Biogen XLRP Gene Therapy Fails Late-Stage Study

Rare Daily Staff

Photo: Katherine Dawson, head of the therapeutics development unit at Biogen

Biogen said topline data from its phase 2/3 trial of an experimental gene therapy failed to meet the primary endpoint in patients with X-linked retinitis pigmentosa but did indicate positive trends in several prespecified secondary endpoints, such as a clinically relevant measure of visual acuity.

X-linked retinitis pigmentosa (XLRP) is a rare, inherited retinal disease that is associated with progressive vision loss as the light-sensing cells of the retina gradually deteriorate. XLRP primarily affects males and is caused most frequently by mutations in the retinitis pigmentosa GTPase regulator protein (RPGR) gene that result in the loss of photoreceptors, accumulation of retinal pigment deposits and eventual loss of vision. Initial symptoms are difficulty seeing at night, followed by restriction of the field of vision and eventually blindness in most people by the age of 40. Approximately two to four males per 100,000 have a diagnosis of XLRP, and around 75 to 90 percent of XLRP cases with known genetic mutations are caused by RPGR gene mutations. Patients living with XLRP currently have no approved treatments.

Cotoretigene toliparvovec (BIIB112) is an experimental 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, 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.

The phase 2/3 XIRIUS study of cotoretigene toliparvovec (BIIB112), a gene therapy being investigated as a one-time therapy for patients with XLRP, 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.

XIRIUS was a first-in-human, multicenter, randomized, 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.

“Although the phase 2/3 XIRIUS study of cotoretigene toliparvovec did not meet its primary endpoint, we are encouraged by positive trends in other prespecified clinically relevant endpoints, such as a measure of visual acuity under low light conditions,” said Katherine Dawson, head of the therapeutics development unit at Biogen. “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. We are working to further evaluate the data from the XIRIUS study before communicating potential next steps for the cotoretigene toliparvovec clinical development program.”

Most 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.