Pazopanib explored for neovascular age-related macular degeneration

Pazopanib, an investigational topical therapy for age-related macular degeneration (AMD), showed positive beneficial results for treating choroidal neovascularization in a phase IIa trial.

Madison, WI-Pazopanib (GlaxoSmithKline), an investigational topical therapy for age-related macular degeneration (AMD), showed positive beneficial results for treating choroidal neovascularization (CNV) in a phase IIa trial.

Patients who received the highest dose of pazopanib had a significant increase in visual acuity (VA) at the end of the trial, said Ronald P. Danis, MD.

Pazopanib is a small-molecule inhibitor of receptor tyrosine kinases that transduce intracellular signaling for multiple growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, and stem cell growth factors-all of which are implicated in the development and progression of CNV in AMD, according to Dr. Danis. He is professor of ophthalmology, Department of Ophthalmology and Visual Sciences, and director, Fundus Photograph Reading Center, University of Wisconsin-Madison.

Low levels of drug also were detected in the blood with topical application. A rat model showed that the CNV was markedly inhibited with application of pazopanib.

Pazopanib has been tested extensively in humans and has been approved for use as an oral agent to treat renal cell carcinoma. The most common adverse effect is reversible but significantly elevated liver function test results.

A phase I double-masked, randomized trial of safety and tolerability of topical pazopanib has been completed in 50 healthy patients, all of whom had subfoveal minimally classic or occult CNV and a central subfield thickness exceeding 300 μm. Patients were included in this 29-day study if they had been treated previously with anti-VEGF therapy, if the eye had responded to the treatment, and if the treatment occurred more than 60 days before entrance into the study.

The primary endpoint was a change in the baseline central retinal thickness on optical coherence tomography (OCT). The secondary endpoint was a change in the baseline best-corrected visual acuity.

Seventy patients were randomly assigned to one of three doses: 5 mg/ml three times daily (27 patients), 2 mg/ml three times daily (27 patients), or 5 mg/ml once daily (16 patients). The last dose was discontinued because of slow study enrollment.

Patients could receive rescue therapy for worsening CNV. Some subjects went on to an extension study at the end of the 29 days, Dr. Danis said. Of the 70 patients enrolled, 42 eyes were naïve and 28 eyes had received previous treatment.

A major study endpoint was safety, he said. No serious ocular adverse events were related to the study drug. Two mild to moderate transient adverse events were considered to be related to pazopanib: ocular pain and keratoconjunctivitis sicca. Seven patients, only one in the high-dose group, received rescue therapy before the end of the study. One patient had atrial fibrillation, which was not related to pazopanib. One patient had elevated blood pressure, which was considered to be related to pazopanib.

Dr. Danis noted that there was a small (about 20 μm) and non-significant change in the central retinal thickness with the two higher doses.

"The change in [VA] improved significantly in the high-dose group," Dr. Danis said. "The mean change from baseline was +4.3 letters at day 29. The trend for improvement began at 8 days after the initiation of treatment. VA in the other groups remained unchanged until day 29."

Study subjects were genotyped for complement factor H polymorphisms, which are risk factors for progression to advanced AMD. Some studies have reported that these polymorphisms have a differential response to treatment; the TT genotype has the most favorable outcomes, he said.

In the study patients with the TT genotype assigned to the 5 mg/ml three-times-daily group, there was a significant increase in VA with an allele dosage effect, he added.

"In concordance with the VA data, there was a significantly decreased OCT central retinal thickness in the high-dose patients with the TT genotype. The worst outcome was with the CC genotype, and the outcome with the CT genotype was intermediate," he said.

Investigators concluded that the safety profile of pazopanib warrants continued investigation of the drug. In addition, there was a significant increase in VA with the highest dose of the drug at day 29.

FYIRonald P. Danis, MD

Dr. Danis is a consultant to GlaxoSmithKline. The drug will be evaluated further in a large phase IIb study.

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