In Light of Positive Initial Results, Ultragenyx Seeks to Add Higher Dose Cohort to Trial for Wilson Disease Gene Therapy UX701

Eric Crombez, MD

Ultragenyx intends to submit a protocol amendment for 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, in order to evaluate a higher dose cohort and optimized immunomodulation regimen.¹

The new cohort would be added to stage 1 of the trial, which has previously dosed 15 patients across 3 sequential dosing cohorts. Ultragenyx noted that the fourth cohort would use a “moderately increased” dose and that the optimized immunodulation regimen would be aimed at improving efficiency and efficacy. The results of this cohort will help inform dose selection for UX701 in stage 2 of the trial, which will take the form of a dose expansion study and randomly assign patients in a 2:1 ratio to be treated with either the gene therapy or a placebo.

Ultragenyx pointed out that as of an August 2024 data cutoff date, 6 of the 15 patients treated in the first 3 cohorts have fully tapered off treatment with standard of care (SOC) chelator and/or zinc therapy and 1 additional patient has begun the process of the tapering of SOC treatment. Furthermore, in the patients who fully tapered off SOC, stabilization of nonceruloplasmin bound copper (NCC) to healthy levels had occurred. Elevations in ceruloplasmin-copper activity deemed in line with improvement in the function of the disease-targeted ATP7b gene were also noted. In terms of safety, Ultragenyx stated that there no significant immunologic safety events and no unexpected treatment-related adverse events. The gene therapy product was characterized as “well-tolerated”.

“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,” Eric Crombez, MD, chief medical officer at Ultragenyx, said in a statement.¹ “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.”

Completion of dosing for the patients in the study’s first 3 cohorts was originally announced by Ultragenyx in January 2024.² The therapy has previously received orphan drug designation from both the FDA and the European Commission.^3,4

“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 2020.⁴ “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.”

In addition to UX701, Ultragenyx is also developing several other gene therapy products for other indications. For example, the company is currently seeking an accelerated approval pathway for a future biologics license application (BLA) submission for UX111 (ABO-102), its AAV vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome).⁶ Ultragenyx is also developing DTX401, an investigational AAV serotype 8 vector-based gene therapy expressing the human G6PC gene, which the company reported earlier this year had significantly reduced daily cornstarch intake compared to placebo treatment in patients with glycogen storage disease type Ia (GSDIa) who were treated in the phase 3 GlucoGene clinical trial (NCT05139316).⁵

REFERENCES
1. Ultragenyx provides update on stage 1 cohorts in pivotal phase 1/2/3 Cyprus2+ study evaluating UX701 gene therapy for the treatment of Wilson disease. News release. Ultragenyx Pharmaceutical Inc. October 3, 2024. Accessed October 8, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-provides-update-stage-1-cohorts-pivotal-phase-123
2. 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 October 8, 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
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 October 8, 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 October 8, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-orphan-drug-designation-ux701-treatment
5. Ultragenyx announces positive top-line results from phase 3 study of DTX401 gene therapy for glycogen storage disease type Ia (GSDIa). News release. Ultragenyx Pharmaceutical Inc. May 30, 2024. Accessed October 8, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-top-line-results-phase-3-study