Genmab Initiates Clinical Trials With HuMax-IL15; Second Genmab Product in Clinical Trials
COPENHAGEN, Denmark, Oct. 3 /PRNewswire/ -- Genmab A/S (CSE: GEN and Neuer Markt: GE9D) announced today that it has initiated a Phase I/II clinical trial with its fully human antibody HuMax(TM)-IL15 to treat patients with active rheumatoid arthritis. This multi-center, placebo-controlled study will test up to 6 dose levels and include approximately thirty patients. It is designed to provide safety data about both single and multiple doses of HuMax-IL15, with a secondary goal of gathering information about the efficacy of the antibody.
HuMax-IL15 is a high-affinity, fully human antibody against Interleukin-15 (IL-15) being developed through a collaboration with Immunex Corporation. HuMax-IL15 is Genmab's second product in the clinic; it joins HuMax-CD4, which is currently in Phase II clinical trials.
IL-15 is a cytokine, an immune system signaling molecule, that appears early in the cascade of events that ultimately lead to inflammatory disease. IL-15 is a particularly interesting disease target because it is involved in several steps of the inflammation cycle. IL-15 induces both the production of TNF-alpha, another cytokine that has been shown to play a pivotal role in inflammation, as well as the recruitment of inflammatory T cells. These T cells in turn promote the production of more IL-15, and the cycle escalates.
HuMax-IL15 has the potential to treat a wide range of patients as it is designed to block the activity of IL-15 and thus interfere broadly with the inflammatory processes involved in diseases such as rheumatoid arthritis, psoriasis and Crohn's disease.
``Millions of patients suffer from inflammatory diseases and do not respond adequately to current therapies,'' said Lisa N. Drakeman, Chief Executive Officer of Genmab. ``Because its mechanism of action is unique compared to other available products, HuMax-IL15 has the potential to treat many new patients who are struggling with these painful and debilitating diseases.''
Genmab A/S is a biotechnology company that creates and develops fully human antibodies for the treatment of life-threatening and debilitating diseases. Genmab has multiple products in development to treat cancer, rheumatoid arthritis and other inflammatory conditions, and intends to assemble a broad portfolio of new therapeutic products arising from research into the human genome. At present, Genmab's commercial opportunities are based upon research conducted at leading international companies, including Roche, Immunex Corporation, Oxford GlycoSciences Ltd., Gemini Genomics plc, Eos Biotechnology Inc., Medarex Inc., deCode Genetics and Glaucus Proteomics B.V., as well as in its own laboratories. A broad alliance provides Genmab with access to Medarex Inc.'s array of proprietary technologies, including the UltiMAb(TM) platform, for the rapid creation and development of fully human antibodies to virtually any disease target. For more information about Genmab, visit www.genmab.com.
Except for the historical information presented, certain matters discussed in this press release are forward-looking statements that are subject to a number of risks and uncertainties that could cause actual results to differ materially from results, performance or achievements expressed or implied by such statements. Such risks and uncertainties are associated with product discovery and development including statements regarding the Company's clinical development programs and the expected timing of clinical trials and regulatory filings. Such statements are based on management's current expectations, but actual results may differ materially.
UltiMAb(TM) is a trademark of Medarex, Inc. HuMax is a trademark of Genmab A/S.
HuMax(TM)-IL15 Background Information
Rheumatoid Arthritis and the Need for New Treatments
Rheumatoid arthritis (RA) is a severe, progressive autoimmune disease that causes painful and debilitating inflammation in the joints and tendons. The therapies currently available for RA cannot cure the disease, and are often only partially effective, particularly in severe and progressive cases. Certain treatments may diminish progression in some patients, but often at the cost of significant toxicity. It is, therefore, a high priority to develop new drugs with fewer side effects that will also limit and decrease the inflammatory processes that are associated with this disease.
Role of IL-15 in Inflammatory Disease
The cytokine Interleukin-15 (IL-15), an immune system signaling molecule, plays an important part in the progression of inflammation in RA(i, ii). A new drug having anti-IL-15 properties could be expected to provide significant clinical benefit for patients afflicted with this disease(iii). Genmab's newest product to enter human clinical trials, HuMax(TM)-IL15, is designed to block the activity of IL-15.
Immune system T cells, and in particular CD4+ T-helper cells, are involved in the initiation and maintenance of inflammatory processes in RA. TNF-alpha, another cytokine, is involved in the inflammatory pathways which ultimately lead to joint destruction and incapacitation of the patient with RA. Recent research into this disease indicates that local synthesis of IL-15 plays a key role both in the activation and recruitment of T cells and in the induction of TNF-alpha and other inflammatory cytokines(ii). A positive feed-back loop has been suggested(ii), whereby IL-15 synthesized by macrophages induces T cell recruitment. The activated T cells then: 1) maintain macrophage activation and 2) induce TNF-alpha production. Stimulated macrophages promote the synthesis of more IL-15 and T cell activation, and the cycle continues (see figure below). In addition to its effects on TNF-alpha and macrophages, IL-15 is also predicted to activate neutrophils and affect local B cell immunoglobulin secretion, particularly rheumatoid factor synthesis(ii).
In vivo Studies Targeting IL-15
Animal models for rheumatoid arthritis have further elucidated the role of IL-15. In a murine model of arthritis, an injection of IL-15 into the joint significantly increased the number of T cells in the resulting tissue inflammation(iv). In another murine model of arthritis, an antagonist to IL-15 suppressed the development of collagen induced arthritis (CIA) and delayed the initiation of both humoral and cell-mediated immune responses(v). In SCID mice engrafted with inflamed RA joint tissue, IL-15 was shown to enhance T cell movement into the inflamed tissue(vi).
Because RA is an autoimmune disease, there is a strong rationale to pursue immunomodulators as therapeutic entities. Many recent therapeutic options are exploring biological approaches for the treatment of RA. Two recently commercialized products target TNF-alpha's role in the inflammation process.
Its early and multifaceted role in the inflammatory cascade makes IL-15 a particularly promising target for breaking the cycle of rheumatoid arthritis progression. Genmab's HuMax-IL15 is a fully human, high-affinity neutralizing antibody against IL-15 being developed through a collaboration with Immunex Corporation. Following extensive pre-clinical studies, HuMax-IL15 is now in a Phase I/II clinical trial to treat patients with active rheumatoid arthritis.
References:
(i) McInnes IB, et al. IL-15 mediates T-cell-dependent regulation of
TNF-alpha production in RA. Nature Med 1997;3:189-5.
(ii) McInnes IB and Liew FY. IL-15: a proinflammatory role in RA
synovitis. Immunol Today 1998;19:75-9.
(iii) Fehninger and Caligiuri. IL-15: biology and relevance to human
disease. Blood 2001;97:14-32
(iv) McInnes IB, et al. The role of interleukin-15 in T cell migration
and activation in rheumatoid arthritis. Nat Med 1996;2:175-82.
(v) Ruchatz H, et al. Soluble IL-15 receptor a-chain administration
prevents murine collagen-induced arthritis: a role for IL-15 in
development of antigen-induced immunopathology. J Immunol
1998;160:5654-60.
(vi) Oppenheimer-Marks N, et al. IL-15 is produced by endothelial cells
and increases the transendothelial migration of T cells in vitro
and in the SCID mouse-human rheumatoid arthritis model in vivo. J
Clin Investig 1997;101:1261-72. |
