Genmab A/S (COPENHAGEN, Denmark), a biotechnology company that creates and develops human antibodies for the treatment of rheumatoid arthritis (RA) and other inflammatory conditions, cancer, and infectious disease, announced it has completed enrollment in the HuMax-CD20â„¢ (ofatumumab) phase II study to treat patients with active RA who have failed treatment with one or more disease-modifying anti-rheumatic drugs (DMARDs), including biologics. A total of approximately 200 patients have been enrolled in the study. Patients will be randomized into four treatment groups. In each group, 50 patients will receive two infusions of 300-, 700-, or 1000-mg doses of HuMax-CD20 or placebo. The doses will be given 2 weeks apart. Patients receiving a stable dose of methotrexate between 7.5 and 25 mg per week at the time of screening will continue this regimen. Patients will be followed for 24 weeks to evaluate safety and efficacy and then every 12 weeks until B-cell counts return to baseline levels.

Results from a phase I/II study show that 73% (19/26) of patients who received two doses of HuMax-CD20 obtained ACR20. On an intent-to-treat analysis, which included six patients who did not receive both doses of HuMax-CD20, 63% (20/32) obtained an ACR20 response. None of the seven patients who received placebo achieved ACR20. Thirty-eight percent (10/26) patients who received two doses of HuMax-CD20 achieved ACR50 and 15% (4/26) achieved ACR70. Three dose levels were assessed in the study. In the lowest dose group (300 mg), 75% (6/8) patients who received both doses obtained ACR20. In both the 700- and 1000-mg dose groups, 78% of patients who received both doses obtained ACR20 (7/9 patients per group). The study included 39 patients and 33 received either two infusions of HuMax-CD20 or placebo, given 2 weeks apart. The primary objective of the study was safety, and efficacy was assessed by the ACR score at week 24. Patients in this phase I/II study had previously failed at least one DMARD. In addition, 26 of the 39 patients had previously received treatment with tumor necrosis factor (TNF) inhibitors. Twenty-two were intolerant or refractory to TNF inhibitors and four stopped treatment for other reasons. Efficacy among these patients was in the same range as that of the rest of the group on an intent-to-treat basis. Two infusion-related serious adverse events and a common terminology criteria (CTC) grade 3 event were observed in the 300-mg cohort. Consequently, pre-medication with corticosteroids was implemented and further intensified for the 700-mg and 1000-mg cohorts, in which 2 patients reported infusion-related CTC grade 3 events. In August 2005 Genmab announced the expansion of the study into a phase II trial.

HuMax-CD20 is a fully human, high-affinity antibody targeted at the CD20 molecule in the cell membrane of B-cells. The CD20 antigen is a transmembrane protein on pre-B and mature B lymphocytes. CD20 appears to act as a calcium ion channel and to regulate early steps in B lymphocyte activation. The molecule is not shed from the cell surface, and is not internalized upon antibody binding. In laboratory tests and animal studies, HuMax-CD20 has been shown to deplete B-cells effectively. B-cells are crucial pathogenic elements in the induction and pathogenesis of RA.

In vivo data of HuMax-CD20 in cynomolgus monkeys showed treatment with HuMax-CD20 resulted in rapid and more sustained B-cell depletion than rituximab (currently comarketed by Biogen Idec and Genentech in the US and Roche in the EU). In laboratory experiments, HuMax-CD20 appears to induce more effective killing of targets expressing low levels of CD20 than does rituximab. A panel of cell lines expressing varying amounts of CD20 molecules per cell (4500-135,000 molecules) was generated. HuMax-CD20 appeared to be highly superior in the induction of complement-mediated lysis of cells for all CD20 expression levels as compared to rituximab. HuMax-CD20 appeared to induce significant lysis of cells at the lowest CD20 expression level tested, whereas such cells seemed resistant to rituximab. Complete lysis was achieved by HuMax-CD20 at intermediate expression levels of CD20, whereas complete lysis with rituximab was not seen.

—A. Techman