Impact of Disease Activity Criteria on Dosing Interval Assignment in Clinical Trials in nAMD

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EP: 1.Impact of Disease Activity Criteria on Dosing Interval Assignment in Clinical Trials in nAMD

Marco Zarbin, MD, PhD, FACS: Hi, my name is Marco Zarbin and on behalf of my coauthors, Christina Weng, Audrey Souverain, Ivaylo Stoilov, and Philippe Margaron, I’d like to present a talk titled “An Assessment of the Impact of Disease Activity Criteria on Dosing Interval Assignment in Clinical Trial Patients with Neovascular AMD.”

This is a presentation that we made at the ASRS [American Society of Retina Specialists] meeting in the fall of 2023. The take-home message of this talk is that the definition of active disease in clinical trials affects the estimates of the durability of the agents that are tested in those trials.

As I think we all know, of necessity, treatment decisions in clinical trials have to be driven by specific disease activity criteria. Now I think for most of us in practice, we judge the presence of active neovascular AMD [age-related macular degeneration] to exist if there’s a loss of vision or if there’s increased disease activity on the OCT [optical coherence tomography] or if there’s a presence of new macular hemorrhage.

Unfortunately, different disease activity criteria have been used in different trials, which complicates our ability to compare the durability of different agents tested in different clinical trials.

So, for example, in the Phase II CANDELA trial, 2 mg aflibercept was compared with 8 mg aflibercept and disease activity assessments were done at weeks 24, 28, and 36, and 40.

And in this trial, active disease was judged to be present and thus mandating an injection if there was either a loss of vision of 5 or more letters or if there were anatomic findings that were considered to be vision threatening. And in contrast, in the Phase III PULSAR trial, where 2 mg aflibercept every 8 weeks was compared with 8 aflibercept every 12 weeks and 8 aflibercept every 16 weeks, disease activity assessments were done at weeks 16, 20, and 24. But in this trial, active disease was judged to be present if there was both a loss of vision of more than 5 letters and a change in the OCT or new macular hemorrhage.

And it may not be surprising that the durability estimates were not the same. In CANDELA, where either a change in vision or a change in anatomy mandated an injection, about 53% of the patients could be maintained with injections every 12 weeks, whereas in the PULSAR trial, where both a change in vision and a change in anatomy were required to mandate an injection, durability increased such that 83% of the patients could be maintained with injections every 12 weeks or longer.

Well, in TENAYA and LUCERNE, which were the registration trials for faricimab, 2 mg aflibercept every 8 weeks was compared with faricimab 6 mg, and disease activity assessments were done at weeks 20 and 24. In this trial, active disease was judged to be present if there was either a loss of vision or a change in the OCT or a new macular hemorrhage. And using these criteria, by year 2, about 80% of the patients on faricimab could be maintained with dosing intervals of every 12 to 16 weeks.

In this trial, it turned out that the change that most frequently mandated injection was a change in the OCT, which was the case for about 70% of the time that injections were administered. But about a quarter of the time, it was a change in vision that indicated the presence of active disease, and about 10% of the time, it was a presence of new macular hemorrhage.

My point, though, is that if any one of the above events occurred at weeks 20 or 24, clinicians administered faricimab treatment as each event independently indicated the presence of active neovascular AMD.

Well, we wondered, what would the durability of faricimab be if we changed the disease activity criteria such that both a change in vision and a change in OCT were required to mandate an injection using the criteria employed in the PULSAR trial? And this was a post hoc analysis of the TENAYA and LUCERNE data, recalling that in TENAYA and LUCERNE either a change in vision or OCT or new macular hemorrhage resulted in 78% of the patients being maintained at injection intervals of 12 to 16 weeks.

In contrast, when we required both a change in vision and a change in OCT, the durability seemed to increase such that 96% of the patients could be maintained with injections every 12 to 16 weeks.

So just by changing the disease activity criteria, we changed the estimate of the durability of faricimab.So in TENAYA and LUCERNE, the disease activity criteria, which was either a change in vision or anatomy, requiring an injection, I think more accurately reflect routine clinical practice. And as we found in the trial and as I think is the case in practice, the majority of the time, the change in disease activity criteria that mandates the injection is a change in the OCT.

Now when we apply the requirement that both a change in vision and a change in anatomy are needed in order to maintain to mandate an injection, we increase the assignment to longer dosing intervals. And this was observed both in TENAYA and LUCERNE, where we moved from 78% to 96% of the patients being maintained with injections every 12 to 16 weeks just by requiring change in anatomy and vision, as well as in the CANDELA and PULSAR trials.

I think that criteria that reflect real-world clinical practice increase the likelihood of clinical trial results being reduced in our clinical practice. Thank you for your attention.

Transcript is AI-generated and edited for clarity and readability.