Drs Lim, Holekamp, and Regillo discuss the introduction of the drug faricimab as a therapy option for age-related macular degeneration and the data from the TEYANA and LUCERNE clinical trials.
Karl Csaky, MD, PhD: Jennifer, can you talk a bit about one of the newer agents? Let’s talk about faricimab. We’ve been hearing about some of the trial results and talk a bit about what is faricimab and what excites you, and then I’ll hear from Nancy as well.
Jennifer I. Lim, MD: Faricimab is an exciting molecule. It’s a bispecific antibody, it binds VEGF, and it also binds angiopoietin-2, and because of this bispecific binding, it attacks not only the VEGF pathway, but also the angiopoietin pathway. What it does is, angiopoietin-2 is antagonistic to angiopoietin-1 if you will, they both bind to the same receptor. Angiopoietin-1 you want there because it stabilizes blood vessels in terms of vessel maturation. Under certain conditions where there’s poor blood flow, hypoxia, ischemia, inflammation, angiopoietin-2 is upregulated, and it displaces angiopoietin-1 from this receptor, and it causes and potentiates neovascularization. In the setting of age-related macular degeneration [AMD], if you can then block the angiopoietin-2 as well as block the VEGF, you get an anti-VEGF response, and anti-inflammatory response. That’s why this novel molecule is going to be useful to us in our armamentarium.
In the AMD studies, known as TENAYA and LUCERNE, which are phase 3 studies, these have shown early on that this drug, when compared to aflibercept after loading and then dosed q8 [every 8 weeks], was noninferior. The way the faricimab was dosed was after loading, it was either given q8 or it was given in a precise dosing interval, and this interval could be up to 16 weeks between injections during the study. The results were great in terms of mean visual acuity, it was about the same, between 6 and 7 letters mean improvement at year 1. In terms of improvements in vision, again about the same in terms of improving 3 or more lines of vision. Losing 3 or more lines of vision is very rare for both aflibercept, and it was rare also with faricimab.
The beauty of this drug, though, was that if you look at the OCT [optical coherence tomography], it dried the retina as well as aflibercept, but you didn’t have to dose it as frequently. Half of the patients were able to go 16 weeks, and 70% could be dosed every 12 weeks, and this is to get the same visual acuity and the same drying effect. That’s a game changer for a lot of our patients, because in year 2—the data are not yet out there—but in year 2, if you can dose them every 12 to 16 weeks, you’re basically talking 3 to 4 injections a year. That’s the best part about faricimab for me, and that’s what excites me about this drug.
Karl Csaky, MD, PhD: Nancy, you’ve heard and talked about the data. What was your initial thought and impression when you saw the data first presented? Share with us Nancy Holekamp’s inside-the-brain view of faricimab and what you saw as the interesting aspects of TENAYA and LUCERNE,
Nancy M. Holekamp, MD: We’ve had 15 years of anti-VEGF monotherapy. This is the first play at hitting a different target at the same time. As Jennifer mentioned, it’s a biphasic molecule. Whereas we’ve had anti-VEGF 1.0, this is anti-VEGF 2.0, and it brings us into the realm of oncology, where they’re targeting more than one pathophysiology or mechanism of action. I’m excited about adding on to something besides VEGF. The angiopoietin pathway does seem to be a good target based on preclinical studies, and I believe that they were validated in the phase 3 clinical trials. Jennifer beautifully described those phase 3 clinical trials and the fact that you could get the same drying and noninferior visual acuity outcomes with far less dosing.
The other thing, we’ve been talking about is treat and extend, and in these AMD trials, they didn’t treat and extend. They thought that you could pick an interval after 4 loading doses with monthly monitoring, which is an interesting concept. If the patients were immediately assigned to a q12 week dose or a q16 week dose, they stayed there for the rest of the year, and they didn’t drop back. As Jennifer said, when we look at the 12-month visual acuity results, they’re noninferior to aflibercept being q8 weeks. It makes me think that targeting a second pathway is going to be validated in our clinics for our patients. I’m excited to see the year-2 data because if the extended patients remain extended to q16 weeks, then we will have the ability to decrease the treatment burden and maintain vision for our patients long term. It’s an exciting next step for us in our field and for our patients.
Karl Csaky, MD, PhD: Carl, Nancy pointed out that while it was conceptually treat and extend, it wasn’t, right, because you were given that opportunity at one time. An interesting fact is that you did have rescue opportunities. Patients were seen monthly, and only 2 or 3 patients out of both studies needed rescue because they were dropped. What is your thought about that approach? How would you compare that to what you’ve taught us about treat and extend? How do you compare kind of classic treat and extend to what they did in this trial design?
Carl Regillo, MD, FACS: The way a study is designed is not necessarily the way we’re going to use the drug. That’s been proven, of course, consistently time and time again. The reason for that is because when you have the individual patient in the chair, your goal is to keep the macula in the best possible shape, and you do whatever is necessary. You’re going to adjust the follow-up and fine-tune it. These studies, they’re really not designed to fine-tune individual patient treatment regimens. The FDA doesn’t like to see individual investigator decisions being made; they like to see a greater consistency. It makes for cleaner data, and that’s certainly understandable.
It gives us useful data. I agree with Jennifer and Nancy by saying this is clearly a drug that stands out in terms of its greater durability. To put that in perspective, all the treat and extend studies done, a lot that came out of my group and so forth, they showed the drugs we’ve been using, specifically the original 3, have a median durability of 8 to 9 weeks, with a range of 4 to 12 weeks. There are some patients who can probably go beyond 12 weeks. As Lloyd mentioned, that’s about 40% of patients or so who get comfortably to the 12-week regimen. If you extrapolate what you’re seeing with the data, we’re looking at a drug that has a mean durability of 12 weeks, and a range of 8 to 16 weeks. This is a big step forward in durability. It’s not another week or two, which is what we were probably getting out of brolucizumab compared to the earlier drugs. This is truly next generation.
On top of all this, it’s been mentioned that we’re getting the same vision outcomes, exactly the same vision outcomes to on-label use of aflibercept, with less frequent dosing, and we should throw in the very necessary, good safety profile. We’re not seeing issues that look different than the drugs we’ve been originally using with a safe profile. Put that all together, and you’re going to have a drug that’s going to be FDA approved and utilized to a great degree once it’s in our hands. Payers, again, may have some say in terms of what drugs we use first as Lloyd alluded to, but ultimately I’d like to see a lot of patients on this. I’d like to see patients on this drug who are getting existing drugs very frequently so that they don’t have that same level of burden and have to come to the office every 4, 6, or 8 weeks.
In practice, to answer your question, I’m going to use this drug in a traditional treat and extend approach, although I may extend a little faster, or maybe use 3- or 4-week intervals rather than 2-week intervals from the get-go. I’m looking at the data saying, that may be what we can do safely and comfortably.
This transcript has been edited for clarity.