Empaveli Drug Information

Paroxysmal Nocturnal Hemoglobinuria

The efficacy and safety of EMPAVELI in patients with PNH were assessed in two open-label, randomized-controlled Phase 3 studies: Study APL2-302 (NCT03500549) and Study APL2-308 (NCT04085601). All patients who completed the studies were eligible to enroll in a separate long-term extension study. In both studies, patients were vaccinated against Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib), either within 2 years prior to Day 1 or within 2 weeks after starting treatment with EMPAVELI. Patients vaccinated after initiation of treatment with EMPAVELI received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In addition, prophylactic antibiotic therapy was administered at the discretion of the investigator in accordance with local treatment guidelines for patients with PNH receiving treatment with a complement inhibitor.

A dose of 1,080 mg twice weekly was used for patients randomized to the EMPAVELI group of each study. If required, the dose of EMPAVELI could be adjusted to 1,080 mg every 3 days. EMPAVELI was administered as a subcutaneous infusion; the infusion time was approximately 20 to 40 minutes.

Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302) The study enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least the previous 3 months and with Hb levels less than 10.5 g/dL. Eligible patients entered a 4-week run-in period during which they received EMPAVELI 1,080 mg subcutaneously twice weekly in addition to their current dose of eculizumab. Patients were then randomized in a 1:1 ratio to receive either 1,080 mg of EMPAVELI twice weekly or their current dose of eculizumab through the duration of the 16-week randomized controlled period (RCP). Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4) and platelet count at screening (<100,000/mm 3 ; ≥100,000/mm 3 ). Following completion of the RCP, all patients entered a 32-week open-label period (OLP) and received monotherapy with EMPAVELI. Patients initially randomized to eculizumab entered a second 4-week run-in period during which they received EMPAVELI in addition to eculizumab before continuing on to receive EMPAVELI monotherapy. All patients who completed the 48-week period were eligible to enroll in a separate long-term extension study.

A total of 80 patients were randomized to receive treatment, 41 to EMPAVELI and 39 to eculizumab. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 5 ). The median times from PNH diagnosis to Day -28 were 6 and 9.7 years, respectively, for EMPAVELI and eculizumab. The baseline mean total PNH RBC clone sizes (Type III) were 47% for EMPAVELI and 50% for eculizumab.

Twenty-nine percent and 23% of patients had a history of major adverse vascular events, and 37% and 26% had a history of thrombosis for patients receiving EMPAVELI or eculizumab, respectively. Within 28 days prior to the first dose of EMPAVELI or eculizumab, respectively, 34% and 31% of patients used anti-thrombotic agents (anti-platelet and/or anticoagulants). During Study APL2-302, 37% and 36% of patients on EMPAVELI and eculizumab, respectively, used antithrombotic agents. A total of 38 patients in the group treated with EMPAVELI and 39 patients in the eculizumab group completed the 16-week RCP and continued into the 32-week OLP. Because of adverse reactions of hemolysis, 3 patients were discontinued from the EMPAVELI group during the RCP. Two out of 41 patients in the EMPAVELI group needed the dose adjustment to 1,080 mg every 3 days.

Table 5: Patient Baseline Demographics and Characteristics in Study APL2-302 Parameter Statistics EMPAVELI (N=41) Eculizumab (N=39) Age (years) Mean (SD) 50.2

Sex Female n (%) 27 22 Race Asian n (%) 5 7

Black or African American n (%) 2 0 White n (%) 24 25 Other n (%) 0 1 Not reported n (%) 10 6 Ethnicity Hispanic or Latino n (%) 2 1 Not Hispanic or Latino n (%) 29 32 Not reported n (%) 10 6 Hemoglobin level (g/dL) Mean (SD) 8.7

Absolute reticulocyte count (10 9 cells/L) Mean (SD) 218 216

LDH level (U/L) Mean (SD) 257.5

Number of transfusions in last 12 months prior to Day -28 Mean

(SD) 6.1 6.9 <4 n (%) 20 16 ≥4 n (%) 21 23 The efficacy of EMPAVELI was based on change from baseline to Week 16 (during RCP) in hemoglobin level. Baseline was defined as the average of measurements recorded prior to taking the first dose of EMPAVELI. Supportive efficacy data included transfusion avoidance, defined as the proportion of patients who did not require a transfusion during the RCP, and change from baseline to Week 16 in absolute reticulocyte count (ARC). EMPAVELI was superior to eculizumab for the change from baseline in hemoglobin level at Week 16 ( p <0.0001). The adjusted mean change from baseline in hemoglobin level was 2.37 g/dL in the group treated with EMPAVELI versus -1.47 g/dL in the eculizumab group (Figure 1), demonstrating an adjusted mean increase of 3.84 g/dL with EMPAVELI compared to eculizumab at Week 16 (95% CI, 2.33-5.34). Figure 1: Adjusted Mean (± SE) Change from Baseline to Week 16 in Hemoglobin (g/dL) in Study APL2-302 Treatment effect estimates from a mixed model are shown. The mixed model contained the categorical effects of treatment, visit, treatment by visit interaction, and stratification factors (transfusion history and platelet count at screening), and the continuous covariate of baseline value.

Non-inferiority was demonstrated in the endpoints of transfusion avoidance and change from baseline in ARC at Week 16. The adjusted means, treatment differences, and confidence intervals (CIs) for additional efficacy results are shown in Table 6. Table 6: Additional Efficacy Results at Week 16 in Study APL2-302 EMPAVELI (N=41) Eculizumab (N=39) Difference (95% CI) Transfusion avoidance, n (%) 35 (85%) 6 (15%) 63% Difference in percentages and 95% CI were based on the stratified Miettinen–Nurminen method. (48%, 77%) Change from baseline in ARC (10 9 cells/L), LS LS = Least square mean (SE) SE = Standard error -136 28 -164 (-189.9, -137.3) Efficacy was generally similar across subgroups based on sex, race, and age. All 77 patients who completed the RCP entered the 32- week OLP, during which all patients received EMPAVELI, resulting in a total exposure of up to 48 weeks. Between Week 16 and Week 48, 10 patients discontinued the study, all due to adverse reactions, and thirteen patients had a dose adjustment to 1,080 mg every three days.

The efficacy results at Week 48 were generally consistent with those at Week 16. Study in Complement-Inhibitor Naïve Adult Patients with PNH (Study APL2-308) Study APL2-308 enrolled patients with PNH who had not been treated with any complement inhibitor within 3 months prior to enrollment and with Hb levels less than the lower limit of normal (LLN). Eligible patients were randomized in a 2:1 ratio to receive EMPAVELI or supportive care through the duration of the 26-week treatment period. Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4). At any point during the study, a patient assigned to the control arm treatment group who had Hb levels ≥2 g/dL below baseline or presented with a PNH associated thromboembolic event was offered cross-over to EMPAVELI for the remainder of the study. A total of 53 patients were randomized, 35 to EMPAVELI and 18 to the control arm.

Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 7 ). The mean times from PNH diagnosis to Day 1 were 5.7 and 5.5 years, respectively, for EMPAVELI and the control arm. The baseline mean total PNH RBC clone sizes (Type III) were 31% for EMPAVELI and 28% for the control arm. In the EMPAVELI group, 2.9% of patients had a history of major adverse vascular events.

Two patients (5.7%) in the EMPAVELI group and 3 patients (16.7%) in the control arm group had a history of at least 1 type of thrombosis. Within 28 days prior to the first dose of EMPAVELI or the control arm, respectively, 17.1% and 27.8% of patients used anti-thrombotic agents (anti-platelet and/or anticoagulants). During Study APL2-308, 8.6% and 0% of patients on EMPAVELI and the control arm, respectively, used antithrombotic agents. Eleven of 18 patients randomized to the control transitioned to cross-over therapy with EMPAVELI due to a decreased Hb level ≥2 g/dL below baseline.

Three patients treated with EMPAVELI required dose adjustment to 1,080 mg every 3 days. Three patients (5.7%; two patients in the EMPAVELI group and one patient in the control arm group) discontinued the study, none due to an adverse reaction. Table 7: Patient Baseline Demographics and Characteristics in Study APL2-308 Parameter Statistics EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) Age (years) Mean (SD) 42.2

Sex Female n (%) 16 8 Race American Indian or Alaska n

(%) 9 2 Native Asian n (%) 23 16 Black or African American n (%) 2 0 Other n (%) 1 0 Ethnicity Hispanic or Latino n (%) 12 2 Not Hispanic or Latino n (%) 23 16 Hemoglobin level (g/dL) Mean (SD) 9.4

Absolute reticulocyte count (10 9 cells/L) Mean (SD) 230.2 180.3

LDH level (U/L) Mean (SD) 2151

Number of transfusions in last 12 months prior to Day -28 Mean

(SD) 3.9 5.1 <4 n (%) 21 8 ≥4 n (%) 14 10 The efficacy of EMPAVELI was based on the percentage of patients achieving hemoglobin stabilization, defined as avoidance of a >1 g/dL decrease in hemoglobin levels from baseline in the absence of transfusion, and the change from baseline in LDH level. Supportive efficacy data included change from baseline in absolute reticulocyte count (ARC), change from baseline in hemoglobin, and transfusion avoidance, defined as the proportion of patients who did not require a transfusion through Week 26. Baseline was defined as the average of measurements recorded prior to taking the first dose of EMPAVELI or prior to randomization to the control arm treatment group. Efficacy results are shown in Table 8 below.

Table 8: Efficacy Results During the 26-Week Study in Study APL2-308 EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors) Difference (95% CI) (N=18) p-value Data collected after cross-over from the control arm is excluded in analyses. Hemoglobin Stabilization Patients who crossed over from the control arm group to the EMPAVELI group, withdrew from the study, or were lost to follow up are considered as failing to achieve the criteria. (n, %) 30 (85.7%) 0 (0%) 73% (57%, 89%) p<0.0001 p-value is obtained by stratified Cochran-Mantel-Haenszel test. Change from Baseline in LDH The post baseline missing values (including the values after cross-over from the control arm) are imputed using a multiple imputation method. (LS LS = Least square Mean CFB, SE SE = Standard error ) -1870 -400 -1470 (-2113.4, -827.3) p<0.0001 Change from baseline in ARC (LS Mean CFB, SE ) -123 -19 -103 (-158.9, -48.7) p = 0.0002 Change from baseline in Hb (LS Mean CFB, SE ) 2.9 0.3 2.7 p = 0.0019 Transfusion Avoidance (n, %) 32 (91%) 1 (6%) 72% (56%, 89%) p<0.0001 Figure 1

C3 Glomerulopathy (C3G) or Primary Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

The efficacy of EMPAVELI in reducing proteinuria in adult and pediatric patients aged 12 years and older with native kidney C3G, native kidney IC-MPGN, or recurrent C3G following kidney transplant was demonstrated in Study APL2-C3G-310. Safety and effectiveness of EMPVAELI in patients with recurrent IC-MPGN following kidney transplant have not been established. APL2-C3G-310 is a randomized, double-blind, placebo-controlled study that included 124 adult and pediatric patients aged 12 years and older and weighing at least 30 kg with biopsy-proven, native kidney or post-transplant recurrent C3G, or native kidney primary IC-MPGN, eGFR ≥30 mL/min/1.73 m 2, proteinuria ≥1 g/day, and urine protein-to-creatinine ratio (UPCR) ≥1 g/g (NTC 05067127). For at least 12 weeks before randomization and throughout the 26-week placebo-controlled period, patients were required to be on stable and optimized doses of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and/or sodium-glucose cotransporter-2 (SGLT2) inhibitors. Immunosuppressant medication doses (e.g., steroids no higher than 20 mg daily, mycophenolate mofetil, tacrolimus) had to be stable for at least 12 weeks before randomization and throughout the 26-week placebo-controlled period.

Patients were randomized (1:1) to EMPAVELI or placebo, administered twice weekly as a subcutaneous (SC) infusion for 26 weeks. Randomization was stratified by post-transplant recurrence and by kidney biopsy obtained within 28 weeks of screening. Adults and pediatric patients weighing 50 kg or more received EMPAVELI 1,080 mg (20 mL) twice weekly.

Pediatric patients weighing 35 kg to less than 50 kg received 648 mg (12 mL) for the first infusion and 810 mg (15 mL) for each infusion thereafter. Pediatric patients weighing 30 kg to less than 35 kg received EMPAVELI 540 mg (10 mL) for the first 2 infusions and 648 mg (12 mL) twice weekly thereafter. Patients were vaccinated against Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib) at least 14 days prior to randomization, unless documented evidence existed that participants received the recommended vaccinations or were non-responders to vaccination.

At baseline, the mean age was 26 years (range 12 to 74 years); 57% were female, 73% White, 15% Asian, 1% Black or African American, and 11% others. The study population included 55 pediatric patients 12 years to less than 18 years of age; mean age 14.7 years (28 randomized to EMPAVELI and 27 to placebo). Disease type was reasonably balanced between the treatment groups. Overall, 88 patients (71%) had native kidney C3G, 27 patients (22%) had native kidney primary IC-MPGN, and 8 patients (6%) had post-kidney transplant recurrent C3G. At baseline, mean UPCR from triplicate first morning urine (FMU) collections was 3.1 g/g and 2.5 g/g in the pegcetacoplan and placebo groups, respectively; mean eGFR (mL/min/1.73 m 2 ) was 79 and 87 in the pegcetacoplan and placebo groups, respectively; and mean baseline serum albumin was approximately 3.4 g/dL in both treatment groups.

Approximately 91% of patients were treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), 72% with immunosuppressants (e.g., mycophenolate mofetil, tacrolimus), 40% with systemic corticosteroids, and 11% with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Use of each of these medications was balanced between the treatment groups. The primary efficacy endpoint was the log-transformed ratio of UPCR (sampled from first morning urine collections) at Week 26 compared to baseline.

At Week 26, the geometric mean UPCR ratio relative to baseline was 0.33 (95% CI: 0.25, 0.43) and 1.03 (95% CI: 0.91, 1.16) in the EMPAVELI and placebo groups, respectively, resulting in a 68% reduction in UPCR from baseline in the EMPAVELI group compared to placebo (p<0.0001). The treatment effect was consistent across all subgroups including disease type, age, transplant status (C3G), sex, race, baseline disease characteristics (eGFR and UPCR), and immunosuppressant use. Figure 2 shows the geometric mean UPCR ratio compared to baseline over time. Abbreviations: FMU = first-morning spot urine; UPCR = urine protein-to-creatinine ratio.

Figure 2: Geometric Mean of UPCR Ratio Compared to Baseline Over 26 Weeks of Treatment - Study APL2-C3G-310 During the 26-week placebo-controlled period, 49% of patients in the EMPAVELI group achieved a composite renal endpoint defined as a ≥50% reduction in UPCR and stable eGFR (≤15% reduction from baseline) compared with 3% of patients in the placebo group (odds ratio of 27, p<0.0001). Sixty percent of patients in the EMPAVELI group achieved a 50% or greater reduction in UPCR from baseline to Week 26 compared with 5% in the placebo arm, and 68% of patients in the EMPAVELI group had a stable eGFR (≤15% reduction from baseline to Week 26) compared with 59% in the placebo group. Over the first 6 months of treatment, EMPAVELI reduced the loss of kidney function compared to placebo (Figure 3). The efficacy of EMPAVELI in pediatric patients 12 years of age and older was similar to adults. Abbreviations: LS = least square LS Mean (95% CI) of difference between EMPAVELI and placebo at Week 26 is 6.31 mL/min/1.73m 2. Figure 3: LS Mean of eGFR Compared to Baseline Over 26 Weeks of Treatment - Study APL2-C3G-310 Figure 2 Figure 3