Astellas Pharma Inc. reported that the FDA has issued a company response letter (CRL) for its supplemental new drug application (sNDA) for IZERVAY (avacincaptad pegol intravitreal), indicated for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
Give me a refresher on this drug.
IZERVAY is a complement C5 inhibitor formulated to slow GA progression.
Per its prescribing information (PI): A 2 mg (0.1 mL of 20 mg/mL solution) is to be administered via intravitreal injection to each affected eye once a month (EM) for up to 12 months.
Hold up … isn’t it already FDA-approved?
Indeed it is. The federal agency granted IZERVAY regulatory approval in August 2023.
The significance: This was the first and only GA treatment with a statistically significant reduction in the rate of GA progression at the 12-month primary endpoint.
So what’s this sNDA in regards to, exactly?
This application was seeking to include positive 2-year data within IZERVAY’s PI.
The basis for this: New data from the phase 3 GATHER2 clinical trial, which evaluated the safety/efficacy of IZERVAY when dosed EM and every other month (EOM) through year 2.
- Note: GATHER2 was conducted following the conclusion of GATHER1.
How this compares to IZERVAY’s existing supporting data:
- The drug’s PI currently only includes data up to the 12-month point for EM and EOM dosings from the phase 3 GATHER1 (NCT04435366) and GATHER2 (NCT04435366) trials.
Give it to me simply, please.
In other words: Astellas is seeking to add 24-month supporting data to IZERVAY’s approved on-label use that would allow the drug to be used EM for 24 months—12 months longer than it’s currently approved for.
To clarify: This 24-month dosing would extend to both EM and EOM dosing of IZERVAY, the company confirmed to Glance.
Gotcha. Now some background on this GATHER2 trial.
While Astellas originally reported positive topline data from the trial in September 2023 (notably, one month after IZERVAY was granted FDA approval), the company’s completed data was unveiled in November 2023.
The setup: In year 2 of the GATHER2 trial (n = 448), IZERVAY-treated patients were re-randomized to be administered IZERVAY EM (n = 96) or EOM (n = 96).
- Sham-treated patients (n = 203) from year 1 continued to be administered sham in year 2.
And the goal?
To determine if (after re-randomization) IZERVAY continued to slow GA growth rate for IZERVAY EM vs sham-treated patients.
So what did the 24-month data find?
As we previously reported, IZERVAY demonstrated a reduction in the rate of GA lesion growth as early as 6 months for both IZERVAY-treated patients (EM and EOM dosings) versus sham.
This reduction continued to increase over time through the full 24 months.
The numbers:
- IZERVAY EM: 14% statistically significant year-over-year reduction in the mean rate of GA growth at 2 years from baseline vs sham (p=0.0165)
- IZERVAY EOM (after 1 year of EM dosing): 19% reduction in the mean GA growth rate at 2 years vs sham (nominal p-value=0.0015).
See our full coverage—including reported adverse events and choroidal neovascularization (CNV) incidence.
Alrighty, now circling back to this sNDA … why is the FDA rejecting it?
In its Nov. 15 CRL—notably, just days ahead of its previously-set Prescription Drug User Fee Act (PDUFA) date of Nov. 19—the agency stated it could not approve the sNDA “in its present form.”
The reasoning: Per Astellas, the FDA’s comments focused “on a statistical matter related to labeling language proposed” by the company.
Important to note: This rejection was not based on IZERVAY’S safety and benefit/risk of use.
Well, that’s pretty vague reasoning.
It sounds like the company thinks so, too, as it’s reportedly looking to “seek clarification” from the agency and “quickly address” the feedback.
And how has the company responded to this letter?
Astellas’ Marci English, senior vice president, Biopharma and Ophthalmology Development, noted that, while the FDA’s decision is “a disappointment for” patients and physicians, the company is standing by IZERVAY’s clinical profile.
English added that Astellas “will continue to work with the FDA to advance solutions for those suffering from GA.”
As always, stay tuned for updates!