Medarex, Inc. has announced it has initiated a Phase 1b clinical trial for MDX-1106 (ONO-4538: development code of Ono Pharmaceutical Co., Ltd.), a fully human anti-PD-1 antibody for the treatment of cancer.
Studies suggest that the PD-1 signaling pathway may play an important role in tumor evasion and escape from host immune responses and may also promote the persistence of certain chronic viral infections.
The Phase 1b clinical trial is designed to primarily evaluate the safety and tolerability of repeated dosing of MDX-1106 in adult patients with solid tumors and will also provide a preliminary assessment of the anti-tumor activity of multiple doses of MDX-1106 (1, 3 or 10 mg/kg) in these patients. The tumors to be studied include malignant melanoma, renal cell cancer, castrate-resistant prostate cancer and non-small cell lung carcinoma. This open label study is expected to enroll up to 76 patients and will be conducted in multiple sites in the United States.
"We believe that anti-PD-1 antibodies could represent the next stage in immunotherapy with a promising mechanism of action and potential for marked synergy with anti-CTLA4 antibodies," said Geoffrey M. Nichol, MBChB, Senior Vice President of Product Development at Medarex. "Preliminary results from our single-dose Phase 1 study demonstrated an acceptable safety profile and initial evidence of anti-tumor activity in cancer. We look forward to the further development of this novel immunotherapy in cancer and, in a separate clinical trial, hepatitis C."
In May 2005, Ono entered into a collaboration agreement with Medarex to research and develop a fully human anti-PD-1 antibody for the treatment of cancer. The two companies plan to share the costs and responsibilities of research and product development up to the completion of a Phase 2 clinical study in each party's territory. Thereafter, each company will be fully responsible for any continued development and any commercialization in its exclusive territory; Medarex's exclusive territory is North America, and Ono's exclusive territory is all areas outside of North America.
MDX-1106/ONO-4538 is a novel fully human antibody designed to target and inhibit the function of PD-1 (programmed cell death 1), a receptor expressed on the surface of activated lymphocytes (T-cells). The binding of PD-1 with one of two ligands (PD-L1 or PD-L2) is an important negative regulation pathway that suppresses or inhibits activated lymphocytes. Recent research has noted increased PD-1 expression levels on antigen specific T-cells in both the oncology and chronic infectious disease settings, as well as a strong correlation between increased PD-L1 expression on tumors and a negative survival prognosis in cancer patients. Preclinical studies indicate that antibodies targeting the PD-1 signaling pathway reinvigorate antigen-specific T-cell responses and promote an immune response to fight tumors and infectious diseases.
As previously presented at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO), interim Phase 1 data in patients with recurrent or treatment-refractory cancer indicated preliminary evidence of anti-tumor activity or tumor regression in patients with recurrent or treatment-refractory cancer, as well as a favorable safety, tolerability and pharmacokinetic profile of single-dose MDX-1106. Data from the completed Phase 1 study are expected to be presented at an upcoming medical meeting.
MDX-1106/ONO-4538 is being investigated in both the oncology and infectious disease settings. In addition to the Phase 1b study in cancer, a Phase 1 trial is ongoing for the treatment of hepatitis C. In September 2008, Ono filed an IND to allow the initiation of a single and multi-dose Phase 1 clinical study in patients with advanced solid malignancies in Japan. MDX-1106/ONO-4538 may also have the potential to be used synergistically in combination with other treatment modalities, including with anti-CTLA-4 blockade.