Interview with Dr. Lou Vaickus, Tolerx, Question 4

LV: The first thing that distinguishes otelixizumab is that we took many years to study it and identify an optimal dose before we started pivotal Phase 3 clinical trials. We evaluated our product up, down, and sideways(break)  — in many patients, of different ages, genders, weights, under different conditions, different infusion rates, at a wide range of dose and number of dosing days, using a battery of sophisticated immunologic tests, and with long-term (4 years) follow up to catch any late-occurring side effects. We felt compelled to do this and establish an optimal dose before we were ready for “prime time.” We discussed the results of this work with many experts, consulted with FDA all along the development path, and had help from the best diabetes doctors and immunologists in the world to understand our product as best we could.  

All this rigorous scientific work led to an optimized low dose regimen that is given as a single course. The doses are given once a day for 8 consecutive days. In Phase 2 studies, this regimen had a side effect profile that was well tolerated and which appeared to have a good effect on the disease itself in that residual insulin-producing cells were preserved for a reasonably long time (12 months). So, only after all these years of studying otelixizumab were we ready to enter the final phase of development.  

The first Phase 3 study was begun in 2008 and the second Phase 3 was just started in June of 2010. These two large clinical studies will be the “acid test” of whether, in an even larger and more diverse group of subjects with recently diagnosed Type 1 diabetes, we can prove that an optimized, low dose, single short treatment course of otelixizumab is not only safe and well tolerated, but effective in the way we expect. And, both these Phase 3 studies have as their primary endpoint C-peptide level as a surrogate of endogenous insulin secretion — which is right in line with the 2008 FDA guidance on what to assess in these Type 1 diabetes trials with immune modulators.  

The second difference is that, put simply, not all anti-CD3 antibodies are the same. Otelixizumab is fundamentally and structurally different from other anti-CD3 antibodies.

It was molecularly engineered to have decreased side effects and no significant batch-to-batch variability when we manufacture it in the quantities needed to do clinical studies and commercialize it. Also, although no head-to-head tests have been done to compare with other anti-CD3 antibodies, based on reports in scientific journals, we have not seen several important and unexpected side effects that the others have reported. We don’t know why exactly, but we suspect that the difference lies either in our optimized regimen and/or in otelixizumab’s unique structure.