Phase 2 Wet AMD Study Halted Due to Toxicity Concerns

Michael N. Cohen, MD

Despite positive efficacy results, a phase 2 trial testing X-82 in patients with wet age-related macular degeneration (AMD) was stopped because of concerns over treatment toxicity.

A team, led by Michael N. Cohen, MD, Wills Eye Hospital presented findings at the American Society of Retina Specialists 2020 (ASRS 2020) Virtual Sessions, evaluating the safety and efficacy of X-82 for the treatment of wet AMD.

X-82 is a multi-kinase VEGF/PDGF inhibitor that blocks the kinase activity associated with all receptor subtypes for the 2 conditions.

In the preceding phase 1 trial, the investigators examined 35 patients, 7 of which were treatment naïve. Each participated received a varied dose of the drug over the course of the 6 month trial, with 60% of patients requiring no anti-VEGF injections.

In the phase 2, randomized, double-masked, placebo-controlled trial, the investigators examined 157 patients with a prior diagnosis of exudative AMD having received at least 2 intravitreal injections of anti-VEGF therapy across 39 sites in the US.

Each subject was randomized to receive either 50 mg, 100 mg, or 200 mg of daily dosages of X-82 or a placebo tablet.

For the phase 2 study, the investigators sought primary outcomes of the change in ETDRS VA from Day -1 to Week 52 following randomization. They also sought secondary outcomes of anti-VEGF injections, retinal thickness, the loss of >15 ETDRS letter, and rate of conversion in fellow eye.

At each four-week interval, each individual was assessed to determine if recruit treatment was necessary with anti-VEGF therapy due to any increase in macular fluid or thickness compared or new or increased, macular hemorrhage.

Lab work and urinalysis was also performed monthly.

However, the study was stopped prematurely because of an insufficient benefit to risk ratio after the second planned interim analysis where 90% of the patient population had reached week 36. Ultimately there was a concern for hepatobiliary toxicity.

A total of 103 (65.6%) of patients completed the study up to and including the week 56 follow-up visit. The intent-to-treat population started with a mean visual acuity of 71.0 (n=157) and ended with a mean of 72.3 (n = 81) at week 52, while the placebo population started with a mean ETDRS BCVA score of 71.7 letters (n = 92) and ended with a mean of 71.2 letters (n = 68) at week 52.

Statistically significant non-inferiority of visual acuity was demonstrated at the week 52 visit in all treatment groups when compared to the placebo group.

Overall, 95.6% of patients lost fewer than 15 ETDRS letters by week 52 (P <0.001).

Subjects completing the study in the treatment population (n = 81) required an average of 6.4 intravitreal injections over the 52-week period, with the 50 mg (n = 23), 100 mg (n = 19), 200 mg (n=17), and placebo (n=22) group requiring 7.5, 5.4, 4.3, and 7.9 injections, respectively.

There was also a noticeable dose-dependent trend towards not requiring another injection following the screening treatment among participants receiving X-82 with 7.5%, 10.3%, and 20.5% in the 50 mg, 100 mg, and 200 mg groups not requiring another injection compared to 2.6% in the placebo group.

“X-82 oral therapy in combination with PRN anti-VEGF injections showed non-inferiority in visual acuity outcomes while achieving a dose-dependent decrease in the number of anti-VEGF injections compared with placebo,” the authors wrote. “Given the limited tolerability and safety issues observed, X-82 does not have a sufficient benefit to risk profile in treatment of patients with AMD.”

The study, “APEX: A Phase II Clinical Trial Evaluating the Safety and Preliminary Efficacy of X-82 Administered Orally in the Treatment of Exudative Macular Degeneration,” was published online by ASRS.