Otelixizumab, an experimental drug which could offer a potential eight-day course of daily intravenous infusions reducing the amount of insulin they need to inject on a daily basis to control blood sugar in type 1 diabetes patients, is currently in human studies.
Otelixizumab may help preserve patients’ natural ability to produce insulin for years in type 1 diabetes, according to Tolerx Inc, the developer of the drug.
Otelixizumab, a target T cell immunomodulator, is a monoclonal antibody that binds to CD3, a T lymphocyte receptor involved in normal cell signaling.
Otelixizumab is thought to work by blocking the function of T effector cells that attack the body’s tissues and cause autoimmune disease while inducing a subset of T cells known as T regulatory cells. It is thought that the T regulatory cells may protect against T effector cell damage well after the drug has been eliminated from the body.
Otelixizumab (TRX4) is under development in collaboration with GlaxoSmithKline (GSK) for the treatment of autoimmune new-onset type 1 diabetes, with the potential to be developed in other indications, such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease.
In a study involving patients with new-onset type 1 diabetes otelixizumab helped preserve the function of insulin-producing beta cells in the pancreas, and reduced the amount of insulin needed to control blood glucose levels, for 18 months after only 6 days of otelixizumab administration.
This multicenter study included 80 subjects newly diagnosed with type 1 diabetes. New-onset type 1 diabetes subjects had been treated with insulin for less than four weeks and were randomly assigned to receive either otelixizumab or placebo for 6 consecutive days.
No additional courses of otelixizumab were administered. During the 18 months following treatment, subjects reported how much insulin they took.
The amount of natural insulin produced by the subjects’ beta cells was assessed by measuring c-peptide, a protein that is always produced along with insulin.
At 6, 12, and 18 months, beta cell function was maintained better in otelixizumab-treated subjects than in placebo-treated subjects.
In addition to 18 months of follow-up, there was a significant decrease in insulin use at 24, 36, and 48 months of follow-up as compared with placebo. Subjects who received otelixizumab produced more c-peptide than the placebo group, meaning that their beta cells were producing more natural insulin. Otelixizumab did have some side effects.
During the 6 days of otelixizumab administration, especially on the first day, subjects had headaches, nausea, body aches, and other flu-like symptoms.
A few weeks later, subjects had a flare-up of a virus called EBV, the same virus that causes mononucleosis. Most subjects had symptoms such as sore throat and swollen glands. All of these symptoms were temporary and most were mild.
Tolerx is conducting a Phase 3 study called DEFEND-1 as well as a Phase 2 study — called TTEDD — of otelixizumab in subjects with type 1 diabetes.
TTEDD is an ongoing dose-ranging and safety study in subjects with new-onset or established type 1 diabetes 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.
Tolerx has completed enrolling subjects in a multi-national Phase 3 study, DEFEND-1. The DEFEND-1 study is investigating the ability of otelixizumab to preserve beta cell function, which may reduce the risk of both short- and long-term complications of the disease.
Patients will be monitored during the 12-month follow-up period and c-peptide levels (a surrogate measure of beta cell function) will be measured as the primary endpoint. Secondary endpoints will evaluate the patient’s ability to maintain excellent glycemic control as measured by HbA1c levels and the amount of daily injected insulin required.
Tolerx plans to conduct a second confirmatory Phase 3 study of otelixizumab in new-onset autoimmune type 1 diabetes, entitled DEFEND-2.
Otelixizumab is also being tested in moderate-to-severe psoriasis, multiple dosing studies in type 1 diabetes, and may initiate additional clinical studies with GSK in patients with other autoimmune diseases, Tolerx stated.
Approximate 20.8 million people in the U.S. have diabetes, of which 5%-10% have type 1 diabetes, according to the Centers for Disease Control and Prevention (CDC).
In the U.S., 36,000 new patients are diagnosed each year, including over 15,000 children.
Type 1 diabetes is an autoimmune disease in which the body’s immune system attacks and destroys the insulin-producing cells (the beta cells) of the pancreas.
Current treatment for type 1 diabetes consists of managing blood glucose levels through diet, exercise, and injections of insulin.
While this approach can be effective, it does not affect the underlying cause of the disease, which is the loss of beta cell function resulting from an autoimmune attack.
Some natural insulin production in those with type 1 diabetes results in better metabolic control, and may reduce the risk of the long-term effects of the disease (such as serious eye disease, cardiovascular disease, and nervous system, kidney, and vascular disorders), and may reduce the need for administered insulin.
Headquartered in Cambridge, MA USA.Tolerx, Inc is developing novel therapies intended to treat autoimmune diseases, diabetes, and cancer by specifically modulating T-cell activity.
The company’s pipeline includes MTRX1011A, an anti-CD4 antibody that is being developed in collaboration with Genentech, Inc. for the treatment of autoimmune indications; and two pre-clinical candidates, TRX518 and TRX385, that enhance immune responses and are being evaluated for potential benefit in the treatment of cancer, chronic viral diseases, and as vaccine adjuvants, besides its lead candidate, otelixizumab.