Retina Subspecialty Day, the Year in Review, and AMD

Two topics struck me as highlights from this year’s American Academy of Ophthalmology meeting - age-related macular degeneration (AMD) and imaging. The first because there have been multiple, informative data releases over the last year, and the latter because it reflects the likely trajectory of the field over the next few years with the expansion of our understanding of the utility of optical coherence tomography angiography (OCTA).

But let’s start with AMD (OCTA will be the topic of the next blog…)

The greatest unmet need in retina across the country is geographic atrophy (GA), the end-stage of AMD for which we have no treatment.

The field was disappointed by data from the phase 3 Spectri and Chroma trials evaluating lampalizumab as an inhibitor of complement factor D. Both trials, involving more than 1,800 patients, failed to meet their primary endpoint at 1 year of slowing GA growth. But, Genentech has proven successful repeatedly in the past at mining data from large trial datasets. There is much to be learned about this devastating disease process, and there is tremendous opportunity for insight to be gleaned from analyses of the phenotypic and genotypic data obtained from these patients..

In my mind, the complement cascade remains a viable pharmacologic target, apparently important to the underlying pathophysiology based on the known genetic loci that impact a patient’s risk

We saw the release of the FILLY phase 2 data, which found a statistically significant 28.6% decrease in the growth rate of GA with monthly APL-2 (Apellis) dosing, an inhibitor of complement C3, through the 12-month primary endpoint. There were a couple of signals from FILLY that echoed a biologic impact of the dug. First, there appeared to be a dose response. There were two active arms (monthly and every-other-month), with a greater decrease in growth rate among patients dosed monthly. Second, the effect of APL-2 on slowing GA growth appeared to accelerate in the second 6 months of FIlLY. We will see what happens through the final 18 month follow-up of FILLY in 2018.

Ophthotech is also studying  complement, with a C5 inhibitor in an ongoing phase 2/3 trial.  While lampalizumab theoretically blocks a rate limiting step of the alternative pathway and was hypothetically an elegant target to blunting overactivation of the inflammation associated with complement activation, possibly it didn’t work due to the ability of complement to be activated both downstream and parallel routes. In comparison, C3 and C5 represent the final common pathway leading to the MAC, the cytolytic end product of the complement cascade.

While right now it seems as though C3 may be a promising target, FILLY is a phase 2 study, and the efficacy signal needs to be validated in a phase 3 trial, which is planned to begin in 2018.  

Turing to the other end-stage form of AMD, neovascularization, two themes come to mind. First, data from two well-designed trials this year indicated that PDGF blockade did not add visual or anatomic benefit to anti-VEGF monotherapy . Ophthotech’s Fovista and Regeneron’s CAPELLA trials both failed to meet their primary endpoints. I think these results reinforce that anti-VEGF monotherapy is an impressive treatment option, setting a high standard that combination therapy will need to breach to become clinically relevant. Five ongoing phase 2 trials evaluating the role of angiopoietin-2 blockade in wet AMD management are anticipated to have data in the near future and will hopefully yield more positive data than the anti-PDGF trials.  Second, extended delivery devices may help address two other unmet needs: durability and visual gain when managing wet AMD. The ongoing phase 2 LADDER trial from Genentech evaluating their port delivery system may have data to share in 2018. This device may allow substantially fewer clinical visits for patients, through improved durability, and achieve more steady-state anti-VEGF drug levels which may translate into improved long-term visual gains by avoiding periods of under-treatment.

- Charles Wykoff, MD