PERTH, Australia – Melbourne, Australia-based Opthea Ltd. announced positive top-line results of its phase IIa trial evaluating safety and efficacy of OPT-302 administered with Eylea (aflibercept, Regeneron Pharmaceuticals Inc.) in treatment-refractory patients with persistent diabetic macula edema (DME).

OPT-302 is a soluble form of vascular endothelial growth factor receptor 3 (VEGFR-3) or “trap” molecule that blocks the activity of VEGF-C and VEGF-D, which causes blood vessels to grow and leak.

The trial met the primary efficacy endpoint with 52.8% of patients achieving a gain of five or more letters in Best Corrected Visual Acuity (BCVA) at week 12. The co-primary endpoint of safety was also met, with 2-mg OPT-302 in combination with 2-mg Eylea being well-tolerated with a similar safety profile to the Eylea control group.

“The significance for the patient is that really there is only one class of drugs that is available for patients, and the only option physicians have if their patients don’t do so well on these drugs is to switch from one to the other,” Opthea CEO Megan Baldwin told BioWorld.

“There is really very little improvement of options,” she said, noting that Opthea’s OPT-302 is an add-on therapy to existing standard-of-care VEGF inhibitors.

Megan Baldwin, CEO, Opthea

“We set out to see if patients did better with our drug, and this may help with resistance. The trial achieved what we set out to achieve, and that is to identify evidence of activity of our molecule that it benefits patients with DME.”

The trial wasn’t designed to show a difference between the two groups, she said. Rather, Opthea wanted to understand if there were signals of activity.

The phase IIa trial is a randomized, double-masked, sham-controlled, proof-of-concept trial conducted at 53 sites in the U.S., Israel, Australia and Latvia. The trial recruited 144 participants, with 115 evaluable patients. All participants were diagnosed with persistent DME despite regular intravitreal administration of prior anti-VEGF-A monotherapy.

Eligible participants had a BCVA in the study eye of 20/40 to 20/320 Snellen equivalent and central subfield thickness (CST) of ≥ 320 µm. Participants were randomized in a 2-to-1 ratio to receive either OPT-302 (2 mg) plus Eylea (2 mg) or sham plus Eylea (2 mg). Study treatments were administered by intravitreal injection once every four weeks, with a total of three doses, and study outcomes were assessed from baseline through week 12.

The proportion of patients with a one step or greater improvement in diabetic retinopathy severity score (DRSS) was 21.4% with OPT-302 combination therapy and 17.5% in the Eylea control group. The proportion of patients who had a severity score of between 47 and 53, representing moderately severe to severe nonproliferative diabetic retinopathy (NPDR), was 65.3% at baseline and 54.8% following OPT-302 combination therapy to week 12. There was no change in the Eylea monotherapy group, with 60% of patients having moderately severe to severe NPDR at baseline and week 12.

The tolerability of OPT-302 combination therapy was consistent with Eylea standard of care in DME patients, and there were no observed safety concerns, consistent with previous experience with OPT-302 in clinical trials in wet age-related macular degeneration (AMD). No ocular serious adverse events were reported and the incidence of intra-ocular inflammation in the study eye was low, occurring in one patient in each treatment group.

The phase IIa trial is ongoing, with the final participants due to complete the long-term week 24 follow-up visit later this month.

Subgroup analysis shows promise

An exploratory subgroup analysis was conducted in patients with a prior anti-VEGF-A treatment history of only receiving previous Eylea to assess the effects of OPT-302 combination therapy following the most optimal first-line standard of care used to achieve maximal VEGF-A inhibition.

In that subgroup, the mean change in BCVA at week 12 compared to baseline was 8.6 letters for OPT-302 plus Eylea and five letters in patients who continued on Eylea monotherapy. The proportion of patients in the subgroup gaining 10 or more and 15 or more letters from baseline to week 12 was 50% and 16.7% in the OPT-302 combination group, respectively, and 0% for both parameters in the Eylea control.

The percentage of patients losing one or more letters from baseline to week 12 was 8.3% in the OPT-302 plus Eylea group, and 12.5% for the Eylea control.

“That is really important data for us because it says that for patients maxing out on Eylea, which is the best drug in its class, those patients who received our drug in addition to Eylea could see better,” Baldwin explained. “Comparatively, the Eylea group didn’t do that well, so that would suggest that our drug is having an additive benefit.”

The trial provides a data package that shows the drug is safe in combination with Eylea, which gives Opthea more options for its next series of studies in wet AMD and DME.

“We now have a drug that is effective in an additional indication in DME, which makes the molecule more commercially attractive,” she said.

Opthea announced positive phase IIb results in August 2019 that demonstrated that OPT-302 combination therapy met the primary endpoint of superiority in mean visual acuity gain at 24 weeks compared to Lucentis (ranibizumab, Roche Holding Inc./Novartis AG) monotherapy in treatment-naïve patients with wet AMD.

About half of patients receiving VEGF-A therapies for wet AMD are considered nonresponders, Baldwin said, noting that OPT-302 blocks VEGF-C and VEGF-D, which cause vessels to grow and leak and are hallmarks of wet AMD disease progression.

Combination therapy of OPT-302 and a VEGF-A inhibitor achieves more complete blockage of members of the VEGF family, blocking mechanisms contributing to suboptimal responses to selective VEGF-A inhibitors and has the potential to improve vision outcomes by more completely inhibiting the pathways involved in disease progression.

Opthea raised AU$50 million (US$35 million) in December 2019 in a private placement to advance OPT-302 to phase III trials in wet AMD, and the funds raised were used to manufacture the compound for two concurrent phase III pivotal trials.

Baldwin said the phase III program is still in the planning stages, and the company has an end-of-phase-II meeting scheduled with the FDA for the third quarter.

Opthea’s shares on Australia’s Securities Exchange (ASX:OPT) were down 9.2%, trading at AU$3.05 per share. The company has a market cap of AU$904 million.

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