Arzerra (Ofatumumab) - Description and Clinical Pharmacology

DESCRIPTION

ARZERRA (ofatumumab) is an IgG1κ human monoclonal antibody with a molecular weight of approximately 149 kDa. The antibody was generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line (NS0) using standard mammalian cell cultivation and purification technologies.

ARZERRA is a sterile, colorless, preservative-free liquid concentrate for intravenous administration. ARZERRA is supplied at a concentration of 20 mg/mL in 10 mL single-use vials. Each single-use vial contains 100 mg ofatumumab in 5 mL of solution. Inactive ingredients include: 8.55 mg/mL sodium citrate and 0.195 mg/mL citric acid monohydrate as buffering agents, 5.85 mg/mL sodium chloride as an isotonic agent, and Water for Injection, USP as the solvent. The pH is 6.5.

CLINICAL PHARMACOLOGY

Mechanism of Action

Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocyte) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding.

The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.

Pharmacodynamics

In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating CD19-positive B cells was 91% (n = 50) with the 8^th infusion and 85% (n = 32) with the 12^th infusion. The time to recovery of lymphocytes, including CD19-positive B cells, to normal levels has not been determined.

Pharmacokinetics

Pharmacokinetic data were obtained from 146 patients with refractory CLL who received a 300-mg initial dose followed by 7 weekly and 4 monthly infusions of 2,000 mg. The C_max and AUC_(0-∞) after the 8^th infusion in Study 1 were approximately 40% and 60% higher than after the 4^th infusion in Study 2. The mean volume of distribution at steady-state (V_ss) values ranged from 1.7 to 5.1 L. Ofatumumab is eliminated through both a target-independent route and a B cell-mediated route. Ofatumumab exhibited dose-dependent clearance in the dose range of 100 to 2,000 mg. Due to the depletion of B cells, the clearance of ofatumumab decreased substantially after subsequent infusions compared to the first infusion. The mean clearance between the 4^th and 12^th infusions was approximately 0.01 L/hr and exhibited large inter-subject variability with CV% greater than 50%. The mean t_1/2 between the 4^th and 12^th infusions was approximately 14 days (range: 2.3 to 61.5 days).

Special Populations: Cross-study analyses were performed on data from patients with a variety of conditions, including 162 patients with CLL, who received multiple infusions of ARZERRA as a single agent at doses ranging from 100 to 2,000 mg. The effects of various covariates (e.g., body size [weight, height, body surface area], age, gender, baseline creatinine clearance) on ofatumumab pharmacokinetics were assessed in a population pharmacokinetic analysis.

Body Weight: Volume of distribution and clearance increased with body weight. However, this increase was not clinically significant. No dosage adjustment is recommended based on body weight.

Age: Age did not significantly influence ofatumumab pharmacokinetics in patients ranging from 21 to 86 years of age. No pharmacokinetic data are available in pediatric patients.

Gender: Gender had a modest effect on ofatumumab pharmacokinetics (14% to 25% lower clearance and volume of distribution in female patients compared to male patients) in a cross-study population analysis (41% of the patients in this analysis were male and 59% were female). These effects are not considered clinically important, and no dosage adjustment is recommended.

Renal Impairment: Creatinine clearance at baseline did not have a clinically important effect on ofatumumab pharmacokinetics in patients with calculated creatinine clearance values ranging from 33 to 287 mL/min.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

Reproductive and Developmental Toxicology

Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown.

The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

CLINICAL STUDIES

Study 1 was a single-arm, multicenter study in 154 patients with relapsed or refractory CLL. ARZERRA was administered by intravenous infusion according to the following schedule: 300 mg (Week 0), 2,000 mg weekly for 7 infusions (Weeks 1 through 7), and 2,000 mg every 4 weeks for 4 infusions (Weeks 12 through 24). Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy population. Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab. The main efficacy outcome was durable objective tumor response rate. Objective tumor responses were determined using the 1996 National Cancer Institute Working Group (NCIWG) Guidelines for CLL.

In patients with CLL refractory to fludarabine and alemtuzumab, the median age was 64 years (range: 41 to 86 years), 75% were male, and 95% were White. The median number of prior therapies was 5; 93% received prior alkylating agents, 59% received prior rituximab, and all received prior fludarabine and alemtuzumab. Eighty-eight percent of patients received at least 8 infusions of ARZERRA and 54% received 12 infusions.

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). There were no complete responses. Anti-tumor activity was also observed in additional patients in Study 1 and in a multicenter, open-label, dose-escalation study (Study 2) conducted in patients with relapsed or refractory CLL.