Type of information: Results
Company: Biogen (USA - MA)
Product: cotoretigene toliparvovec (BIIB112)
Action mechanism: gene therapy..XLRP is characterized by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene leading to a lack of active protein transport in photoreceptors. This abnormality leads to loss of the photoreceptor cells, resulting in retinal dysfunction by adolescence and early adulthood, progressing to legal blindness when patients reach their 40s. Cotoretigene toliparvovec (BIIB112 -NSR-RPGR) is comprised of an AAV vector administered by subretinal injection which provides a functioning RPGR gene and thus expression of the RPGR protein, which is critical for protein transport in photoreceptors. The restoration of photoreceptor function is intended to slow, stop, or potentially reverse the decline in vision. Phase 1/2 data from the dose escalation portion of the XIRIUS trial for NSR-RPGR demonstrated an increase in central retinal sensitivity. The Phase 2/3 dose expansion portion of the XIRIUS trial is currently ongoing.
Disease: X-linked retinitis pigmentosa (XLRP)
Therapeutic area: Rare diseases - Genetic Diseases - Ophthalmological diseases
Country: UK, USA
Trial details: 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. (NCT03116113)
Latest news: * On May 14, 2021, Biogen announced topline results from phase 2/3 gene therapy study of cotoretigene toliparvovec (BIIB112), a gene therapy being investigated as a one-time therapy for patients with X-linked retinitis pigmentosa (XLRP), a rare inherited retinal disease that ultimately leads to blindness in most people with the condition. 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. “Although the Phase 2/3 XIRIUS study of cotoretigene toliparvovec did not meet its primary endpoint, we are encouraged by positive trends in other pre-specified clinically relevant endpoints, such as a measure of visual acuity under low light conditions,” said Katherine Dawson, M.D., 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. 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. Tvestigational 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.