Atsena Therapeutics reported interim six-month data from Part B of the Phase III LIGHTHOUSE trial evaluating ATSN-201 in X-linked retinoschisis, showing foveal schisis closure in four of six treated adults and no serious adverse events across adult or pediatric cohorts, as the company moves into pivotal enrollment with a biologics license application targeted for 2028.
The LIGHTHOUSE trial (NCT05878860) is a Phase III open-label, dose-escalation and dose-expansion study enrolling patients with RS1-associated X-linked retinoschisis across sites in North America and Europe, structured across three sequential parts and six cohorts.
Part B enrolled nine adults across three arms — two evaluating different injection volumes and one untreated control arm — alongside three pediatric patients aged 8 to 12 years in a separate cohort. At six months, foveal schisis closure was confirmed in 67% of treated adults (four of six) in Cohort 4, while none of the three untreated control subjects and none of the six untreated contralateral eyes showed closure. The company reported that microperimetry response kinetics in Part B mirrored those seen in Part A at the same timepoint. No serious adverse events, macular hole formation, retinal detachment, or subject discontinuations were observed in any Part B cohort. Subretinal deposits in a subset of Cohort 4 adults resolved with transient steroid treatment. The pediatric cohort showed no subretinal deposits, no serious adverse events, and no discontinuations.
XLRS is a monogenic X-linked condition caused by mutations in the RS1 gene, which encodes retinoschisin, a protein secreted by photoreceptors and localized to the extracellular surface of rods, cones, and bipolar cells. The resulting abnormal splitting of retinal layers produces visual acuity impairment that is not correctable with glasses and progresses toward blindness. Approximately 30,000 males in the US and EU carry the diagnosis, and no pharmacological therapy holds regulatory approval for the condition. Off-label use of carbonic anhydrase inhibitors such as dorzolamide or acetazolamide can transiently reduce macular fluid accumulation, but neither addresses the underlying genetic defect, and responses are variable and non-durable.
ATSN-201 delivers a functional RS1 expression cassette using AAV.SPR, a proprietary capsid designed to spread laterally beyond the subretinal injection bleb to transduce foveal cones without requiring surgical foveal detachment. That delivery characteristic is directly relevant to the XLRS setting, where prior gene therapy attempts — including a program from Applied Genetic Technologies Corporation that was placed on clinical hold — encountered inflammation-related complications. The ability to avoid foveal detachment while achieving central retinal transduction at clinically relevant doses distinguishes the AAV.SPR platform mechanically from earlier-generation AAV vectors. Cross-trial comparisons are limited by differences in patient populations, dosing, and endpoint definitions, so the structural and functional signals reported here cannot be directly benchmarked against prior XLRS gene therapy attempts.
The pivotal Part C cohort, which constitutes the Phase III portion of the LIGHTHOUSE study, is now enrolling. It targets 76 patients randomized to treatment or a 12-month observation control period, after which control patients may receive ATSN-201. The FDA and EMA have both aligned on microperimetry at 52 weeks as the primary endpoint, with best-corrected visual acuity and optical coherence tomography as key secondary endpoints. Enrollment is expected to complete by the end of the first quarter of 2027.