Immunomodulator Otelixizumab Appears to Preserve Beta Cell Function in Type 1 Diabetes

Alison Palkhivala

October 27, 2009

October 27, 2009 (Montreal, Quebec) — Otelixizumab, an investigational immunomodulator, has shown promise in phase 2 dose-optimization trials as a means of safely preserving beta cell functioning in type 1 diabetes. The drug is moving on to phase 3 trials, according to research presented here at the International Diabetes Federation (IDF) 20th World Diabetes Congress.

Otelixizumab is a chimeric/humanized aglycosylated anti-CD3 monoclonal antibody directed against the T-cell antigen CD3e, which has been developed by Tolerx, Inc., as a treatment for autoimmune disorders, including type 1 diabetes.

Phase 2 Dose-Optimization Studies Identify Best Regimen

Senior investigator Louis Vaickus, MD, chief medical officer at Tolerx, presented the cumulative experience to date with their phase 2 studies with otelixizumab and provided an introduction to the international phase 3 trial, known as Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes (DEFEND), which has begun enrollment.

"The phase 2 studies were designed to look at the optimization of a dose regimen so that we would increase patient safety and tolerability while retaining efficacy in important markers of immune modulation," Dr. Vaickus told Medscape Diabetes and Endocrinology. "Those studies were done over a period of about 4 and a half years and involved about 14 different cohorts of patients. We continued to tweak the dose until we came upon the one that we've now launched into a phase 3 clinical trial."

In the phase 2 trials, the investigators tested 11 different dosing regimens, with total doses ranging from 0.3 to 6.85 mg. They involved more than 150 patients with various types of autoimmune disorders, including more than 100 with type 1 diabetes. Dosing regimens were 3, 4, or 8 days long. Outcome measures included serum concentrations of cytokines, otelixizumab, antiotelixizumab antibodies, and other standard safety parameters, as well levels of various viruses, including Epstein–Barr and cytomegalovirus. Stimulated C-peptide levels were measured at baseline and up to 12 months after the administration of the drug.

The dose with the best balance of safety and efficacy was determined to be 3.1 mg administered over 8 days. "It's given as an intravenous infusion over 30 minutes," said Dr. Vaickus. "We start out with 0.1 mg [on day 1], then we go to 0.2 [mg], then to 0.3 [mg], [on subsequent days]. Then we give 0.5 mg [a day] for 5 days."

Adults with type 1 diabetes who received the selected dose had increases in CD4, CD25, FOXP3, and T regulatory cells in their peripheral blood. Among those younger than 35 years who received this dose, stimulated C-peptide levels measured 12 months after receiving the drug remained similar to the levels found at study entry, suggesting preservation of residual beta cell function.

Importantly, no lymphocyte depletion or other cytopenias were noted. There were also no cases of electrolyte abnormalities, clinically significant changes in liver function tests, rashes, immunogenicity, perturbation of viral immunity, or other unexpected adverse events.

Phase 3 Trial Undergoing Enrollment

The phase 3 DEFEND trial is currently undergoing enrollment, which is projected to be completed by the end of this year. Patients will be followed for 2 years after receiving 1 administration regimen of otelixizumab. They will be given the option to be followed for another 2 years, for a total follow-up period of 4 years.

The primary end point is preservation of beta cell function 12 months after receiving a single dosing regimen of the drug, as determined by stimulated C-peptide levels measured over a 120 minute period after a mixed meal.

Larry C. Deeb, MD, a pediatric endocrinologist at the University of Florida College of Medicine in Tallahassee, points out that otelixizumab is 1 of several drugs currently being studied for the preservation of islet cell functioning. The potential benefits of such a drug, if it is shown to be safe and effective, are enormous.

"Preserving islet cell function is a critical step prior to curing [type 1 diabetes]," he said. "The difference between having diabetes in the fourth month vs the fourth year is dramatic. Any pancreatic support really changes the diabetes landscape for the individual family."

Drugs such as these, said Dr. Deeb, involve a benefit–risk analysis: How much can one expect to benefit from the drug vs how much difficulty is involved in taking it? In this light, the apparently good tolerability profile of otelixizumab is promising. A hurdle is the difficult administration, which involves daily intravenous infusions for 8 days. Dr. Vaickus said, however, that Tolerx is working on a subcutaneous version of the drug that could potentially be self-administered.

This research was conducted by entirely by Tolerx, Inc. Dr. Deeb has disclosed no relevant financial relationships.

International Diabetes Federation (IDF) 20th World Diabetes Congress: Abstract O-0397. Presented October 21, 2009.

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