Trial for Wilson Disease Gene Therapy UX701 Starts Dosing Second Cohort

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The initiation of dosing the second cohort in Ultragenyx’s study was recommended by the Data Safety Monitoring Board after a review of safety results from the trial’s first cohort.

Ultragenyx has begun dosing patients in the second cohort of the phase 1/2/3 Cyprus2+ clinical trial (NCT04884815) evaluating UX701, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Wilson disease.1

UX701 utilizes an AAV9 vector and is intended to deliver a functional copy of ATP7B, the disease-targeted gene. ATP7B encodes for a copper transporter protein; its deficiency in patients with Wilson disease leads to accumulation of copper in tissues resulting in a myriad of adverse effects. The current standard of care (SOC) for Wilson disease is life-long chelation therapy.

The initiation of dosing Cyprus2+’s second cohort was recommended by the study’s Data Safety Monitoring Board after a review of safety results from the trial’s first cohort, which treated patients at a dose of 5.0x1012 GC/kg, was completed. Ultragenyx noted that as of the July 11, 2023, data cutoff, the gene therapy was well-tolerated among patients treated in the first cohort and that there were no unexpected treatment emergent adverse events reported. In the second cohort, which is treating patients at a dose of 1.0x1013 GC/kg, 1 patient has been dosed so far and 4 additional patients have undergone screening.

“We are encouraged by the safety data and early signals of the establishment of normal trafficking of copper observed in Cohort 1 and with acceleration of enrollment following improvements in study design and entry criteria,” Eric Crombez, MD, the chief medical officer of Ultragenyx, said in a statement.1 “The shift to open label design and broadening of inclusion criteria allows us to enroll subjects who may not be well managed on current standard of care with chelators and/or zinc.”

Both the first and second cohorts are part of Cyprus2+’s first stage; a planned third cohort in the first stage will enroll 5 additional patients to be treated at a dose of 2.0x1013 GC/kg. The study’s planned second stage will recruit a new group of patients to be randomly assigned in a 2:1 ratio to either receive treatment with the gene therapy at a dose selected based on the results of phase 1 or a placebo. At the end of the second stage, which consists of a 52-week evaluation period, patients will undergo the primary efficacy and safety analysis. The primary efficacy end points in the second stage are the change in 24-hour urinary copper concentration from baseline and the percent reduction in SOC medication. Both end points will be evaluated for superiority. In the planned third stage of the trial patients will undergo long-term follow-up lasting at least 5 years from the time of treatment; long-term safety and clinical benefit will be assessed.

Cyprus2+ is being carried out at multiple sites across the United States under an investigational new drug application that Ultragenyx submitted to the FDA in December 2020 and that was cleared in January 2021.2,3 The study is also recruiting patients at locations in Canada, Portugal, Spain, and the United Kingdom. Initiation of the trial was announced in October 2021, with Ultragenyx reporting at that time that screening and enrollment activities were in progress.4 UX701 has received orphan drug designation (ODD) from both the FDA and the European Commission.2

“Current treatment options involve the often complicated and lifetime use of medications that block the absorption of copper from the diet or remove copper by chelation,” Crombez said in a statement made when UX701 received ODD from the FDA in December 2020.5 “UX701 is designed to directly address the underlying cause of disease by restoring normal copper metabolism in the liver. By correcting copper trafficking and removal, this one-time treatment has the potential to better address the many serious effects of this disease and improve the lives of patients.”

REFERENCES
1. 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 August 1, 2023. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-initiation-dosing-second-cohort-pivotal
2. 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 August 1, 2023.https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-progress-across-broad-gene-therapy
3. Ultragenyx announces FDA clearance of investigational new drug (IND) application for UX701, a new gene therapy for the treatment of Wilson disease. News release. Ultragenyx Pharmaceutical Inc. January 21, 2021. Accessed August 1, 2023. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-fda-clearance-investigational-new-drug-ind
4. 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. Accessed August 1, 2023. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-initiates-cyprus2-pivotal-clinical-trial-evaluating
5. Ultragenyx announces orphan drug designation for UX701 for the treatment of Wilson disease. News release. Ultragenyx Pharmaceutical Inc. December 9, 2020. Accessed August 1, 2023. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-orphan-drug-designation-ux701-treatment
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