Product
Arzerra
Approval Date
October 26, 2009
Release Date
Mid-November 2009
Company
GlaxoSmithKline and Genmab
Class
A CD20-directed cytolytic monoclonal antibody
Indication
Refractory chronic lymphocytic leukemia (CLL)
Active Ingredient
Ofatumumab
Agency Roster
Medicus Life Brands (professional)
Torre Lazur McCann
Marketing Strategy/Execution
Arzerra (ofatumumab) is approved for patients with chronic lymphocytic leukemia (CLL) whose cancer is no longer being controlled by other forms of chemotherapy. The product was approved under the FDA’s accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. Products may receive accelerated approval based on a surrogate endpoint, such as a reduction in the size of the tumor or decrease in the number of cancerous white cells or in an enlarged spleen or lymph nodes. These indirect measures for clinical outcomes are considered reasonably likely to predict that the drug will allow patients to live longer or with fewer side effects of a disease.
In late January, GlaxoSmithKline (GSK) and Genmab announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for Arzerra, for the treatment of refractory CLL. The CHMP recommended the conditional marketing authorization of ofatumumab in the EU for the treatment of patients with CLL who are refractory to fludarabine and alemtuzumab.
A conditional marketing authorization is granted to a medicinal product with a positive benefit/risk assessment that fulfils an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required. A conditional marketing authorization is renewable annually. As part of the conditions of the conditional marketing authorization for ofatumumab, GSK will be required to provide further data.
Arzerra launched in mid-November. Genmab announced that the US net sales for Arzerra during the fourth quarter of 2009 were approximately $5.5 million USD. Under the terms of the collaboration with GSK, Genmab expects to receive a royalty payment of approximately $1.1 million USD.
Physician Outlook
Arzerra is a humanized anti-CD20 antibody whose initial approval is for patients with CLL who have relapsed after prior therapy and has shown promising efficacy in that setting. It has the same target as Rituxan (rituximab, Genentech), which is the most commonly used biologic in the management of CLL and is considered one of the most useful agents in the management of hematologic malignancies. Because Arzerra is humanized (unlike rituximab, which is chimeric), it should lack the anaphylactic infusion reactions that are occasionally seen with Rituxan. It is unclear, however, whether there is any difference in efficacy between the two agents, and the resolution of this question awaits head-to-head clinical trials.
—Michael Galvin, Ph.D., Vice President, Research & Consulting, GfK Healthcare
Also in the Pipeline (courtesy of Adis R&D Insight)
Drug: Anti-CD52 monoclonal antibody
Manufacturer: Bayer HealthCare Pharmaceuticals
Indication: Chronic lymphocytic leukaemia
Active ingredient: Alemtuzumab
Phase: Launched
Drug: CC 5013
Manufacturer: Celgene Corporation
Indication: Multiple myeloma (Combination therapy, Second-line therapy)
Active ingredient: Lenalidomide
Phase: Launched
Drug: Augmerosen
Manufacturer: Genta
Indication: Chronic lymphocytic leukaemia (Combination therapy)
Active ingredient: Oblimersen
Phase: Preregistration
Drug: 2′-Deoxycoformycin
Manufacturer: Hospira/ Kaketsuken
Indication: Hairy cell leukaemia
Active ingredient: Pentostatin
Phase: Launched
Drug: IDEC 102
Manufacturer: Biogen Idec/ Chugai Pharmaceutical
Indication: Chronic lymphocytic leukaemia (First-line therapy)
Active ingredient: Rituximab
Phase: Launched
Source: Wolters Kluwer Pharma Solutions
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Pharmacology
Ofatumumab, a cytolytic IgG1k human monoclonal antibody, binds specifically to both the small and the large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocytes) 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, causing B-cell lysis in vitro. Data suggests that possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.
The approval of this product was based upon the demonstration of durable objective responses; no data have shown an improvement in disease related symptoms or increased survival. In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating CD19-positive B cells was 91% with the 8th infusion and 85% with the 12th infusion. The time to recovery of lymphocytes, including CD19-positive B cells, to normal levels has not been determined.
Ofatumumab is eliminated through both a target-independent route and a B-cell mediated route. Due to the depletion of B cells, the clearance of ofatumumab decreases substantially after subsequent infusions compared to the first infusion.
Clinical Trials
The efficacy of ofatumumab was examined in a single-arm, multicenter study involving 154 patients with relapsed or refractory CLL. Oftamumab was administered by IV infusion according to the following schedule: 300mg (Week 0), 2000mg weekly for 7 infusions (Weeks 1 through 7) and 2000mg every 4 weeks for 4 infusions (Weeks 12 through 24). The efficacy population was comprised of patients with CLL refractory to fludarabine and alemtuzumab. 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. The investigator-determined overall response rate in patients with fludarabine- and alemtuzumab-refractory CLL was 42%, with a median response of 6.5months. There were no complete responses. Antitumor activity was also seen in additional patients in this study and in a multicenter, open-label dose-escalation study conducted in patients with relapsed or refractory CLL.
Adverse Reactions
Neutropenia, thrombocytopenia, anemia, pneumonia, pyrexia, cough, fatigue, dyspnea, rash, GI upset, bronchitis, upper respiratory tract infections; infusion reactions (eg, bronchospasm; laryngeal, pulmonary, or angioedema; flushing, hyper- or hypotension, syncope, cardiac ischemia, back or abdominal pain, fever, urticaria) (interrupt infusion and monitor; do not restart if grade 4 reaction occurs), progressive multifocal leukoencephalopathy (discontinue if occurs and monitor), intestinal obstruction, infections (eg, sepsis).
Adults
Premedicate with acetaminophen (oral), antihistamine (oral or IV), corticosteroid (IV); see literature. Give by IV infusion (use in-line filter; rate varies with dose and during infusion). Initially 300mg once, then 1 week later 2000mg weekly for 7 doses, then 4 weeks later 2000mg every 4 weeks for 4 doses.
Children
Not recommended.
Precautions
Monitor CBC, platelets, and for neurological changes. Pre-screen for hepatitis B in high-risk patients; discontinue if viral hepatitis emerges. Pregnancy (Cat.C). Nursing mothers.
Interactions
Avoid vaccination with live viral vaccines.
