Faricimab for DME

On January 28, 2022, the FDA approved intravitreal faricimab for the treatment of wet age-related macular degeneration (AMD) and diabetic macular edema (DME). 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 trials that evaluated the durability of faricimab compared with aflibercept in untreated patients with wet AMD and mostly untreated patients with DME. Here, we will briefly review the YOSEMITE and RHINE trials that investigated faricimab for DME.

The trials randomized adults with center-involving DME (central subfield thickness > 325 µm) 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 6.0 mg on a personalized treatment interval (PTI) (with 4 initial monthly doses), and (3) intravitreal aflibercept 2.0 mg 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 a few noteworthy items to describe the patient population. The patients were ~75% treatment naive, ~55% had mild to moderate nonproliferative diabetic retinopathy, and <10% of patients had proliferative diabetic retinopathy (PDR). Notable exclusion criteria include no HbA1C over 10%, no dialysis, no high-risk PDR, and no recent history of cardiovascular incident.

The PTI arm is worth discussing. A reference central subfield thickness (CST) was established for each patient, defined as the CST value when the initial CST criteria were met for possible extension (CST <325 µm 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from the reference CST and the letter change in ETRDS letters from the reference BVCA, treatment intervals were either withdrawn or extended in 4-week segments.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 q8 week and PTI arms compared with aflibercept q8 weeks but all events except two 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. The PTI trail design was the first of its kind in retina, which may have implications for future trials.