For this month's Retina Minute, I have the pleasure of interviewing my dear friend, Professor Gemmy Cheung, who is chairman of the medical retina department at Singapore Eye Hospital.
Professor Cheung, recently at Angiogenesis and Macula Society, you presented first-time data from the SALWEEN study. Can you explain to our readers what the study is?
We learned about the efficacy and safety of faricimab (Vabysmo, Genentech) in neovascular age-related macular degeneration from the TENAYA and LUCERNE trials, but the inclusion and exclusion criteria in those trials did not specifically say anything about polypoidal choroidal vasculopathy (PCV). The studies included clauses that excluded eyes with large hemorrhages involving the fovea, which are common features in patients presenting with PCV. As a result, we saw few cases with PCV when we looked at the post-hoc analysis for TENAYA/LUCERNE. There were less than 40 cases in total, which meant we were not able to draw a conclusion about the efficacy and safety of faricimab for PCV from TENAYA and LUCERNE. SALWEEN is studying an open-label use of faricimab in patients diagnosed with PCV. It is a trial in eight to nine regions across Asia, and 135 patients have already been recruited. The trial is ongoing, and as you said, we are excited about the presentation of the week 16 data.
Can you explain the trial design?
The design follows what was used in TENAYA/LUCERNE. It is a single arm, open label study, so all patients received faricimab. Every eye received four initial monthly injections at baseline and weeks 4, 8, and 12, and then they were assessed at week 16. Patients also had disease activity assessments at weeks 20 and 24, and they continued according to the Q16-week interval if they did not show any disease activities. Those who developed disease activity at week 20 were dropped to Q12 weeks or Q8 weeks—the shortest retreatment interval—which is also similar to TENAYA/LUCERNE. The primary endpoint is the average of weeks 40, 44, and 48, again similar to TENAYA/LUCERNE. We are continuing the second year of the study with a treat-and-extend protocol.
To clarify, the longest patients could be extended in year 1 was 12 or 16 weeks?
Sixteen. The shortest is 8 weeks
In year 2, what is the longest patients can be extended?
20 weeks.
How does SALWEEN define disease stability?
It is a combination of best-corrected visual acuity (BCVA) and central subfield thickness (CST), as well as any evidence of new hemorrhage. If any of those criteria are met, the interval is dropped down.
What did you find?
Baseline characteristics have been in keeping with what we commonly see in PCV. The baseline age was in the 70s, with a male predominance. In terms of BCVA, patients started off with 64 letters, which is quite high. CST was just over 400 μm, which was also as expected and demonstrated presence of disease activity.
Jumping to week 16, we saw a BCVA gain on average of slightly more than seven letters. Considering the relatively high starting BCVA, I think that result is encouraging. We also saw a robust reduction in CST after the first four injections, and a reduction in the proportion of patients without subretinal or intraretinal fluid.
We were particularly interested in looking at the polyp closure rate, which was rated according to indocyanine green angiography (ICG). The rate at week 16 currently stands at 51%, which is one of the highest based on previous studies that reported using a monotherapy approach.
We also had another anatomical criterion called inactivation of polypoidal lesion, meaning either there were no polyps on ICG or polyps were accompanied by activity, which we observed with a combination of ICG and OCT. We had two types of confirmation in ICG grading, and based on the criteria, the grading was determined by the investigators. All 135 eyes were analyzed. We will also have a reading center confirmation analysis, so we will see if there is agreement between the investigators and the reading center.
Based on those two criteria, we found that more than 80% of eyes had no active polyps. It was reassuring that disease activity was well controlled. We look forward to the later primary endpoint data to see if this result will be sustained or even increase. We will also look at the proportion of eyes in the retreatment interval.
Although the ICG anatomic endpoint is important, it was not used in your decision-making tree to extend or not, correct?
Correct.
What percent of patients are considered stable enough to start extension? And when you do extend, do patients who received treatment every 4 weeks extend to 8 weeks, or do you jump to 12 weeks?
If they did not show any disease activity, they stayed on Q16 weeks. Nonetheless, from a clinical perspective, there is a debate of the significance of ICG closure. As you said, in the trial we did not actually use the ICG finding to determine whether we would drop the interval, but we could extrapolate early closure as early as week 16. Patients were most likely to have a higher chance of maintaining stability and have a lower risk of reopening. This is where we are going to see whether the closure rate is at least as good as it was at week 16 when we use a less frequent retreatment interval. It will also reflect in the proportion of eyes that can stay on a long retreatment interval. Assuming there is some polyp activity—either persistent activity or reopening—we would expect that visual acuity will not be as well maintained.
You started by saying there was a small percentage of patients with PCV in the original TENAYA and LUCERNE studies. Did they respond like you have seen in SALWEEN so far? Is there head-to-head cross-trial comparison that shows agreement, or was there a difference in how they responded at the same point in time?
In TENAYA/LUCERNE there were slightly less than 40 patients, and less than 20 were allocated to the faricimab arm vs the aflibercept (Eylea, Regeneron) arm. We cannot read too much into such small subgroups, but in terms of BCVA and CST response, as well as the proportion of patients who were maintained on the longer retreatment interval, those subgroups behaved similarly, if not numerically even more favorable compared to the overall non-PCV group. Overall results seem to be in keeping with the BCVA and CST data that we see now in SALWEEN. Of course, we did not have the ICG grading based on the subgroup analysis in TENAYA/LUCERNE, which is added in SALWEEN.
As we look at SALWEEN going forward, when can we expect the 12-month primary output to be at least fully enrolled and then possibly presented?
It should be sometime this year.
Assuming this medicine shows what we think it will show, where does that play a role in your treatment of patients with PCV?
I think over the past 10 or 15 years, at the time of the EVEREST-II trial when ranibizumab (Susvimo, Genentech) was the agent of choice, we started off being quite procombination when initiating treatment. Subsequently, with the aflibercept trials, I think we saw a shift in the paradigm toward monotherapy being more commonly accepted. However, one bugbear about monotherapy is the need to maintain retreatment, and we always worry about disease recurrence, especially if we have not achieved polyp closure.
I think where the SALWEEN study data can fill the gap is continuing to build our confidence in monotherapy with anti-VEGF, and acceptance from clinicians and patients to use faricimab as the primary or the first-line therapy for PCV helps with our confidence of long-term maintenance of vision gains with less retreatment and longer retreatment intervals.
We know that faricimab is not a simple anti-VEGF. It has the additional property of anti-Ang 2, which is a new area that we are exploring. We have quite a lot of anatomical analysis going on, including OCT angiography. We also hope to look into any new biomarkers that suggest there may be some vascular stabilization in terms of PCV structure.
This is great information. I have watched you give lectures on PCV over the years, and it is interesting how our paradigm has, like you said, shifted away from photodynamic therapy toward the anti-VEGFs that now are lasting longer. Although I do not see many cases where I live, there are many places in the United States and around the world where PCV is a persistent problem, and these early results give us encouragement. Thank you for making the time.
It was my pleasure. Thank you.
This editorial content was supported via unrestricted sponsorship.
