Next-generation CTLA4-Ig for the Treatment of Rheumatoid Arthritis and Transplant Rejection
MAXY-4 is a preclinical program with the goal of creating next-generation CTLA4-Ig therapeutics with improved potency relative to Orencia® and Belatacept (LEA29Y, a modified CTLA4-Ig), both developed by Bristol-Myers Squibb. By binding to human B7 ligands with high avidity, CTLA4-Ig fusion proteins inhibit B7-mediated co-stimulation of T cells via the CD28 receptor, thereby decreasing activation of T cells and thus decreasing immune system activation. Maxygen used its MolecularBreeding™ directed evolution platform to generate novel CTLA4-Ig proteins with significantly higher specific binding to human B7 ligands.
On September 18, 2008, we entered into a global co-development and commercialization agreement with Astellas Pharma Inc. Under the terms of the agreement, Astellas received worldwide rights to commercialize MAXY-4 for autoimmune disease and transplantation. As consideration, Maxygen received a $10 million initial payment. Astellas also paid for the first $10 million of certain preclinical costs related to development of MAXY-4 candidates. This agreement was assigned to Perseid Therapeutics LLC, a majority-owned subsidiary of Maxygen, in September 2009, in connection with the consummation of the joint venture arrangement between Maxygen and Astellas.
Under the Maxy-4 agreement, Perseid and Astellas will co-develop MAXY-4 for rheumatoid arthritis and other autoimmune diseases, and Astellas will exclusively develop MAXY-4 for transplant rejection. The companies share preclinical and development costs of MAXY-4 candidates for autoimmune disease indications in North America and European countries. Astellas will be responsible for development costs for autoimmune disease indications in the rest of the world and for transplant rejection indication worldwide.
Under the agreement, Perseid is eligible to receive up to $165 million in pre-launch milestone payments. Perseid is also eligible to receive tiered double-digit royalties on all sales. If Perseid exercises its option to co-promote for autoimmune indications within North America, revenues from any such products will be subject to a profit-sharing arrangement between the parties instead of royalty payment.
How MAXY-4 Was Created
Using our proprietary MolecularBreedingTM Directed Molecular Evolution platform, we have generated a family of novel CTLA4-Ig proteins with significantly higher specific binding to human B7 receptors compared to Orencia® and Belatacept. We have selected a set of lead molecules based upon preclinical data and are in the process of selecting the clinical candidate based upon additional preclinical data.
MAXY-4 Mechanism of Action. Optimal T-cell activation requires costimulation of 2 signals: MHC-Ag + TCR and B7 + CD28. Like Orencia, MAXY-4 blocks the availability of B7 receptors, thereby preventing activation of T-cells
Clinical Proof-of-Concept Clinical proof-of-concept for blocking T cell co-stimulation has already been demonstrated by Orencia®, which has been approved in the U.S., Canada and the European Union. This product has demonstrated clinical efficacy in the treatment of juvenile [1] and adult rheumatoid arthritis (RA) patients with inadequate response to methotrexate [2] or tumor necrosis factor (TNF) inhibitors [3]. Bristol-Myers Squibb has ongoing clinical studies of Orencia® for the treatment of other autoimmune diseases such as Crohn’s disease, lupus, psoriatic arthritis and ulcerative colitis. Clinical development of Belatacept for the prevention of kidney transplant rejection is also underway. Market Opportunity – Rheumatoid ArthritisThe worldwide market for rheumatoid arthritis, a key opportunity for MAXY-4, has grown to over $10 billion. The increasing global incidence of severe rheumatoid arthritis and the emergence of new therapies with improved clinical benefit are predicted to sustain market expansion in this disease area. A significant segment of the RA population continues to be refractory to current biological DMARDs and clinical benefit (as measured by ACR50 score) is estimated at less than 50% at six months post therapy. Hence, significant opportunity remains available for the introduction of new biologic therapies, such as MAXY-4, that may provide a differentiated benefit over existing therapies. Other indications in the autoimmune disease field, including Crohn’s disease, lupus, psoriasis, multiple sclerosis and ulcerative colitis, represent additional large market opportunities for the MAXY-4 program. Market Opportunity – Transplant RejectionThe worldwide market opportunity for solid organ transplant rejection was over $3 billion in 2007. Calcineurin inhibitors (e.g. Prograf®, CellCept® and cyclosporine) are currently the only approved therapeutic class for maintenance of transplant rejection, but significant unmet need exists due to the high toxicity of such compounds. Clinical studies using Belatacept have demonstrated equivalent efficacy and lower toxicity relative to calcineurin inhibitors [4], and thus represent an emerging therapeutic class with strong potential to dominate the transplantation market.
[1] Ruperto (2008) Lancet 372, 383-391
[2] Kremer (2006) Ann Intern Med 144, 865-876
[3] Genovese (2005) NEJM 353, 1114-1123
[4] Vincenti (2005) NEJM 353, 770-781
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