MONTREAL — An investigational bispecific antibody for retinal disease achieved faster and numerically greater short-term improvements in visual acuity and retinal anatomy versus faricimab (Vabysmo), a randomized, proof-of-concept trial showed.
Patients randomized to either of two doses of OLN324 had a two-letter improvement in visual acuity versus faricimab at 20 weeks, more rapid improvement in retinal fluid, and faster and numerically greater reductions in pigment epithelial detachment thickness (PED). Durability was comparable as 82% of patients treated with the higher dose of OLN324 went 12 weeks without retreatment, as did 81% of patients assigned to faricimab.
No patient assigned to the investigational angiopoietin 2 (Ang2)/VEGF inhibitor developed intraocular inflammation, retinal vasculitis, occlusive retinal vasculitis, or endophthalmitis, reported David Eichenbaum, MD, of Retina Vitreous Associates of Florida in St. Petersburg, at the American Society of Retina Specialists meeting.
During a discussion, moderator Charles Wykoff, MD, PhD, of Retina Consultants of Texas in Houston, who was a co-author on the study, asked about progress toward finding biomarkers to identify patients who need Ang2 inhibition in addition to VEGF inhibition.
“Prospectively, it’s tough,” said Eichenbaum. “I think the best Ang2 biomarker we have to show differentiation with that blockade is still fluorescein angiography and diabetes [to look for retinal leakage]. That is a narrative we can build on with other novel biologies, too. Is there something to reduce leakage? Is there something in the blood-retinal barrier? Is there something that Ang2 or other biologies are doing that’s beneficial that we just don’t see with OCT [optical coherence tomography]? We’ve got to figure that out.”
Two gene therapies for retinal disease also showed promise for slowing progression of neovascular age-related macular degeneration (nAMD) and preserving vision. Continued follow-up in a phase II trial of ixoberogene soroparvovec (ixo-vec) intravitreal gene therapy showed durable vision preservation and maintenance of retinal anatomy at 2 years. Additionally, two-thirds to three-fourths of patients treated with two different doses of the therapy averaged one or fewer injections per year, said Shawn Kavoussi, MD, of the Texas Retina Center in Houston.
Initial clinical data for the adeno-associated virus (AAV) gene therapy NG101 showed preservation of vision and retinal anatomy for up to a year and a 90% reduction in annualized injections of anti-VEGF therapy. No dose-limiting toxicities or NG101-related serious adverse effects (SAEs) have occurred, said Peter J. Kertes, MD, of the University of Toronto.
OLN324
Like faricimab, OLN324 inhibits both Ang2 and VEGF but has 60 times greater potency for Ang2 inhibition, said Eichenbaum. A smaller molecular size facilitates better tissue penetration, and the bispecific has a higher molar dose than faricimab 6 mg and aflibercept (Eylea) 2 mg and 8 mg.
The bispecific antibody was evaluated in the randomized phase I JADE trial comparing two doses of OLN324 and faricimab. The trial included 80 patients with previously untreated nAMD and 84 with diabetic macular edema (DME). Eichenbaum reported findings only for the nAMD group.
The primary objective was safety and tolerability at week 12 with continued follow-up to week 20. Visual acuity and various measures of retinal anatomy were exploratory efficacy objectives.
The primary objective was met. Improvement in visual acuity was evident within a week after the initial injection of OLN324, and both doses of the bispecific led to numerically greater improvement through week 20 (+8.6 and +8.4 letters vs +6.4 letters with faricimab). All three treatment groups had rapid and sustained improvement in retinal fluid, and at 20 weeks the mean change from baseline in central subfield thickness (CST) was -128 and -142 µm with OLN324 and -142 µm with faricimab. PED thickness declined within the first week in all three groups and remained numerically greater in the OLN324 groups.
A phase III trial of OLN324 in DME and nAMD is expected to begin later this year, according to a statement from Ollin Biosciences.
Ixo-Vec
The gene therapy promotes continuous production of aflibercept with the goal of preserving vision and retinal anatomy while reducing treatment burden. Kavoussi reported 2-year follow-up data from the phase II LUNA trial involving 60 patients with stable nAMD treated with an average of 10 anti-VEGF intravitreal injections in the previous year. An earlier report showed no significant deterioration of visual acuity or retinal anatomy at 52 weeks, and 54-69% of patients remained injection free for 12 months.
The update continued to show stable visual acuity and minimal change in CST. Annualized injection frequency declined from 10 at baseline to 0.9 to 1.1 at 2 years, approximately a 90% reduction.
No SAEs, episcleritis, vasculitis, retinitis, choroiditis, occlusive events, or hypotony occurred with either dose of ixo-vec. All patients received corticosteroid prophylaxis (randomized 2:1 to local or oral), and criteria for aflibercept rescue were an increase in CST >75 µm from baseline, loss of ≥10 letters of vision, or new vision-threatening hemorrhage.
Two phase III trials of the gene therapy are ongoing.
NG101
Administered by subretinal injection, the gene therapy uses an AAV vector to deliver a construct that includes a proprietary CAT311 promoter to achieve sustained high-level aflibercept expression, said Kertes. The construct allows for dosing that is orders of magnitude lower than other gene therapies.
The phase I SENSE trial in nAMD consisted of three cohorts and a cumulative total of 20 patients treated with one of three doses of NG101. The patients had a mean age of 76, best corrected visual acuity of 57.3 letters (minimum of 20), and at least three anti-VEGF injections in the previous 6 months. The primary endpoint was incidence and severity of adverse events at 24 weeks
The trial met the safety/tolerability endpoint. Preliminary efficacy data for the first two cohorts (n=12, follow-up 44 to 52 weeks) showed that the patients had annualized anti-VEGF injection rates of 8-10, which was reduced by about 90% in both groups to 0-1. Best corrected visual acuity improved by 0.2-2.4 letters, and mean CST increased by 57 µm in one group and 31 µm in the other.
A phase IIb trial is expected to begin during the first quarter of 2027, said Kertes.
