CLINICAL TRIAL SPOTLIGHT

Pfizer Launches First siRNA Trial for DME

Landmark DME trial may change the landscape of retinal treatments.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

Genetics may be the wave of the future in medicine, and this applies to retina as well. The last year has seen a growing number of clinical trials testing small interfering RNA (siRNA) as a treatment for age-related macular degeneration (AMD).

In June, Pfizer (New York, NY) and Quark Pharmaceuticals (Fremont, CA) launched the Prospective, Randomized, Multi-Center, Comparator Study Evaluating Efficacy and Safety of PF-04523655 Versus Laser in Subjects With Diabetic Macular Edema or DEGAS trial, a phase 2, randomized, single-blind, parallel-assignment safety/efficacy study. Retinal Physician spoke with Dario Paggiarino, MD, executive director of ophthalmology at Pfizer about PF-04523655 and the DEGAS trial.

"PF-04523655 is a novel siRNA drug candidate that uses RNA interference (RNAi) technology to ‘turn off’ the RTP-801 gene believed to be involved in the development of abnormal blood vessels and vessel leakage in the eye," Dr. Paggiarino said. "RNAi is a relatively new area of science that may enable therapies that turn off or ‘silence’ disease-causing genes. The ability to silence genes via this mechanism could provide a new mechanism of action to treat a wide range of human diseases, including neovascular AMD and diabetic macular edema (DME)." This is what makes PF-04523655 different from other siRNAs being used or in development to treat wet AMD and DME.

A unique aspect of the DEGAS study is that it is a DME trial; other siRNAs have only been tried so far for AMD. "There are currently no approved pharmacological treatment options for patients with DME," Dr. Paggiarino said, "which is one reason why we are very interested in studying PF-04523655 for DME in this trial. Inhibition of TRP-801 produced inhibition of new blood vessels and increased vascular permeability in preclinical models. This latter property suggests atherapeutic effect of PF-04523655 in DME, where increased vascular permeability causes increased retinal thickness and eventually visual acuity loss."

"Physicians today have few treatment options for DME patients," Dr. Paggiarino said. "There remains a clear need to provide additional options — especially ones that provide significant visual benefit while also avoiding treatment-related ocular side effects, such as the inherent retinal ablation from laser, or IOP increases and cataract formation from off-label corticosteroid use." Dr. Paggiarino referred to a study conducted by the Diabetic Retinopathy Clinical Research Network using laser and triamcinolone in DME and is now in follow-up. "This trial confirms the value of laser in DME," Dr. Paggiarino said. "However, a significant proportion of patients still lose vision over time."

Asked about possible side-effects or adverse affects that might have been observed in the phase 1 trial of PF-04523655, Dr. Paggiarino responded, "We have not published or presented results of the phase 1 trial. Based on the outcome of that trial, however, we are proceeding with the phase 2 study of PF-04523655 in DME and considering an additional phase 2 clinical trial in patients with neovascular AMD." He added, "In early studies to date, PF-04523655 has shown promise that it could be an effective therapy for these indications."

Asked about the future of siRNA drugs for treatment of retinal disease, Dr. Paggiarino said, "Despite recent medical advances in the treatment of neovascular AMD, significant opportunities remain to improve outcomes for patients, since not all patients respond to anti-vascular endothelial growth factor (VEGF) therapy. VEGF is just one of several disease mechanisms targeted by researchers studying neovascular AMD. The observation that inhibition of RTP-801 produces inhibition of neovascular growth in preclinical models supports potential effects in AMD."

For now, however, the DME trial is the main focus. "The phase 2 study is designed to provide evidence of efficacy of different doses of PF-04523655 compared to laser in the treatment of DME," Dr. Paggiarino said. "We look forward to learning more from the trial." RP