Regeneron Pharmaceuticals Inc. markets the highly successful anti-VEGF injection EYLEA (aflibercept), which is FDA approved for neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), and diabetic macular edema (DME) and diabetic retinopathy (DR) in patients with DME. Global EYLEA sales in 2015 totaled $4.1 billion, including OUS sales by Bayer. In the first half of 2016, EYLEA global sales increased 38% to $2.5 billion.
Retina specialist David Boyer, MD, provided an update regarding developments in combination therapy involving aflibercept, which may synergistically target different pathways and lead to increased efficacy and/or durability versus aflibercept alone. Regeneron is focusing on two new treatment targets: platelet derived growth factor receptor beta (PDGFR-beta) and angiopoietin2 (Ang2).
The PDGFR-beta antibody rinucumab, co-formulated in a single intravitreal injection with aflibercept, is currently in a 500-patient Phase II study (CAPELLA) for patients with wet AMD. Preliminary results from this study are expected in the second half of this year. Dr. Boyer noted that PDGF may act to make blood vessels more sensitive to anti-VEGF therapy. In a Phase I study, the combination was well tolerated and more effective than either drug alone in mural cell stripping and regression of newly formed vasculature.
The Ang2 antibody nesvacumab, also co-formulated with aflibercept, is in Phase II clinical trials for wet AMD (ONYX Trial, n = 360 patients) and DME (RUBY Trial, n = 300 patients). According to Dr. Boyer, Ang2 also plays a major role in the development and regression of new blood vessels. In a preclinical model of chronic vascular leakage, and in a Phase I study, the drug combination increased the duration of anti-leak action versus aflibercept alone.
David Boyer, MD
David S. Boyer, MD is a Board-certified ophthalmologist specializing in the treatment of diseases of the retina and vitreous. He is Senior Partner at Retina-Vitreous Associates Medical Group with offices in Los Angeles, Beverly Hills, North Hollywood, Torrance, Pasadena and Tarzana, California.
David Boyer, MD: I’m going to talk to you about combination therapy and what’s going on at Regeneron. It’s important to look at why do we need combination therapy. Anti-VEGF therapy has really revolutionized our treatment of AMD and DME. But if you look back to the wet AMD trials in View 1, View 2, only about one-third of patients were three line gainers. And only approximately 70% of patients were dry on OCT. And in DME, if you use protocol T for the first year, about 42% of patients gained 3 lines, and about two-thirds of the patients had a central foveal thickness of less than 250 microns. So there is room that we can do better. And how do we do better? Well, we need new targets. And there are two targets that Regeneron has focused on. One is platelet derived growth factor, or PDGF, and the other being angiopoietin 2. And as you know, PDGF recruits parasites. And the parasites act in a way that they protect the blood vessel, and they make them less sensitive to anti-VEGF therapy. So if you could strip the parasites, such as Fovista has done, you may be able to make the blood vessels go away and make them much more sensitive to anti-VEGF therapy. And angiopoietin 2, Ang-2, also plays a major role in the vessel development and sprouting and regression of the new blood vessels. And I’ll show you how both of them have fared in phase 1 trials. So renicumab is co-formulated anti-PDGF and anti-VEGF. It’s a single 50 microliter intravitreal injection, and it’s a human recombinant antibody that binds to human platelet growth factor receptor B. Now in this study, when used aflibercept alone or if used the anti-PDGF alone, you had very excellent reduction in the [?] stripping and regression of newly formed blood vessels. However, if you do both of them together, the effect was intensified. There was a phase 1 study that was done where four different doses of the anti-PDGF were used: 0.5, 0.3, 1 milligram, and 3 milligrams combined with 2 milligrams of aflibercept. And it was a dose escalating trial. There were four patients in each cohort, and the patients received monotherapy if needed at week 8. There were no dose limiting toxicities. There was no intraocular inflammation, and no serious adverse events. But one patient did develop an RP tear, resulting in a loss of greater than 20 letters. It was not considered related to study drug. Capella is the phase 2 study design is two different doses of the anti-PDGF-R combined with aflibercept 2 milligrams, compared to the gold standard aflibercept, 2 milligrams given monthly. The endpoint will be the readout and best corrected vision at week 12, and the patients will receive the dose. There are 500 patients enrolled in this study. Anti-Ang-2 and anti-VEGF therapy and neovascular AMD and DME, it may be able to be modulated by another drug called nesvacumab, which is combined. And we know that the angiopoietin Tie-2 is a tyrosine kinase receptor, and there’s an Ang-1 and Ang-2. Ang-1 is expressed in normal cells, and it is meant to maintain vascular stability. Ang-2 is found only in pathologic conditions, and very little in normal conditions. If you use, again, looking at this, the bar on the extreme left hand side is post-natal day 4. The other four bars are post-natal 6. The first bar that you see is the control, then aflibercept, and then the Ang-2, and then the combination. As you can see, the combination was much stronger. Here we can see if you combine those, there seems to be a much longer lasting effect, lasting out to 14 weeks. The study design, the phase 1, there were 5 groups. That ranged from 0.5 all the way up to 6 milligrams. And then a 6 milligram dose with no aflibercept. There were no dose limiting toxicities, no serious adverse events in combination. There was one SE. The combination therapy seems to prolong the effect of the aflibercept alone. We now have the Onyx and the Ruby. There are 350 patients that are being in the Onyx, and 300 in the Ruby. Ruby is the AMD and Onyx is the DME. Two different doses combined with aflibercept against aflibercept. So in summary, there seems to be synergistic targets. We will have a report of the anti-PDGF in the second half of this year, and it seems that these are well tolerated with no serious adverse events. Thank you.