Currently there are several effective treatments available for wet age-related macular degeneration (wAMD), but the market still lacks treatments for dry AMD (dAMD), which is a significant unmet need of the AMD space.

Following the failed Phase III Spectri trial of Roche’s lampalizumab, whether any of the dAMD pipeline products will emerge as an effective therapy for the late-stage or atrophic form of dAMD, called geographic atrophy (GA), in the next 10 years, is unclear.

dAMD is a highly prevalent, slowly progressing disease among individuals over 50 years of age, which can result in central vision loss in the later stages of the disease, due to death (atrophy) of photoreceptor cells in the macula.

A lack of treatment for a large market

GlobalData estimates that over 69 million people had some form of dAMD in 2016 across the seven major markets (7MM), which includes the US, France, Germany, Italy, Spain, the UK, and Japan. Nearly as many AMD patients presented with GA as those with wAMD. GA is typically a bilateral disease, making this AMD segment potentially even more lucrative than wAMD, which GlobalData estimated was worth $4.9M in 2016 across these countries.

GlobalData’s primary research also revealed that about 26% of wAMD patients receiving anti-VEGF therapy also develop GA, which can eventually become the primary cause of sight loss in these patients.

Most of the pipeline drugs in development for dAMD are currently designed for the treatment of GA, with the aim to slow the progression of atrophic lesion(s) in the macula. GlobalData has identified four drugs in late stages of development (Phase IIb/III) for GA that could potentially launch within 10 years.

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A string of failures

In recent years, there has been a very high rate of dAMD drug failures in both the middle and late stages of development, prompting key opinion leaders (KOLs) interviewed by GlobalData to remain apprehensive regarding the likely success of these drugs until Phase III data have been published.

Research has highlighted a link between complement protein polymorphisms and the development of AMD. Despite numerous pharmaceutical and biotechnology companies targeting the complement pathway, however, no product of this type has reached the market.

The disappointing result of the Phase III lampalizumab trial announced on September 8, 2017 decreased earlier optimism surrounding Roche’s anti-complement program, although results of the second Phase III trial, Chroma, remain to be revealed in November 2017. Another limitation of lampalizumab, according to KOLs, is that it is likely to be effective only in those dAMD patients with GA who are positive for CFI mutation, which is a more uncommon variant, with only 20–50% of patients who have GA having the mutation. If that is the case, its prescription would most likely warrant prior genetic testing, which is currently not a routine diagnostic method in the large majority of practices.

Growing competition expanding options

Around the same time as this discouraging anti-complement news, Apellis announced that APL-2, a complement C3 inhibitor, met its primary endpoint of slowing the rate of GA lesion growth in patients with GA due to AMD, and that the company is planning to initiate the Phase III program of APL-2 in GA as soon as possible.

In the knowledge of its competitors’ recent conflicting pipeline results, Roche’s lampalizumab and Apellis’ APL-2, Ophthotech decided to continue its Zimura program. Zimura is a complement C5 inhibitor, which blocks all three complement pathways (similar to APL-2), while lampalizumab blocks only the alternative complement pathway through targeting complement factor D.

Withered by the failure of its wAMD drug, Fovista, however, Ophthotech is in the process of modifying the Zimura program for dAMD to accelerate the anticipated timeline to obtain topline data and thereby reduce the cost to complete the study. As part of this strategy, the modified study design will incorporate patients in the Phase III trial who have already been enrolled in the Phase II portion of the Phase II/III clinical trial.

With its accelerated program, Zimura is definitely a drug to look out for in the dAMD space; however, with the lack of interim data, it is hard to predict its efficacy. Nonetheless, according to KOLs, Zimura could be even more successful than lampalizumab, because it has a broader target; specifically, it is not restricted to the CFI mutation-positive GA population. While APL-2 has shown efficacy in the Phase II trial, its utility in dAMD will also need to be proved by large-scale Phase III trials.

Ophthotech also aims to leverage from Zimura in wAMD within the AMD space, and has announced the initiation of a Phase IIa trial of Zimura in combination with Lucentis, in the hope that complement inhibition during anti-VEGF therapy may have therapeutic benefit over anti-VEGF monotherapy.

The latest stage

The only product in late stages of development for GA in dAMD that does not target the complement system is Allergan’s Brimonidine Drug Delivery System (Brimo DDS), which is aimed to preserve macular function by preventing apoptosis of retinal pigment epithelial (RPE) cells and photoreceptors in patients with GA due to AMD, and thereby halt or slow the progression of GA. As such, should complement inhibitors fail, Brimo DDS will be one drug that could succeed.

Based on experience with Brimo DDS sustained-release implant and brimonidine in other ophthalmology indications, KOLs interviewed by GlobalData expressed hopes and a need for such a cyto/neuroprotective agent in the treatment of GA. Furthermore, Brimo DDS will be administered by intravitreal injection either every three months or every six months, which is an advantage over the monthly anti-complement agents currently in development.

GlobalData believes that the companies that manage to set foot in the dAMD space in the next 10 years will benefit substantially from this market, with their drugs potentially reaching blockbuster status within four to five years of launch. Provided efficacy is demonstrated, GlobalData expects that with its complement inhibitor, Ophthotech could arise as a frontrunner of the dAMD space, although there will be plenty of opportunities for the other companies to carve out a generous slice of this foreseeable highly lucrative market.