CLINICAL TRIAL SPOTLIGHT

Going the Distance

An anti-VEGF agent under investigation in a DME trial may promise longer periods between injections.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

A number of pharmacological treatments for diabetic macular edema have come to the fore over the last several years. While corticosteroids and NSAIDs have competed with inhibitors of vascular endothelial growth factor, the approval of ranibizumab (Lucentis, Genentech) for age-related macular degeneration has focused much of the attention in treating DME on the role of VEGF.

With this trend in mind, the Zürich-based Molecular Partners AG has developed an anti-VEGF drug, MP0112, which is set to begin enrolling a phase 1 safety/efficacy study in the United States for DME, alongside a European AMD trial of the same agent. The principal investigator on the US-based trial, Peter A. Campochiaro, MD, spoke with Retinal Physician about MP0112.

DARPINS AND VEGF

Dr. Campochiaro explained that MP0112 comes from a family of compounds called designed ankyrin repeat proteins (DARPins). “These are proteins that bind to other proteins, but not in the same way as an antibody,” said Dr. Campochiaro. “They can be designed so that they recognize the tertiary structure of another protein and bind tightly to it. Because the interactions are much more extensive than with a typical epitope, the strength of the binding is generally substantially more.” MP0112 is a DARPin that recognizes all isoforms of VEGF-A — which is itself a protein and a key player in choroidal neovascularization — and binds to it with very high affinity

As a result, MP0112 should have a very long duration of action, particularly compared to anti-VEGF agents already available and in use. For example, ranibizumab, while not itself a protein, was derived from an antibody that binds with high affinity to VEGF-A.

However, several studies have shown that the on-label dosing of ranibizumab once monthly can be either too much or too little, depending on the patient. The risk in waiting longer periods between doses, however, is that vision may decrease greatly between doses. But more frequent intravitreal injections increase the odds of having complications.

Because MP0112 has higher affinity for VEGF than ranibizumab, it should have a longer duration of action, requiring fewer injections and decreasing the likelihood of vision loss between treatments.

ANTI-VEGF AGENTS IN DME

While ranibizumab has been tested in the READ phase 2 trials as well as in the ongoing RISE and RIDE — and while Regeneron's VEGF Trap-Eye is also being tested in patients with diabetic macular edema — no anti-VEGF agent has yet been approved by the FDA for the treatment of DME.

“Lucentis works quite well in diffuse diabetic macular edema,” Dr. Campochiaro said, commenting on the phase 2 trials. “It markedly reduces edema and improves vision. The problem is that, for an anti-VEGF agent to be viable by itself, it has to have a long duration of effect. We don't know exactly how long. If you could get away with every three or six months, that might be sufficient by itself,” he explained.

Whether MP0112 will be able to meet that standard will be determined, in part, by dose escalation. Thirty-six patients will be given one of a number of doses of MP0112 and will be followed closely for 12 weeks for improvement in vision and reduction in edema measured by optical coherence tomography. (Preclinical trials in rabbits and primates did not result in severe adverse effects.)

TRIAL DETAILS

With Dr. Campochiaro only awaiting approval of institutional review boards, the trial is expected to begin enrolling any day. Final data collection will take place in December 2010, with reporting on the trial to likely to be made available early next year. RP