FDA Approves Faricimab for nAMD and Diabetic Macular Edema

The US Food and Drug Administration (FDA) today approved faricimab (Vabysmo, Genentech/Roche) to treat diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD).

Compared with antivascular endothelial growth factor (VEGF) drugs currently in use, faricimab requires fewer intravitreal injections on average, so it may reduce the burden on both patients and their physicians while achieving similar or greater benefits, researchers say.

“I think it’s exciting,” said Charles Wykoff, MD, PhD, first author on a paper in The Lancet reporting 1-year results from the identical phase 3 YOSEMITE and RHINE trials of faricimab in DME. “I like more tools in the tool box.”

For nAMD, the FDA recommended that faricimab be given every 4 weeks for the first four doses, and then every 8, 12, or 16 weeks, depending on optical coherence tomography (OCT) and visual acuity, for a year.

For DME, it recommended two alternatives. The drug could be given every 4 weeks for the first four doses, then, based on OCT measurements, the interval can be extended in 4-week increments (or reduced, if necessary, in 8 week increments) for a year. Alternatively, faricimab could be given every 4 weeks for the first six doses, then at intervals of every 8 weeks, for a year.

Nearly 80% of patients taking faricimab for DME and 70% of those taking faricimab for nAMD were able to go 12 weeks or more between injections while getting the same benefit as patients taking aflibercept (Eylea, Regeneron) every 8 weeks.

While achieving equivalent visual acuity improvements in both nAMD and DME, patients taking faricimab had less edema than the control groups taking aflibercept. In addition, the drug’s safety profile was comparable to that of aflibercept; there were few signs of the dangerous intraocular inflammation that has dampened enthusiasm for brolucizumab (Beovu, Novartis), which was also touted for its durability.

Faricimab also stands out because of its novel mechanism of action. The other drugs used in intravitreal injection to treat AMD and DME — aflibercept, brolucizumab, ranibizumab (Lucentis, Genentech), and bevacizumab (Avastin, Genentech) — block VEGFs, which cause excess blood vessels to form. Faricimab also blocks VEGFs, but, in addition, it blocks angiopoietin-2 (Ang-2), which makes blood vessels weaker.

In both DME and nAMD, excess amounts of Ang-2 neutralize angiopoietin-1 (Ang-1), which normally stabilizes blood vessels. Ang-2 also makes blood vessels more sensitive to inflammatory agents, including VEGF-A. By blocking both VEGF-A and Ang-2, faricimab stops unnecessary blood vessels from forming while also preventing leakage from existing blood vessels, Wykoff said.

In the two identical AMD trials, Tenaya and Lucerne, the researchers randomly assigned 1329 people with AMD to receive either 6.0 mg of faricimab or 2.0 mg of aflibercept through intravitreal injections administered at fixed intervals.

After administering four loading doses 4 weeks apart, the investigators evaluated the patients receiving faricimab at weeks 20 and 24. Those who had active disease at week 20 received a dose then, and every 8 weeks after that. Those with active disease that first returned at week 24 received doses that week and every 12 weeks after that. And those who had no active disease at week 20 or 24 received doses every 16 weeks.

Almost half of the people (45.7% in Tenaya and 44.9% in Lucerne) received their doses every 16 weeks. About a third (34.0% in Tenaya and 32.9% in Lucerne) received doses every 12 weeks.

At the end of a year, the gains in best-corrected visual acuity (BCVA) were almost the same between the faricimab and aflibercept groups. Reductions in central subfield thickness were comparable.

If patients can get the same result with fewer injections, they may be more inclined to return for all the doses they need and may be able to maintain their visual acuity for a longer time, said Jeffrey Heier, MD, director of Retina Research at Ophthalmic Consultants of Boston, and first author on The Lancet nAMD paper. “What we’re looking with faricimab is the potential to have the same excellent anti-VEGF outcomes that we’ve come to expect, but to be able to do that with a reduction in treatment burden,” he told Medscape Medical News.

This could address the gap that has emerged for the other anti-VEGF drugs between results seen in clinical trials and results seen in the real world. “The treatment burden associated with those often doesn’t allow us to get the outcomes that we see in the phase 3 studies,” he said.

Results were similar in the two identical DME trials, which had a total of 1891 patients assigned to three treatment arms: aflibercept at fixed 8-week intervals, faricimab at 8-week intervals, or faricimab in a regimen similar to treat-and-extend, with dosing intervals ranging up to 16 weeks. Patients in the simulated treat-and-extend regimen returned every 8 weeks, but some visits were for sham injections, and measurements taken at these visits were not used to determine the interval for the next injection.

Otherwise, intervals were extended in the treat-and-extend arm whenever patients’ central subfield thickness dropped below 325 μm. About half the patients (52.8% in YOSEMITE and 51.0% in RHINE) reached dosing of every 16 weeks, and one in five (21.0% in YOSEMITE and 20.1% in RHINE) reached dosing of every 12 weeks.

This trial did not include a treat-and-extend arm for aflibercept. But in other trials that have used this regimen for aflibercept, about a third of patients can go for 12 weeks or more between treatments, said Jayanth Sridhar, MD, associate professor of clinical ophthalmology at the Bascom Palmer Eye Institute in Miami, Florida, who was not involved in the trials.

At the end of a year, as in the AMD trials, the improvements in BCVA were similar among all the groups in the two DME trials.

On the other hand, improvements in central subfield thickness were greater for faricimab than for aflibercept in the DME trials. For example, in YOSEMITE, the patients receiving faricimab every 8 weeks lost 206.6 μm, those receiving faricimab on the treat-and-extend regiment lost 196.5 μm, and those receiving aflibercept lost 170.3 μm.

In both the DME and nAMD trials, the number of ocular adverse events was larger in the faricimab groups than in the aflibercept groups, but fewer than 5% of patients in any of the study arms of any of the trials had a treatment-related ocular adverse event.

Thirty patients taking faricimab had intraocular inflammation in the four trials compared with 12 of the patients taking aflibercept. No patients had retinal vasculitis. Three patients taking faricimab had retinal vein occlusion, one had retinal artery occlusion, and one had retinal artery embolism. One patient taking aflibercept had retinal artery embolism.

In the DME trials, two patients taking faricimab withdrew because of uveitis. One had uveitis and keratic precipitates associated with best-corrected visual acuity loss of at least 30 ETDRS letters. Another had uveitis and chorioretinitis associated with BCVA loss of at least 15 ETDRS or more letters.

Brolucizumab’s risks did not become evident at this stage in its development, so clinicians will closely track postmarket data and most won’t make the drug their first choice to start with, Sridhar said. “I don’t think we’re going to start with treatment naive patients or even those patients keen to extend right away,” he said. “We want to wait a few months, to make sure we’re not going to have any unexpected issues like there were [with] brolucizumab.”

He expects to try faricimab first in patients who are not getting benefit from the older treatments. In a few months, if no concerns have arisen, he may try it for patients who want to increase the interval between injections. What happens after that will depend on the cost of the drug and how readily payers are willing to reimburse for it, he said.

Wykoff reports research support from Adverum, Aerie, Aldeyra, Alimera, Allergan, Amgen, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Gemini, Genentech, Graybug Vision, Gyroscope, Ionis, iRenix Medical, Iveric Bio, Kodiak, Lowy Medical Research Institute, Neurotech, NGM Bio, Novartis, Oxurion, RecensMedical, Regeneron, Regenxbio, Roche, SamChunDang Pharm, Samsung Bioepis, Taiwan Liposome Company, and Xbrane BioPharma. He reports consulting fees from Adverum, Aerie, Aerpio, Allergan, Allgenesis, Apellis, Arrowhead, Bausch and Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong, Clearside, EyePoint, Genentech, Gyroscope, Iveric Bio, Janssen, Kato, Kodiak, Long Bridge Medical, NGM Bio, Novartis, OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea, Oxurion, Palatin, PolyPhotonix, RecensMedical, Regeneron, Regenxbio, Roche, Santen, Surrozen, Takeda, Verana Health, and Vitranu . He reports other personal fees from Regeneron, stock or stock options from ONL Therapeutics, PolyPhotonix, RecensMedical, and Visgenx, and has served on advisory boards for Kato. Heier reports support from Genentech/Roche, grants from Apellis, AsclepiX, Bayer, Gyroscope, Hemera, Iveric Bio, Kanghong, Kodiak, NGM, Notal Vision, Novartis, Regeneron, Regenxbio, and Stealth, and consulting fees from Apellis, AsclepiX, Bayer, Gyroscope, Hemera, Iveric Bio, Kanghong, Kodiak, NGM, Notal Vision, Novartis, Regeneron, Regenxbio, and Stealth. Sridhar reports a financial relationship with Regeneron.

Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH.

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