Atsena Therapeutics present positive clinical data for XLRS gene therapy program

What is XLRS?

X-linked Retinoschisis (XLRS) is an inherited retinal condition that causes early loss of mainly central vision in males. Vision loss is caused by the splitting of the layers of cells within the retina (termed retinoschisis), which disrupts transmission of signal from the light-sensitive cells called photoreceptors to the brain. As an X-linked disease, XLRS occurs primarily in males.

XLRS is typically diagnosed in childhood with the first signs being poor visual acuity that is not correctable with glasses. The condition can present with a wide range of severities depending on the amount and location of retinoschisis.

What causes it and who is affected?

XLRS has an estimated prevalence of 35,000 cases in the United States and Europe. It is caused by mutations in the RS1 gene on the X chromosome.

Females have two X chromosomes and can carry the disease gene on one of their X chromosomes. However, because they have a healthy version of the gene on their other X chromosome, female carriers are usually minimally affected. Males, however, only have one X chromosome (paired with one Y chromosome) and are therefore genetically susceptible to X-linked diseases. Males with XLRS may never pass their condition onto their sons, but their daughters may become carriers of the condition. Find out more at RetinaUK.org.uk/genetics/inheritance-patterns.

ATSN-201:

There is currently no cure for XLRS, however, ATSN-201 from Atsena Therapeutics is currently progressing through clinical trial stages.

ATSN-201 is a gene therapy delivered via a subretinal injection by a novel spreading capsid called AAV.SPR. AAV.SPR allows the gene therapy to be delivered to the central retina in a potentially more effective way than typical adeno-associated viral vector delivery, allowing the treatment to spread beyond the margins of the injection bleb and reach more photoreceptors.

The trial:

This phase 1/2/3 trial, known as LIGHTHOUSE, will evaluate the safety and efficacy of ATSN-201 in participants with XLRS over six years of age. It is a multicentre trial, taking place across four sites in the US.

The study is open label and designed in three parts: a dose escalation phase (part A), a dose expansion phase (part B) and a randomized, controlled phase (part C).

This means that both participants and researchers know who is getting which treatment or dose. It also means that:

In part A of the trial, the dose is gradually increased across groups of participants. In early-stage clinical trials, this is common because the main focus is on safety and trying to identify the dose that is the most effective and safe.

In part B of the trial, the identified dose is given to a larger group of people. This is because the primary goal of dose expansion is to further evaluate the safety and preliminary efficacy of the selected dose across a larger, more diverse population.

In part C of the trial, eligible participants who enrol in this study will be randomly assigned to be treated with ATSN-201 or to have no treatment. Those assigned to ATSN-201 will receive the drug as a one-time subretinal injection in one eye or both eyes, depending on whether only one or both eyes meet criteria for treatment. Participants will have regular assessments for one year as part of the main study period and additional assessments over the next four years as part of the extension study period. Those allocated to the control group will not receive ATSN-201, but can choose to receive ATSN-201 in one or both eyes after the one-year main study period if eligible

Update:

Atsena therapeutics recently presented 12-month safety and efficacy results from part A of the phase 1/2/3 LIGHTHOUSE Trial. They found that:

• ATSN-201 continued to demonstrate a favourable safety profile across all nine adult participants, with no drug-related serious adverse events, no dose-limiting toxicities and no discontinuations.
• Foveal schisis closure (the healing of the split in the retinal layers at the fovea, which is the very centre of the retina responsible for sharp central vision) was maintained in seven of nine treated eyes at 12 months. This was not observed in untreated eyes.
• Statistically significant improvements in microperimetry, best-corrected visual acuity, and low-luminance visual acuity were observed in treated eyes.

Participant recruitment is underway for part C of the LIGHTHOUSE trial, the study’s pivotal phase 3 portion, with enrolment expected to complete by end of Q1 2027 and a Biologics License Application (BLA) filing targeted for 2028.

Atsena has also received Orphan Drug designation from the U.S. Food and Drug Administration (FDA). Orphan Drug designation means that companies  are given incentives like market exclusivity, fee reductions and support for development. This is often more important for attracting investors and helping companies fund trials than for proving the treatment works. It’s a positive milestone, but an early one. As the designation is regulatory body-specific, even if a promising treatment has received Orphan Drug status in the US, it will not have the same status or incentives in the UK unless the UK regulatory body (MHRA) grants it.

To find out more about Atsena Therapeutics or ATSN-201, please visit their website here.