Regulatory Decision Summary for Empaveli

The efficacy and safety of Empaveli for the treatment of adult patients with PNH was evaluated in the pivotal Phase 3 PEGASUS (APL2-302) study which was a randomized, open label, active-comparator controlled study (pegcetacoplan versus eculizumab). The study treatment period consisted of three parts: a 4-week run-in period, a 16-week randomized controlled period (RCP), and a 32-week open-label period (OLP). The primary efficacy endpoint of the pivotal PEGASUS study was change from baseline (CFB) to Week 16 (during RCP) in hemoglobin (Hb) level. In the intent-to-treat (ITT) population (N = 80), the least-square (LS) mean CFB in Hb at Week 16 in the Empaveli and eculizumab groups was 2.4 g/dL (24 g/L) and -1.5 g/dL (-15 g/L), respectively. Empaveli was superior to eculizumab in regard to CFB in Hb level, resulting in a statistically significant adjusted mean increase of 3.8 g/dL (38 g/L) [95% Confidence interval (CI) 2.33, 5.34; p<0.0001]. Non-inferiority was demonstrated in key secondary endpoints of transfusion avoidance and CFB to Week 16 in absolute reticulocyte count (ARC).

The long-term efficacy of Empaveli was evaluated during the OLP, during which 77 patients were treated with Empaveli monotherapy resulting in a total exposure of up to 48 weeks. The results at Week 48 were generally consistent with those at Week 16 and supportive of sustained efficacy.

In the RCP, the most common (>10%) treatment-emergent adverse events (TEAEs) in the Empaveli group were diarrhea, injection site erythema and hemolysis. The most common adverse reactions as assessed by investigators included injection site erythema, injection site reaction, injection site swelling, injection site induration and hemolysis. The most common serious adverse event (SAE) reported during the RCP for the Empaveli group was hemolysis. Despite an increased risk of serious infections caused by encapsulated bacteria for patients treated with Empaveli, none were reported in the PEGASUS study.

The bioassays to detect anti-pegcetacoplan peptide antidrug antibody (ADA) and neutralizing antibody (NAb) were not adequate to fully assess the incidence of ADAs and their effect on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan. Redevelopment and revalidation of both assays by the Sponsor are ongoing and samples from pivotal clinical studies will be reanalyzed. Health Canada will receive relevant updates on immunogenicity in Periodic Safety Update Reports.

A Risk Management Plan (RMP) for Empaveli was submitted by Swedish Orphan Biovitrum AB (publ) to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Due to its mechanism of action, the use of Empaveli may predispose individuals to serious infections caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseriameningitidis, and Haemophilus influenza. In order to minimize this risk, Empaveli will only be available through a Controlled Distribution Program (CDP) under which prescribers must enroll patients and confirm vaccination against encapsulated bacteria and treatment with prophylactic antibiotic, as applicable. Prescribers must also counsel patients about the risk of serious infection and provide them with a Patient Card and a Patient/Caregiver Guide.

The efficacy of Empaveli has been established in the PEGASUS study as Empaveli was superior to eculizumab for the primary endpoint of CFB in hemoglobin. These results are corroborated by the key secondary efficacy endpoints of transfusion avoidance and CFB in ARC. Results were also consistent across all supportive analyses, including when post-transfusion data were included. On the basis of the information reviewed, Empaveli presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-harm-uncertainty profile of this product, it is recommended that Empaveli be granted authorization for the treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor.