HuMax-CD4® is a high-affinity, fully human antibody that targets the CD4 receptor on T-cells and is currently in development for cutaneous T-cell lymphoma (CTCL) and non-cutaneous T-cell lymphoma (NCTCL). HuMax-CD4 has been designated a Fast Track Product by the US Food and Drug Administration (FDA), covering patients with CTCL who have failed currently available therapy. HuMax-CD4 has also been granted Orphan Drug status in the US,  Europe and Australia for the treatment of refractory CTCL and for the treatment of refractory NCTCL in Europe. Genmab and the FDA have also reached an agreement on the design of its pivotal study protocol for HuMax-CD4 to treat CTCL under the Special Protocol Assessment process (SPA).

Cutaneous T-Cell Lymphoma (CTCL)

CTCL covers a range of diseases characterized by infiltration of the skin by malignant T-cells that express the CD4 receptor, including mycosis fungoides and Sézary syndrome. Mycosis fungoides represents around 75% of all CTCLs.  Most patients show symptoms even at the earliest stage of the disease with severe and sometimes debilitating itching and susceptibility to recurrent skin infections, and the majority suffer moderate to severe cosmetic disfigurement. The disease is incurable except at a very early stage and is life threatening in the advanced stages.  Defective apoptosis (or programmed cell death) has been documented in several groups of CTCL patients, which may contribute to the difficulty of killing these types of tumors.

T-cell lymphomas positive for the CD4 receptor constitute around 5% of non-Hodgkin’s lymphomas. There are about 1,600 new cases of CTCL per year in the US and the prevalence of the disease is estimated at 22,000 to 26,000. CTCL patients tend to have a lifespan of 10 to 30 years and therefore could be treated several times during disease progression. An anti-CD4 antibody that depletes CD4 positive cells in vivo may have the potential to induce a clinical response in these patients.

Ongoing Clinical Studies

Phase III Pivotal Study
The pivotal study will include patients with the most common form of CTCL, mycosis fungoides, who are refractory to or intolerant of Targretin® and one other standard therapy, and will consist of two stages.  As Genmab has changed the manufacturer for HuMax-CD4 in order to prepare for potential commercial launch, Genmab agreed with the FDA under an SPA, to treat a total of 18 patients at three doses prior to treating the remaining 70 patients in a randomized manner at the two higher doses.

The first stage of the trial is open-label and consists of three dose cohorts in each of which six patients will receive 4 mg/kg, 8 mg/kg or 14 mg/kg of HuMax-CD4.  In an average size person weighing 70 kg, these doses would be 280 mg, 560 mg and 980 mg. The second stage of the trial is blinded and will include 70 patients randomized to either 8 mg/kg or 14 mg/kg of HuMax-CD4 once weekly for 12 weeks.

The primary endpoint of the Phase III trial will be the complete and partial response rate during treatment and an eight week follow up period.  Responses must last at least four weeks and will be assessed by the Physician’s Global Assessment (PGA) which takes all disease manifestations into account.  With this assessment, partial responses are improvements of at least 50% in PGA score and complete responses are 100% improvements.

Preliminary results from the first stage of the pivotal study were reported in December 2006. Clinical response was shown in 5 of 12 patients (42%) in the two highest dose groups. A partial response was obtained by 1 of 6 patients (16%) in the 8 mg/kg dose group and 4 of 6 patients (67%) in the 14 mg/kg dose group. Patients were also treated at the 4 mg/kg dose level, with no responses observed.

In October 2007, Genmab amended the design of the pivotal study to include patients with Sézary Syndrome.  Furthermore, due to higher response rates observed at the 14 mg/kg dose level during the first part of the study, the 8 mg/kg dose level will be discontinued, with all patients to be treated with 14 mg/kg of HuMax-CD4.  These study amendments have been agreed to by the FDA under the Special Protocol Assessment agreement already in place.

View poster of preliminary study results presented at ASH in 2006.

Previous Clinical Studies

Phase II Results
Genmab reported results from two Phase II studies concurrently – one for early stage CTCL and one for late stage. In both studies, patients were refractory or intolerant to previous therapy and treatment regimen involved a 280 mg, 560 mg or 980 mg dose of HuMax-CD4 once a week for 16 weeks. Patients were followed for at least 4 weeks after the end of treatment or until disease progression.  The objective of the studies was to determine the efficacy and safety of HuMax-CD4 in the treatment of CTCL. Clinical response was evaluated using the Composite Assessment of Index Lesion Disease Activity (CA) Score, with results as follows.

At the 280 mg dose level, 36% (4 of 11) early stage MF patients obtained a CA score reduction of more than 50%. One patient achieved a complete response (100% CA score reduction and histological confirmation).  Twenty-two percent (2 of 9) of the advanced stage MF patients obtained partial responses with 280 mg treatment.

In early stage MF patients treated at the 560 mg dose level, 50% (7 of 14) obtained a CA score reduction of more than 50%, including two patients who achieved complete response.  Seventy-five percent (3 of 4) of advanced stage patients treated with 980 mg of HuMax-CD4 obtained partial responses.

Nine patients with Sézary syndrome were also treated in the Phase II studies, also at dose levels of 280, 560 and 980 mg of HuMax-CD4.  Forty-four percent (4 of 9) obtained a 50% CA score reduction with one obtaining a partial response.  The observed response in these patients was generally short-lived and depletion of CD4 T-cells was limited.  This patient group constitutes approximately 5% of CTCL patients and is not included in the pivotal study.

At the high dose levels of 560 mg and 980 mg, 13 MF patients had objective responses lasting between 8 and 91 weeks, with median response duration of 81 weeks (20.3 months). Nine of the responses lasted more than 20 weeks.  Three MF patients treated at the 280 mg dose had responses lasting 12, 13 and 24 weeks and discontinued the study before disease progression. Furthermore, analysis of the time to response showed that 85% of the responding patients (11/13) obtained clinical response within 8 weeks.

In total, 47 patients were treated in the Phase II CTCL studies. Based on judgments by the treating physicians, only five grade three events (hypersensitivity, elevated liver enzymes, aggravated pruritus [2 patients], and muscle fiber rupture) were considered related and six additional events, including five grade three and one grade four event were considered unrelated to HuMax-CD4 treatment.

View poster of preliminary study results presented at SID in 2004 

Non-Cutaneous T-Cell Lymphoma (NCTCL)

Approximately half of all non-cutaneous T-cell lymphomas express the CD4 receptor on their cell surface and they originate predominantly in the lymph nodes. This includes peripheral T-cell lymphoma unspecified and angioimmunoblastic T-cell lymphomas, of which 75% are CD4 positive, and anaplastic large cell lymphomas of which 20% are CD4 positive. Their prevalence in the US is approximately 9,000 to 19,000. 

Ongoing Clinical Studies

Phase II Combination Study
A Phase II study of HuMax-CD4 in combination with CHOP chemotherapy is underway for the treatment of non-cutaneous T-cell lymphoma. 

Previous Clinical Studies

Phase II
Genmab has conducted a Phase II study of HuMax-CD4 to treat patients with refractory or relapsed non-cutaneous T-cell lymphoma. The international multi-center trial included 21 patients. During the study, patients received 980 mg of HuMax-CD4 once weekly for 12 weeks and were followed until disease progression. The primary endpoint of the study was objective tumor response from start of treatment to week 18. Responses were assessed by using standard response criteria for non-Hodgkin's lymphoma.

Positive final results were reported in November 2007.  Objective tumor response was obtained in 5 of 21 patients (24%).  Three patients obtained partial responses lasting 43 and 51 days with one patient not relapsing at 182 days.  Two patients obtained a complete response unconfirmed, one lasting 46 days and one showing no relapse after 252 days.

HuMax-CD4 was generally well tolerated in this patient population.  During the study period, a total of 6 serious adverse events were assessed as related to HuMax-CD4 treatment and included 4 infusion related events.  The patients with related serious adverse events completely recovered.

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

Selected Scientific References:

Kim, Y., M. Duvic, E. Obitz, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma.  Blood 2007; 109: 4655-2662.

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

Obitz, E., Kim, Y. H., Iversen, L., Österborg, A., Jensen, P., Baadsgaard, O., and S. J. Knox. [Abstract #2383] HuMax-CD4, a Fully Human Monoclonal Antibody: Early Results of an Ongoing Phase II Trial in Cutaneous T Cell Lymphoma (CTCL). 45th Annual Meeting of American Society of Hematology, December 2003. Session Type: Poster Session 554-II.  Abstract #2383 appears in Blood 2003; 102 (11) November 16, 2003.

Knox, S., R. T. Hoppe, D. Maloney, I. Gibbs, S. Fowler, C. Marquez, J. Cornblest, and R. Levy.  Treatment of Cutaneous T-Cell Lymphoma with Chimeric Anti-CD4 Monoclonal Antibody.  Blood 1996; 87 (3): 893-899.

Diamandidou, E., Cohen, PR, and Kurzrock, R. Mycosis Fungoides and Sezary Syndrome. Blood 1996; 88: 2385-2409.