General Information

Arzerra (ofatumumab) is an anti-CD20 monoclonal antibody. It targets a membrane-proximal (close to the cell surface), small loop epitope (a portion of a molecule to which an antibody binds) on the CD20 molecule on B-cells. This epitope is different from the binding sites targeted by other CD20 antibodies currently available. The CD20 molecule is a key target in CLL therapy because it is highly expressed in most B-cell malignancies.

Arzerra is specifically indicated for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.

Arzerra is supplied as a liquid concentrate (20 mg/mL) for dilution designed for intravenous administration. The recommended initial dose and schedule is 12 doses administered as follows:
300 mg initial dose (Dose 1), followed 1 week later by
2,000 mg weekly for 7 doses (Doses 2 through 8), followed 4 weeks later by
2,000 mg every 4 weeks for 4 doses (Doses 9 through 12)

Administration
Dose 1: Initiate infusion at a rate of 3.6 mg/hour (12 mL/hour)
Dose 2: Initiate infusion at a rate of 24 mg/hour (12 mL/hour)
Doses 3 through 12: Initiate infusion at a rate of 50 mg/hour (25 mL/hour)

Clinical Results

FDA Approval
The FDA approval of Arzerra is based on a single-arm, multicenter study in 154 subjects 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). Subjects with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population. The primary endpoint was objective tumor response rate. The overall response rate was 42%, with a median duration of response of 6.5 months. 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.

Mechanism of Action

Arzerra is an anti-CD20 monoclonal antibody. It 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.

Literature References

Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 2008 Feb 1;111(3):1094-100.

Hagenbeek A, Gadeberg O, Johnson P, Pedersen LM, Walewski J, Hellmann A, Link BK, Robak T, Wojtukiewicz M, Pfreundschuh M, Kneba M, Engert A, Sonneveld P, Flensburg M, Petersen J, Losic N, Radford J First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008 Jun 15;111(12):5486-95