Interpreting the LUGANO Trial

Jay S. Duker, MD, discusses LUGANO’s missed primary endpoint, EyePoint’s ad hoc analysis of the data, and what the findings could mean for the ongoing phase 3 wet AMD program and Duravyu’s development in DME.

On August 17, EyePoint, Inc. reported topline results from the phase 3 LUGANO trial of Duravyu (vorolanib intravitreal insert, or EYP-1901) for neovascular (wet) age-related macular degeneration (AMD). LUGANO, the first of 2 pivotal phase 3 trials in the company’s wet AMD program, did not meet its primary endpoint of noninferiority to on-label aflibercept 2 mg (Eylea; Regeneron) for change in best-corrected visual acuity in the full analysis population. However, EyePoint reported a 42% reduction in treatment burden and said an ad hoc analysis excluding 9 Duravyu-treated patients who lost at least 15 letters for reasons considered unrelated to wet AMD met the prespecified noninferiority criterion. Topline results from LUCIA, the second phase 3 trial, are expected in the fourth quarter of 2026.

Jay S. Duker, MD, president and chief executive officer (CEO) of EyePoint, spoke with Retinal Physician about the trial results, the patients who lost vision for non–AMD-related reasons, the outlook for LUCIA, and the implications for regulatory program.

The following transcript has been edited for clarity.

I’m Jay S. Duker, MD, president and CEO of EyePoint, Inc. Today, I’m going to talk about the LUGANO trial, which is a phase 3 pivotal trial testing the vorolanib intraocular insert, known as Duravyu, in wet age-related macular degeneration (AMD).

Retinal Physician: What are the key findings and takeaways from LUGANO?

Dr. Duker: The most important takeaway from the trial is that in patients with wet AMD, Duravyu worked. LUGANO was the first phase 3 trial that compared a sustained-release tyrosine kinase inhibitor (TKI) to on-label standard of care. We were able to show that in the majority of patients, their wet AMD disease was well controlled on Duravyu, with significantly fewer injections and a favorable safety profile.

The other really important take-home message is that the anatomic control in the eyes that received Duravyu was strong. At the end of the study, at week 56, there was only a 4-µm difference between Duravyu and on-label aflibercept 2 mg.

The safety was also clean. There were no significant differences between the study arm and control arm in issues like cataract, elevated intraocular pressure, or intraocular inflammation.

The reduction in treatment burden between Duravyu and the control was 42%. This corresponds to the possibility of patients with wet AMD having 2 fewer injections per year if Duravyu is approved, with continued anatomic control and, hopefully, visual stability.

Retinal Physician: LUGANO did not meet its prespecified primary endpoint in the full dataset, but EyePoint has highlighted an ad hoc analysis that excludes 9 Duravyu-treated patients who lost at least 15 letters for reasons the company says were unrelated to wet AMD. Can you walk us through what happened in those 9 patients and the basis for determining that their vision loss was unrelated to wet AMD or inadequate disease control?

Dr. Duker: While the primary visual acuity endpoint was not met in the full analysis set, driven by an imbalance of patients who lost vision from causes unrelated to wet AMD, the broader dataset tells a consistent story. Prespecified secondary endpoints, supportive analyses, and the safety and durability profile all point in the same direction. This is also consistent with what we observed in our phase 2 DAVIO 2 trial, which did meet its primary endpoint.

The 9 patients who lost vision for non–wet AMD reasons included 6 patients who had good anatomic control of their wet AMD but lost vision due to geographic atrophy, or dry AMD. Two patients lost vision from severe glaucoma. One patient had a retinal detachment that, while successfully repaired, resulted in the patient developing a significant cataract and an epiretinal membrane following the repair of the detached retina.

However, in all of these cases, retina specialists who examined the OCTs and the results of the treatment agreed that the eyes primarily, or almost exclusively, lost vision for non–wet AMD reasons.

Retinal Physician: The patient population in LUGANO was broader than in DAVIO 2 because it included both treatment-naïve and previously treated patients. What have you learned so far about how Duravyu performed across these different patient populations?

Dr. Duker: In DAVIO 2, all the patients were not naïve. They had received prior treatment. In DAVIO 2, the number of injections leading into the trial suggested that these were a very tough-to-treat population. In LUGANO and in the second trial, LUCIA, we enrolled 75% treatment-naïve patients and 25% treatment-experienced patients.

The results from a visual acuity perspective were similar in both arms. But once again, if you take away those 9 outlier patients, then the results would show noninferiority among all of the dataset.

If we go back and look at the DAVIO 2 data and ask the question, “How many eyes in the aflibercept group at week 56 lost 15 letters?” the answer is 7.7%. In LUGANO, it was only 0.5%. This represents an order of magnitude less than essentially all the reported phase 3 trials that included 2-mg Eylea on label. Generally, we expect a 4% to 5% rate of 15-letter losers.

In DAVIO 2, the phase 2 trial, in the treatment arm only 4.3% lost 15 or more letters. So again, in DAVIO 2, the trend for worse visual acuity was actually in the Eylea arm. So this huge difference that came to be in the LUGANO trial came as quite a surprise to us based on DAVIO 2.

Retinal Physician: With LUCIA using a similar design, what does the LUGANO data mean for how you are thinking about the second trial, as well as the potential regulatory path for Duravyu?

Dr. Duker: The LUCIA trial enrolled a very similar patient population, although the trial was slightly larger, at 475 patients. But the protocol is essentially identical.

Given the investigations that we have done into the eyes that lost vision of 15 letters or more in the LUGANO trial, we believe that this occurred primarily due to a mismatch in the location of the GA at the start of the trial. We have shown data from the LUGANO trial that the reading center noted more patients with new GA in the control arm than in the Duravyu arm at the end of the trial, giving strong evidence to the notion that vorolanib does not lead to increased GA. In fact, there’s no physiologic reason to believe that it would.

Given that data, we are quite optimistic about the LUCIA results, especially in light of all the secondary endpoints, which look so promising for our drug. We are confident that the LUCIA data will show that our drug can be a real game changer for patients with wet AMD, the hope being that they can maintain their vision and their anatomy for the long term with fewer injections.

Retinal Physician:What additional LUGANO analyses will be most important for retina specialists to see when the full dataset is presented?

Dr. Duker: I think the most important result, frankly, is the LUCIA result. If LUCIA shows a regression to the mean in 15-letter losers, then we would be confident that our drug would be shown to be noninferior. So, even without continued analysis in LUGANO, which we intend to do and report, the LUCIA data really is what we’re looking forward to.

I mentioned already that the reading center identified that the patients who started with GA appeared to have it closer to the fovea in the Duravyu eyes than in the control eyes. We expect to be able to report that officially in an upcoming release and quite possibly at the Retina Society [meeting in mid-September].

We have already reported that the reading center showed that there was no increased rate of new GA in the Duravyu eyes. We will take a look at things like fibrosis and the integrity of the outer retina, all of the things that our reading center has measured and is in the process of providing for us. So some of these additional analyses, I think, should make physicians more comfortable that this was probably due to chance alone. But ultimately, the result of the LUCIA trial will drive us forward.

Retinal Physician: What haven’t I asked about the Duravyu trials that retina specialists should know?

Dr. Duker: I’m going to answer that in 2 ways. The first thing we didn’t talk about is diabetic macular edema (DME). We also have 2 DME studies ongoing [COMI and CAPRI], which should read out in a little over a year. We’re very optimistic about DME, based not only on the phase 2 VERONA trial, but also on the safety profile and the control of fluid that we saw in LUGANO. I think this speaks very well for our drug in DME.

But the other thing I think we should think about is, if one were a retina specialist and were offered a drug for their patients that could result in 2 fewer injections, with the potential of long-term, every-6-month dosing and stable anatomy and stable visual acuity, I think the majority of my colleagues would be very excited to use a new medication like that.