It has been ~5 years since I approached Genzyme with a hypothesis to derisk alemtuzumab. I first posted on the topic of derisking alemtuzumab on the blog in 2014. I discussed derisking infusion reactions and secondary autoimmunity.
The immune system has many mechanisms in place to prevent autoimmunity. When you learn how the immune system works it is really quite surprising that autoimmunity is so uncommon. What the immunologists tell us is that there must be a series of underlying biological processes that are causing secondary autoimmunity and if we can work out what these are we can intervene and prevent this complication. This is what the Professor Alasdair Coles, and Dr Joanne Jones, have been trying to do in Cambridge. They think that because the immune system reboots itself from peripheral memory cells it is more likely to result in an aberrant autoimmune responses. They have done a trial to encourage rebooting of the immune system using more naïve cells from the thymus. They have treated MSers after alemtuzumab with a hormone called, Palifermin, that stimulates the thymus to produce more naïve T-cells. The study is called the Cam-Thy study.
We have a different take on what is responsible for the secondary autoimmunity and wanted to test a different strategy; we hypothesised several years ago that it was due to B-cell hyperproliferation. Based on our hypothesis Palifermin should exacerbate the problem; increasing reconstitution with naive cells without regulation will increase secondary autoimmunity.
In response to the challenge above the Mouse Doctor and DrK have analysed the alemtuzumab reconstitution data in more detail and the analysis strongly supports this hypothesis. Where to from here? I think we could still do a proof-of-concept trial, but focusing on anti-drug antibodies, i.e. anti-alemtuzumab antibodies as the readout. Alemtuzumab is a humanised antibody and the incidence of anti-drug antibodies should be very low. Alemtuzumab appears to break immune tolerance and the mechanisms that underlie anti-drug antibodies may be the same as those that underlie secondary autoimmunity.
Baker et al. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017 Jun 12. doi: 10.1001/jamaneurol.2017.0676.
IMPORTANCE: Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.
OBJECTIVE: To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.
DESIGN, SETTING, AND PARTICIPANTS: Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016.