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Novel anti-VEGF agent

Trap for VEGF-C/VEGF-D shows early promise as combination treatment

Cheryl Guttman Krader

Posted: Tuesday, March 14, 2017

Pravin Dugel MD

Pravin Dugel MD

The first trial of intravitreal OPT-302 (Opthea) for treatment of wet age-related macular degeneration (AMD) met its primary objective by demonstrating that the novel anti-vascular endothelial growth factor (anti-VEGF) agent, which binds and neutralises the activity of VEGF-C and VEGF-D, was safe and well-tolerated, said Pravin Dugel MD at the 16th EURETINA Congress in Copenhagen, Denmark.

The phase 1 study had a sequential dose-escalation design. It enrolled 20 patients who received three monthly injections of OPT-302 alone or plus 0.5mg ranibizumab (Lucentis®) and then were followed until 12 weeks. There were no dose-limiting toxicities and the maximum tolerated dose was not reached. OPT-302 also showed evidence of biological activity, and a phase 2A study is under way.

“There is a large unmet therapeutic need for neovascular AMD considering that some patients have suboptimal improvement in visual acuity (VA) and persistent retinal fluid when treated with current agents that only target VEGF-A,” said Dr Dugel, Clinical Professor of Ophthalmology, University of Southern California, Los Angeles, and Managing Partner, Retinal Consultants of Arizona, Phoenix, USA.

“Resistance to the available VEGF-A inhibitors may be related to effects of other members of the VEGF family. By achieving more complete suppression of the VEGF/VEGF receptor pathway, OPT-302 is targeting incomplete response to VEGF-A inhibition,” he added.

The phase 1 trial investigated OPT-302 0.3mg, 1.0mg, or 2.0mg with ranibizumab or OPT-302 2.0mg as monotherapy. Fourteen (70%) of the participants had demonstrated a suboptimal response on prior anti-VEGF therapy, receiving a mean of 10.5 anti-VEGF injections.

There is a large unmet therapeutic need for neovascular AMD

FOLLOW-UP

Nineteen patients were evaluable at the week 12 follow-up visit, and 16 (84.2%) maintained or gained vision. All cases of vision loss were limited to ≤3 letters and occurred in patients receiving combination therapy, reported Dr Dugel.

Among 14 evaluable patients receiving combination treatment, VA improved by a mean of eight letters and central subfield thickness (CST) decreased by a mean of 91μm. Results were better among the treatment-naïve patients compared with the previously treated patients for both mean VA gain (+16.5 versus +4 letters) and CST change (-214 versus -42μm).

Three of five patients who received OPT-302 monotherapy did not require rescue therapy. At 12 weeks, their VA improved by a mean of three letters and they had a minimal change in CST (mean +18μm).

Dr Dugel noted that aqueous humour levels of VEGF-C increase significantly in patients with wet AMD after they start intravitreal treatment with a VEGF-A inhibitor. Upregulation of VEGF-C and VEGF-D has also been seen in cancer patients on systemic anti-VEGF-A therapy.

Results from a study conducted in a mouse model of choroidal neovascularisation showed that combination treatment with a VEGF-A inhibitor and OPT-302 was significantly more effective than either agent alone for inhibiting lesion development and vascular leakage.

Pravin Dugel: pdugel@gmail.com