EMPAVELI- pegcetacoplan_injection, solution

Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH. In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 0. 94 g/L at baseline to 3. 80 g/L at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 0. 95 g/L at baseline to 3. 56 g/L at Week 26 [see Clinical Studies (14. 1) The percentage of PNH Type II + III RBCs increased from 66. 2% at baseline to 93. 9% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42. 4% at baseline to 90. 0% at Week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 17. 8% at baseline to 0. 20% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2. 85% at baseline to 0. 09% at Week 26. Cardiac Electrophysiology At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i. , greater than 20 msec) were observed. In patients with PNH, the serum pegcetacoplan concentrations achieved steady-state approximately 4 to 6 weeks following the first dose. The exposure of pegcetacoplan increased proportionally over a dose range from 45 to 1,440 mg (0. 33 times the approved recommended dose). The mean (CV%) trough serum concentration observed at Week 16 was 706 (15. 1%) mcg/mL and sustained through Week 48 (Study APL2-302). In Study APL2-308, mean (CV%) trough serum concentration was 744 (25. 5%) mcg/mL at Week 26. Absorption The median T max Distribution The mean (CV%) volume of distribution of pegcetacoplan is approximately 3. 98 L (32%) in patients with PNH. Elimination The estimated mean (CV%) of clearance (CL) is 0. 36 L/day (30%) and median effective half-life of elimination (t 1/2 Metabolism Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways. Specific Populations There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years old), sex, race (Asian vs. non-Asian), renal impairment, and hepatic function as evaluated by total bilirubin (0. 8 mg/dL), albumin (3. 5 g/dL), aspartate aminotransferase (6. 0-302 IU/L), or alanine aminotransferase (4. 0-209 IU/L). There is insufficient information to characterize the anti-drug antibody response to EMPAVELI and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan products.

EMPAVELI registered EMPAVELI is a complement inhibitor indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

Recommended dosage is 1,080 mg administered subcutaneously twice weekly. 2 EMPAVELI can be administered via a commercially available pump or with EMPAVELI Injector. 3 See Full Prescribing Information for instructions on preparation and administration. 3 Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae Neisseria meningitidis [see Warnings and Precautions (5. 1) If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines for Streptococcus pneumoniae Neisseria meningitidis Healthcare professionals who prescribe EMPAVELI must enroll in the REMS for EMPAVELI [see Warnings and Precautions (5. 2) The recommended dose of EMPAVELI is 1,080 mg administered subcutaneously twice weekly. EMPAVELI can be administered via a commercially available infusion pump with a reservoir of at least 20 mL or with EMPAVELI Injector. Dosage for patients switching to EMPAVELI from C5 inhibitors To reduce the risk of hemolysis with abrupt treatment discontinuation: For patients switching from eculizumab, initiate EMPAVELI while continuing eculizumab at its current dose. After 4 weeks, discontinue eculizumab before continuing on monotherapy with EMPAVELI. For patients switching from ravulizumab, initiate EMPAVELI no more than 4 weeks after the last dose of ravulizumab. Dose Adjustment For lactate dehydrogenase (LDH) levels greater than 2 × the upper limit of normal (ULN), adjust the dosing regimen to 1,080 mg every three days. In the event of a dose increase, monitor LDH twice weekly for at least 4 weeks. Missed Dose Administer EMPAVELI as soon as possible after a missed dose. Resume the regular dosing schedule following administration of the missed dose. EMPAVELI is for subcutaneous administration using: an infusion pump EMPAVELI Injector, a single-use, disposable on body injector EMPAVELI is intended for use under the guidance of a healthcare professional. Train patients and/or caregivers on how to prepare and administer EMPAVELI prior to use. After proper training a patient may self-administer, or the patient's caregiver may administer EMPAVELI, if a healthcare provider determines that it is appropriate. Follow the steps below and use aseptic technique to prepare and administer EMPAVELI, either by an infusion pump or EMPAVELI Injector: Prior to use‚ allow EMPAVELI to reach room temperature for approximately 30 minutes. Keep the vial in the carton until ready for use to protect from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EMPAVELI is a clear, colorless to slightly yellowish solution. Do not use if the liquid looks cloudy, contains particles, or is dark yellow. Discard any unused portion of EMPAVELI. Preparation with Infusion Pump Refer to the EMPAVELI Instructions for Use and the infusion pump manufacturer's instructions for full preparation and administration information. Use a needleless transfer device (such as a vial adapter) or a transfer needle to fill the syringe. Rotate infusion sites (i. , abdomen, thighs, hips, upper arms) from one infusion to the next. Do not infuse where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks. If multi-infusion sets are needed, ensure the infusion sites are at least 3 inches apart. The typical infusion time is approximately 30 minutes (if using two infusion sites) or approximately 60 minutes (if using one infusion site). Preparation with EMPAVELI Injector Refer to the EMPAVELI Injector Instructions for Use, which comes with the device. Use a needleless transfer device (such as a vial adapter). EMPAVELI Injector is for abdominal subcutaneous use only. Rotate the site of each subcutaneous administration. Do not inject where the skin is tender, bruised, red, or hard. Avoid injecting into tattoos, scars, or stretch marks. Injection time is approximately 30 to 60 minutes.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5. 1) Infusion-Related Reactions [see Warnings and Precautions (5. 3) Most common adverse reactions in patients with PNH (incidence >=10%) were injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, pain in extremity, hypokalemia, fatigue, viral infection, cough, arthralgia, dizziness, headache, and rash. 1 To report SUSPECTED ADVERSE REACTIONS, contact Apellis Pharmaceuticals, Inc. at 1-833-866-3346 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Paroxysmal Nocturnal Hemoglobinuria Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302) The data described below reflect the exposure in 80 adult patients with PNH who received EMPAVELI (n=41) or eculizumab (n=39) at the recommended dosing regimens for 16 weeks. Serious adverse reactions were reported in 7 (17%) patients with PNH receiving EMPAVELI. The most common serious adverse reaction in patients treated with EMPAVELI was infections (5%). The most common adverse reactions (>=10%) with EMPAVELI were injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue. Table 1 describes the adverse reactions that occurred in >=5% of patients treated with EMPAVELI in Study APL2-302. Table 1: Adverse Reactions Reported in >=5% of Patients Treated with EMPAVELI in Study APL2-302 Adverse Reaction EMPAVELI Eculizumab General disorders and administration site conditions Injection-site reaction The following terms were combined: Abdominal pain Back pain Chest pain Fatigue Infections Injection-site reaction Respiratory tract infection Systemic hypertension Viral infection 16 (39) 2 (5) Fatigue 5 (12) 9 (23) Chest pain 3 (7) 1 (3) Infections and infestations Infections 12 (29) 10 (26) Respiratory tract infection 6 (15) 5 (13) Viral Infection 5 (12) 3 (8) Gastrointestinal disorders Diarrhea 9 (22) 1 (3) Abdominal pain 8 (20) 4 (10) Musculoskeletal disorders Back pain 3 (7) 4 (10) Nervous system disorders Headache 3 (7) 9 (23) Vascular disorders Systemic hypertension 3 (7) 1 (3) Clinically relevant adverse reactions in less than 5% of patients include: Intestinal ischemia Biliary sepsis Hypersensitivity pneumonitis After the randomized control period, 77 patients continued the study, and all were treated with EMPAVELI monotherapy at the recommended dosing regimen for up to 48 weeks. Serious adverse reactions were reported in 18 patients (23%). Additional adverse reactions reported in >5% of patients treated with EMPAVELI during the open-label part of the study compared to the randomized controlled part in Table 1 were cough (12%), arthralgia (8%), oropharyngeal pain (8%), pyrexia (8%), pain in extremity (7%), thrombocytopenia (7%), abdominal distension (5%), acute kidney injury (5%), anxiety (5%), and myalgia (5%). One patient (1%) died due to COVID-19 infection. Description of Select Adverse Reactions Injection-Site Reactions Injection/infusion-site reactions (e. , erythema, swelling, induration, pruritis, and pain) have been reported during Study APL2-302. These reactions were mild or moderate in severity. Diarrhea Seventeen cases of diarrhea have been reported during the 48 weeks. Fifteen of the cases were mild and two were moderate. Study in Complement-Inhibitor Naïve Adult Patients with PNH (Study APL2-308) The data described below reflect the exposure in adult patients with PNH who received EMPAVELI (n=46) or the control arm (supportive care excluding complement inhibitors) (n=18) in Study APL2-308 [see Clinical Studies (14. 1) Table 2 describes the adverse reactions that occurred in >=5% of patients treated with EMPAVELI in Study APL2‑308. Table 2: Adverse Reactions Reported in >=5% of Patients Treated with EMPAVELI in Study APL2-308 Adverse Reaction EMPAVELI Control Arm Control Arm = supportive care (excluding complement inhibitors) Exposure Adjusted Rate (per 100 pt yrs) Exposure Adjusted Rate (per 100 pt yrs) EMPAVELI (N=46) group includes patients who received EMPAVELI at any point during the study, including patients randomized to EMPAVELI (N=35) and patients randomized to the control arm and crossed over to EMPAVELI treatment (N=11). General disorders and administration site conditions Injection-site reaction The following terms were combined: Infections : Abdominal pain Injection site reaction Viral infection : Peripheral edema : Headache : Rash : Cough : 12 (26) 0 Pyrexia 4(9) 0 Peripheral edema 3 (7) 0 Infections and Infestations Infections 9 (20) 4 (22) Viral infection 6 (13) 2 (11) Musculoskeletal and connective tissue disorders Pain in extremity 6 (13) 0 Arthralgia 5 (11) 0 Musculoskeletal pain 3 (7) 0 Metabolism and nutrition disorders Hypokalemia 6 (13) 2 (11) Nervous system disorders Dizziness 5 (11) 0 Headache 5 (11) 0 Somnolence 3 (7) 0 Gastrointestinal disorders Abdominal pain 5 (11) 1 (6) Skin and subcutaneous tissue disorders Rash 5(11) 0 Ecchymosis 3 (7) 0 Erythema 3 (7) 0 Blood and lymphatic system disorders Thrombocytopenia 3 (7) 1 (6) Respiratory, thoracic and mediastinal disorders Cough 4 (9) 0 Epistaxis 3 (7) 0 Investigations Blood creatinine increased 3 (7) 0.

EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or to any of the excipients [see Warnings and Precautions (5. 3) for initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae [see Warnings and Precautions (5. 1) EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or any of the excipients. ( 4 for initiation in patients with unresolved serious infection caused by encapsulated bacteria.

Risk Summary There are insufficient data on EMPAVELI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations Treatment of pregnant cynomolgus monkeys with pegcetacoplan at a subcutaneous dose of 28 mg/kg/day (2. 9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths compared to controls (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data Animal reproduction studies with pegcetacoplan were conducted in cynomolgus monkeys. Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2. 9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions and stillbirths compared to controls. No increase in abortions or stillbirths occurred at a dose of 7 mg/kg/day (1. 3 times human exposure based on AUC). No maternal toxicity or teratogenic effects were observed in offspring delivered at term. No developmental effects were observed in infants up to 6 months postpartum. Systemic exposure to pegcetacoplan of less than 1% of maternal levels was detected in fetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester. Risk Summary It is not known whether pegcetacoplan is secreted in human milk or whether there is potential for absorption and harm to the infant. There are no data on the effects of pegcetacoplan on milk production. Pegcetacoplan is present in milk of lactating monkeys (see Animal Data Data Animal Data Pegcetacoplan was detectable in milk of lactating monkeys at less than 1% concentration of serum levels but was not detectable in the serum of nursing infants. Contraception Females EMPAVELI may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8. 1) Safety and effectiveness in pediatric patients have not been established. Clinical studies of EMPAVELI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between geriatric and younger patients.

NONCLINICAL TOXICOLOGY
Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted. Pegcetacoplan was not mutagenic when tested in an in vitro in vitro in vivo Effects of pegcetacoplan on fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys. In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (C max.
CLINICAL STUDIES
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 Haemophilus influenzae 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. 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 3 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 2 Table 3: Patient Baseline Demographics and Characteristics in Study APL2-302 Parameter Statistics EMPAVELI Eculizumab Age (years) Mean (SD) 50. 8) Sex Female n (%) 27 (65. 4) Race Asian n (%) 5 (12. 9) Black or African American n (%) 2 (4. 9) 0 White n (%) 24 (58. 1) Other n (%) 0 1 (2. 6) Not reported n (%) 10 (24. 4) Ethnicity Hispanic or Latino n (%) 2 (4. 6) Not Hispanic or Latino n (%) 29 (70. 1) Not reported n (%) 10 (24. 4) Hemoglobin level (g/dL) Mean (SD) 8. 9) Absolute reticulocyte count 9 Mean (SD) 218 (75. 1) LDH level (U/L) Mean (SD) 257. 8) Number of transfusions in last 12 months prior to Day -28 Mean (SD) 6. 7) <4 n (%) 20 (48. 0) >=4 n (%) 21 (51. 0) 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 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 4. Table 4: Additional Efficacy Results at Week 16 in Study APL2-302 EMPAVELI Eculizumab Difference Transfusion avoidance 35 (85%) 6 (15%) 63% Difference in percentages and 95% CI were based on the stratified Miettinenen dashNurminen method. Change from baseline in ARC 9 LS = Least square SE = Standard error -136 (6. 9) -164 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 [excluding complement inhibitors (e. , transfusions, corticosteroids, supplements such as iron, folate, and vitamin B 12 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 4 Table 5: Patient Baseline Demographics and Characteristics in Study APL2-308 Parameter Statistics EMPAVELI Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) Age (years) Mean (SD) 42. 6) Sex Female n (%) 16 (45. 4) Race American Indian or Alaska n (%) 9 (25. 1) Native Asian n (%) 23 (65. 9) Black or African American n (%) 2 (5. 7) 0 Other n (%) 1 (2. 9) 0 Ethnicity Hispanic or Latino n (%) 12 (34. 1) Not Hispanic or Latino n (%) 23 (65. 9) Hemoglobin level (g/dL) Mean (SD) 9. 8) Absolute reticulocyte count (10 9 Mean (SD) 230. 1) LDH level (U/L) Mean (SD) 2151. 7) Number of transfusions in last 12 months prior to Day -28 Mean (SD) 3. 0) <4 n (%) 21 (60. 4) >=4 n (%) 14 (40. 6) 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 6 below. Table 6: Efficacy Results During the 26-Week Study in Study APL2-308 EMPAVELI Control Arm Control Arm = supportive care (excluding complement inhibitors) Difference (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. 7%) 0 (0%) 73% (57%, 89%) 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 = Least square SE = Standard error -1870 (101. 0) -400 (313. 0) -1470 (-2113. 3) Change from baseline in ARC -123 (9. 2) -103 (-158. 7) Change from baseline in Hb 2. 35) Transfusion Avoidance 32 (91%) 1 (6%) 72% (56%, 89%) Figure 1.

Apellis Pharmaceuticals, Inc.

EMPAVELI- pegcetacoplan_injection, solution Product manual source documgent