DARPin delivers promising results in phase II study of exudative AMD:

September 15, 2014

Abicipar pegol was at least as effective as ranibizumab for treatment of exudative age-related macular degeneration, and appeared to have a longer duration of action In a randomized, double-masked phase II study.

 

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Abicipar pegol (Allergan) is an investigational anti-VEGF agent belonging to a new therapeutic class known as DARPins. In a randomized, double-masked Phase 2 study, abicipar pegol was at least as effective as ranibizumab (Lucentis, Genentech) for treatment of exudative age-related macular degeneration, and appeared to have a longer duration of action.

 

 

By Cheryl Guttman Krader; Reviewed by Raj K. Maturi, MD

Indianapolis-A novel anti-vascular endothelial growth factor (VEGF) agent is at least as effective as ranibizumab (Lucentis, Genentech) and shows promise for allowing a longer dosing interval, said Raj K. Maturi, MD.

Such findings are based on results from a phase II study investigating intravitreal abicipar pegol (“abicipar”; Allergan) in patients with treatment-naive exudative age-related macular degeneration (AMD).

“This phase II study was not powered to detect statistically significant differences in efficacy outcomes between treatment groups, but the data are exciting because they suggest that abicipar could offer the benefit of better visual improvement or a prolonged duration of action,” said Dr. Maturi, clinical associate professor of ophthalmology, Indiana University School of Medicine, Indianapolis.

“A phase III study is now being planned,” he said. “Considering the early results with abicipar and other agents in the pipeline, there is great reason for retina specialists and our patients to be very optimistic about what lies ahead.”

Abicipar belongs to a new class of small molecule therapeutics know as designed ankyrin repeat proteins (DARPins) that can be engineered to bind one or more target proteins. Abicipar binds soluble isoforms of VEGF-A.

 

Compared with antibodies or antibody fragments, DARPins have a smaller molecular weight and higher binding affinity.

“The molecular weight of abicipar is 34 kDa compared with 48 kDa for ranibizumab, and 115 kDa for aflibercept (Eylea, Regeneron),” said Dr. Maturi, who is also in private practice, Midwest Eye Institute, Indianapolis.

However, despite its smaller size, abicipar has a longer vitreous half-life than either ranibizumab or aflibercept, 6 days versus 3 and 4.5 days, respectively, in the rabbit vitreous, he noted.

“The early clinical data are encouraging and suggest that abicipar will have a longer duration of therapeutic action than ranibizumab or aflibercept,” Dr. Maturi said.

The double-masked trial was conducted as the third and final stage of a phase II study program. It randomly assigned 64 patients into three groups to receive abicipar 1mg (n = 25), abicipar 2 mg (n = 23), or ranibizumab 0.5 mg (n = 16). All treatments were administered with 3 loading doses at weeks 0, 4, and 8. Thereafter, ranibizumab was continued on a monthly dosing schedule while further treatment in the abicipar groups was with monthly sham injections.

When patients were evaluated at week 16, 4 weeks after the last ranibizumab injection and 8 weeks after the last abicipar injection, mean improvement from baseline visual acuity was greater in the abicipar 1 and 2 mg groups compared with ranibizumab (6.3 and 8.2 versus 5.3 letters, respectively).

The proportion of patients achieving ≥3-line gain from baseline visual acuity was also greater in the higher dose (2 mg) abicipar group compared with ranibizumab.

At week 20, this change in best-corrected visual acuity was observed in 25% of patients treated with the higher dose of abicipar (2 mg) versus 12% for both ranibizumab and the lower dose abicipar (1 mg).

Analyses of optical coherence tomography images showed macular thickening was quickly reduced following intravitreal injection in all treatment arms.

 

All treatments were well tolerated, and there were no serious adverse events recorded during the study. Two patients treated with abicipar 2 mg and in 3 patients treated with the 1 mg dose developed ocular inflammation with decreased vision. They were all treated successfully using topical anti-inflammatory medications and recovered vision.

“There has been an ongoing effort to modify the manufacturing process to address inflammation, and material from the new manufacturing process will be used in the phase III trials,” Dr. Maturi said.

In addition to the potential for having a longer duration of action, the fact that DARPins represent a tunable technology platform that can be modified to bind different target proteins and more than one protein with a single compound is another exciting and attractive feature of this novel therapeutic class, Dr. Maturi said.

For example, the early results of Fovista’s anti-PDGF drug demonstrate a significant potential benefit of suppressing both VEGF and PDGF. A DARPin effective against both of these cytokines could be manufactured simply by linking an anti-VEGF DARPin with an anti-PDGF DARPin to form a single molecule with both binding properties.

Because the pathogenesis of wet AMD and other diseases being treated with anti-VEGF agents is complex, there is strong believe that combination treatment will likely be more effective than a monotherapy approach.

“Therefore, the potential to provide multimodal treatment using a single agent is very intriguing,” Dr. Maturi said.

 

 

Raj K. Maturi, MD

E: rmaturi@gmail.com

This article was adapted from Dr. Maturi’s presentation at the 2014 meeting of the American Society of Retina Specialists. Dr. Maturi is a consultant to Allergan and has received grant support for clinical studies as well as for investigator initiated trials. Allergan has an exclusive license to abicipar from Molecular Partners.