Back to the Drawing Board

Otelixizumab is one of those drugs whose names are tongue-twisters that seem invented by someone's computer-name-generating program. Sometimes known as TRX4, it's a monoclonal antibody, and is being developed for treatment of type 1a (autoimmune) diabetes and possibly for other autoimmune diseases. Biologics in this class have been implicated in the cytokine release syndrome, an adverse event that is uncomfortable and in rare cases fatal. Hence, otelixizumab's good effects to treat any autoimmune disorder must clearly outweigh the potential side effects.

A few years back, researchers (and press agents) speculated that "the introduction of humanized, nonmitogenic, aglycosylated anti-CD3 antibodies, such as otelixizumab, and promising results reported in newly-diagnosed patients with Type 1 diabetes, have renewed the interest for these antibodies in the treatment of autoimmune diseases." But the early promising results haven't panned out in bigger studies.

Otelixizumab was developed by a Boston-based biopharmaceutical company named Tolerx, and the company had invested well over $150 million in the drug as of 2010. After lots of ups-and-downs, Tolerx went fishing for big pharma to help with the mega-expensive Phase III trials, and GlaxoSmithKline bit. Two big trials were undertaken: DEFEND-1 and DEFEND-2. (DEFEND = "Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes".)

DEFEND-1 was a randomized, placebo-controlled, double-blind, multicenter multinational study including 272 adult patients with new-onset autoimmune T1D. The primary endpoint of the study was to see if there was a change in C-peptide (as a surrogate for insulin production). The authors concluded that "Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control." In other words, the study fizzled. (And so did Tolerx -- they seem to have disappeared.) Or, in the words of the GSK scientific lead, “Clearly these are disappointing data, but we are committed to working with Tolerx to better understand the results of this study and determine the way forward.” These results, which were released in 2011, were finally published this month (July 2014), Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes.

Well, what about DEFEND-2? It's also been recently published: Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study. The authors of DEFEND-2 concluded that "Efficacy and tolerability of otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required."

Now what? Give up and admit defeat? Never -- not when personalities, company survival, big bucks, and vague hopes of some far-off future profiting from curing type 1 diabetes are involved. Start another study, and hope that a different dose will do something worthwhile. This new trial plans to enroll 40 young adults (aged 16 to 27) with recent-onset type 1a diabetes. Enrollment has just started and results are expected in January 2021.

Clearly, GSK is going back to the drawing board.