We can make alemtuzumab safer by preventing secondary autoimmunity; why has Genzyme done nothing about it? #GenzymeSpeak #MSBlog #ResearchSpeak
If you read this blog regularly and remember posts from the past some of you may recall that over 2 years ago I posted on derisking alemtuzumab. I discussed derisking infusion reactions and secondary autoimmunity. If I was writing this post today I would include a long section on preventing infections, i.e. herpetic, HPV, PML, TB, nocardiosis, listerioisis, exotic infections, etc.
What gets me is that for over 5-years I have been asking Genzyme to start studies to prevent secondary autoimmunity and nothing has happened. I have put forward two strategies; one was rejected and it looks like tragically the window for doing the second study is rapidly closing.
Once oral cladribine and ocrelizumab are launched most thinking pwMS and neurologists will have a hard time justifying taking the risks of alemtuzumab. Why? You will get similar efficacy from orcelizumab, a maintenance treatment, and if you want to go the PIRT (pulsed immune reconstitution therapy; previously referred to as an induction therapy) route cladribine is much safer than alemtuzumab. With cladribine you get no secondary autoimmunity, no infusion reactions and much fewer infections because cladribine doesn’t take-out innate immunity or deplete T-cells to the same degree as alemtuzumab. Cladribine also has the advantage of being oral and its monitoring requirements will be so much less arduous. The bottom line is would you go into a randomised trial of alemtuzumab vs. alemtuzumab plus a second agent to try and prevent secondary autoimmunity or would you choose ocrelizumab or oral cladribine? I suspect you would choose one of the latter two options. This means we will have lost equipoise and our proposed trial will be unethical.
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. I would imagine the results from this trial will be presented soon.
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. Importantly, when you compare cladribine, another immune system rebooter, with alemtuzumab you can’t help but notice that the B-cell reconstitution profiles are very different. With alemtuzumab they comeback very quickly and overshoot their baseline values. We have hypothesised that if you changed the profile of the B cell reconstitution with a small dose of the B cell depleting antibody rituximab you may be able to prevent this secondary autoimmunity. We are really talking about a very small dose of rituximab, i.e. 50-100mg, just enough to allow to delay B cell reconstitution by 4-6 months. This is the first concept trial that Genzyme rejected several years ago.
Another option is to use alemtuzumab in combination with a small molecule anti-proliferative agent to try and prevent autoimmunity emerging. For example, to start a drug such as methotrexate, azathioprine or teriflunomide after the first course of infusions. The idea would be to prevent naive B-cell proliferation and overshoot, and the subsequent autoimmune B-cell stimulation. My concerns with this strategy is safety; rebooting the immune system in the presence of drugs that are designed to limit T cell proliferation may result in significant immunosuppression. Despite these concerns it is worth trying in the hope we can save alemtuzumab for pwMS. Based on current data I think alemtuzumab has superior efficacy to cladribine and is much safer than HSCT, therefore alemtuzumab should be saved as a treatment option for pwMS. Alemtuzumab, like HSCT, may offer pwMS a potential cure.
Several investigators, including myself, have proposed to Genzyme to bungle alemtuzumab with teriflunomide as a novel way to sequence these two drugs and at the same time derisking alemtuzumab. The problem is may be too late to start and fully recruit such trial. If you work for Genzyme can you please ask why your company is dragging its heels with regard to funding and initiating this trial? Or may be I have misinterpreted your commitment to alemtuzumab and you have written it off.
I have actually heard someone say that alemtuzumab as a MS DMT has a sell by date on it; the date being the day ocrelizumab gets its license. I am beginning to agree with this comment. I didn’t in the past because I foolishly thought we could derisk alemtuzumab in time. Tragically, we did have the time, but sadly it is running down rapidly.
P.S. #GenzymeSpeak = a post for people who work at Genzyme