Drs Eleonora M. Lad, David R. Lally, Jaynath R. Sridhar, and Nancy M. Holekamp discuss pegcetacoplan dose frequency in treating geographic atrophy.
Eleonora M. Lad, MD, PhD: Given these exciting results, what are your thoughts on the frequency of administration, monthly vs every other month? What are your general impressions on efficacy and safety data in this trial? What do you think of the treatment discontinuations given the pandemic? Lastly, if the FDA approves it, what role do you foresee for pegcetacoplan in patients with geographic atrophy?
Jayanth Sridhar, MD: These are great questions, and that’s a great summary of these results. First, it’s hard to do clinical trials for geographic atrophy. One year is not a long time to get results. If you look at DERBY, it didn’t meet its end point at 1 year. But if you look at the 2-year results, it became statistically significant. It’s interesting to see how the sham group diverges from the treatment groups over time. What does it look like at 3, 4, or 5 years? Because as you said, these patients aren’t getting treatment for just a year. They’re going to be living with this disease for the rest of their lives. With today’s longevity, that could be decades.
It’s very encouraging, I like that you get good efficacy, both monthly and every other month. Built-in flexibility for a real-world application is going to be huge. The efficacy data in terms of safety are good. There was efficacy that was statistically significant at 2 years for both trials. The pooled data at 1 year was statistically significant. There were no significant safety signals that will prevent retinal specialists from implementing this in their practices.
The billion-dollar question is, how do we use this in our practices? It’s going to be utilized for those patients, depending on the label, who qualify and who are motivated and understand what they’re committing to. One of the hard things is that, unlike our treatments for wet [age-related] macular degeneration and other diseases that we inject for, there are no trial data on what extension looks like and making these intervals different from every 2 months. All we know are the data for monthly and every-2-month injections and now up to 2 years.
The questions that providers and patients have, we simply don’t have the answers to yet. But we’re going to implement for these patients. From my hands, I have a subset of patients who are highly motivated and keenly following this news, and they’re waiting to see if this will be approved. To your point, Eleonora, the biggest thing is that we haven’t had other options. Anytime you’re looking at a disease that is pervasive, prevalent, and progressive and does not have other treatment options, we must be inclusive of thinking about options. When we have data like this, it will be compelling to people to start certain treatment.
Nancy M. Holekamp, MD, FASRS: I agree. I have patients who are waiting for this treatment. They’re waiting for any treatment, but it’s likely that this will be the first 1. It’s encouraging that this treatment can alter the slope of the growth rates compared with sham. There was a post hoc analysis that looked at the disease progression in 6-month blocks. When we look at 18 to 24 months, we see the greatest diversions of the lines. This suggests that over time it may be more effective or takes a longer amount of time for us to see the benefit.
We going to have to motivate patients to stay on a therapy even where they’re not getting better but worse at a much slower rate. Patients who know that they’re losing vision, will be motivated to be on this treatment. One big question for me is I didn’t expect the every-other-month dosing to do as well as it did. It’s a 2%, 3% difference in DERBY and OAKS if you look at them independently. I have a conversation with my patients. Do they want to have every-month treatment or every-other-month treatment? We use clinical trial guidelines, but I might start people on monthly treatment with an option to go every other month because I’m eager to get some biological effect on board quickly. David, I’m interested in how you’re going to think about dosing patients.
David R. Lally, MD: Jay and Nancy, you hit the nail on the head again. This is a very heterogeneous disease, and it’s a complex and tough disease to study. The phenotypes of geographic atrophy that we see are extensive. Some patients have a single unifocal lesion, some have multifocal lesions, some are associated with subretinal drusenoid deposits, and some have a lot of pigment abnormalities associated with it. It’s such a complex disease that it’s very tough to study.
The way I’m going to absorb this information is that the totality of the evidence supports that it works. Whether there’s a few percentage points here or there based on 1 group or not, the totality is that it’s influencing the disease. The effect is not a massive effect, but that’s only at 1 year. These patients live with this disease for much longer than what we’ll see in our clinical trial data. A small effect over a long period of time could make a big difference for a patient, especially if they’re 65 years old. Most patients with geographic atrophy are older, but not all. A reasonable number of patients in my clinic are 65 years old, driving, working or want to work. They’re asking me, when do you think I’m not going to be able to work again? When am I going to have to stop working? These therapies may prolong the ability for them to drive and continue working for multiple years.
In terms of how I will talk to them about dosing, it will be an individual conversation with the patient. Each patient is going to have a different result, whether we go ahead with monthly or every-other-month dosing. If they’re an older patient, it might be difficult to get them in each month. If it’s a patient who’s working and concerned, they’re going to lose their ability to drive, they may be motivated to come in monthly to get the maximal durability of that drug to lower their risk.
Jayanth Sridhar, MD: The biggest thing is that even for those patients who are very motivated and want to do monthly, for the provider and the patient, having peace of mind if something happens in your life and you can’t make that monthly appointment and it becomes 2 months—there’s a pandemic, you get sick, something happens in your life, a hurricane—then you don’t have to deal with that. It’s going to be OK. There’s a percentage difference there that’s real, but you’re still going to get treatment effect if you look at the whole trial population. There may be some heterogeneity. There probably will be in terms of patients who can’t get that same efficacy. But it’s good to know from the trial data that you have that flexibility built in, even for patients who want to keep those monthly appointments. As we know, sometimes they just don’t happen because life happens to all of us.
Transcript edited for clarity