This article was originally published in a sponsored newsletter.
For this month’s Retina Minute, I have the pleasure of interviewing my dear friend, Dr. Arshad M. Khanani, who is professor of surgery at the University of Nevada School of Medicine and Director of Clinical Research at Sierra Eye Associates, Reno, Nevada.
Dr. Khanani, at the recent ASRS meeting in Stockholm you presented some incredibly interesting first-time data on the extension of the YOSEMITE and RHINE studies called RHONE-X. Can you explain the original studies and how the extension was formatted?
Thanks, Dr. Singer. It is a pleasure to speak you about my recent presentation. As you recall, YOSEMITE and RHINE were the phase 3 trials that led to the approval of faricimab (Vabysmo, Genentech) for the treatment of diabetic macular edema (DME). In YOSEMITE and RHINE, we studied 2 different arms of faricimab treatment. The first arm was 6 mg Q8 weeks, where patients received 6 loading doses followed by fixed treatment with faricimab every 8 weeks. The second arm was faricimab 6 mg, treat and extend, where patients received 4 doses of faricimab, followed by a treat-and-extend regimen based on pre-specified central subfield thickness (CST) and BCVA criteria. Patients could be treated every 4 weeks, or up to every 16 weeks. The faricimab arms were then compared to on-label aflibercept 2 mg, which is Q8 weeks after 5 loading doses.
After YOSEMITE and RHINE were finished, patients had an opportunity to enroll in the RHONE-X extension study to evaluate the long-term safety and efficacy of faricimab treat and extend. RHONE-X is a phase 3 multicenter, open-label, long-term extension study. Every patient who completed either YOSEMITE or RHINE without discontinuation of the study treatment was included in this trial, and patients were followed for an additional 2 years. All patients from the 3 different arms that I discussed were rolled into faricimab treat and extend up to Q16 weeks in the RHONE-X study.
What was the retention rate?
It was 81.7%, which is impressive, in my opinion, because patients were not coming in just for evaluation. They were only coming in when their treatment was due, whether that was at 8, 12, or 16 weeks. There was much less treatment burden for patients, and I think that is why the retention was excellent.
What did the data show?
I think one of our most important findings was that the robust improvements in vision and CST that we saw in in YOSEMITE and RHINE with faricimab treatment were maintained in RHONE-X with faricimab treat and extend. More than 90% of patients had absence of DME by the end of RHONE-X, which is remarkable. But to me, the results for how patients did when they switched to faricimab treat and extend are the most interesting, especially the faricimab Q8-week group, and the aflibercept 2 mg (Eylea, Regeneron) Q8-week group. For the faricimab Q8-week group and the treat-and-extend group, 89% and 87% of patients respectively had absence of DME in YOSEMITE and RHINE. At the end of RHONE-X, 94% and 92% of patients respectively had no DME. They maintained absence of DME with less frequent dosing.
In the aflibercept 2 mg Q8-week group, 81.7% had absence of DME at the end of YOSEMITE and RHINE, and at the end of RHONE-X that number increased to 95.4%. These results highlight what we have seen in the real world where, once you switch patients with persistent disease activity from aflibercept 2mg to faricimab, approximately 15% more patients have absence of DME. All of this was achieved with 80% of patients on Q12-week dosing or greater.
These are impressive results. Were there any new safety signals? What safety signals were seen?
This is the first time in a large clinical trial setting that we are evaluating the long-term safety of faricimab and it was well-tolerated through years 3 and 4 in RHONE-X. There were no new safety signals in the nature of adverse events. Everything we saw was consistent with the YOSEMITE and RHINE parent trials without any cases of retinal vasculitis or occlusive retinal vasculitis.
Given the fact that a much larger number of patients were able to become dry in the aflibercept arm, were there any specific patient features that might preclude them from getting dry quicker when switched over, in terms of intraretinal and subretinal fluid?
That is a great question, and I think it is something to look into. We have seen, though, that in YOSEMITE and RHINE, patients who were treated with faricimab had faster clearance overall in terms of DME. We not only saw more patients without DME, but we also saw faster clearance of fluid with faricimab’s dual mechanism of action. However, this is the largest extension trial to date, and we have a lot to investigate that will be presented in the future.
Will there be further extension after 4 years?
No, after 4 years patients finished the study and there is no extension past that.
How does your significant experience with faricimab help you when you see your patients in clinic?
The last 2 years of real-world experience using faricimab in clinic, along with our work in TAHOE looking at its efficacy and safety for DME, have been notable and we are using faricimab as first-line treatment in our clinic. We have seen that patients who start treatment with faricimab get rapid improvement in anatomy and disease control with extension of treatment intervals beyond standard of care. Patients who switch to faricimab from other agents also have an anatomic and durability benefit. This trial has given us switch data to establish and confirm the benefit of faricimab’s dual inhibition.
In YOSEMITE and RHINE, 25% of the patients were previously treated. Was there any difference in any of the outcomes between this subset and the treatment-naive patients in RHONE-X?
We do not have that data yet, but it is something important to look into in the future. I think the totality of the data from YOSEMITE, RHINE, and RHONE-X can give confidence to clinicians who are already using faricimab because it confirms what we are already seeing in the real world. For clinicians who are not using faricimab, I think the RHONE-X data gives them a reason to start, especially in switch patients, to get the benefits of drying the retina and better disease control and durability.
Dr. Khanani, it is always great talking to you. You are at the forefront with new information that we can use literally the same day in our clinics. Thank you for sharing the extension data with us. I am excited to hear what is next in your pipeline.
Thanks, Dr. Singer. It is always a pleasure speaking with you.
