Otelixizumab (TRX4) is a targeted T cell immunomodulator designed to induce immunologic remission in patients with T cell mediated autoimmune diseases with a single short course of therapy, thereby inhibiting further disease progression. Otelixizumab is under development in collaboration with GlaxoSmithKline (GSK) for the treatment of new-onset autoimmune type 1diabetes (T1DM) and rheumatoid arthritis, with the potential to be developed in all T cell mediated autoimmune indications. We have completed enrolling patients in DEFEND-1, a Phase 3 study in new-onset autoimmune T1DM and are now initiating a confirmatory Phase 3 study, DEFEND-2 in new-onset autoimmune T1DM. We also have an ongoing Phase 2 study, TTEDD, which is assessing multiple dose regimens of otelixizumab, and our partner GSK is conducting a subcutaneous administration of otelixizumab study in T1DM and has begun studies in rheumatoid arthritis. We have completed two Phase 1 studies in moderate-to-severe psoriasis, multiple dosing studies in T1DM, and may initiate additional clinical studies with GSK in patients with other autoimmune diseases.

Otelixizumab is a monoclonal antibody that targets the CD3 molecule, which is part of the T cell receptor complex that is found on all mature T cells. Otelixizumab is thought to work by downregulating inappropriately activated T effector cells that attack the body’s tissues and cause autoimmune disease while upregulating T regulatory cells that may prevent further autoimmune attack. It is thought that the T regulatory cells activated by otelixizumab therapy may protect against T effector cell damage well after the drug has been eliminated from the body.

Otelixizumab in Type 1 Diabetes

Tolerx has completed enrolling patients in DEFEND-1, the first of two multinational Phase 3 studies of otelixizumab. DEFEND-1 is investigating the ability of otelixizumab to preserve beta cell function, which may reduce the risk of both short- and long-term complications of T1DM. Patients will be monitored during the 12-month follow-up period and C-peptide levels will be measured as the primary endpoint. C-peptide is the gold standard for measuring beta cell function and is an FDA-approved endpoint for T1DM clinical trials. Secondary endpoints will evaluate patients' ability to maintain excellent glycemic control, as measured by HbA1c levels, as well as the amount of daily injected insulin required. A confirmatory Phase 3 study of otelixizumab in new-onset autoimmune T1DM (DEFEND-2) will be enrolling patients shortly. For more information about DEFEND, please visit www.DefendAgainstDiabetes.com.

TTEDD is an ongoing dose-ranging and safety study in patients with new-onset or established T1DM that have detectable beta cell function, as measured by C-peptide at study entry. The primary objective of TTEDD is to explore multiple dosing regimens of otelixizumab and to enhance efficacy, safety, convenience of dosing, or all three. To date more than 14 different dosing regimens have been evaluated in more than 150 patients. This has led to the identification of a dosing regimen that is expected to result in enhanced tolerability, no immunogenicity, and an improved safety profile.  The selected regimen is now being evaluated in the DEFEND Phase 3 program.  

Otelixizumab was previously evaluated in an investigator-sponsored Phase 2 study conducted by the Belgian Diabetes Registry (BDR). The BDR study was a multicenter, randomized, placebo-controlled study of patients between the ages of 12 to 39 with new-onset T1DM. Patients were randomly assigned to receive a single course of either otelixizumab or placebo for six consecutive days. Patients who received otelixizumab had significantly less deterioration in beta cell function and endogenous insulin production (as assessed by C-peptide levels and insulin use) than patients who received placebo when assessed 18 months after dosing [Keymeulen B, et al N Engl J Med. 2005;352:2598-2608]. Long-term follow-up showed that C-peptide levels remained significantly higher in the otelixizumab group than in the placebo group 36 months post-dosing and that insulin use in the otelixizumab group remained significantly less than in the placebo group 48 months after receiving a single course [Keymeulen B, et al.Diabetologia. 2010; 53:614-623].

The dosing regimen used in the BDR study, which was higher than the regimen currently being used in the Phase 3 DEFEND program, did have some side effects. During the six days of otelixizumab administration, patients had headaches, nausea, body aches, and other flu-like symptoms. Many patients receiving otelixizumab also experienced symptoms similar to acute mononucleosis, which appeared 16 to 21 days after starting treatment and resolved within 7 to 12 days. This appeared to be due to a transient increase in Epstein-Barr virus. No patients experienced late-onset side effects attributable to otelixizumab treatment after 48 months of follow-up. 


About Type 1 Diabetes

Type 1 diabetes mellitus is a progressive autoimmune disease in which inappropriately activated T effector cells direct an attack on the beta cells of the pancreas, which produce insulin and other key hormones. Over time, as the beta cells are destroyed, the body becomes unable to produce its own insulin.

According to the Centers for Disease Control and Prevention (CDC), 20.8 million people in the U.S. have diabetes, of which 5% to 10% haveT1DM. In the U.S. 36,000 new patients are diagnosed with T1DM each year, including over 15,000 children.

T1DM can have a number of serious and debilitating short- and long-term complications, including death, blindness, heart attack and stroke, kidney disease, neuropathy (nerve damage), and limb amputation. T1DM also puts a significant burden on the healthcare system; it was estimated that T1DM cost the U.S. $10.5 billion in direct medical care and $4.4 billion in indirect costs (loss of productivity) in 2007.

Current treatment for T1DM consists of managing blood glucose levels through diet, exercise, and injections of exogenous insulin. While this approach can help patients maintain control of blood glucose levels and can decrease the incidence of diabetic complications, it does not affect the underlying cause of the disease, which is the loss of beta cell function resulting from the autoimmune attack. People with T1DM who retain some natural insulin production achieve better control of their blood glucose levels and have a significantly reduced risk of the long-term effects of the disease (such as serious eye disease, cardiovascular disease, and nervous system, kidney, and vascular disorders). They may also have a reduced need for administered insulin.

Click here for more information about type 1 diabetes.

About Rheumatoid Arthritis

The Arthritis Foundation estimates that RA affects more than one million Americans. RA is a chronic, debilitating disease that occurs when the immune system inappropriately attacks joint tissue, causing chronic inflammation and irreversible destruction of cartilage, tendons, and bone. This destruction often results in chronic pain, loss of function, and disability. There is no cure for RA and current treatments focus on treating pain and relieving inflammation.

Click here for more information about RA.