Integrin peptide therapy on horizon

In animal models and early-stage trials with human subjects, investigators have found that the synthetic anti-integrin oligopeptide ALG-1001, being developed by Allegro Ophthalmics, inhibits endothelial cell proliferation by multiple pathways and has a long-lasting effect.

Based on a small molecule discovered by Allegro Ophthalmics' founders in collaboration with researchers at the California Institute of Technology, ALG-1001 has the potential to serve as stand-alone therapy or as complementary therapy to the current standard of care, inhibition of vascular endothelial growth factor (VEGF), said Dr. Kuppermann, professor and chief, Retina Service, and vice chairman, Clinical Research, at the Gavin Herbert Eye Institute in the Department of Ophthalmology, University of California, Irvine.

"What's exciting is that it is a new, small molecule that has several distinct mechanisms of action that make it particularly appealing," Dr. Kuppermann said. The principal mechanism is mediation of the integrin alpha5-beta1; the peptide works in the extracellular matrix to inhibit activation of the fibronectin ligand as part of the assembly of new blood vessels. It also inhibits tyrosine kinase, preventing activation of the endothelial cells.

Its third mechanism affects the vitreous, causing posterior vitreous detachments and liquefying the vitreous. This may be a distinctive process that inhibits angiogenesis or macular edema through enhanced turnover of VEGF. Dr. Kuppermann explained that a liquefied vitreous is more oxygenated, and oxygen is a strong inhibitor of VEGF. Also, if the vitreous scaffolding does not exist, there is less tugging on the retina and potentially less likelihood of development or progression of retinal vascular diseases.

Current anti-VEGF therapy works to inhibit activation of endothelial cells in neovascular tissue and thereby minimizes or halts bleeding and fluid leakage into the eye. In contrast, ALG-1001 works both upstream and downstream to VEGF by multiple, distinct mechanisms of action and could have additive or multiplicative effects to enhance outcomes, Dr. Kuppermann said.

"That's something that is currently being explored with this compound specifically," he said.

Although Dr. Kuppermann has not been directly involved with the early clinical trials, he is familiar with the work and expects to participate in upcoming studies in the United States.

Targeting integrin receptor sites is not a new concept. There have been several attempts to do so with large antibodies rather than with oligopeptides, but these target only a single receptor site and one pathway, and some of these integrin inhibitors have shown a therapeutic effect that can be short-lived, Dr. Kuppermann said.

Following successful in vitro and animal model studies, the first clinical trial of ALG-1001 was conducted from February to September 2011 in Eastern Europe. The open-label, single-dose safety and initial efficacy study enrolled 15 subjects with advanced DME; many of them had early proliferative diabetic retinopathy as well. Best-corrected visual acuity (BCVA) was 20/100 or worse, and many participants had disease that was refractory to current treatment options.

The drug demonstrated significant efficacy signals, albeit in a limited number of patients, Dr. Kuppermann said. No patients lost BCVA, while eight of the 15 gained three or more lines after 90 days. In addition, eight of 15 subjects had improvement of at least 30% in central macular thickness (CMT) by optical coherence tomography (OCT). There was no clinically significant change in the BCVA or OCT CMT of the seven with no response.

These early results also show that the treatment was long-lasting.

"The efficacy data showed that after three doses, at day zero, 30, and 60, there was stability of results out through day 150," Dr. Kuppermann said. "Ninety days after the last injection, there was no observed decay of the results in the group of eight [patients with response]."

At this time, investigators have not identified any patient characteristics that distinguish those who had a response to the novel treatment and those who did not, he added. No significant adverse events were reported.

"To have a fairly significant efficacy response in about half of the population in what was a small phase I safety trial was gratifying, but there is still much study that needs to be done," Dr. Kuppermann said.

Two further phase IA/IIB trials of integrin peptide therapy with ALG-1001 are in progress. In the first, 30 additional patients with DME are enrolled, while the second includes 20 subjects with wet AMD. A phase II trial in about 75 subjects with wet AMD is planned for the United States later this year.

Because the molecule is so small, having a molecular weight of about 1,000 daltons, it has the potential for development as topical therapy, Dr. Kuppermann said. He emphasized that Allegro Ophthalmics is not yet pursuing this avenue of research and development.

FYIBaruch D. Kuppermann, MD, PhDPhone: 949/824-6256
E-mail: bdkupper@uci.edu

Dr. Kuppermann is a consultant to Allegro Ophthalmics.