Faricimab and DME: YOSEMITE and RHINE (Phase 3 Trial)
Written by: Edward Wood, MD
Austin Retina Associates
Wykoff, C. C., F. Abreu, A. P. Adamis, and K. Basu. 2022. “Efficacy, Durability, and Safety of Intravitreal Faricimab with Extended Dosing up to Every 16 Weeks in Patients with Diabetic Macular Oedema (YOSEMITE and RHINE): two randomized, double-masked, phase 3 trials. The Lancet. 2022 Feb 19;399(10326):741-755.
On January 28, 2022, the FDA approved intravitreal faricimab (Vabysmo, Roche/Genentech) for the treatment of wet AMD1 and DME2. Faricimab is the first drug of its kind to target two distinct biological pathways (Ang-2 and VEGF-A) that are contributors to retinal disease and vision loss. The FDA approved faricimab based on the results of four large (Phase 3) clinical trials1,2 that evaluated the durability of Vabysmo compared with aflibercept (Eylea, Regeneron) in untreated patients with wet AMD and mostly untreated patients with DME. Here, we will briefly review the YOSEMITE and RHINE2 that investigated faricimab for DME.
The trials randomized adults with center-involving DME (CST > 325 um) with VA of 20/40 to 20/320 to three arms: (1) intravitreal faricimab 6.0 mg every 8 weeks (with 6 initial monthly doses), (2) intravitreal faricimab 6.0mg on a personalized treatment interval (PTI) (with 4 initial monthly doses), and (3) intravitreal aflibercept 2.0mg every 8 weeks (with 5 initial monthly doses as per label). The primary outcome was mean change in BCVA averaged over weeks 48, 52, and 56 (~one year).
Baseline characteristics were well balanced but there are few noteworthy items to describe the patient population. The patients were ~75% treatment naive, ~55% had mild to moderate NDPR, and <10% of patients had PDR. Notable exclusion criteria include no HbA1C over 10%, no dialysis, no high risk PDR, and no recent history of cardiovascular incident.
The personalized treatment interval (PTI) arm is worth discussing. A reference CST was established for each patient defined as the CST value when the initial CST criteria were met for possible extension (CST <325 microns at or after the week 12 visit). A reference BCVA was established for each patient defined as the mean of the three best BCVA scores obtained at any previous active dosing visit. Depending on the percentile change in CST from the reference CST and the letter change in ETRDS letters from the reference BVCA, treatment intervals were either withdrawn or extended in 4 week segments.
Both trials showed that vision gains with faricimab q8 weeks (+10.7 letters Yosemite, +11.8 letters Rhine) and faricimab PTI (+11.6 letters Yosemite, +10.8 letters Rhine) were noninferior to aflibercept q8 weeks (+10.9 letters Yosemite, +10.3 letters Rhine) at the averaged 1 year endpoint. In the PTI arm, ~70% of patients were able to be extended to 12 weeks or more between injections, and ~50% were able to be extended to 16 weeks between injections. Faricimab was well tolerated, with slightly numerically higher intraocular inflammation events in both the q8week and PTI arms compared with aflibercept q8 weeks but all events except 2 entirely resolved at week 56.
Overall, this landmark trial showed efficacy, durability, and safety of the novel bi-specific (anti-Ang-3 and anti-VEGF) agent faricimab (Vabysmo). The PTI trail design was the first of its kind in retina which may have implications for future trials.
- Heier, Jeffrey S., Arshad M. Khanani, Carlos Quezada Ruiz, Karen Basu, Philip J. Ferrone, Christopher Brittain, Marta S. Figueroa, et al. 2022. “Efficacy, Durability, and Safety of Intravitreal Faricimab up to Every 16 Weeks for Neovascular Age-Related Macular Degeneration (TENAYA and LUCERNE): Two Randomised, Double-Masked, Phase 3, Non-Inferiority Trials.” The Lancet. https://www.sciencedirect.com/science/article/pii/S0140673622000101.
- Wykoff, C. C., F. Abreu, A. P. Adamis, and K. Basu. 2022. “Efficacy, Durability, and Safety of Intravitreal Faricimab with Extended Dosing up to Every 16 Weeks in Patients with Diabetic Macular Oedema (YOSEMITE and RHINE) ….” The Lancet. https://www.sciencedirect.com/science/article/pii/S0140673622000186.