Pipeline for dry AMD features diverse compounds

Take-home message: A number of drugs are being investigated in clinical trials as treatment for slowing the growth of geographic atrophy that is secondary to age-related macular degeneration.

By Cheryl Guttman Krader; Reviewed by Philip J. Rosenfeld, MD, PhD

Miami-Though there are currently no treatments for geographic atrophy (GA) secondary to age-related macular degeneration (AMD), and the development of several investigational agents was halted because of disappointing results, other promising drugs are continuing to move through the therapeutic pipeline.

“Treatments that are now in clinical trials aim to slow the growth of GA,” said Philip J. Rosenfeld, MD, PhD.

“They represent several different strategies,” said Dr. Rosenfeld, professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami.

Complement inhibition has progressed to a phase III clinical trial based on data from a phase II trial of one of these inhibitors-lampalizumab (Genentech)-which showed a signal that it may work, he noted.

Complement inhibition

Lampalizumab is an antigen-binding fragment from an antibody that blocks the complement 3/complement 5 (C3/C5) alternative pathway convertase. It is administered as an intravitreal injection and advanced into the phase II study, known as MAHALO, after demonstrating favorable safety in a phase I trial.

MAHALO evaluated lampalizumab administered monthly and every other month. The patients enrolled had bilateral GA with visual acuity ranging from 20/50 to 20/400. Results after 18 months showed treatment effect was statistically significant based on an aunconventional p-value cut-off of p = 0.2. However, in a genetic subset of patients carrying the complement factor I (CFI) at-risk allele in which GA appeared to growth faster, the rate of GA growth was reduced 44% by lampalizumab (p < 0.005).

The phase III lampalizumab study program is under way. The two intervention trials, Chroma and Spectri, plan to enroll 1872 patients with visual acuity of 20/100 or better; 60% of patients being entered will carry the CFI+ allele. Lampalizumab is being administered monthly or every 6 weeks.

Blocking pathways

Dr. Rosenfeld noted that lampalizumab blocks only one of the three pathways of complement activation. In contrast, the investigational agent APL-2 (Apellis Pharmaceuticals) inhibits C3 activation and blocks all three pathways of complement activation.

APL-2 is a reformulated version of POT-4 (Potentia), which was shown to be safe and well-tolerated as an intravitreal injection in initial clinical testing.

However, POT-4 formed a gel-like deposit in the vitreous that did not fully dissolve, Dr. Rosenfeld explained.

APL-2 is now being investigated in a randomized phase II study where it is being given monthly or every other month for 12 months. Follow-up will continue to 18 months.

LFG316 (Alcon), a monoclonal antibody against C5 in the complement pathway, is also being investigated as an intravitreal injection in two studies-one in which it is being administered as monotherapy and the other where it is being given in combination with CLG561, a drug that inhibits another complement pathway protein known as properdin.

At the Angiogenesis, Exudation, and Degeneration 2016 meeting in February, Novartis reported that CLG561 did not slow the enlargement of GA in the phase II study. The combination trial with CLG561 and LFG316 is ongoing.

Alternative approaches

Visual cycle modulation is another strategy being looked at as a treatment for GA, and is represented by emixustat (Acucela). By inhibiting RPE65, emixustat prevents isomerization of 11-trans-retinal to 11-cis-retinal and thereby suppresses rod photoreceptor function.

Emixustat is being evaluated as a once daily oral medication at three different doses in a Phase 2/3 study.

Two other investigational modalities for GA related to AMD are being developed as neuroprotective agents. One is an anti-amyloid ß antibody (GSK933776, GlaxoSmithKline) being studied as a monthly intravenous infusion at three different doses.

“Amyloid accumulates in the back of the eye and activates complement,” Dr. Rosenfeld said. “The goal of this treatment is to leach ß -amyloid out of the tissue of concern.”

In addition, brimonidine (Allergan) is being pursued as an intravitreal treatment. It is currently in a phase II study in which patients are being randomly assigned to receive a 0.40 mg brimonidine implant or sham every 3 months.

Stem cell therapy for GA is also under investigation in phase II trials. One company (Ocata Therapeutics) is developing a subretinal injection of fully differentiated human embryonic stem cells that are differentiated to RPE cells.

“The phase I study with the Ocata stem cells had good safety outcomes and some encouraging visual acuity data,” Dr. Rosenfeld said.

StemCells Inc. also reported encouraging phase I data, but its phase II study has been suspended pending additional funding. Additional phase 1 studies are under way in the United States, Europe, and Asia.

Philip J. Rosenfeld, MD, PhD

E: prosenfeld@med.miami.edu

This article is based on Dr. Rosenfeld’ presentation at the 2015 meeting of the American Academy of Ophthalmolgoy. Dr. Rosenfeld receives research grants and/or consults for several companies that are developing treatments for geographic atrophy related to age-related macular degeneration.