Biogen’s XLRP Gene Therapy Fails in Phase 2/3 Clinical Trial

Biogen recently announced that its gene therapy for X-linked retinitis pigmentosa (XLRP), Cotoretigene toliparvovec (BIIB112), failed in a Phase 2/3 study.

The trial, XIRIUS, evaluated BIIB112 as a one-time therapy for patients with XLRP. XLRP is a rare, inherited retinal disease that is associated with progressive vision loss as the light-sensing cells of the retina gradually deteriorate. 

Overall, XIRIUS did not meet its primary endpoint of a statistically significant improvement in the proportion of treated study eyes with ≥7 dB improvement from baseline. 

The assessment was performed at 12 months and compared the study eye of patients randomized to the untreated control group.

Although the trial did not yield statistically significant results, Biogen did report some modestly positive news. The most common adverse events in the trial were ocular in nature, mild-to-moderate in severity, and resolved. The researchers noted that positive trends were observed across several clinically relevant prespecified secondary endpoints, such as visual acuity. 

“We are encouraged by positive trends in other pre-specified clinically relevant endpoints, such as a measure of visual acuity under low light conditions,” Katherine Dawson, MD, head of the therapeutics development unit at Biogen, said in the announcement. 

“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,” Dawson continued. 

XLRP affects approximately one in 15,000 people annually. The disease is caused by a defect in the RPGR gene which is located on the X-chromosome. 

Initial symptoms of XLRP include difficulty seeing at night, restriction of the field of vision, and eventually blindness in most individuals by 40 years of age. Currently, there are no approved treatments for XLRP. 

The natural form of the RPGR gene has an unusual genetic code which makes it very difficult to work with. 

But in March 2017, the first person in the world received the gene therapy for XLRP in an operation conducted at the John Radcliffe Hospital in Oxford and led by Professor Robert MacLaren.

And most recently, MacLaren and his research team reprogrammed the genetic code of the RPGR gene to make it more stable. The reprogramming technique involved putting normal copies of the affected RPGR gene back into the cells of the retina, which helped the cells to function normally, but did not affect the gene’s overall function. 

The research team launched the first-in-human Phase 1/2/3 clinical trial in 2020. The trial enrolled over 60 XLRP patients in the UK and US. Results of the trial are expected in the near future. 

In the recent announcement, Biogen highlighted that it is advancing its portfolio strategy for various eye diseases. 

First, the company is evaluating the safety and efficacy of timrepigene emparvovec (BIIB111/AAV2-REP1), a gene therapy for the one-time treatment of choroideremia. 

Choroideremia a rare inherited retinal disease that mainly affects males. The first symptom is generally an impairment of night vision. 

Biogen also recently entered into 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 intent to treat inherited eye diseases. 

And through a licensing agreement with Massachusetts Eye and Ear, Biogen will 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 treatment of geographic atrophy.

Geographic atrophy is an advanced form of dry age-related macular degeneration that leads to blindness. Currently, this disease has no approved therapies.