This transcript has been edited for clarity.
My name’s Veeral S. Sheth, MD, MBA, FACS, FASRS. I’m a retina specialist in Chicago, and I’m excited today to talk about the COMO and CAPRI trials, which are phase 3 clinical trials looking at Duravyu (EyePoint Pharmaceuticals), a tyrosine kinase inhibitor (TKI) in diabetic macular edema (DME) patients.
Retinal Physician: Can you briefly describe the structure of the COMO and CAPRI trials—who’s being enrolled, how the study arms are structured, and the main goals of the trials?
Dr. Sheth: The COMO and CAPRI trials are large phase 3 clinical trials looking at patients who have diabetic macular edema. The goal of the study is really to look at Duravyu, which is the only tyrosine kinase inhibitor in development for diabetic macular edema patients. We’re looking to administer Duravyu every 6 months and see if it can achieve similar visual outcomes to on-label aflibercept (Eylea; Regeneron) while treating our patients well in terms of vision, best-corrected visual acuity (BCVA), and central subfield thickness (CST), and looking at an overall reduction in treatment burden.
If we look at why these trials are structured this way, we’re really looking at a regulatory pathway. We’re looking at satisfying US Food and Drug Administration (FDA) regulations and making sure we can get these TKIs to our patients.
The trials themselves have 2 arms. One patient arm is going to get the investigational product, Duravyu 2.7 mg, which is the TKI. They’ll get that at the beginning of the study and every 6 months. They are going to be compared to patients receiving aflibercept every 8 weeks, and both groups will receive loading doses of aflibercept as well. The treatment group receiving Duravyu will get 3 doses of aflibercept: day 1, week 4, and week 8. The comparator arm will get aflibercept every 4 weeks for 5 loading doses. Both groups can get supplemental aflibercept along the way. Just to be clear, aflibercept is the 2 mg dose that will be used in this trial.
In terms of enrollment, each trial will enroll approximately 240 patients who will be randomly assigned to 1 of these 2 groups. The primary endpoint for this study is noninferior change from baseline in BCVA, with a blend between weeks 52 and 56, vs the aflibercept control group. The secondary endpoints include safety, superiority and reduction in treatment burden, the percentage of eyes free of supplemental aflibercept injections, and anatomic results as measured by OCT.
The DME program is informed by the positive phase 2 VERONA study, where we saw DME patients treated in this fashion. That helped inform the structure of this phase 3 trial.
RP: Duravyu targets VEGF, PDGF, and IL-6 pathways. How do these combined mechanisms translate into potential clinical benefits for patients with DME?
Dr. Sheth: One question that comes up is that we already have great treatments for DME. Why do we need to look for more treatments? I agree that we do have very good treatments, and the bar has been set high with some of our anti-VEGF therapies.
But what we’ve seen consistently through many studies over time is that not all patients respond to anti-VEGF therapy. In many studies, 40%, 50%, or even 60% of patients still have residual fluid despite frequent anti-VEGF therapy or require a high treatment burden. Because of that, we’re looking for different mechanisms of action and different levels of durability in our treatments.
Duravyu is one example of that, with TKIs having a broad targeting effect. Duravyu targets VEGF, PDGF, and IL-6 pathways, and we know each of those pathways can play a role in vascular permeability, leakage, and neovascular changes. It’s important to look at these alternate mechanisms of action to address the needs we still have for our patients.
The results of the VERONA trial demonstrated early and sustained vision and anatomic improvements. We often see treatments work well initially but have durability issues where the treatment effect runs out with traditional approaches. With Duravyu, we saw that it worked early and that the effect was prolonged. So, one of the aspects is this prolonged, consistent therapeutic approach. That’s different from what we do today with standard anti-VEGF treatments, where we give a bolus injection and then follow a treat-and-extend approach. Giving something that works quickly and lasts for a long time makes sense in patients with chronic disease who need consistent disease management.
When we look at durability, a consistent release of treatment may minimize fluctuations in the anatomy of these patients. When we treat with a bolus of anti-VEGF, we see a nice anatomic response and drying effect. But as the medicine wears off, we start to see fluid come back, and that can have an effect on vision, retinal structure, and long-term visual outcomes. With Duravyu’s longer-acting approach and more consistent therapeutic effect, we see less of that “see-saw” fluctuation that can occur with traditional bolus therapy.
RP: What insights do investigators hope to gain by enrolling both treatment-naïve and previously treated patients?
Dr. Sheth: In clinic, we see patients every day who are coming in for routine repeat care for DME, but we also see brand-new patients with DME. So, when we’re investigating treatments, we want to understand how they work for patients who have been treated in the past and also for those who have never been treated.
In the real world, when newer treatments become available, we often initiate these therapies first in patients who have already been treated. These are frequently more difficult-to-manage patients. We've been treating them with standard anti-VEGF therapy, but we're looking for something more—maybe they require a lot of treatment and we want to reduce the treatment burden, or maybe we’re not getting the drying effect we want from standard anti-VEGF therapy alone. This is where newer medications with different mechanisms of action can help, to see how these patients can do.
It's important in clinical trials to evaluate both patient populations—those previously treated and those who are treatment-naïve—because sometimes they do behave differently. Results from both groups will inform how we use these treatments in the real world.
RP: What would it mean for clinicians to have a TKI as an option for treating exudative diseases such as wet AMD and DME?
Dr. Sheth: Any treatment that comes out today, whether it’s an anti-VEGF, a dual-mechanism therapy, or a TKI, needs to be usable broadly across our patient population. That includes 2 of the most common diagnoses we see every day: DME and neovascular AMD. I'm glad that with Duravyu, we’re looking at phase 3 programs in both nAMD and DME. Our choices are becoming more numerous, and the simplicity of using one treatment for multiple indications is important.
Hopefully we’ll see the phase 3 data from the nAMD studies, as well as from the COMO and CAPRI studies for DME, read out in a way that allows us to get these treatments into our hands and into the hands of our colleagues. RP
