Pegcetacoplan

PNH ( 2.2 ) Recommended dosage is 1,080 mg administered subcutaneously twice weekly. C3G or Primary IC-MPGN ( 2.3 ) Recommended dosage for adults is 1,080 mg administered subcutaneously twice weekly. Recommended dosage for pediatric patients is dependent upon patient weight. See full prescribing information for the recommended dosage in patients with C3G or primary IC-MPGN. EMPAVELI can be administered via a commercially available pump or with EMPAVELI Injector. ( 2.4 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.2 , 2.3 , 2.4 )

2.1 Recommended Vaccination and Prophylaxis Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y and B), according to current ACIP recommendations at least 2 weeks prior to initiation of EMPAVELI therapy [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 and Neisseria meningitidis , according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare professionals who prescribe EMPAVELI must enroll in the REMS for EMPAVELI [see Warnings and Precautions (5.2) ] .

2.2 Recommended Dosage - PNH The recommended dose of EMPAVELI is 1,080 mg administered subcutaneously twice weekly [see Dosage and Administration (2.4) ]. 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.

2.3 Recommended Dosage - C3G or Primary IC-MPGN For adults (18 years and older) The recommended dose of EMPAVELI is 1,080 mg (20 mL) administered subcutaneously twice weekly [see Dosage and Administration (2.4) ] . For pediatric patients (12 years to less than 18 years of age) For pediatric patients 12 years of age and older, administer EMPAVELI dose and volume based upon body weight, according to the schedule in Table 1. Administer the recommended dose of EMPAVELI subcutaneously twice weekly [see Dosage and Administration (2.4) ] . Table 1: Dosing recommendation in C3G or primary IC-MPGN Patient Body Weight First dose (infusion volume) Second dose (infusion volume) Maintenance dose (infusion volume) 50 kg or higher 1,080 mg (20 mL) 1,080 mg (20 mL) 1,080 mg twice weekly (20 mL) 35 kg to less than 50 kg 648 mg (12 mL) 810 mg (15 mL) 810 mg twice weekly (15 mL) Less than 35 kg 540 mg (10 mL) 540 mg (10 mL) 648 mg twice weekly (12 mL) Missed Dose Administer EMPAVELI as soon as possible after a missed dose. Resume the regular dosing schedule following administration of the missed dose.

2.4 Administration EMPAVELI is for subcutaneous administration using: A commercially available infusion pump with a reservoir of at least 20 mL OR EMPAVELI Injector, a single-use, disposable on body injector EMPAVELI is intended for use under the guidance of a healthcare professional. Patients may self-administer or caregivers may administer EMPAVELI after proper training by a healthcare professional on how to prepare and administer EMPAVELI. 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 20°C to 25°C (68°F to 77°F) 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.e., 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.

5 WARNINGS AND PRECAUTIONS Serious infections caused by encapsulated bacteria. ( 5.1 ) Infusion-Related Reactions: Monitor patients for infusion-related reactions and institute appropriate medical management as needed. ( 5.3 ) Interference with Laboratory Tests: Use of silica reagents in coagulation panels may result in artificially prolonged activated partial thromboplastin time (aPTT). ( 5.5 )

5.1 Serious Infections Caused by Encapsulated Bacteria EMPAVELI, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initation of EMPAVELI treatment is contraindicated in patients with unresolved serious infection caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of EMPAVELI, according to the most current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI. Note that, ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including EMPAVELI. The benefits and risks of treatment with EMPAVELI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of EMPAVELI in patients who are undergoing treatment for serious infections. EMPAVELI is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ].

5.2 EMPAVELI REMS EMPAVELI is available only through a restricted program under a REMS called EMPAVELI REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1) ] . Notable requirements of the EMPAVELI REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EMPAVELI. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccinations against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of EMPAVELI. Pharmacies that dispense EMPAVELI must be certified in the EMPAVELI REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of serious infections. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment discontinuation with EMPAVELI. Further information is available at www.empavelirems.com or 1-888-343-7073 5.3 Infusion-Related Reactions Systemic hypersensitivity reactions (e.g., facial swelling, rash, urticaria, pyrexia) have occurred in patients treated with EMPAVELI, which may resolve after treatment with antihistamines. Cases of anaphylaxis leading to treatment discontinuation have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved.

5.4 Monitoring PNH Manifestations after Discontinuation of EMPAVELI After discontinuing treatment with EMPAVELI, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH levels along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues EMPAVELI for at least 8 weeks to detect hemolysis and other reactions. If hemolysis, including elevated LDH, occurs after discontinuation of EMPAVELI, consider restarting treatment with EMPAVELI.

5.5 Interference with Laboratory Tests There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels.

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) ] The 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. ( 6.1 ) The most common adverse reactions in patients with C3G or primary IC-MPGN (incidence ≥10%) were infusion site reactions, pyrexia, nasopharyngitis, influenza, cough, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apellis Pharmaceuticals, Inc. at 1-833-866-3346 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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 2 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2-302. Table 2: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-302 Adverse Reaction EMPAVELI (N=41) n (%) Eculizumab (N=39) n (%) General disorders and administration site conditions Injection-site reaction Grouped terms Term includes injection-site erythema, injection-site reaction, injection-site swelling, injection-site induration, injection-site bruising, injection-site pain, injection-site pruritus, vaccination site reaction, administration site swelling, injection-site hemorrhage, injection -site edema, injection-site warmth, administration site pain, application site pain, injection-site mass, injection-site rash, vaccination site pain 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.g., erythema, swelling, induration, pruritus, 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) ] . One patient (2%) who received EMPAVELI died due to septic shock. Serious adverse reactions were reported in 6 (13%) patients with PNH receiving EMPAVELI. The most common adverse reaction (≥10%) in patients treated with EMPAVELI were injection site reactions, infections, viral infection, pain in extremity, hypokalemia, arthralgia, dizziness, abdominal pain, rash, and headache. Table 3 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2‑308. Table 3: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-308 Adverse Reaction EMPAVELI (N=46) n (%) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) n (%) 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 Grouped terms Term includes injection-site bruising, injection-site hemorrhage, injection-site swelling, application site reaction, infusion-site pruritus, injection-site erythema, injection-site rash, puncture site reaction. 12 (26) 42 0 0 Pyrexia 4(9) 14 0 0 Peripheral edema 3 (7) 11 0 0 Infections and Infestations Infections 9 (20) 32 4 (22) 74 Viral infection 6 (13) 21 2 (11) 37 Musculoskeletal and connective tissue disorders Pain in extremity 6 (13) 21 0 0 Arthralgia 5 (11) 18 0 0 Musculoskeletal pain 3 (7) 11 0 0 Metabolism and nutrition disorders Hypokalemia 6 (13) 21 2 (11) 37 Nervous system disorders Dizziness 5 (11) 18 0 0 Headache 5 (11) 18 0 0 Somnolence 3 (7) 11 0 0 Gastrointestinal disorders Abdominal pain 5 (11) 18 1 (6) 18 Skin and subcutaneous tissue disorders Rash 5(11) 18 0 0 Ecchymosis 3 (7) 11 0 0 Erythema 3 (7) 11 0 0 Blood and lymphatic system disorders Thrombocytopenia 3 (7) 11 1 (6) 18 Respiratory, thoracic and mediastinal disorders Cough 4 (9) 14 0 0 Epistaxis 3 (7) 11 0 0 Investigations Blood creatinine increased 3 (7) 11 0 0 C3 Glomerulopathy or Primary IC-MPGN Study in Adult and Pediatric Patients 12 Years of Age and Older with C3G or Primary IC-MPGN (Study APL2-C3G-310) The data described below reflects the exposure in adult (n=35) and pediatric patients 12 years of age and older (n=28) with native kidney C3G (n=46), native kidney primary IC-MPGN (n=12), or recurrent C3G following kidney transplant (n=5) who received EMPAVELI at the recommended dosing regimens during the 26-week placebo-controlled period of Study APL2-C3G-310. Serious adverse reactions due to viral infections resulting in hospitalizations occurred in 2 (3%) patients with C3G or primary IC-MPGN receiving EMPAVELI and 1 (2%) patient on placebo. One patient (2%) on EMPAVELI with native kidney C3G died because of respiratory failure due to COVID-19 pneumonia; there were no deaths in the placebo arm. Table 4 describes the adverse reactions that were reported in ≥5% of patients (adults and pediatric patients 12 years of age and older) treated with EMPAVELI and at a greater incidence than placebo in Study APL2-C3G-310. Adverse reactions in pediatric patients were similar to those seen in adults. Following the 26-week placebo-controlled period in Study APL2-C3G-310, 118 patients were treated with EMPAVELI at the recommended dosing regimen for a 26-week open-label period. The safety profile was consistent with that observed during the 26-week placebo-controlled period. During the open-label period, one patient with native kidney C3G had a serious adverse event of pneumonia secondary to Streptococcus pneumoniae , and one patient with recurrent C3G following kidney transplant developed herpes zoster meningoencephalitis while on concomitant immunosuppression, leading to treatment discontinuation. Table 4: Adverse Reactions Reported in ≥5% of Patients (adult and pediatric) Treated with EMPAVELI and Greater than Placebo in Study APL2-C3G-310 Adverse Reaction EMPAVELI (N=63) n (%) Placebo (N=61) n (%) General disorders and administration site conditions Infusion-site reactions Term includes the following reactions at the infusion site: erythema, pruritus, swelling, bruising, induration, pain, hemorrhage, discomfort, oedema, rash, and hypoaesthesia. 16 (25) 14 (23) Pyrexia 12 (19) 6 (10) Fatigue 4 (6) 1 (2) Infections and infestations Nasopharyngitis 11 (18) 7 (12) Influenza 7 (11) 3 (5) Gastrointestinal disorders Nausea 6 (10) 4 (7) Respiratory, thoracic and mediastinal disorders Cough 6 (10) 1 (2) Study in Adult Recurrent C3G or Primary IC-MPGN Following Kidney Transplant (Study APL2-C3G-204) In a study in 13 adults with recurrent C3G or primary IC-MPGN after kidney transplant (NCT#04572854), one patient with primary IC-MPGN experienced a serious adverse event of Pneumocystis jirovecii pneumonia while on EMPAVELI and concurrent immunosuppressive medications.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of EMPAVELI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to EMPAVELI exposure. Anaphylaxis and urticaria [see Warnings and Precautions (5.3) ]

12.1 Mechanism of Action 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 C3G and primary IC-MPGN, complement dysregulation and overactivation causes deposition of C3 fragments in glomeruli, which contributes to the pathogenesis of C3G and is thought to contribute to the pathogenesis of primary IC-MPGN. Pegcetacoplan binds C3 and its activation fragment C3b, therefore inhibiting C3 activation, decreasing C3 glomerular fragment deposition, and decreasing C5 convertase activity and subsequent assembly of C5b-9.

12.2 Pharmacodynamics In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 94 mg/dL at baseline to 380 mg/dL at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 95 mg/dL at baseline to 356 mg/dL 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% at Week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 17.8% at baseline to 0.2% 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. In patients with C3G or primary IC-MPGN administered pegcetacoplan SC infusion twice weekly, mean (SD) serum C3 levels increased from 62 (48) mg/dL at baseline to 371 (120) mg/dL at Week 26 compared to no change with placebo. These increases were sustained through Week 52. Mean (SD) plasma soluble C5b-9 levels decreased from 903 (698) ng/mL at baseline to 290 (249) ng/mL at Week 26 with EMPAVELI compared to no change with placebo. These decreases were sustained through Week 52. Of patients with evaluable kidney biopsies (n=69), 74% of patients on pegcetacoplan had a decrease in C3 complement staining by at least 2 orders of magnitude from baseline to Week 26 compared to 12% on placebo (Study APL2-C3G-310). Cardiac Electrophysiology At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i.e., greater than 20 msec) were observed.

12.3 Pharmacokinetics 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 (0.04 to 1.33 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. In patients with C3G or primary IC-MPGN, serum pegcetacoplan concentrations reached steady state approximately 4 to 8 weeks following twice weekly SC infusion. The mean (CV%) trough serum concentrations ranged between 716 (31%) and 766 (23%) mcg/mL from Week 4 to Week 26 and were maintained through Week 52 (Study APL2-C3G-310). Absorption The median T max of pegcetacoplan is between 108 and 144 hours (4.5 to 6 days) after a single dose. Distribution The mean (CV%) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH. The estimated mean (CV%) volume of distribution of pegcetacoplan is approximately 4.79 L (38%) and 4.58 L (29%) in patients with C3G or primary IC-MPGN, respectively. Elimination The estimated mean (CV%) of clearance (CL) is 0.36 L/day (30%) and median effective half-life of elimination (t 1/2 ) is 8.6 days in patients with PNH. The estimated mean (CV%) of clearance (CL) is 0.32 L/day (54%) and median t 1/2 is 10.2 days in patients with C3G. The estimated mean (CV%) of clearance (CL) is 0.3 L/day (51%) and median t 1/2 is 10.8 days in patients with primary IC-MPGN. 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 (0.06‑8.8 mg/dL), albumin (1.8‑5.5 g/dL), aspartate aminotransferase (6‑302 IU/L), or alanine aminotransferase (4‑209 IU/L). In patients with C3G or primary IC-MPGN, there were no clinically significant differences in pharmacokinetics of pegcetacoplan based on age (12 to 74 years old), diagnosis (C3G vs primary IC-MPGN), and urine protein-to-creatinine ratio (UPCR) (133-13300 mg/g).

12.6 Immunogenicity PNH 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 in PNH patients. C3G or primary IC-MPGN The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies. During the 52-week period in Study APL2-C3G-310, 36 of 123 participants (29%) with C3G or primary IC-MPGN exposed to pegcetacoplan developed anti–pegcetacoplan peptide antibodies. Eight of 36 participants with anti–pegcetacoplan peptide antibodies (22%) developed anti–pegcetacoplan peptide neutralizing antibodies (Study APL2-C3G-310). There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan over the treatment duration of 52 weeks.