Results unveiled from phase 2/3 gene therapy study for XLRP

David Hutton

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OT Staff Reports

While Biogen’s XIRIUS study did not meet its primary endpoint of demonstrating a statistically significant improvement in treated eyes, positive trends were observed across several clinically relevant prespecified secondary endpoints.

Biogen Inc. on Friday announced topline results from the Phase 2/3 XIRIUS study of cotoretigene toliparvovec (BIIB112), a gene therapy being investigated as a one-time therapy for patients with X-linked retinitis pigmentosa (XLRP).

Patients living with XLRP currently have no approved treatments. The company noted that the XIRIUS study did not meet its primary endpoint of demonstrating a statistically significant improvement in the proportion of treated study eyes with ≥ 7 dB improvement from baseline at ≥ 5 of the 16 central loci of the 10-2 grid assessed by Macular Integrity Assessment (MAIA) microperimetry.

This assessment was performed at 12 months and compared to the study eye of patients randomized to the untreated control group. Positive trends were observed across several clinically relevant prespecified secondary endpoints.

Cotoretigene toliparvovec (BIIB112) is an investigational AAV8 vector-based gene therapy administered by subretinal injection, designed to provide full-length functioning retinitis pigmentosa GTPase regulator (RPGR) protein in patients with X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene.

By replacing the gene, cotoretigene toliparvovec leads to increased levels of the RPGR protein which may potentially slow, stop or prevent further degeneration of photoreceptors in patients with RPGR-associated XLRP.

Katherine Dawson, MD, head of the therapeutics development unit at Biogen, noted that while the Phase 2/3 XIRIUS study of cotoretigene toliparvovec did not meet its primary endpoint, the company is encouraged by positive trends in other pre-specified clinically relevant endpoints, such as a measure of visual acuity under low light conditions.

“XLRP is a serious, early-onset form of retinitis pigmentosa, and people living with it face almost certain blindness by the end of the fourth decade, commonly leading to loss of independence, depression and unemployment,” she said. “We are working to further evaluate the data from the XIRIUS study before communicating potential next steps for the cotoretigene toliparvovec clinical development program.”

According to the company, most of the adverse events were ocular in nature, mild-to-moderate in severity, and resolved.

Complete analysis of the XIRIUS study is ongoing, and detailed results will be shared in a future scientific forum.

Biogen is advancing its multi-franchise portfolio strategy by pursuing modalities including gene therapy to address significant unmet medical needs. In ophthalmology, in addition to cotoretigene toliparvovec, the company is currently evaluating the safety and efficacy of timrepigene emparvovec (BIIB111/AAV2-REP1), a gene therapy being investigated for the one-time treatment of choroideremia, a rare inherited retinal disease.

The company also announced a global collaboration and licensing agreement with ViGeneron GmbH to develop and commercialize gene therapy products based on adeno-associated virus (AAV) vectors with the aim of treating inherited eye diseases as well as a licensing agreement with Massachusetts Eye and Ear to develop a gene therapy for the potential treatment of inherited retinal degeneration due to mutations in the PRPF31 gene. In addition to Biogen’s gene therapy candidates for various ophthalmic conditions, the company also entered into an agreement with Catalyst Biosciences to develop and commercialize pegylated CB 2782 for the potential treatment of geographic atrophy, an advanced form of dry age-related macular degeneration that leads to blindness that has no approved therapies.

XIRIUS was a first-in-human, multicenter, randomly assigned, three-arm dose-escalation and dose-expansion study of a single subretinal injection of cotoretigene toliparvovec in males with a genetically confirmed diagnosis of X-linked retinitis pigmentosa. Part I was a 24-month dose-escalation study (n = 18, ≥ 18 years of age); Part II was a 12-month dose expansion study (n = 32 randomized ≥ 10 years of age), with a high dose and low dose selected from Part I based on a benefit/risk assessment and a third untreated group to allow for a controlled comparison of efficacy and safety. At study completion, treated subjects in Parts I and II have been invited to participate in a separate long-term follow-up study that will collect efficacy and safety data up to five years from treatment.