This article was originally published in a sponsored newsletter.

For this month's Retina Minute, I have the pleasure of interviewing my good friend Dr. Jerry Brown, who is currently a partner physician at Retina Consultants of America in Texas.

Dr. Brown, recently at AAO Subspecialty Day, you presented new data on the ELEVATUM study. Can you tell our readers what the study was, how it was designed, and what it showed?

All of us in retina see diabetic retinopathy every day. Often, underrepresented minorities seem to have worse disease: more aggressive retinopathy, worse macular edema, more exudates, and often poorer outcomes. Unfortunately, in a lot of the clinical trials, the numbers of these patients are small. Genentech recently set a goal to increase the number of underrepresented minorities in research. One part of their strategy was to design a study of diabetic macular edema to boost the numbers of patients in their database who have this condition and to measure those patients’ response to faricimab (Vabysmo, Genentech). The study enrollment goal was 45% African American patients, 45% Hispanic Latino patients, and 10% American Indian Pacific Islander/Native Hawaiian patients.

While there were a lot of concerns in the beginning with this study—from enrollment numbers to compliance—the study filled quickly, and 87% of patients completed all required visits.

How long was the study?

It was one year. Genentech has made the decision to do an extension study, which I can describe later.

Great. Tell us how the trial was designed.

ELEVATUM was an open-label, single-arm study that was designed to treat everybody with 6 introductory monthly injections, followed by Q8-week injections for a year, and a final visit at 1 year. Results from the trials were consistent with what we saw in YOSEMITE and RHINE.

What is great is that most patients want to continue to the extension study, which will be the personalized treatment interval. They will be allowed go as long as 24 weeks for the second year to see how many patients can extend and how their vision is after this protocol.

So, to summarize, the ELEVATUM study focused on the fixed dosing arm of the faricimab trial. What were the criteria to get into the trial? Could patients be treatment-naïve, or did they have to be previously treated?

Patients had to be treatment-naïve for ELEVATUM. That was one difference from YOSEMITE and RHINE, where there was a certain percentage that could be wash-outs.

What were the results?

The results were amazing. Hispanic patients' CST were 491.1 μm at baseline. Black patients' CST were 467.4 μm at baseline. However, while the Hispanic patients started out with worse vision and thicker retinas, they also did the best at the end of the study: They gained up to 14 letters at the end of year 1, which was even better than the overall gains in YOSEMITE and RHINE. Hispanic patients also achieved the best drying effect by the end of the study.

African American patients gained an average of 11.3 letters from baseline at one year and had less gain in terms of drying, but they also did not have as much to gain because their baseline retina was not as thick as the other groups.

Where was most of the increase in vision and the decrease in swelling seen in these patients? Was it seen early in the 6-month loading phase, or was it stepwise?

It was early, and that was the exciting thing: Within the first 3 injections, most of those gains in both thickness and visual acuity occurred.

Another interesting thing was staging in terms of the diabetic retinopathy severity scale (DRSS). Hispanic Americans had 2 steps of improvement, which was the best improvement seen in all groups. That also happened early: Within the first 20 weeks, 40% of the patients had gained 2 DRSS steps, and that improvement continued to the end of the study, where it concluded at 41%.

This is amazing data. Can you tell us about the safety of faricimab in this patient population?

Yes, the safety basically behaved the same way it did in YOSEMITE and RHINE. There were only 3 cases of intraocular inflammation—iritis, specifically—and they were deemed mild by the investigators. Those patients received treatment for the inflammation and stayed in the study. There were no cases of vasculitis, and out of 124 patients from 40 sites, there was only one case of endophthalmitis.

How about APTC (Antiplatelet Trialists’ Collaboration) events?

Fortunately, there were no APTC events in the study.

African Americans tend to have higher incidences of IOP-related complications. Was that trend seen in this population?

I do not have the number of IOP related events available at this time, but this important adverse event will be studied further.

Interestingly, African American patients had higher systemic blood pressure, which was seen in YOSEMITE and RHINE as well, so I am looking forward to analyses that will dive further into the interplay of those systemic factors.

Something else that I found exciting was the frequent aqueous humor taps performed throughout the study. After the first top-line data that I presented at AAO, we will be looking at aqueous humor, different cytokine levels, and differences in the genetics of VEGF receptors. There is much more to come from this study.

Fascinating. You mentioned that in year 2 of the extension trial, patients will be on personalized treatment regimens. What are the requirements to be extended and what are the requirements to be contracted?

The extension criteria from YOSEMITE and RHINE will be used for this extension trial. In short, it is either increasing fluid or decreased vision. The one difference is that patients can extend out to 24 weeks here while YOSEMITE and RHINE only went out to 20 weeks.

Dr. Brown, this sounds like amazing data. Showing that this significantly understudied population has so much potential for improvement encourages us, as a specialty, to do a better job in identifying this patient population sooner and treating them aggressively.

Yes, to that point, a previous study found that African Americans actually responded more poorly to a single injection of bevacizumab (Avastin, Genentech).¹ However, in practice, insurance requirements often force us to use bevacizumab as the initial treatment. This data emphasizes that if we can get these patients onto a more effective agent—such as faricimab—earlier in their treatment course, we can get good results.

This is important data because we have a tendency to treat everybody the same, but it sounds like there may be subpopulations that are even more exquisitely sensitive to our second-generation medications. Hopefully, we can use this data to help our patients get better medicine sooner. Thank you for your insights, Dr. Brown.

I agree. Thanks for having me, Dr. Singer.

Reference:

1. Osathanugrah P, Sanjiv N, Siegel NH, Ness S, Chen X, Subramanian ML. The impact of race on short-term treatment response to bevacizumab in diabetic macular edema. Am J Ophthalmol. 2021 Feb;222:310-317. doi:10.1016/j.ajo.2020.09.042

Michael A. Singer, MD Dr. Michael Singer is a board-certified Vitreoretinal Specialist and Director of Clinical Research at Medical Center Ophthalmology Associates in San Antonio, TX. He is currently the Clinical Professor of Ophthalmology at the University of Texas Health Science Center in San Antonio.