100-week results of KESTREL, KITE push brolucizumab toward FDA approval

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Dr. Carl Regillo discusses the 100-week results of KESTREL and KITE, two pivotal Phase 3 studies for brolucizumab for the treatment of diabetic macular edema.

At the Angiogenesis, Exudation and Degeneration meeting, Carl D. Regillo, MD, presented his talk, “Brolucizumab for the Treatment of DME: 100-Week Results from the Two Pivotal Phase III KESTREL and KITE studies.”

Video transcript

David Hutton: I'm David Hutton of Ophthalmology Times. The Bascom Palmer Eye Institute at the University of Miami is hosting its Angiogenesis, Exudation and Degeneration 2022 virtual edition. Joining me today is Carl Regillo, MD, who is presenting brolucizumab, for the treatment of DME: 100-week results from the two pivotal Phase 2 KESTREL and KITE studies. Thank you for joining us today. Tell us about your presentation.

Dr. Regillo: Thanks, pleasure to join in here. I had the privilege of presenting the 100-week, or essentially two-year, results of the two pivotal Phase 3 KESTREL and KITE studies, which is for brolucizumab for the treatment of diabetic macular edema.

KITE and KESTREL are very similar global Phase 3 randomized clinical studies that compared brolucizumab to aflibercept for the treatment of DME. We’re all aware of the favorable one-year primary endpoint results. And what I presented here were the two-year results.

The KESTREL was very similar across the entire two-year timeframe. In this study, it was 3 or 6 milligrams of brolucizumab compared to aflibercept, on-label, with the brolucizumab having a loading phase of five injections dosed every six weeks, and then in the maintenance phase dosed either every eight or 12 weeks through Week 100, depending on disease activity. And then the aflibercept arm, of course, the standard five loading doses monthly. And then every eight weeks thereafter, and that stayed through the 100-week endpoint.

The KITE study was a little different. It started the same, in many ways, as KESTREL did. It was only 6 milligrams of brolucizumab versus aflibercept on-label; the aflibercept arm was the same. But here in the second year, starting week 72. In the KITE study design, there was the option based on the presence or absence of disease activities potentially, re-extend the treatment interval from eight to 12 weeks or 12 to even 16 weeks. So there's an extended dosing in the KITE by design in year two. Baseline characteristics among the arms of both studies were well balanced with no significant differences, as was the baseline diabetic retinopathy severity. Again, between the studies and between the treatment arms.

We know that brolucizumab was found to be non-inferior to aflibercept at the primary endpoint, which is 52 weeks, but now we have extended the two-year data out to week 100 for both studies, and the visual gains are well maintained compared to aflibercept over the entire study timeframe of both studies.

And that meant within just a couple letters, brolucizumab 6 milligrams versus aflibercept 2 milligrams all the way up to week 100.

And the same goes for disease control as measured by central subfield thickness. Looking at the OCT change from baseline, we see brolucizumab at 6 milligrams performing comparatively to aflibercept 2 milligrams throughout the entire study timeframe through year two. And this is with reduced dosing in the brolucizumab arm compared to aflibercept again in both studies.

In fact, there's trends particularly with the KITE study to have better drying. And in fact looking at the proportion of patients with effectively a dry macula, defined as central subfield thickness of less than 280 microns at week 52 and week 100. Despite lower numbers of injections with brolucizumab 6 milligrams, there's actually a higher percentage of patients, so numerically favoring brolucizumab compared to aflibercept at both weeks 52 and weeks 100 of both studies.

What we observed in terms of treatment intervals. Again, KESTREL was just the option of eight weeks versus 12 weeks, and at end of study week 100 in KESTREL, about 1/3 of patients on brolucizumab were being treated every 12 weeks. And in the KITE study nearly 50% were either 12 or 16 weeks with about a quarter, 24.8%, achieving in every six-week dosing interval. So extended even more in the second year in KITE for the 6 milligram arm.

We're looking at DRSS of course in these diabetic retinopathy studies, and again brolucizumab 6 milligrams compared favorably to aflibercept in terms of the proportion of patients gaining two or more steps in DRSS score at weeks 52 and weeks 100. In fact, some trends again with brolucizumab showing slightly higher percentages of two or more step improvement.

And then when it came to safety, brolucizumab’s overall safety profile at week 100 in both studies was very similar to what we've known in how brolucizumab has looked previously at the primary endpoint in both of these DME studies, and also comparable to the wet AMD studies. What we didn't see though were a lot of new cases of retinal vasculitis; there were some cases of vascular occlusion, but not related to inflammation or retinal vasculitis.

And so the year-two safety profile actually looked a bit more favorable compared to year one. Rates of interactive inflammation was about the same again; not a lot of new cases in year two. Came out to, in the 6 milligram arms, 4.2% for intraocular inflammation in the KESTREL study and 2.2%, in KITE, and that was compared to aflibercept at 1.1% in KESTREL to 1.7% in KITE. So there's actually very little difference in the IOI rates in the KITE study.

So in summary, the vision gains achieved with brolucizumab 6 milligrams in both KITE and KESTREL were very comparable to aflibercept all the way out now to week 100, despite fewer injections. Atomically, the 6 milligram dose performed very well; in fact, yielded higher percentages of patients with complete macular drying in these DME patients. And this was achieved with less dosing. In KITE 25% of patients approximately were able to be extended to 16-week treatment animals by the 100-week endpoint.

And with regards to overall safety, safety profile is similar to previous studies, both DME and wet AMD intraocular inflammation imbalance with higher rates, of course, brolucizumab that we’ve seen before, but very few new cases of inflammation and no new cases of retinal vasculitis or vascular occlusions.

David Hutton: Both of these are Phase 3, so what's the next step?

Dr. Regillo: So the next step is potential FDA approval. So these are registration studies for the indication of DME. Brolucizumab is FDA approved for the treatment of neovascular AMD, and this would sort of complete that process, potentially to be improved for this disease state.

David Hutton: And what can this mean for patients?

Dr. Regillo: Well, what brolucizumab looks to be doing here for DME is a bit better drying, which is important because that is correlated to better vision outcomes for some patients at least. So we had to have a drug that dries better for DME for our patients is potentially important as a way to get better vision gains. And it also looks to be a little more durable. And so potentially we can get better outcomes with less treatment.

Note: This transcript has been lightly edited for clarity.