The CD20 molecule appears to act as a calcium ion channel and regulate early steps in B lymphocyte activation. The molecule is not shed from the cell surface and is not internalized upon antibody binding.  CD20 is found on over 90% of B-cell lymphomas, as well as other lymphoid tumors of B-cell origin. In types of cancer such as these, the B-cells can over-proliferate and treatment is needed to reduce their number.  Based on data from clinical cancer trials and commercialization activities conducted by other biotechnology and pharmaceutical companies using CD20 antibodies, we believe that an antibody targeting CD20 may be an effective treatment for B-cell lymphoma.

B-cells are also crucial pathogenic elements in the induction and pathogenesis of RA. As B-cells are involved in various cellular interactions with immune cells, B-cell depletion after ofatumumab treatment may affect RA disease activity.

In laboratory tests and animal studies, ofatumumab has been shown to deplete B-cells effectively. Ofatumumab is also effective at binding to the disease target and releases very slowly from the target over time.

Non-Hodgkin's Lymphoma 

Follicular NHL is a subgroup of NHL and is the second most common lymphoma in the US and Europe, accounting for 11 to 35% of all NHL.

Ongoing Clinical Studies

Phase III Pivotal Study
Ofatumumab is currently in a pivotal study to treat follicular NHL patients who are refractory to rituximab in combination with chemotherapy or to rituximab given as maintenance treatment. The study design has been amended to a single arm trial that will now include approximately 81 patients. All patients will receive one infusion of 300 mg of ofatumumab followed by 7 weekly infusions of 1000 mg of ofatumumab. The original study design included approximately 162 patients who would have received one infusion of 300 mg of ofatumumab followed by 7 weekly infusions of either 500 or 1000 mg of ofatumumab.

In order to establish that ofatumumab is efficacious in this refractory setting, reducing the number of patients in the trial will help to expedite a result.  The 500 mg dose was dropped to reduce the total number of patients to be accrued and ensure that these very sick patients receive the maximum dose.  Data from patients who were already treated in the 500 mg dose group will be analyzed  for safety and included in the secondary efficacy analysis, but will not be included in the primary efficacy analysis.

Disease status will be assessed every 3 months until month 24. The objective of the pivotal study is to determine the efficacy and safety of ofatumumab. The primary endpoint is objective response as measured over a 6 month period from start of treatment as assessed by an Independent endpoints Review Committee according to the standardized response criteria for NHL.

Planned Clinical Studies

Phase II Retreatment and Maintenance Study
In August 2008, Genmab announced plans to initiate a study examining the retreatment and maintenance treatment of refractory follicular NHL patients who participated in the ongoing Phase III NHL study and had disease progression following at least 6 months objective response to or stable disease on ofatumumab.  Eligible patients will receive one infusion of ofatumumab at 300 mg followed by 7 once weekly infusions at 1000 mg.  Maintenance treatment will consist of one 1000 mg infusion every two months for two years.  The primary objective of this study is to evaluate the safety of ofatumumab retreatment and maintenance treatment.  The study is expected to begin in 2008.

Previous Clinical Studies

Phase I/II Results
The Phase I/II dose escalation trial was designed for 40 patients divided into 4 dose cohorts to receive 4 weekly infusions of ofatumumab at doses of 300, 500, 700 and 1000 mg and were followed for 12 months. Patients in the study had relapsed or refractory follicular NHL and had previously received a median of 2 treatment regimens, including the possibility of rituximab.

In 37 evaluable patients, objective responses at each dose level were 63% (300 mg), 33% (500 mg), 20% (700 mg) and 60% (1000 mg). These response rates include 5 complete responses (CR), 2 complete responses unconfirmed (CRu) and 9 partial responses (PR). A CRu meets and exceeds the criteria for partial response.

The objective response rate in patients who previously responded to rituximab treatment was 64% (9 of 14 patients), including 3 CR, 1 CRu and 5 PR for a 29% complete response rate. Immediate, profound depletion of B-cells was seen at all dose levels. This depletion was generally maintained during the follow up period.

The median duration of response and median time to disease progression in responding patients had not been reached after 12 months of follow up. Of the 16 patients who responded to treatment, 12 had not progressed at the end of the follow up period.

Ofatumumab was well tolerated by the patients in the study. No dose limiting toxicities were reported during the study and the maximum tolerated dose was not reached. The most frequently reported adverse events were rigors, fatigue, headache and rash. Hematological toxicity was low with only 6 of 40 patients reporting grade 1 neutropenia and no patients reporting thrombocytopenia.

View poster of preliminary study results presented at ASH in 2004 

Chronic Lymphocytic Leukemia   

CLL is the most common leukemia in adults in the US and most of Western Europe. The incidence is 8,100 to 12,500 new cases in the US per year and 85-95% of the cases are of B-cell origin. CLL together with another subgroup of NHL, small lymphocytic lymphoma (SLL), corresponds to around 20% of all NHL cases.

Ongoing Clinical Studies

Phase III Pivotal Study
A Phase III pivotal study with ofatumumab to treat patients with refractory B-cell CLL is ongoing. The study has been amended to include approximately 200 CLL patients and two different patient populations. The main patient populations to be examined in the study are: patients who are refractory to both fludarabine and alemtuzumab and fludarabine refractory patients who are considered inappropriate candidates for alemtuzumab due to bulky tumor in their lymph nodes. Each group will consist of approximately 100 patients and will be analyzed separately. Due to the high unmet medical need amongst these patients, registration of ofatumumab could be possible in each indication, depending on the data generated from this study.

All patients in the pivotal trial will receive 8 weekly infusions of ofatumumab, followed by 4 monthly infusions of ofatumumab. Patients will receive 300 mg of ofatumumab at the first infusion and 2000 mg of ofatumumab at each subsequent infusion. Disease status will be assessed every 4 weeks until week 28 and then every 3 months until disease progression or month 24.

The objective of the study is to evaluate the efficacy and safety of ofatumumab and the primary endpoint is objective response over a 24 week period from start of treatment. The responses will be assessed by an Independent Endpoints Review Committee according to the NCI Working Group guidelines.

Genmab and GSK reported positive top-line results from an interim analysis of the study in July 2008. At the interim analysis, the study met the primary endpoint in both populations and the results from the secondary endpoints also support the primary endpoint. The data will be presented at the American Society of Hematology meeting in December 2008. 

The activity of ofatumumab was evaluated in 154 patients in the interim analysis of whom 138 patients with refractory CLL were evaluable. Fifty-nine patients in the study were refractory to both fludarabine and alemtuzumab (double refractory) and 79 were refractory to fludarabine and considered inappropriate candidates for alemtuzumab due to bulky tumor in their lymph nodes (fludarabine refractory). An objective response rate of 51% (p<0.0001) consisting of 30 partial responses (PR) was achieved in the double refactory group. Stable disease was achieved by 39% of double refractory patients.  In the fludarabine refractory, alemtuzumab inappropriate patient group, an objective response rate of 44% (p<0.0001) was achieved, including 1 complete response (CR), and 34 PR. Stable disease was achieved by 43% of patients in the fludarabine refractory group.  Achievement of the reported objective response rates are based on evaluations by an independent committee and are subject to review and confirmation by the regulatory authorities.

In the double refractory patient group, the median time to next CLL therapy was 9 months and median overall survival was about 14 months.  In the fludarabine refractory group, median time to next CLL therapy was 8 months and median overall survival was 15 months.  Responses were significantly correlated to overall survival.

Ofatumumab was generally well tolerated by CLL patients in the study and there were no unexpected safety findings. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of double refractory patients and 38% of fludarabine refactory patients.  These events generally subsided with subsequent infusions.  The most common grade 3 or 4 toxicites were infiections and hematologic events including neutropenia and anemia.  None of the 33 patients tested for human anti-human antibodies (HAHA) demonstrated their presence at 12 months.

We continue to discuss these data with the FDA for the potential submission of a BLA in 2008. There is also the potential to submit to the EU regulatory authorities in this time frame.

Phase II FC Combination Study
A Phase II study of ofatumumab in combination with fludarabine and cyclophosphamide (FC) to treat CLL in previously untreated patients is ongoing.  A total of 56 patients will be enrolled in the open label front line study.  Patients will be randomized into two treatment groups of 28 patients each.  Each patient will receive 6 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. 

Disease status will be measured every 4 weeks until week 24 according to NCI Working Group Guidelines and every 3 months thereafter until disease progression or 24 months.  Patients not having progressive disease at 24 months will be followed for disease progression at 6 month intervals until 48 months.  The objective of the study is to determine the efficacy of ofatumumab in combination with FC in previously untreated CLL patients.  The primary endpoint is complete remission measured from start of treatment until 3 months after last infusion. 

Phase III Front Line Chlorambucil Combination Study 
An open-label, parallel-arm study including 444 patients with previously untreated CLL was initiated in November 2008.  Patients in the study will be randomized to receive ofatumumab in combination with chlorambucil or chlorambucil alone.  Patients receiving ofatumumab in combination with chlorambucil will receive one infusion of ofatumumab at 300 mg, one infusion at 1000 mg a week later, followed by up to 11 monthly infusions at 1000 mg.  Patients will be evaluated for disease status one month following last treatment then every 3 months for 5 years.  The primary objective of the study is to evaluate the progression free survival of ofatumumab in combination with chlorambucil therapy versus chlorambucil therapy alone for the treatment of front line CLL. 

Planned Clinical Studies

Phase II Retreatment and Maintenance Study
In August 2008, Genmab announced plans to initiate a study to examine the retreatment and maintenance treatment of refractory CLL patients who participated in the ongoing Phase III CLL study and had disease progression following at least an objective response or stable disease during a 24 week treatment period of ofatumumab.  Eligible patients will receive one infusion of ofatumumab at 300 mg followed by 7 once weekly infusions at 2000 mg.  Maintenance treatment will consist of 24 once monthly infusions of 2000 mg of ofatumumab.  The primary objective of this study is to estimate the proportion of objective responses over 52 weeks.  The study is expected to begin in 2008.

Previous Clinical Studies

Phase I/II Results
Positive results in the Phase I/II study showed that ofatumumab induces rapid responses in patients with relapsed CLL. Responses generally appeared early with 67% of evaluable patients treated at the highest dose level (2000 mg) responding to treatment at week 4, including 16 patients who showed responses by physical examination and peripheral blood evaluation. Ten patients showed complete responses by absence of enlarged lymph nodes, spleen and liver, and by normalization of blood counts at any time point during the 19 week follow up period. 

Thirteen of 26 evaluable patients (50%) treated at the highest dose level obtained objective responses lasting at least 8 weeks by the NCI working group guidelines for CLL at week 26 including one nPR confirmed by CT scan and one patient who qualified as nPR but had residual lymphadenopathy revealed by CT.   

Ofatumumab also induced marked effects in the bone marrow of several patients in the study. By the NCI Working Group Guidelines for CLL, complete responses must be confirmed with CT scan and bone marrow samples. Under the study protocol, these were not scheduled to occur until week 19 at the minimum and could take place up to week 26, which could be over 5 months since the response was initially observed.

The median time to disease progression in all patients treated at the highest dose level was approximately 16 weeks, ranging from 15 to 23 weeks.  In the patients responding to ofatumumab treatment, the median time to disease progression was 23 weeks, ranging from 20 to 31 weeks.  The median time to next anti-CLL treatment was 52 weeks.  These survival endpoints correlated to the patients’ total exposure to ofatumumab over time and to the clearance of the antibody.

The pharmacokinetics in the study support the use of ofatumumab in CLL and indicate that responses and their duration may further improve with continued treatment.

Ofatumumab was well tolerated by CLL patients in the study and the maximum tolerated dose was not reached. Investigators reported 5 serious adverse events assessed as potentially related to ofatumumab: hepatic cytolysis, herpes zoster, neutropenia (2 patients) and one death from pneumonia. The pneumonia event was reported 4 weeks after the last treatment. The patient suffered from CLL for 10 years and had a history of 3 episodes of interstitial pneumonia in the years up to enrollment in the trial.

The open-label escalation trial enrolled 33 patients who were treated at three dose levels of ofatumumab: 3 patients received an initial dose of 100 mg, followed by 3 weekly doses of 500 mg; 3 patients received an initial dose of 300 mg, followed by 3 weekly doses of 1000 mg; 27 patients received an initial dose of 500 mg, followed by 3 weekly doses of 2000 mg.

The total follow up period for this study was 12 months from treatment start and the primary endpoint of the trial was objective response over the period from screening to week 19. 

View poster of preliminary study results presented at IWCLL in 2005
View poster of preliminary study results presented at EHA in 2006
View poster of additional study results presented at ASH in 2006 

Rheumatoid Arthritis   

RA is a systemic inflammatory disease which affects 0.8-1.0% of all populations.

Ongoing Clinical Studies

The objective and primary endpoint of Part A of the study is to characterize the safety and tolerability of ofatumumab when administered subcutaneously. The primary endpoint for Part B is to characterize the pharmacokinetics/pharmacodynamics of subcutaneous dosing.  Patients in both Part A and Part B are allowed to continue a stable dose methotrexate therapy. 

Part A will be a randomized, single-blind, placebo controlled, repeat dose, parallel group, dose-range finding study of approximately 40 patients. Administration of ofatumumab for Part A will occur in a hospital based unit in order to ensure safety. 

Part B will be a blinded, randomized, placebo controlled study. On the basis of findings in Part A of the study selected doses will be taken forward for administration in Part B. Dosing for Part B is planned to be conducted on an outpatient basis.

Previous Clinical Studies

Phase II Study
The Phase II trial is an extension of a previous Phase I/II trial and included 200 additional patients randomized into four treatment groups. In each group, 50 patients received two infusions of 300, 700, or 1000 mg of ofatumumab or placebo, given two weeks apart. Patients receiving a stable dose of methotrexate between 7.5 and 25 mg per week at the time of screening continued with it. Patients were followed for 24 weeks to evaluate safety and efficacy and then every 12 weeks until B-cell counts return to baseline levels. 

Positive primary efficacy data from the study was presented at EULAR 2007.  A total of 225 patients with active RA who have previously failed one or more disease-modifying anti-rheumatic drugs (DMARDs) were enrolled in the Phase II study.  In the intention-to-treat study population, comprising 224 patients, ACR20 was achieved by 46% of all patients receiving ofatumumab, ACR50 was achieved by 24% and ACR70 was achieved by 6% of ofatumumab patients compared to 15%, 5% and 0% in the placebo group.  Evaluated by dose groups, an ACR20 response was obtained by 41% (p=0.002), 49% (p<0.001) and 46% (p<0.001) of patients receiving 300 mg, 700 mg and 1000 mg of ofatumumab.  An ACR50 response was obtained by 19%, 26% and 26% of patients receiving the varying doses of ofatumumab, with 9%, 4% and 6% obtaining an ACR70 response. These scores indicate a 20%, 50% or 70% improvement respectively in the number of swollen and tender joints, as well as improvements in other disease-activity measures.

In the subgroup of patients receiving concomitant stable doses of methotrexate, comprising 178 patients, results across the three dose levels of ofatumumab studied showed that an ACR20 response was obtained by 42% (p=0.006), 56% (p<0.001) and 50% (p=0.001) of patients in the 300 mg, 700 mg and 1000 mg dose groups, respectively compared to 16% in the placebo group.  An ACR50 response was obtained by 21%, 26% and 26% of patients receiving the varying doses of ofatumumab, with 8%, 2% and 5% obtaining an ACR70 response. The corresponding responses for the placebo group were 7% and 0%.

At 24 weeks, the patients’ immune responses to study medication (ofatumumab or placebo) were also evaluated by testing for the presence of human anti-human antibodies (HAHAs).  All patients tested negative at 24 weeks.

Overall, 72% (300 mg p<0.001; 700 mg p=0.001; 1000 mg p=0.001) of patients treated with each of the ofatumumab doses experienced at least a moderate (moderate or good) EULAR response compared to 40% of patients receiving placebo at week 24. 

The data also showed that ofatumumab appeared well tolerated, with no increased frequency of serious infections. Approximately half of the adverse events occurred on infusion days (51%) with the most frequently reported being mild or moderate (CTC grade 1-2 events), including throat irritation, dyspnoea and rash.

Phase I/II Results
Genmab has conducted a study of ofatumumab to treat patients with active RA who have failed one treatment with one or more disease modifying anti-rheumatic drugs (DMARDs). Initial results announced in March 2006 showed a 77% (20/26 patients) ACR20 response rate in patients who received two doses of ofatumumab. Even on an intent to treat basis, which included six patients who did not receive both doses of ofatumumab, 63% (20/32) of patients obtained an ACR20 response. For comparison, none of the seven patients who received placebo achieved ACR20.

Three dose levels were treated 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 ofatumumab 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.

Twenty-six of the 39 patients in the study had previously received treatment with 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 for the rest of the group on an intent to treat basis.

The maximum tolerated dose was not reached. 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 where 2 patients reported infusion-related CTC grade 3 events.

The Phase I/II study was expanded into a Phase II study in August 2005.

Diffuse Large B-Cell Lymphoma   

Ongoing Clinical Studies

Phase II Study
A Phase II study of ofatumumab to evaluate treatment of relapsed DLBCL in patients ineligible for or relapsed following a stem cell transplant was initiated in December 2007.  Approximately 75 patients will be enrolled in the study.  In the open label trial, each patient will receive 8 weekly infusions of ofatumumab.  The first infusion will be 300 mg and the 7 subsequent infusions will be 1000 mg of ofatumumab.  Disease status will be assessed 4 weeks after the last infusion and then every 3 months for a total of 24 months after treatment start according to the "Revised response criteria for malignant lymphoma."  After 24 months, patients will be followed until initiation of alternative DLBCL treatment or month 60.  The objective of the study is to determine the efficacy of ofatumumab in patients with relapsed DLBCL inegligible for transplant or relapsed after transplant.  The primary endpoint of the study is objective response over a 6 month period from start of treatment.

Multiple Sclerosis (MS)   

MS is an inflammatory disease of the central nervous system.  MS is twice as common in females as in males, occurs with a peak incidence at the age of 35 years and incidence varies widely in different populations and ethnic groups.  The etiology of MS remains unknown, but the geographic variation points towards possible environmental and genetic factors.  The most common form of MS is relapsing remitting MS (RRMS) characterized by unpredictable recurrent attacks where the symptoms usually evolve over days and are followed by either complete, partial or no neurological recovery.  No progression of neurological impairment is experienced between attacks.

Ongoing Clinical Studies

Pre-clinical Studies   

Data from pre-clinical laboratory tests showed that ofatumumab appeared to kill tumor cells that were resistant to rituximab. The antibody was highly effective in inducing complement mediated cytotoxicity (cell destruction) of B-cell tumors. Additional data appears to show ofatumumab is also effective in inducing Natural Killer cell-mediated cytotoxicity of B-cell tumors. Ofatumumab was far more effective than rituximab in eradicating B-cell tumors in SCID mouse models, as well as in depleting B-cells from peripheral blood and lymph nodes in Cynomolgus monkeys.

In addition, ofatumumab appears to induce more effective killing of targets expressing low levels of CD20 than rituximab in laboratory experiments. When low levels of CD20 are present on tumor targets, rituximab does not appear effective in killing the tumor cells. Ofatumumab, however, is effective when CD20 is expressed at both high and very low levels. In this experiment, a panel of cell lines expressing varying amounts of CD20 molecules per cell (4,500-135,000 molecules) was generated by retroviral transduction of CEM tumor cells. Ofatumumab appeared to be highly superior in the induction of complement-mediated lysis of cells for all CD20 expression levels as compared to rituximab. Ofatumumab 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 ofatumumab at intermediate expression levels of CD20, whereas complete lysis with rituximab was not seen.

Selected Scientific References:

Glennie, M.J., and J.G.J. van de Winkel. Renaissance of cancer therapeutic antibodies. Drug Discovery Today 2003; 8: 503-510.

Cragg, M.S., Morgan, S. M., Chan, H. T. C., Morgan, B. P., Filatov, A.V., Johnson, P. W. M., French, R. R., and M. J. Glennie. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid "rafts." Blood 2003; 101: 1045-1052.

Cragg, MS., and Glennie, MJ. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Epub Blood 2003, October 9.

Kennedy, A. D., Solga, M. D., Schuman, T. A., Chi, A. W., Lindorfer, M. A., Sutherland, W. M., Foley, P.L., and R. P. Taylor. An anti-C3b(i) mAb enhances complement activation, C3b(i) deposition, and killing of CD20+ cells by rituximab. Blood 2003; 101: 1071 - 1079.

Manches, O., Lui, G., Chaperot, L., Gressin, R., Molens, J., Jacob, M., Sotto, J., Leroux, D., Bensa, J, and J. Plumas. In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 2003; 101: 949 - 954.

Cerny, T., Borisch, B., Introna, M., Johnson, P., and A. L. Rose. Mechanism of action of rituximab. Anticancer Drugs. 2002 Nov; 13 Suppl 2:S3-10. Review.

Dechant, M., Teeling, J., Beyer, T., Repp, R., Kunzendorf, U., Glennie, M. J., van de Winkel, J.G.J., and T. Valerius. [Abstract #349] Novel fully human CD20 antibodies with different mechanisms of action. 45th Annual Meeting of American Society of Hematology, December 2003. Session Type: Oral Session. Abstract #349 appears in Blood 2003; 102 (11) November 16, 2003.

Edwards JCW., and Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 2001; 40: 205-211.

McLaughlin, P., Grillo-Lopez, A.J., Link, B.K., et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four dose treatment program. J. Clin. Oncol. 1998; 16:2825-2833.

O'Brien, S.M., Kantarjian, H., Thomas, D.A., Giles, F.J., Freireich, DE.J., Cortes, J., Lerner, S., and Keating, M.J. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J. Clin. Oncol. 2001; 19:2165-2170.

Teeling JL, French RR, Cragg MS, van den Brakel J, Pluyter M, Huang H, Chan C, Parren PW, Hack CE, Dechant M, Valerius T, van de Winkel JG, Glennie MJ. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004 Sep 15;104(6):1793-800.