Fresh off of receiving two FDA designations for its X-linked retinoschisis (XLRS) gene therapy, Atsena Therapeutics, Inc. is reporting new positive clinical findings from Part A of its ongoing phase 1/2 LIGHTHOUSE study.
Let’s start with the basis for this gene therapy.
ATSN-201 is part of Atsena’s pipeline of next-gen treatments for inherited forms of blindness (including XLRS).
What makes these treatments unique: They’re based on adeno-associated virus (AAV) technologies that involve novel:
- Laterally-spreading capsids
- Intravitreal capsids
- Dual vectors
And which tech is used with ATSN-201?
Atsena’s dual vector technology.
- What it does: Targets two significant problems associated with standard (single) AAVs:
- Limited packaging capacity
- Inability to deliver gene constructs larger than 5 kilobases (kb)
- How: Via the use of dual AAV vectors to deliver larger payloads for genetic mutations typically too large to treat with a single AAV vector.
See here for step-by-step details on the delivery process—and click here for a visual.
Now tell me about the candidate itself.
ATSN-201 utilizes AAV.SPR—a capsid involved in treating XLRS and, notably, not associated with vision-compromising limitations often seen with intravitreally (IVT)-delivered AAVs or with the surgical risks of foveal detachment.
- What it does: Spreads laterally beyond the subretinal injection site (bleb margins) to deliver retinoschisin (RS1; proteins involved in XLRS development) to photoreceptors within the central retina and fovea.
- Its resulting potential: Regulated therapeutic levels of gene expression in photoreceptors, resulting in retinal structure and function restoration in XLRS patients.
And how many FDA designations has it received?
Four, including:
Next up: this clinical trial.
We’ll start with the basics of this ongoing phase 1/2 study (NCT05878860).
- The design: Open-label, dose-escalation, and dose-expansion trial
- The participants: 21 male patients (aged 6 to 64) diagnosed with XLRS
- The setup: Patients divided into four cohorts (Cohorts 1-3: age ≥ 18 and < 65 years; Cohort 4: age ≥ 6 and < 18 years) and subretinally-administered varying dose injections of ATSN-201
- Cohort 1: Low dose
- Cohort 2: High dose
- Cohort 3 (partially masked): two experimental + one control sub-groups
- Experimental: High dose and high volume
- Experimental: Low dose and low volume
- Control: No intervention
- Cohort 4: High dose (pediatric)
- The outcome measures (measured from baseline to Week 52):
- Primary: ATSN-201’s safety and tolerability; treatment-emergent adverse events (TEAEs)
- Secondary: Changes in best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), and contrast sensitivity (see here for more)
And the findings?
To note: The data thus far is based only on Part A of the study, which evaluated three varying doses of ATSN-201 in nine patients—three patients per cohort (for Cohorts 1-3).
Per Atsena: ATSN-201 was safe and well tolerated (up to 1 year post-treatment) in all nine patients, with no reports of any serious TEAEs.
- The majority of reported AEs were reportedly Grade 1-2 in severity and related to the surgical procedure
Any unrelated AEs?
Just one—a serious AE involving a fever “of unknown origin with negative workup.”
There were also no dose-limiting toxicities (a primary outcome measure) and, importantly, no participants discontinued the study.
Talk efficacy.
Atsena reported that preliminary evidence showed efficacy was demonstrated across “all dose levels,” with seven of the nine treated eyes exhibiting foveal schisis closure (which was not the case in untreated eyes).
On microperimetry: Two-thirds (67%) of treated eyes showed an improvement of ≥ 7 dB in the 5 or more loci with the lowest sensitivity at baseline.
- Company input on this (per Chief Medical Officer Kenji Fujita, MD): “We’re particularly pleased that the foveal schisis closure seen in 7 of 9 patients validates AAV.SPR’s ability to spread laterally beyond the subretinal injection blebs and enable safe gene delivery to the central retina.”
How about visual acuity?
For both BCVA and LLVA: Investigators observed “statistically significant improvements."
Plus: “Structural improvements correlated with improvements in function,” the company stated.
Nice! Now to the significance.
With no treatment currently approved to treat XLRS, these findings underscore ATSN-201’s potentially groundbreaking ability to target and treat this disease.
So what’s next for this study?
That would be Part B, which is reportedly currently enrolling an additional nine adults and three pediatric patients diagnosed with XLRS.
A couple of notes for this setup:
- The adult cohort will receive one of three doses (two ATSN-201 or a control)
- The control arm group to be observed for 1 year before having the option to receive treatment.
- The pediatric cohort will be dosed following an evaluation of preliminary data from the Part B adult cohort
As for what will be measured: Similar to Part A, investigators will evaluate safety and efficacy—microperimetry, VA, and macular structure.
Stay tuned for updates!