Yosemite/Rhine Studies: a critical analysis
The Yosemite and Rhine Studies were twin randomized, double-masked, multicenter non-inferiority trials comparing the efficacy of faricimab (Vabysmo) vs aflibercept (Eylea) in the treatment of diabetic macular edema.
The study abstract begins with the statement, “To reduce treatment burden and optimize patient outcomes in diabetic macular oedema, we present the 1-year results from two phase 3 trials of faricimab, a novel angiopoeitin-2 and vascular endothelial growth factor-A bispecific antibody.” However, analysis of the data reveals the study report did NOT demonstrate reduced treatment burden at one year. It did demonstrate potential non-inferiority of faricimab compared with aflibercept with an increased treatment burden in the faricimab arms of the studies.
Treatment burden was greater in both faricimab treatment arms of both studies compared with aflibercept. Table 1 reveals 25% greater injections in the faricimab q8 week group compared with aflibercept. The faricimab group received 10 injections at 52 weeks compared with aflibercept at 9 injections. The faricimab group did not experienced a reduced treatment burden compared with aflibercept. Moreover, the faricimab group sustained a more intense treatment burden to meet the “non-inferiority” assessment compared with aflibercept.
Table 1. Injection schedule for faricimab (Fq8) and aflibercept (Aq8) q8 week study arms.
| wk# | 1 | 4 | 8 | 12 | 16 | 20 | 24 | 28 | 32 | 36 | 40 | 44 | 48 | 52 | total |
| Fq8 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 10 |
| Aq8 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 9 |
There was only one subgroup of eyes that received one less injection of faricimab at one year compared with aflibercept. There were 63 eyes of 286 (22%) in Yosemite and 66 eyes of 308 (21%) in Rhine who underwent 7 faricimab injections within the group randomized to “personalized treatment interval” (PTI) compared with 8 injections in the aflibercept group. Unfortunately, the visual and anatomic outcomes of this subgroup of faricimab eyes were reported a part of the entire PTI group, which overall had more injections than the aflibercept group.
The primary outcome of the study was the number of letters of improvement on the standard ETDRS chart. However, because of the uneven staggered injection schedule between the q8 week treatments groups, the method to calculate the visual improvement outcome favored faricimab over aflibercept. The study design called for averaging the measurements of visual improvement over a three-month time frame (i.e. at week 48, 52, and 56). As a result, the three averaged measurements for faricimab (Fq8) was 4 weeks, 8 weeks, and 4 weeks post-injection (average 5.3 weeks), while the three measurements for aflibercept (Aq8) were 8, 4, and 8 weeks post injection (average 6.6 weeks). Thus, the unevenly staggered injection schedule resulted in a final visual endpoint measurement inappropriately in favor of faricimab.
Even in the subgroup of faricimab (Fpti) that touted one 16week treatment interval, the visual acuity measurements were taken at 16weeks, 4weeks, and 8 weeks post-injection. This represents an average of 9.3 weeks post-injection; this is nowhere near the measurement taken at 16 weeks. In addition, the acuity outcomes in the Fpti group were reported as a group without reporting the acuity gains made specifically by the subgroup of eyes extended to a 16-week interval. Therefore, the reported acuity gains do not apply to this subgroup with extended treatment.
A secondary outcome of the study was the central subfield macular thickness (CST). This measurement shows the anatomic improvement in macular edema. The slope of the thickness curve trended toward a more rapid decrease in both arms of faricimab compared with aflibercept during the monthly injection stage (initial loading stage). Analysis of the results after the loading stage (monthly injections), both faricimab and aflibercept showed a similar jagged curve demonstrating a drop-off of treatment effect during the no-treatment month. A similar jagged response is not seen in the Fpti group as the treatment intervals varied within that group. The rebound in edema seen in both faricimab and aflibercept suggests the durability of the treatment effect may be similar. These studies did not perform a direct comparison of faricimab and aflibercept on the same personalized treatment interval protocol.
Remarkably, these limitations of the study were not discussed in the published article and the FDA granted approval of faricimab for use in the United States based on these data drawn from an imperfect study design that favored faricimab. More research is needed in order to determine if faricimab is truly non-inferior to aflibercept and whether faricimab may offer a reduced treatment burden.
UPDATE Oct 2022: I have been using Vabysmo in the office. I am please with the results in patients with wet AMD in that I can extend the treatment interval further than with older drugs. However, patients with large serous pigment epithelial detachments (PED) appear to be at greater risk of vision loss from rips in the PED. I have not been impressed with superior effectiveness of Vabysmo in patients with diabetic retinopathy.
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