Investigative Oral Retina Drug APX3330 Shows Favorable Safety, Tolerability

Positive phase 1 and 2 findings support an ongoing efficacy assessment of the Ref-1 inhibitor for diabetic retinopathy and diabetic macular edema.

Investigative oral drug APX3330 has been associated with generally favorable safety and tolerability outcomes in early-phase trial patients, according to a new combined report of 11 clinical trials presented at the American Society of Retina Specialists (ASRS) 2021 Scientific Meeting this weekend.

The phase 1 and 2 safety and tolerability findings—though observed in nonophthalmic use—support the continued assessment of the novel drug for possible treatment of retina diseases including diabetic retinopathy (DR), diabetic macular edema (DME), and neovascular age-related macular degeneration (AMD).

APX3330 is a small molecule Ref-1 inhibitor, targeting the signaling pathway of key vascular and inflammatory properties associated with DR, DME, and AMD. Prior to assessing its efficacy in treating the retina diseases, investigators sought safety data from 300-plus trial participants in phase 1 and 2 trials.

Presented by Michael J. Allingham, MD, PhD, of the Duke Eye Center, the ASRS 2021 report featured systemic and ocular safety and tolerability results from 6 phase 1 and 5 phase 2 nonophthalmic trials assessing APX3330.

The patient population included 300-plus healthy volunteers and patients with chronic hepatitis who received doses ranging from 20 mg to 600 mg daily. Allingham and colleagues additionally obtained safety data from a sixth phase 1 trial including 19 patients with solid tumors receiving twice-daily APX3330 doses, up to 720 mg daily.

A majority of patients received the investigative drug for a mean 75 days. The phase 1 trials observed single doses up to 240 mg and repeat doses up to 600 mg daily. Fewer than 10% of patients receiving APX3330 reported mild diarrhea, versus 0% of patients receiving placebo. The sixth phase 1 trial showed 2 patients with a diffuse skin rash that quickly reversed while receiving the 600 mg daily dose, which was defined as the maximum tolerated dose.

In phase 2 trials including 200-plus patients, investigators observed adverse events in fewer than 5% of all patients, with a similar rate between APX3330 and placebo arms. Mild diarrhea again occurred in a small rate of treated patients. Another patient reported mild orbital discomfort.

“Based on preclinical data and its clinical safety profile, APX3330 (600 mg/day for 24 weeks) is being tested in a phase 2 trial for the treatment of subjects with moderately severe to severe (non-proliferative diabetic retinopathy) or mild PDR,” investigators wrote.

Allingham and colleagues concluded APX3330’s safety and tolerability profile was favorable across all 11 studies. The unique properties of the oral inhibitor, combined with these outcomes, support future clinical efficacy assessment for ophthalmic disease.

“APX3330 has an anti-angiogenic and anti-inflammatory mechanism relevant to the treatment of retinal disease,” they concluded. “These safety data support ZETA-1, an ongoing, randomized, placebo-controlled Phase 2 trial evaluating the safety and efficacy of APX3330 in the treatment of DR and DME.”

The study, “APX3330, an Oral Drug in Trial for DR and DME, Demonstrated a Favorable Safety and Tolerability Profile in Multiple Phase 1 and 2 Studies,” was presented at ASRS 2021.