Study finds integrin peptide therapy may treat vascular eye diseases

ALG-1001 is a synthetic anti-integrin oligopeptide that interferes with the angiogenic cascade at multiple steps and inhibits cell adhesion.

Baruch D. Kuppermann

Integrin peptide therapy is an emerging class of treatment for vascular eye diseases that has shown promising safety and efficacy results in a phase 1 study.

The novel injectable treatment has a distinct mechanism of action that differs from that of anti-VEGF compounds.

“Integrin peptide has multiple mechanisms of action because it intervenes with several of the integrin families, working primarily with the extracellular matrix,” Baruch D. Kuppermann, MD, PhD, said. “[Integrin peptide] works in a certain sense both upstream and downstream of VEGF. The peptide has multiple binding sites and a good half-life. It also appears to have significant duration of action in the phase 1 trial.”

Its potency is likely attributable to the therapy interacting with the angiogenic cascade at multiple locations.

The 15 study participants in a phase 1 trial had advanced diabetic macular edema, and many had proliferative diabetic retinopathy. After three monthly injections of the synthetic anti-integrin oligopeptide ALG-1001 (Allegro Ophthalmics) and 3 months off treatment with follow-up to 150 days, there was no degradation of effect, Dr. Kuppermann told OSN Retina.

“We’ll have to see, though, if that lack of degradation is borne out in phase 2,” he said.

The study results were presented at Macula 2012.

Characteristics of the therapy

ALG-1001 inhibits the formation of new blood vessels through extracellular interaction (eg, fibronectin) and contains a tyrosine kinase inhibition component, which provides more of an anti-VEGF effect.

“[ALG-1001] liquefies the vitreous, which is somewhat of a surprising finding to me,” Dr. Kuppermann said. “It has been proposed that liquefying the vitreous lowers VEGF and may alter the course of disease.”

Another unique benefit of integrin peptide therapy is that it consists of a small peptide rather than a large antibody.

“Large antibodies have primarily one binding site,” Dr. Kuppermann said. “But a small molecule allows for binding in more than one site. A stronger bond forms. One of the concerns of some of the large anti-integrin molecules is a short intraocular half-life.”

ALG-1001 binds in three different places in the same region.

“So, we think that the half-life is significantly longer. However, this is not a function of it being small; it is a function of structure,” Dr. Kuppermann said.

Still, the small molecule enables it to be considered for topical therapy.

“Large molecules will not penetrate either the cornea or the sclera very effectively,” Dr. Kuppermann said.

Study results

Of the 15 study participants, eight were responders and seven were nonresponders.

Among the responders, retinal thickness decreased on average from 500 µm preoperatively to 300 µm at 5 months. Best corrected visual acuity also increased by three, four or five lines compared with baseline.

“So, there was a general good response both anatomically and functionally,” Dr. Kuppermann said. “A number of these patients started with pretty low vision, like count fingers, so an improvement to 20/80 or 20/100 represented multiple lines of vision improvement.”

Nonresponders, on the other hand, did not exhibit a similar response.

“Their baseline vision was the same as their vision 5 months later, as was their retinal thickness. Although these patients did not get any worse, the therapy did not provide much impact,” Dr. Kuppermann said.

The study investigators were unable to determine why an individual patient did or did not respond to treatment.

Dr. Kuppermann said that the phase 1 study has a small sample size with very early data on integrin peptide therapy.

“Nonetheless, the safety profile seems excellent to date. And to achieve an efficacy signal in such a small, early-phase trial certainly is compelling,” he said. “This is a new mechanism of action, a new molecule. The hope is that because of its distinct characteristics and multiple mechanisms of action, it can be used either as stand-alone therapy or in combination with anti-VEGF therapy.” – by Bob Kronemyer

Baruch D. Kuppermann, MD, PhD, can be reached at University of California, Irvine, Gavin Herbert Eye Institute, Department of Ophthalmology, 118 Med Surge I, Irvine, CA 92697-4375; 949-824-6256; fax: 949-824-4015; email: bdkupper@uci.edu.
Disclosure: Dr. Kuppermann is a paid consultant to Allegro Ophthalmics.