Durable Intravitreal Treatment of DME: Phase 3 YOSEMITE and RHINE Trials
Bispecific antibody demonstrates promising efficacy and safety at one year in ongoing pivotal trials. Cheryl Guttman Krader reports
Bispecific antibody demonstrates promising efficacy and safety at one year in ongoing pivotal trials. Cheryl Guttman Krader reports. The two pivotal phase three studies investigating two different dosing regimens of faricimab (Roche) for treatment of centre-involved diabetic macular oedema (DME) met their primary endpoints at one year. The studies showed mean BCVA gains were noninferior in eyes treated with the novel bispecific antibody inhibitor of VEGF-A and angiopoietin-2 (Ang-2) compared to aflibercept (Eylea, Regeneron) injected every eight weeks.
The one-year results also showed durability of the faricimab treatment benefit with a dosing interval of up to 16 weeks, better anatomic outcomes with faricimab versus aflibercept, and no safety signals for faricimab, said John A Wells MD, reporting findings from the YOSEMITE and RHINE trials at the virtual ARVO 2021 meeting.
“YOSEMITE and RHINE are ongoing, 2-year studies, and an additional two-year extension study, RHONE-X, will give us up to four years of data in the future. It will be important to see how many eyes that have achieved a 16-week dosing interval at one year maintain a durable response,” explained Dr Wells, a retina specialist in West Columbia, South Carolina, USA.
Together YOSEMITE and RHINE enrolled a total of 1,891 patients at 353 sites worldwide. Eligible patients were adults with centre-involved DME (central subfield thickness [CST] ≥ 325 μm) and BCVA ranging from 73 to 25 ETDRS letters (Snellen equivalent ~20/40 to 20/320). Patients with either treatment naïve or previously treated DME were eligible, although the latter patients had to undergo a three-month washout period and were capped at 25% of the total enrolment.
Patients in each study were randomised equally into three groups to receive faricimab 6 mg every eight weeks (Q8W) after six monthly doses, faricimab 6 mg administered on a personalised treatment interval (PTI), or aflibercept 2 mg Q8W after five monthly doses. Dr Wells explained PTI is a treat and extend concept in which patients receive monthly dosing (minimum of four doses) until DME resolves (CST <325 microns). Then the dosing interval is increased in four-week increments up to Q16W as long as the CST and vision are stable. The interval is maintained if CST worsens and reduced if both CST and BCVA worsen. The three arms in both studies were well-balanced at baseline with respect to both patient and ocular characteristics. Mean BCVA was about 62 letters (Snellen 20/63), mean CST ranged from 465 to 495 μm. Some 50% of eyes had mild to moderate nonproliferative diabetic retinopathy and less than 10% had proliferative diabetic retinopathy. The primary endpoint for the two studies analysed mean change in BCVA from baseline averaged over weeks 48, 52, and 56. More than 90% of patients in all treatment arms completed the primary endpoint. The results showed mean BCVA gains in the faricimab Q8W, faricimab PTI, and aflibercept arms were 10.7, 11.6, and 10.9 letters, respectively, in YOSEMITE and 11.8, 10.8, and 10.3 letters, respectively, in RHINE. In both studies, approximately 30% to 35% of eyes in all groups showed a BCVA gain at least 15 letters while just 1% to 2% of eyes lost 15 letters or more. “Importantly, a similar proportion of eyes in the PTI arms gained at least 15 letters despite receiving less frequent dosing. In addition, the data showing that very few patients on PTI lost more than 15 letters indicates that less frequent dosing with faricimab was not harmful,” Dr Wells said. The durability of the response to faricimab was assessed based on the proportion of patients being dosed at 4-, 8-, 12-, and 16-week intervals at week 52. The results were similar in both studies and showed that just over 50% of eyes achieved the Q16W dosing interval and another 20% were being maintained with faricimab dosing Q12W. “Approximately two-thirds of patients in the PTI arms achieved Q12W week or Q16W dosing without dropping below Q12W dosing through week 52,” Dr Wells added. In both studies, faricimab-treated eyes showed greater decreases in mean CST compared with aflibercept-treated eyes. More eyes treated with faricimab than with aflibercept achieved CST < 325 microns (80% vs. 70%), and more faricimab-treated eyes had resolution of intraretinal fluid at week 56 (~45% vs. ~25%). Subretinal fluid was present at baseline in about one-third of eyes in all treatment arms and was completely resolved at week 56 in nearly all eyes. “Less frequent dosing of faricimab was not associated with a lesser anatomic effect,” Dr Wells said. A key secondary endpoint analysis of Diabetic Retinopathy Severity Scores showed that approximately 45% of eyes in all faricimab arms achieved a two-step or better improvement from baseline. Rates of ocular and systemic adverse events, including Anti-Platelet Trialists Collaboration events, were similar in all groups in both studies, and serious ocular adverse events were infrequent. “In the wake of brolucizumab, it is notable that the rate of inflammatory adverse events with faricimab was less than 1%, and the rate of endophthalmitis was also less than 1%. No cases of retinal vasculitis were reported and five cases of retinal venous or arterial obstruction were reported across all study arms at one year,” Dr Wells said. Jack Wells: (803) 931-0077 (Office); firstname.lastname@example.org