 GC/kg, and 2.0 x 1013 GC/kg.

This news comes a little more than 6 months after the initiation of dosing of patients in the second cohort in Stage 1 of the study, which was announced in Summer 2023.2 The initial efficacy and safety data from this stage are anticipated to be read out in the first half of 2024, with dose selection and the corresponding initiation of Stage 2 expected to occur in the second half of the year.1

Eric Crombez, MD, the chief medical officer at Ultragenyx, expressed in a statement1 the company’s gratitude for the support from the patient and physician communities, noting that this milestone “moves us one step closer to beginning Stage 2, the pivotal, randomized placebo-controlled stage of the study. Beyond the seamless nature of this study, another important differentiator of this program is that it leverages our Pinnacle PCL platform, which enabled a single run to support Stage 1, demonstrating that the productivity improvements generated by our platform are able to support larger-scale clinical programs.”

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In the study’s second stage, a third cohort of patients will be randomly assigned in 2:1 fashion to receive the selected dose of UX701 or placebo, with the primary safety and efficacy analyses planned for Week 52 of Stage 2. The primary efficacy end points are the change in 24-hour urinary copper concentration and the percent reduction in standard-of-care medication. After the initial 52-week study period, all patients will have long-term follow-up for at least 5 years—this will be Stage 3.

Patients with Wilson disease experience deficiency in the ATP7B protein, which results in an accumulation of copper in tissues that, in turn, causes a variety of adverse effects. The current standard of care for Wilson disease is life-long chelation therapy. UX701 is designed to deliver stable expression of the ATP7B copper transporter following a single intravenous infusion, aiming to normalize copper metabolism in patients.

UX701 has additionally received an orphan drug designation from both the FDA and the European Commission,3,4 at which time Crombez noted that “by correcting copper trafficking and removal, this 1-time treatment has the potential to better address the many serious effects of this disease and improve the lives of patients.”

Ultragenyx noted that data it presented in October 2023 at its Company Analyst Day5 showed UX701 had been well tolerated to date in the first dose cohort, with no unexpected treatment-related emergent adverse events (AEs) reported as of the data cut-off on October 8, 2023. In total, 4 of 5 patients enrolled in Cohort 1 had started tapering standard-of-care treatment, occurring 12 weeks after dosing, including 2 patients that came completely off chelators and/or zinc therapy (Patient 2 at week 70; Patient 3 at week 44). Only 1 patient, (Patient 1 at week 82) had reported no reduction of standard-of-care.5

1. Ultragenyx Announces Completion of Dosing Across Stage 1 Cohorts in Pivotal Phase 1/2/3 Cyprus2+ Study Evaluating UX701 Gene Therapy for the Treatment of Wilson Disease. News release. Ultragenyx Pharmaceuticals. January 25, 2024. Accessed February 1, 2024. https://www.globenewswire.com/news-release/2024/01/25/2817385/20739/en/Ultragenyx-Announces-Completion-of-Dosing-Across-Stage-1-Cohorts-in-Pivotal-Phase-1-2-3-Cyprus2-Study-Evaluating-UX701-Gene-Therapy-for-the-Treatment-of-Wilson-Disease.html
2. Ultragenyx announces initiation of dosing in second cohort of pivotal phase 1/2/3 Cyprus2+ trial evaluating UX701 gene therapy for the treatment of Wilson disease. News release. Ultragenyx Pharmaceutical Inc. July 31, 2023. Accessed February 1, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-initiation-dosing-second-cohort-pivotal
3.Ultragenyx announces progress across broad gene therapy portfolio and positive longer-term data from multiple phase 1/2 gene therapy studies. News release. Ultragenyx Pharmaceutical Inc. January 8, 2021. Accessed February 1, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-progress-across-broad-gene-therapy
4.Ultragenyx announces orphan drug designation for UX701 for the treatment of Wilson disease. News release. Ultragenyx Pharmaceutical Inc. December 9, 2020. Accessed February 1, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-orphan-drug-designation-ux701-treatment
5. Kakkis E. Analyst Day. Ultragenyx website. October 16, 2023. Accessed February 1, 2024. https://ir.ultragenyx.com/static-files/5964f507-e463-4f50-ad2b-9a6cb516aeb6
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