Opus Genetics, Inc. recently announced positive 3- and 6-month data from cohort 1 of the phase 1b/2a BIRD-1 clinical trial of OPGx-BEST1 and completion of a FDA Type C meeting for a phase 3 trial in the future.
Let’s start with a refresher on Opus Genetics.
Based in Research Triangle Park, North Carolina, the clinical-stage biopharmaceutical company’s main focus is developing gene therapies to restore vision and prevent blindness in patients with inherited retinal diseases (IRDs).
Its pipeline: includes seven adeno-associated virus (AAV)-based gene therapy assets, with two leading candidates:
- OPGx-LCA5 for the treatment of Leber congenital amaurosis (LCA) type 5, caused by biallelic mutations in the LCA5 gene
- OPGx-BEST1 for the treatment of bestrophine-1 (BEST1)-related IRDs
Moving on to OPGx-BEST1.
BEST1-related inherited retinal diseases, or bestrophinopathies, are rare forms of inherited macular degeneration caused by mutations in the BEST1 gene that disrupt the normal function of retinal pigment epithelium (RPE) cells, leading to retinal lesions, progressive degeneration, and vision loss.
- Note: BEST1-related diseases include Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB)—and there are currently no approved therapies that treat the underlying genetic cause of these diseases.
To address this: OPGx-BEST1 uses an AAV vector to deliver a functional copy of the BEST1 gene to retinal pigment epithelial cells.
Go it. Now talk about the study.
The ongoing BIRD-1 clinical trial (NCT07185256) is an adaptive, open-label phase 1b/2a clinical trial evaluating the safety and efficacy of single-eye subretinal administration of OPGx-BEST1 in adults with BVMD or ARB.
Cohort 1 enrolled five participants treated at 1.5 x 109 vg/eye comprising:
- Three participants with BVMD who reached 3 months of follow-up
- Two participants with ARB who reached 6 months of follow-up
What are the main outcome measures?
The primary outcome measures include the number and severity of:
- Dose-limiting toxicity (DLT) events at the dose tested
- Procedure-related adverse events (AEs)
- AEs related to OPGx-BEST1
Secondary outcomes evaluate changes from baseline in:
- Retinal morphology assessed by spectral-domain optical coherence tomography (SD-OCT), 55-degree fundus autofluorescence (FAF), and ultra-wide angle FAF
- Neovascularization measured via OCT
- Retinal sensitivity
- Best-corrected visual acuity (BCVA)
- Low-luminance VA (LLVA)
- Participant-reported outcomes
Findings?
All five participants demonstrated clinically meaningful improvement in visual function following treatment with OPGx-BEST1:
- BCVA improved in 60% of participants (3/5)
- LLVA improved in 40% of participants (2/5)
- Contrast sensitivity (CS) improved in 40% of participants (⅖
Among evaluable participants, 75% (3/4) demonstrated clinically meaningful improvement in retinal sensitivity by microperimetry.
Anything notable on those gains?
These were concentrated in the treated retinal pigment epithelial (RPE) transitional zone, where viable photoreceptors remain, with the greatest functional improvements observed in participants with less advanced disease.
The greatest functional gains were observed in participants with less advanced disease, supporting the potential benefit of treating patients while viable retinal tissue remains.
So how did it perform in terms of structural changes?
Structural improvements were observed in four of five participants, with reductions in vitelliform material, the hallmark of BVMD, in 67% (2/3) of BVMD participants and reductions in intraretinal fluid in 100% (2/2) of ARB participants.
- The third BVMD participant had possible—but not definitive—reduction in vitelliform material.
Talk about safety.
OPGx-BEST1 demonstrated a favorable safety and tolerability profile, with no serious AEs or dose-limiting toxicities, intraocular inflammation (IOI), or vital-sign or safety-laboratory findings of note.
All treatment-related AEs were mild or moderate in severity.
Anything else?
In BVMD, vitelliform material accumulates early and is the defining structural feature of the disease, while subretinal fluid appears late and pools in areas of established atrophy.
- Meaning: Reduction of vitelliform material is therefore the more direct measure of restored RPE function in this population—in addition to being the structural change that corresponded with functional improvement in those participants.
On the other hand: In ARB, where intraretinal fluid is the dominant structural manifestation, fluid reduction was substantial and consistent in both participants.
Any comments from the company?
“We are encouraged by the localization of functional gains to areas of viable, but compromised retina and by the opportunity to apply these insights prospectively as OPGx-BEST1 is advanced into cohort 2 and potential pivotal development,” stated Mark Pennesi, MD, PhD, clinical trial investigator and chief medical officer at the Retina Foundation and adjunct professor of ophthalmology, Casey Eye Institute, Oregon Health & Science University.
“From a regulatory perspective, it is particularly exciting to align with the FDA on a >3 decibels change from baseline in microperimetry anchored to patient reported outcomes as a potential pivotal endpoint,” he added.
Catch me up on that meeting with the FDA.
In August, Opus met with the FDA and aligned on a potential pivotal endpoint based on ≥3 dB microperimetry improvement in ≥5 prespecified loci, in conjunction with a patient-reported outcome in a randomized, controlled trial.
- Note: BCVA, LLVA, and CS are also considered acceptable endpoints.
In addition, the company coordinated with the FDA on phase 3 and commercial manufacturing requirements, which it expects to complete in early 2027, with participant dosing expected to begin in 2027.
So when can we expect an update on this?
Based on the safety profile and positive proof-of-concept findings from cohort 1, Opus has advanced to the higher-dose cohort 2, evaluating OPGx-BEST1 at 4.5 x 10⁹ vg/eye.
Dosing is expected to be completed in Q4 2026, with topline 3-month data following in Q2 2027.
Opus also plans to announce 6-month data for the three participants with BVMD from cohort 1 in Q2 2027.
Speaking of cohorts … what do we know about cohort 2?
Originally designed to enroll five participants, cohort 2 has been over-enrolled with eight participants, most of whom have BVMD.
Data from cohort 2 are expected to further characterize the safety, functional, and structural responses to OPGx-BEST1 at the higher dose and inform the design of a potential pivotal clinical trial.