GlaxoSmithKline (GSK) and Genmab A/S announced the submission of a Biologics License Application (BLA) to the US Food and Drug Administration (FDA) for Arzerra (ofatumumab) to treat patients whose chronic lymphocytic leukaemia (CLL) is resistant (refractory) to previous therapies. If approved, ofatumumab would be the first monoclonal antibody targeted to CD20 available for this patient population.

CLL is the most common form of adult leukaemia in the Western world, affecting more than 90,000 Americans. Patients with refractory CLL need new therapies since less than 25 per cent respond to most current treatments while still having to cope with adverse effects.

"The submission of the BLA for ofatumumab brings us closer to providing a new treatment to patients with refractory CLL," said Lisa N. Drakeman, Ph.D., chief executive officer of Genmab. "This is the first BLA ever filed for an antibody produced by Genmab and is a significant achievement in our partnership with GSK."

The submission is based on an analysis that included 138 patients with CLL who showed limited or no response to both fludarabine and alemtuzumab treatment (fludarabine alemtuzumab refractory) and patients who were refractory to fludarabine and considered inappropriate candidates for alemtuzumab due to bulky tumour masses (>5 cm) in their lymph nodes (bulky fludarabine refractory). The primary endpoint of the study was assessment of response. The overall response rate seen in these patient groups treated with single-agent ofatumumab was 58 per cent for the fludarabine alemtuzumab refractory group (n=59) and 47 per cent for the bulky fludarabine refractory group (n=79).

The most common adverse events (AEs) seen with ofatumumab were related to infusion reactions and infections. AEs seen in at least 10 per cent of patients included fever, cough, diarrhoea, rash, low white blood cell counts, fatigue, pneumonia, anaemia, shortness of breath, and nausea. In clinical trials to date, infusion reactions which were serious yet manageable were seen in three percent of patients. One case of progressive multifocal leukoencephalopathy (PML), a rare brain infection resulting in death or causing severe disability and one case of tumour lysis syndrome were reported. These data were presented at the 50th Annual Meeting of the American Society of Haematology (ASH) in December 2008.

The companies also announced the initiation of an additional phase III study of ofatumumab in combination with fludarabine and cyclophosphamide (FC) for patients with CLL when initial treatment no longer works (second-line treatment). The open-label study will randomize 352 patients to evaluate progression-free survival (PFS) of ofatumumab in combination with FC therapy versus FC therapy alone for the treatment of relapsed CLL. Enrolment for this study will begin shortly.

"Bolstered by the positive results of ofatumumab for advanced stage CLL, we're now investigating ofatumumab in earlier stages in the treatment continuum," said Paolo Paoletti, M.D., senior vice president of oncology R&D, GSK. "The clues we're seeing from ofatumumab also suggest possible activity in other oncology settings, which we're currently evaluating through several clinical trials."

GSK and Genmab will conduct additional studies of ofatumumab in CLL and non-Hodgkin's lymphoma (NHL) settings. In CLL, a phase III front-line study is evaluating ofatumumab combined with chlorambucil in patients with previously untreated CLL. In NHL, an ongoing phase II study will assess ofatumumab in patients with Waldenstrom's Macroglobulinemia - a rare type of slow-growing NHL. Finally, a phase II study is evaluating ofatumumab plus ICE or DHAP chemotherapy regimen in relapsed/refractory diffuse large B cell lymphoma (DLBCL).

Ofatumumab is an investigational monoclonal antibody that 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.

Ofatumumab is being developed to treat chronic lymphocytic leukaemia, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, rheumatoid arthritis, and relapsing-remitting multiple sclerosis under a co-development and commercialization agreement between Genmab and GlaxoSmithKline. It is not yet approved in any country.

The companies intend to submit an application for marketing approval in Europe shortly.

CLL is the most common adult leukaemia and one of the most common malignant lymphoid diseases. Based on 2007 worldwide estimates, leukaemia accounted for more than 330,000 new cases and more than 245,000 deaths.