Hoffmann-La Roche Inc. could find itself paying up to $90 million or more for a preclinical research program with transplant rejection and rheumatoid arthritis applications.

The Nutley, N.J.-based company, an affiliate of the Swiss pharmaceutical giant F. Hoffmann-La Roche Ltd., acquired a product called CRB-15, a human interleukin-15 cytokine receptor blocker, from Cardion AG. In addition to an undisclosed up-front payment and milestone compensation that could total up to $90 million, the Erkrath, Germany-based company is eligible for royalties based on future product sales.

The companies did not disclose more detailed financial terms, but in exchange for Cardion's intellectual property rights to CRB-15, Roche also will assume responsibility for the product's development and potential worldwide commercialization.

"We've been building a portfolio for arthritis and other autoimmune disorders, and we've been particularly interested in addressing different mechanisms for immune modulation, especially those that may lead to long-term, significant clinical changes in the disease," Anthony Manning, Roche's vice president of arthritis research, told BioWorld Today.

In rheumatoid arthritis, Roche is developing MabThera (rituximab), its lead drug already indicated for non-Hodgkin's lymphoma. The product targets B cells, and Roche also recently in-licensed another rheumatoid arthritis candidate, a Phase II-stage product called MRA that targets IL-6.

"With IL-15 approaching the role of T cells in rheumatoid arthritis and transplant, those provide us with a number of different mechanisms by which we believe we could fundamentally address the underlying basis of these diseases," Manning added. "Hence, with the treatments we have, we can be much more than just palliative in treating the symptoms but actually address the underlying immune dysfunctions within the disease itself."

He said the company remains focused on developing multiple products to provide multiple options for patients throughout their disease course. The acquisition also allowed Roche to keep pace with the competition - earlier this month, Thousand Oaks, Calif.-based Amgen Inc. exercised its commercial option for HuMax-IL15, a Phase II candidate from Genmab A/S believed to have potential in a variety of inflammatory diseases such as rheumatoid arthritis. The Copenhagen, Denmark company received an immediate $10 million payment plus the potential of up to $135.5 million in license fees and milestone payments. (See BioWorld Today, July 2, 2003.)

Given the potential of multiple applications for CRB-15, Roche is getting into IL-15 development as well. Its transplant- rejection franchise, which recorded $1.1 billion in total 2002 sales, features three marketed products and another immunosuppressive therapy candidate in clinical development.

Cardion said CRB-15's mechanism of action combines high selectivity with high potency. It acquired the IL-15-targeted protein through its acquisition of a Boston-based immunology firm called Tolerance Pharmaceuticals Inc. in 2001. The compound was invented by the company's founder at Beth Israel Deaconess Medical Center, also in Boston.

Cardion, which maintains a subsidiary in Cambridge, Mass., said it has since developed a preclinical data package including in vitro and animal efficacy validating the compound's immunomodulatory potential.

"In the transplant models, they had very exciting activity in actually generating tolerization of the graft, meaning long-term survival without the need to continue to treat with the agent," Manning said. "In the arthritis models, it showed activity as good as the anti-TNF agents that are in the marketplace. So along with cellular studies showing high levels of IL-15 in cells within the joints of rheumatoid arthritis patients, we felt it was a very good target with the potential for disease modification."

He added that because of CRB-15's ability to target and delete specific memory T cells, the compound could have a role in regulating other autoimmune disorders such as psoriasis, inflammatory bowel disease and asthma. While evaluation in such areas is on Roche's horizon, Manning said clinical studies in the lead indications of rheumatoid arthritis and transplantation figure into nearer-term plans.

Cardion could not be reached for comment, but beyond immunotherapy it continues to focus on cardiovascular gene therapy products and stem cell-derived transplants. Founded in 1996, the privately held firm has since raised more than 160 million.

For its part, Roche's presence is felt worldwide. MabThera is marketed as Rituxan in the U.S. by Genentech Inc. and San Diego-based IDEC Pharmaceuticals Corp., while Roche markets it in the rest of the world except Japan, where it is sold by Chugai Pharmaceutical Co. Ltd. and Tokyo-based Zenyaku Kogyo Co. Ltd.. Roche and Tokyo-based Chugai are jointly developing and promoting MRA.

Roche is a majority owner of both Chugai and South San Francisco-based Genentech.