Ultragenyx Pharmaceutical Inc. is set to explore a higher dose and optimized immunomodulation regimen in its Phase 1/2/3 Cyprus2+ clinical trial evaluating UX701, an investigational adeno-associated virus (AAV) vector-based gene therapy for Wilson disease. This decision follows positive initial results from the first three dosing cohorts, which showed promising clinical activity and improvements in copper metabolism.
The company intends to submit a protocol amendment to the trial (NCT04884815) to add a fourth cohort to stage 1. This new cohort will receive a moderately increased dose of UX701, combined with an enhanced immunomodulation strategy aimed at boosting the therapy's effectiveness. Data from this cohort will inform dose selection for stage 2, a dose expansion study where patients will be randomized 2:1 to receive either UX701 or a placebo.
Initial Trial Results
As of the August 2024 data cutoff, six of the 15 patients treated across the initial three cohorts had completely discontinued standard of care (SOC) chelator and/or zinc therapy. An additional patient had begun tapering off SOC treatment. Notably, those who fully tapered off SOC achieved stabilization of nonceruloplasmin bound copper (NCC) to healthy levels. Furthermore, increases in ceruloplasmin-copper activity, indicative of improved ATP7B gene function, were observed.
According to Ultragenyx, UX701 was well-tolerated, with no significant immunologic safety events or unexpected treatment-related adverse events reported.
Expert Commentary
"We are encouraged by the clinical activity we’re seeing with UX701 at this interim timepoint, with clear signals of transgene expression and improved trafficking of copper in a subset of patients currently enrolled in the study," said Eric Crombez, MD, chief medical officer at Ultragenyx. "These results, in addition to a number of patients tapering off of SOC, give us confidence that this could ultimately be a novel therapy for people living with Wilson disease. A higher dose and optimized immunomodulation should enhance the clinical effect of this gene therapy and the ability to remove current SOC in an even broader set of patients."
Wilson Disease and UX701
Wilson disease is a rare genetic disorder caused by mutations in the ATP7B gene, leading to impaired copper transport and accumulation in the liver and other tissues. Current treatments involve lifelong medication to block copper absorption or remove excess copper through chelation. UX701 is designed to address the underlying cause of the disease by restoring normal copper metabolism in the liver.
Study Design
The Cyprus2+ study is a three-stage trial. Stage 1 involves evaluating the safety and efficacy of multiple UX701 dose levels. To date, 15 patients have been enrolled into three sequential dosing cohorts to evaluate doses of 5.0 x 10^12 GC/kg, 1.0 x 10^13 GC/kg, and 2.0 x 10^13 GC/kg. A fourth dosing cohort will be added and all patients in Stage 1 will be evaluated over the course of 52 weeks.
Stage 2 will randomize a new patient cohort 2:1 to receive either the selected dose of UX701 or a placebo. The primary safety and efficacy analyses will be conducted at Week 52 of Stage 2. The primary efficacy endpoints are change in 24-hour urinary copper concentration and percent reduction in standard-of-care medication by Week 52. All patients will have long-term follow up in Stage 3 after the initial 52-week study period.
