David A. Eichenbaum, MD, FASRS, and Caroline Baumal, MD, review the dual mechanism of action of faricimab as well as the 2-year update in the TENAYA, LUCERNE, YOSEMITE, and RHINE trials.
David A. Eichenbaum, MD, FASRS: This is a huge question, and I don’t think there’s necessarily an answer. But we see this great data set, this dramatic extension. We see about two-thirds of patients on every 16 weeks and over 80% at greater than 12 weeks by week 112, which is an unprecedented extension. We see comparable visual acuity and atomic improvements to every-8-week aflibercept, and we see a very safe agent. We don’t see any retinal vasculitis or occlusive disease in any of the faricimab patients across either the neovascular macular degenerative disease set or the diabetes disease set, which we’ll get to. In macular generation, do you think the vascular stabilization from angiopoietin-2 inhibition—as supported by the basic science—is giving us some of this extension? Is this second mechanism of action unlocking something new in wet AMD [age-related macular degeneration]?
Caroline Baumal, MD: There are preclinical data to support the effect of ang-2 causing increased durability on anti-VEGF, on VEGF inhibition. There’s preclinical supporting data. If we look at the diabetic data, there certainly appears to be some OCT [optical coherence tomography]–driven data that show that the patients with diabetes are drier. There’s probably some dual-mechanism approach that helps with the durability in AMD. Is it related to the mechanism of the molecule? Time will tell, but there’s certainly more durability in some patients. Some people will look at the study design. Aflibercept wasn’t tested in the exact same way. It was used on label with 3 loading doses every 8 weeks throughout the study. It wasn’t used the same way as faricimab, but it did show durability signals. That’s another positive way we can think about the ang-2 effect, anti–ang-2 effect.
David A. Eichenbaum, MD, FASRS: As you said, time will tell. That’s 1 of the things I really like about this series. For TENAYA and LUCERNE, we know there’s a long-term extension called AVONELLE-X, which is going out to collect several more years of data. We should have a 4-year data set, following the conclusion of AVONELLE-X. It’s looking at not just whether there’s this ongoing durability benefit but also long-term safety, which is something we’re going to be doing more of pending our recent experience with intraocular inflammation and intravitreal injectable agents. We’re going to see if time does tell in neovascular macular generation, if the durability hold up, if the durability is real.
We started talking about the diabetes data set. The 2-year data in YOSEMITE and RHINE were released slightly earlier than the 2-year data in TENAYA and LUCERNE, but they were very close temporally. They were very similar trials with regard to enrollment, conclusion, and data-lock timeline. In YOSEMITE and RHINE, the design of the study was a little different. The personalized treatment interval started in the first year and continued throughout the second year in the PTI [personalized treatment interval] arm that was randomized in the first year. There was extended dosing up to 16 weeks in that first year, which also increased in proportion through the second year while preserving the comparable best-corrected visual acuity gains.
As you alluded to, Caroline—and you’re an OCT expert and an international speaker—there’s some OCT signal in the apples-to-apples [dose for dose] phase of the study that there’s greater anatomic reduction with faricimab than there is with aflibercept until the dosing changes. There’s this signal in diabetes that might speak more to the dual MOAs [mechanisms of action] or the additional MOA of angiopoietin-2 inhibition. Focusing on the second year of YOSEMITE and RHINE, the increased proportion of patients who have extension in the diabetic macular edema [DME] population, does that in combination with the early anatomic suggestion of superiority in the first year of YOSEMITE and RHINE make you think that the dual mechanisms of action may be apparent or more apparent in diabetic macular edema?
Caroline Baumal, MD: Absolutely. That’s a key finding. The reduced central retinal thickness, the reduced intraretinal fluid in the faricimab-treated eyes, point to those dual mechanisms of action. I’m also excited to see the breakdown of diabetic retinopathy severity scores. When we get that information, some of the secondary end points will also be useful in showing the dual mechanisms of action.
I’m going to add 1 more thing before we get off the topic of neovascular AMD. I’m happy that this is a single dose of faricimab, or Vabysmo, that’s going to be used for 2 different diseases. It’s very useful that it’s the similar makeup of the medicine. As opposed to some other agents, as opposed to Lucentis, or ranibizumab, which had 2 different doses, this is using a single dose that will make it easier to use and track.
David A. Eichenbaum, MD, FASRS: That’s certainly a convenience piece that’s important in the United States, where we use 2 different doses of ranibizumab for diabetes and diabetic retinopathy and then everything else: neovascular macular degeneration, RVO [retinal vein occlusion], myopic CNV [choroidal neovascularization]. You touched on an important point: to find and tease out this angiopoietin effect, the DRSS [Diabetic Retinopathy Severity Score] didn’t show a difference in YOSEMITE and RHINE with the data we have.
There’s a really interesting study called ALTIMETER, which looks at multimodal imaging of aqueous humor biomarkers in patients with treatment-naïve diabetic eye disease being treated with faricimab. The ultra-wide field color fundus photography, angiography, and retinal periphery may actually tell us more. We don’t have a consistent ultra-wide field data set in YOSEMITE and RHINE, and we’re getting that in ALTIMETER. We need to bear out if we can, to the best of our ability, the impact of the second mechanism of action vs the impact of study design and the impact of other things with faricimab, like bioavailability or potency of antiangiogenic anti-VEGF molarity. We really want to tease out the impact of the second MOA.
We have some suggestions for that, looking at the anatomy and the dose match phase in YOSEMITE and RHINE but also at the remarkable durability in both DME and AMD that we’ve achieved even in the first year of wet AMD and diabetic macular edema treatment. Getting these wide field images and seeing more will be even more helpful. Perhaps they’ll help us get a cleaner elucidation of the antiangiopoietin effect.
The Rhone-X trial is an extension study that, like AVONELLE, goes out significantly further for 4 years of data in patients with diabetic eye disease and diabetic macular edema. We’re going to be able to assess the long-term safety, efficacy, and durability in patients with diabetes. We’ve also seen, as we talked about earlier, no intraocular inflammatory events with severity, such as vasculitis or occlusive retinitis. Both aflibercept and faricimab patients in these studies showed some low incidence of intraocular inflammatory events, but there were no occlusive events in any arm of this study. This also supports the well-established safety of aflibercept in very large data sets.
Transcript edited for clarity