IZERVAY Intravitreal solution Ref.[107401] Active ingredients: Avacincaptad pegol

Increased GA area growth is reflective of loss of photoreceptors and AMD disease progression. Reductions in the rate GA growth were observed from baseline through the first year of treatment across avacincaptad pegol treatment groups in studies GATHER1 and GATHER2.

Absorption/Distribution

Following a single dose of avacincaptad pegol, maximum avacincaptad pegol plasma concentrations (C_max) are estimated to occur approximately 7 days post-dose and mean (CV%) free avacincaptad pegol plasma C_max is estimated to be 68.4 ng/mL (57.8%) in neovascular AMD (nAMD) patients. The AUC_0-28 days following a single 2 mg dose is 1064 day∙ng/mL. Based on a population pharmacokinetic analysis of patients with nAMD, predicted steady state avacincaptad pegol C_max is 83.9 ng/mL after monthly intravitreal administration of avacincaptad pegol 2 mg.

In humans, avacincaptad pegol plasma concentrations are predicted to be approximately 7,000-fold lower than vitreal concentrations.

Metabolism/Elimination

Metabolism and elimination of avacincaptad pegol has not been fully characterized. Avacincaptad pegol is expected to be catabolized by endonucleases and exonucleases to oligonucleotides of shorter lengths which may be excreted renally, in similar manner to the elimination of endogenous RNA. The estimated apparent systemic half-life of avacincaptad pegol is approximately 12 days.

Specific Populations

Following repeat monthly intravitreal dose administration of 2 mg avacincaptad pegol, no differences in the systemic pharmacokinetics of avacincaptad pegol were observed based on age, gender, and body weight. No special dosage modification is required for any of the populations that have been studied (e.g., age, gender, and body weight). The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of avacincaptad pegol is unknown. As significant increases in plasma avacincaptad pegol exposures are not expected with intravitreal route of administration, no dosage adjustment is needed based on renal or hepatic impairment status.

Carcinogenesis

No studies have been conducted on the carcinogenic potential of avacincaptad pegol.

Mutagenesis

Avacincaptad pegol was negative in in vitro (bacterial reverse mutation assay, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Studies to evaluate the effect of avacincaptad pegol on male or female fertility in animals have not been performed.

The safety and efficacy of IZERVAY were demonstrated in two randomized, multi-center, double-masked, sham-controlled, 18- and 12-month studies (GATHER1-NCT02686658 and GATHER2-NCT04435366, respectively) in patients with GA due to AMD. Patient ages ranged from 51 to 97 years with a mean of 77 years. In total, 292 patients were treated with avacincaptad pegol 2 mg, and 332 patients received sham.

In GATHER1 and GATHER2, the mean rate of GA growth (slope) from baseline to Month 12, measured by Fundus Autofluorescence (FAF) was evaluated at 3 time points: baseline, Month 6, and Month 12. Data are available through month 18 for GATHER1 and month 12 for GATHER2. At any time during the GATHER2 study, patients that developed choroidal neovascularization were concomitantly treated with anti-VEGF therapy.

In each study, over a 12-month period, there was a statistically significant reduction of the rate of GA growth (0.10 mm/year; p<0.01 in GATHER1 and 0.05 mm/year; p<0.01 in GATHER2 with square root transformed data) in patients treated with IZERVAY compared to sham. The observed results are shown in Table 2, Figure 1, and Figure 2 below.

Table 2. Efficacy Outcomes at Month 12 in GATHER1 and GATHER2 Studies:

^a = non-transformed GA growth slope analysis
^b = % difference is calculated by 100*(difference)/(least squares mean from Sham)
MMRM = Mixed Models for Repeated Measures

Figure 1. Mean Change in GA Area (mm²) From Baseline in GATHER1 (Observed data):

Figure 2. Mean Change in GA Area (mm²) in GATHER2 (Observed data):

Treatment effects in all pre-specified subgroups (e.g., age, gender, baseline GA disc area) were consistent with the results in the overall population.