ot-304 program for cancer and inflammatory diseases

Recently, Othera began the OT-300 series program to design a series of novel therapeutic agents with the goal of identifying orally-deliverable, potent and selective inhibitors of NF-kB. Most of Othera’s newly synthesized OT-300 series compounds have completed initial characterization in a battery of in vitro and in vivo assays. Among these compounds, Othera has identified a lead candidate, OT-304, which shows promising pre-clinical activity in cancer-associated thrombosis, as well as strong anti-tumor activity.

Othera plans to develop OT-304 to a preclinical stage that includes in vivo data from one or more animal models of disease, as well as preliminary toxicology and pharmacology findings that are supportive of an investigational new drug (IND) filing and/or corporate partnering activity. In addition, Othera is continuing to screen additional OT-300 series candidates for activity in oncology-related and inflammatory diseases.

Oncology-Related Therapeutics

Cancer-Associated Thrombosis

Cancer-associated thrombosis (blood clotting) is a serious and often life-threatening condition prevalent among cancer patients. Epidemiology data identify thrombosis as the second leading cause of mortality in cancer patients, following the disease itself. The risk of death is three-fold higher in patients with thrombosis and malignancy compared to non-cancer patients experiencing thrombosis. It has been estimated that one in seven hospitalized cancer patients who die do so from a pulmonary embolism.
Acute, symptomatic deep vein thrombosis, or DVT, is a subset of the overall anticoagulant market. DVT occurs when a blood clot develops in the deep veins of the legs. If not effectively treated, DVT can lead to pulmonary embolisms that, in turn, can result in death. Cancer patients are particularly at risk to develop DVT, either from the disease itself or as a side effect of certain cancer treatments. The estimated prevalence of DVT in cancer patients ranges from 15-20%. Further, according to the American Cancer Society, approximately 1.3 million new cases of cancer occur in the U.S. each year.

Othera's lead candidate in the OT-300 series, OT-304, has demonstrated potent in vitro anti-thrombotic activity. In preclinical testing, OT-304 can delay clot formation in cancer patient blood across a range of tumor types, including glioma and lung cancer. Additionally, OT-304 inhibits thrombosis induced by various chemotherapies in whole blood.

OT-304's anti-thrombotic activity is related to the downregulation of tissue factor (TF), as well as the downstream components that result in clotting. This novel mechanism of action may allow OT-304 to achieve this activity while significantly avoiding the bleeding side effects of existing anti-coagulant therapies.

Anti-Tumor Therapy

In addition to inhibiting thrombosis in cancer patients, OT-304 has recently demonstrated activity against tumors directly in preclinical studies. While Othera is in the early stages of investigating this activity, this compound demonstrates the potential for oral delivery of a safe and efficacious therapeutic against cancer. OT-304 has shown promising in-vivo and in-vitro efficacy in reducing the tumor volume in a number of cancer types, including chemotherapy-resistant breast cancer cells. Additional in vitro and in vivo studies in various tumor types are planned or are in progress.

Inflammatory Disease Therapeutics

Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by inflammation of the joint lining, called the synovium. In RA, a person’s immune system attacks the synovium, resulting in the thickening of the normally thin membrane and degradation of the cartilage and bone at the joint. Though the primary symptoms of RA are pain, stiffness and swelling of joints, additional symptoms may include fatigue, weakness, muscle pain and lumps of tissue under the skin. Tissue damage from the inflammation ultimately results in deformity and disability.

RA is estimated to affect over 2 million people in the U.S., with approximately 100,000 new cases diagnosed each year. It is estimated that approximately 4.3 million people are affected by RA in the U.S., Japan and Europe. Approximately two-thirds of the RA patient population experiences pain, stiffness and fatigue on a daily basis notwithstanding the administration of currently available treatments, leaving a large unmet medical need in the RA patient population for an effective drug therapy.

Initially, a patient presenting symptoms of RA is typically prescribed non-steroidal anti-inflammatory drugs, or NSAIDS. As the disease progresses, the RA patient may be prescribed a regimen of disease modifying anti-rheumatic drugs, or DMARDS, an antibody targeting tumor necrosis factor alpha (TNF-alpha), or other biologics. Othera has identified novel, small molecule inhibitors of TNF-alpha that are currently in animal model testing as potential oral treatments for RA.