ent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlatedwith maximal intravascular hemolysis control and complete terminal complementinhibition.
Complete terminal complement inhibition following initiation of ULTOMIRIS treatmentled to normalization of serum LDH by week 4 in complement-inhibitor naïve patients,
and maintained LDH normalization in patients previously treated with eculizumab [seeClinical Studies (14)].
12.3 Pharmacokinetics
Ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to5400 mg. Ravulizumab-cwvz Cmax and Ctrough parameters are presented in Table 5.
Table 5: Mean ± SD (%CV) Pharmacokinetic Parameters of ULTOMIRIS inPatients with PNH who are Complement Inhibitor-Naïve and Patients
Previously Treated with Eculizumab
N Complement
Inhibitor-Naïve
N Previously Treated
with Eculizumab
Cmax LD 125 771 ± 166 (21.5) 95 843 ± 204 (24.1)
(mcg/mL) MD 124 1379 ± 276 (20.0) 95 1386 ± 268 (19.4)
Ctrough LD 125 391 ± 137 (35.0) 96 405 ± 121 (29.9)
(mcg/mL) MD 124 473 ± 158 (33.4) 95 501 ± 143 (28.6)
LD = Loading Dose; MD = Maintenance Dose
Distribution
The mean (SD) volume of distribution at steady state was 5.34 (0.92) L.
Elimination
The mean (SD) terminal elimination half-life and clearance of ravulizumab-cwvz in
patients with PNH are 49.7 (8.9) days and 0.08 (0.022) L/day respectively.
Specific Populations
No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz wereobserved based on sex, age (18 to 83 years), race, hepatic impairment, or mild to
moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2, estimated by MDRD).
Theeffect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2, estimated by MDRD)on ravulizumab-cwvz pharmacokinetics is unknown.
Body weight was a significant covariate on the pharmacokinetics of ravulizumab-cwvz.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted.Genotoxicity studies have not been conducted with ravulizumab-cwvz.Effects of ravulizumab-cwvz upon fertility have not been studied in animals.
Intravenousinjections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 timesthe equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating orfertility.
14 CLINICAL STUDIES
The safety and efficacy of ULTOMIRIS in patients with PNH was assessed in two openlabel,randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 andPNH Study 302. Study 301 enrolled patients with PNH who were complement inhibitornaïve and had active hemolysis. Study 302 enrolled patients with PNH who were
clinically stable after having been treated with eculizumab for at least the past 6 months.
In both studies, ULTOMIRIS was dosed intravenously in accordance with the weightbaseddosing described in Section 2.1 (4 infusions of ULTOMIRIS over 26 weeks)above. Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenancetreatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a
total of 26 weeks of treatment, according to the approved dosing regimen of eculizumabwhich was the standard-of-care for PNH at the time of studies.
Patients were vaccinated a |
