Biogen's BIIB112 Gene Therapy Falls Short in X-Linked Retinitis Pigmentosa

Biogen announced that the phase 2/3 XIRIUS study of BIIB112 (cotoretigene toliparvovec), a gene therapy being investigated as a one-time treatment for patients with X-linked retinitis pigmentosa (XLRP), did not meet its primary end point 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. Notably, positive trends were observed across several clinically relevant prespecified secondary end points.

BIIB112 is an investigational adeno-associated virus serotype 8 (AAV8) vector-based gene therapy administered by subretinal injection, designed to provide full-length functioning retinitis pigmentosa GTPase regulator (RPGR) protein in patients with XLRP caused by mutations in the RPGR gene.

By replacing the gene, BIIB112 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 BIIB112 did not meet its primary end point, the company is encouraged by positive trends in other prespecified clinically relevant end points, 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 BIIB112, 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 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 BIIB112 in males with a genetically confirmed diagnosis of XLRP. 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 5 years from treatment.