Drug Offers ‘Stunning’ Improvement in Dry AMD

SAN FRANCISCO — Patients with non-exudative (dry) age-related macular degeneration (dAMD) obtained meaningful vision improvement at 6 months with a drug targeting oxidative stress versus sham treatment in a phase II clinical trial reported here.

Results showed that 12 of 25 patients improved by ≥8 ETDRS letters in best corrected visual acuity (BCVA) at 28 weeks with risuteganib as compared with one of 14 patients in the sham group. The difference in mean change from baseline in BCVA, a secondary endpoint, favored risuteganib but did not achieve statistical significance.

The drug was well tolerated, consistent with clinical experience outside the trial, David S. Boyer, MD, of Retina-Vitreous Associates Medical Group in Los Angeles, reported here at the American Academy of Ophthalmology meeting.

“In this phase II study evaluating risuteganib compared to sham, the primary endpoint was met,” said Boyer. “Risuteganib demonstrated a good safety profile in the study. Additionally, 1,200 injections have been given outside the study, with an acceptable safety profile. Planning for a larger trial to confirm these findings is underway.”

Dry AMD arises from oxidative stress in retinal pigment epithelial (RPE) cells. Over time RPE cells may de-differentiate and lose RPE-like qualities and functions that support photoreceptor viability, leading to photoreceptor and/or RPE degeneration.

Risuteganib is an RGD-class (arginylglycylaspartic acid), small molecular-weight peptide that has a long retinal half-life of about 21 days, said Boyer. Preclinical studies provided evidence supporting the drug’s effect against multiple pathologic conditions involved in AMD, including inflammation, cytotoxicity, and mitochondrial dysfunction. The drug’s developer, Allegro Ophthalmics, says it “interferes with integrin functions” and “aims to regulate oxidative stress response upstream before it has a chance to initiate multiple pathways implicated in intermediate dry AMD,” as well as diabetic macular edema.

Boyer presented results from a phase II randomized trial to evaluate the safety and efficacy of risuteganib, administered by intravitreal injection, in patients with intermediate-severity dAMD. Patients were randomized 2:1 to risuteganib or sham injection and followed for 28 weeks. By design, patients in the sham group crossed over to risuteganib at week 16.

The primary endpoint was the proportion of patients who had ≥8 ETDRS letters improvement in BCVA with risuteganib at 28 weeks versus sham treatment at 12 weeks. The endpoint is consistent with a published analysis suggesting that >5 letters improvement in BCVA represented “real clinical change” in dAMD associated with BCVA better than 20/100, said Boyer.

Eligible patients had dAMD associated with BCVA of 33 to 72 ETDRS letters (20/40 to 20/200) and symptomatic decrease in visual acuity in the last 12 months. The patients had evidence of RPE disturbances, one or more large drusen, and/or multiple intermediate-size drusen in the macula. Enrollment criteria also required that patients have reasonably well-preserved central 1 mm of the macula, no signs of neovascular AMD, and no serous pigment epithelium detachment.

Patients randomized to risuteganib received an initial intravitreal injection at baseline and a second injection at 16 weeks. In the control group, patients had a sham injection at baseline, followed by a risuteganib injection at 16 weeks. Investigators at six geographically diverse clinical sites enrolled and randomized 45 patients, 29 to risuteganib and 16 to the control group.

The efficacy analysis included 25 patients from the risuteganib group and 14 from the sham control group. One patient in the control group was excluded because of progression to foveal geographic atrophy and another was excluded at investigator request. In the risuteganib arm, one patient withdrew consent, one discontinued because of an adverse event, and two dropped out after conversion to neovascular AMD.

The data showed that 48.0% of the risuteganib group met the primary endpoint versus 7.1% of the control group (P=0.013). Mean change from baseline in BCVA favored risuteganib but did not achieve statistical significance (6.1 vs 2.1 EDTRS letters, P=0.08).

Additional analyses showed that 14.3% of patients in the control group met the primary endpoint at week 28, after crossover to risuteganib and that 20% of the risuteganib arm had met the primary endpoint by week 12, the interval for the primary analysis of the control group. More patients in the risuteganib group had ≥10 letters and ≥15 letters improvement (32.0% vs 7.1%, 20.0% vs 0%), but the differences were not statistically significant.

Adverse events in the risuteganib group included one patient who developed vitreous floaters, in addition to the two patients who converted to neovascular AMD.

“I think having 50% of intermediate AMD patients who have eight letters of improvement is pretty stunning,” said Paul Sternberg Jr., MD, of Vanderbilt University Medical Center in Nashville. “What’s going on? Why are these patients seeing?”

Boyer suggested a “neuroenhancement” effect of risuteganib might explain the results.

“I think there are cells that are alive but they’re not functioning fully,” he said. “I think the cells are under stress, and reducing the stress allows the cells to function better.”