Gene Therapy BIIB112 Promising for X-Linked Retinitis Pigmentosa

Robert McLaren, FMedSci, FRCOphth

Investigative gene therapy BIIB112 was shown to lead to durable improvements in patients with X-linked retinitis pigmentosa, a group of rare diseases marked by progressive vision loss leading to blindness.

“BIIB112 (NSR-RPGR) is an AAV8 vector–based gene therapy that uses codon optimization to express the full-length, correctly sequenced retinitis pigmentosa GTPase regulator (RPGR) protein in the photoreceptors of individuals with XLRP caused by mutations in RPGR,” noted the University of Oxford investigators, led by Robert MacLaren, FMedSci, FRCOphth.

The estimated prevalence of retinitis pigmentosa in the United States is between 1 in 3500 or 1 in 4000 individuals. Currently, the US Food and Drug Administration (FDA) has approved only 1 therapy — an adeno-associated virus vector-based gene therapy, which is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Therefore, newer therapeutic options—particularly investigative, efficacious, and safe gene therapies—are warranted.

At this year's annual Association for Research in Vision and Ophthalmology (ARVO) Virtual Meeting, MacLaren's team presented their findings from 2 ongoing trials — the Phase 1 dose-escalation Xirius study and Xolaris, a natural disease progression study.

As such, the team evaluated 18 patients from the Xirius study who were treated with BIIB112. All patients were ≥18 years of age. They also looked at a subgroup of patients from Xolaris (N = 69) who met the inclusion criteria for Part I of Xirius and completed 12 months of follow-up.

For the purposes of their analysis, they defined retinal sensitivity responder as an achievement of ≥7 dB improvement from baseline at ≥5 loci.

MacLaren and colleagues reported that treatment with the 4 highest doses (n = 12) resulted in early and durable improvements in central retinal sensitivity. As such, 6 participants showed response at month 1, and 4 maintained response through month 12.

Furthermore, none of the selected participants from Xolaris (untreated eyes) achieved central retinal sensitivity response at any point through month 12.

The team also assessed low-luminance visual acuity (LLVA), defining improvements as gain of ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Thus, they observed improvements in treated eyes as early as Month 1 as well as maintenance through 12 months of follow-up (3/11 participants). There were no untreated eyes that achieved improvements.

Most of the associated reported adverse events were considered mild and resolved. Additionally, there were no dose-limiting toxicities that occurred at any of the studied doses. Inflammation mostly occurred at higher doses, but treatment with oral corticosteroids was considered efficacious and useful.

"Treatment with BIIB112 was well tolerated and, in cohorts 3-6, led to early and durable improvements in 2 measures of visual function," the investigators concluded.

The study, “Visual function improvements with BIIB112 (NSR-RPGR) in X-linked retinitis pigmentosa: XIRIUS (dose-expansion) and XOLARIS (natural disease progression) studies,” was presented at ARVO 2021.