Atsena Therapeutics has announced promising preliminary data from the first cohort of its LIGHTHOUSE Phase I/II clinical trial evaluating ATSN-201, a gene therapy for X-linked retinoschisis (XLRS). The trial represents a significant advancement in treating this progressive genetic condition that affects approximately 30,000 males in the U.S. and EU, for which no approved treatments currently exist.
XLRS is characterized by abnormal splitting of retinal layers (schisis), causing impaired visual acuity that cannot be corrected with glasses and leads to progressive vision loss and ultimately blindness. The condition primarily affects males and is typically diagnosed in early childhood.
Novel Spreading Capsid Shows Clinical Validation
A key innovation in ATSN-201 is the use of AAV.SPR, Atsena's proprietary spreading capsid designed to achieve therapeutic levels of gene expression in photoreceptors of the central retina while avoiding the surgical risks associated with foveal detachment.
In the low-dose cohort, two of three patients demonstrated extensive resolution of schisis beginning at 8 weeks after treatment, with continued improvement observed through week 24, the latest timepoint available. Notably, areas of schisis cavity resolution were found both inside and well outside of the subretinal injection blebs, providing clinical validation of AAV.SPR's ability to spread laterally from the injection sites.
"The favorable safety profile and early efficacy observed in patients treated with ATSN-201 in the low-dose cohort of the LIGHTHOUSE study are very encouraging," said Kenji Fujita, MD, Chief Medical Officer of Atsena Therapeutics. "We're particularly pleased to have clinical validation of AAV.SPR's ability to spread laterally well beyond the subretinal injection blebs."
Functional Improvements Exceed FDA Thresholds
Beyond structural improvements, the trial also demonstrated functional benefits measured by microperimetry. One patient showed improvements of up to 14 dB, with 38 loci demonstrating an improvement greater than 7 dB. This exceeds the U.S. Food and Drug Administration's threshold for clinical meaningfulness, which considers an improvement of at least 7 dB at 5 or more prespecified loci to be significant.
ATSN-201 was well tolerated in all three patients in the first cohort, with no serious adverse events reported. These results demonstrate, for the first time, the ability to safely administer subretinal injections in patients with extensive retinal schisis.
Mechanism of Action and Disease Background
XLRS is a monogenic X-linked disease caused by mutations in the RS1 gene, which encodes retinoschisin, a protein secreted primarily by photoreceptors. RS1 is localized to the extracellular surface of rods, cones, and bipolar cells. The absence of functional retinoschisin leads to the characteristic splitting of retinal layers.
ATSN-201 is designed to deliver a functional copy of the RS1 gene to photoreceptor cells using the AAV.SPR vector. Preclinical studies in non-human primates demonstrated that AAV.SPR promotes transgene expression well beyond subretinal injection bleb margins, in contrast to benchmark AAV vectors that remain confined to the original bleb margins.
Trial Progress and Next Steps
The LIGHTHOUSE study is evaluating ATSN-201 in male patients ages 6 and older with a clinical diagnosis of XLRS caused by mutations in the RS1 gene. Following the positive results from the low-dose cohort, dosing in the mid-dose cohort is now underway.
Safety data from the first cohort will be presented at the Retinal Cell and Gene Therapy Innovation Summit 2024 in Seattle on May 3, 2024, by Dr. Christine Kay, Clinical Ophthalmology Advisor for Atsena Therapeutics.
"With dosing of patients in the mid-dose cohort underway, we look forward to the swift progression of this first clinical trial utilizing our novel spreading capsid and to the continued development of our best-in-class gene therapy candidate for XLRS patients who currently lack an approved treatment option," added Dr. Fujita.
The Phase I/II open-label, dose-escalation, and dose-expansion clinical trial is being conducted at four active study sites and is registered on ClinicalTrials.gov (Identifier: NCT05878860).
About Atsena Therapeutics
Atsena Therapeutics is a clinical-stage gene therapy company developing treatments for inherited retinal diseases. In addition to ATSN-201 for XLRS, the company is also evaluating ATSN-101 in a Phase I/II clinical trial for Leber congenital amaurosis type 1 (LCA1), another common cause of blindness in children.
Founded by pioneers in ocular gene therapy, Atsena's pipeline leverages novel AAV technology tailored to overcome challenges presented by inherited retinal diseases. The company's approach with AAV.SPR represents an important advancement in the field, potentially enabling effective treatment of central retinal pathologies while minimizing surgical risks.
