The GATHER1 and GATHER2 studies are highlighted.
Ryan Haumschild, PharmD, MS, MBA: We know that avacincaptad pegol, or ACP, is one of the coming complement inhibitors that’s being evaluated for use in geographic atrophy [GA]. Dr Khanani, maybe you could discuss the clinical trial evidence for this emerging therapy. Talk about GATHER1 and GATHER2 and how the studies were designed. Then what are your thoughts on these selected end points and impression of the results? And then I’ll get Dr Lally to respond with his thoughts as well.
Arshad Khanani, MD: Absolutely. I think it’s exciting to have multiple options in the pipeline for any disease. We know that avacincaptad pegol has shown positive data in 2 trials, GATHER1 and GATHER2. This is the first therapeutic option to show the benefit of meeting the primary end point in 2 trials. As Dr Lally said, with pegcetacoplan, the primary end point was not met in the DERBY study, but over time we saw the efficacy, and there was significance at 24 months with a nominal P value. What is avacincaptad pegol? It’s a pegylated RNA [ribonucleic acid] aptamer that’s designed to be a specific inhibitor of complement C5. As we discussed the complement system, this is more downstream inhibition compared to C3, and could that bring some benefit? There’s potential that if we block C5, we preserve the anti-inflammatory properties of C3a, and that may lead to less inflammation. Obviously, there is some basic science work that proves that. This is more downstream inhibition of C5, which is more downstream than C3, and we know that it slows inflammation and cell death, which is obviously happening in GA.
In the GATHER1 and GATHER2 studies, we evaluated the efficacy of avacincaptad pegol in patients with GA. Looking at the design of GATHER1, this was a phase 2/3 global, prospective randomized double-masked sham control study, where we randomized patients in 2 parts. In the first part, we randomized the patients to receive 1 mg of ACP, 2 mg of ACP, and then sham. The 1- and 2-mg groups received monthly ACP, and the sham group received the sham injection. Then in the second part, we randomized patients to receive either 2 mg, 4 mg, or sham. This design is unique, but this was designed so that we can do the dose-finding, the best dose to take forward, but also meet the regulatory requirements to have the phase 3 data. Both parts of the studies were masked. Investigators and the patients were masked, so these were double-masked studies. The primary end point was at month 12, looking at the mean change in GA area from baseline to month 12 using a square root transformation. These patients continued in the study for 18 months, so we have 18-month data from the GATHER1 study.
One thing to highlight is that for both GATHER1 and GATHER2, we enrolled patients with nonfoveal involvement, meaning they were not impacted in the center of the fovea. That doesn’t mean this disease wasn’t advanced. That doesn’t mean the lesions were not very close to the fovea. But if they didn’t have center point involvement on OCT [optical coherence tomography] using FAF [fundus autofluorescence], then they were enrolled in GATHER1 and GATHER2.
GATHER2 is a phase 3 study, again a randomized, double-masked global study. Here we took the 2-mg dose forward, and we randomized 448 patients in this trial. Patients were treated monthly with avacincaptad pegol or sham, and the primary analysis is also a month 12. This trial had analysis in terms of slope, so the FDA approved this plan to look at the slope. The primary end point was the mean rate of growth looking at the slope in the GA area from baseline to month 12. I think as we were talking about disease modification, it’s important to look at the slope, Ryan, as you said, instead of 1 static time point. If you’re going to have an effect of a treatment, you’re going to be able to change the slope of the trajectory of the disease. This is a 2-year study, so patients who received ACP monthly will be re-randomized to receive either monthly or every other month ACP in the second year, and the patients randomized to the sham arm will continue in the sham. As Dr Lally said, it’s super important to generate long-term data, so there’s an extension study also ongoing after patients finish 2 years of GATHER2.
Other than the nonfoveal involvement and having GA within 1500 μm from the center of the fovea, the inclusion/exclusion [criteria] in GATHER1 and GATHER2 were very comparable to other studies. In terms of the baseline characteristics, again these are well balanced usually in clinical trials. In terms of efficacy, both GATHER1 and GATHER2 met the prespecified primary end point. In GATHER1, we saw a reduction of 27.4% in GA growth compared to sham at the primary end point. In GATHER2, we saw a 14.3% reduction compared to sham. In both trials, we saw efficacy early with treatment, and improvement or separation of the curves as we continued to treat, just like we saw in the pegcetacoplan trial. Here we saw the effect very early, and that’s why the primary end point was met in both studies. That was the primary end point data using square root transformation. When we look at the non–square root transformation, the observed data, we see the efficacy numbers increase. We saw an efficacy of 35.4% with ACP in GATHER1, and 17.7% with ACP in GATHER2.
We’re seeing an effect that starts early. We see the separation of the curves early, and the effect increases over time. Ryan, one more thing we looked at was subgroup analysis in terms of, is there a specific subgroup that benefits? We looked at the baseline GA lesion size. We looked at visual acuity. We looked at the type of lesion. We looked at everything in terms of multiple parameters, and what we saw was the benefit of ACP was consistent in GATHER1 and GATHER2 in all subgroups we looked at. The other thing was that when you looked at the 18-month data in GATHER1, there is a trend for even more benefit, again highlighting that the longer you treat these patients, the better outcomes you are going to have.
Now in terms of safety, I think it’s important because you are going to be treating patients, many of them have good vision, many of them will have 1 eye. We need to talk about safety. We saw 0 cases of intraocular inflammation in the GATHER2 study. We had 1 case of intraocular inflammation in GATHER1, which was not associated with ACP. We didn’t see any cases of ischemic optic neuropathy at 12 months in GATHER1 or GATHER2. We have seen an increased rate of CNV [choroidal neovascularization] or wet AMD [age-related macular degeneration] in these patients who get a complement inhibitor, just like we saw in the DERBY and OAKS trials. But here in GATHER1, the rate was 9% with ACP compared to 3% or so in the sham group. In GATHER2 the rate was about 6.7% compared to 4.1%, so slightly increased rates. We have to monitor these patients to make sure they are not getting CNV.
The bottom line is a very exciting data set from the avacincaptad pegol GATHER1 and GATHER2 studies. As you are aware, the FDA assigned a breakthrough designation to ACP based on the data. They have the BLA [biologics license application] package, and we hope to hear from the FDA on a decision by August this year.
Ryan Haumschild, PharmD, MS, MBA: Great overview. I’m also looking forward to hearing from the FDA on a potential PDUFA [end of review period] date, just to increase the options we have to treat these patients, especially between the 2 complement inhibitors.
Transcript edited for clarity.