ClinicSpeak: derisking alemtuzumab

Can we make alemtuzumab safer by preventing secondary autoimmunity? #ClinicSpeak #MSBlog #MSResearch

"I am not ignoring alemtuzumab, I only have so many hours in my day to write posts for the blog. However, to reiterate I was at a meeting last week and got into a debate with colleagues about treating MS. I made the point that only the highly-effective treatments are capable of switching off inflammation, allowing spontaneous recovery and preventing end-organ damage; that is in the majority of MSers treated early. Knowing this who would not want to be on a highly-effective treatment? Their response was all about the risks of this strategy, and no necessarily the benefits. If you could make alemtuzumab and natalizumab safe then yes, most neurologists would prescribe them first-line, assuming that they were affordable and available to all. I say this because pharmaceutical pricing is about the risk:benefit ratio and not the manufacturing costs. I note some of you have already commented on the price of Lemtrada compared to Campath, despite them being the same drug.

If the infusion reactions, infections and secondary autoimmunity problems went away who would choose anything but alemtuzumab to treat MS?

Can we reduce the infusion reactions of alemtuzumab? Yes, I think we can.

The oncologists have been using alemtuzumab longer than we have in neurology and they have learnt to pre-treat with steroids starting the night before the first infusion to reduce the infusion reactions. We have also observed that infusion reactions tended to be quite bad on day 4 & 5 during the first course; days that weren't covered by steroid infusions in the trial protocol. We have now included pre-dosing (night before) and give intravenous steroids before all infusions; it works infusion reactions don't seem to be a problem. Another innovation that will come is the subcutaneous route of administration. The oncologists have shown that you get the same therapeutic effect of alemtuzumab, with reduced infusion reaction, when the drug is given by subcutaneous injection, because the cell lysis occurs more slowly. You may be interested that there have already been some exploratory trials of the subcutaneous route in MS (see Perumal et al. abstract below).  

What about preventing or reducing the incidence of 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 Reverend Dr Coles is currently trying to do in Cambridge. He thinks that because the immune system reboots itself from peripheral memory cells it is more likely to result in an aberrant autoimmune responses. He is currently doing a trial to encourage rebooting of the immune system using more naïve cells from the thymus. He is therefore treating 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 and is still recruiting subjects.

Interestingly, 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. 10-20mg, just enough to allow to delay B cell reconstitution by 4-6 months. I proposed this concept to Genzyme several years ago, but without data to support this they were not keen to support an exploratory study. The problem is that we don’t have any animal models of reconstitution autoimmunity to test these hypotheses so the only thing left for us is to test them in MSers. I personally think Genzyme will regret not supporting the rituximab proposal; the secondary add-on studies would have taught us a lot about secondary autoimmunity.

Another option is to use alemtuzumab in combination with an immunomodulatory agent to try and prevent autoimmunity emerging. For example, to start a drug such as azathioprine or teriflunomide 4-8 weeks after completing the first course of infusions. The idea would be to prevent T-cell priming, proliferation and later 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. In addition, using high costs drugs such as teriflunomide may make this strategy too expensive. Several different investigators have proposed to Genzyme to bungle alemtuzumab with teriflunomide as a novel way to sequence these two drugs and at the same time de-risking alemtuzumab. The last I heard was that Genzyme-Sanofi was not interested in this strategy. Why? I think they have their own plans to test a treatment strategy to reduce the secondary autoimmunity. If they have their own plans they should start their trials sooner than later. Assuming ocrelizumab (anti-CD20) makes it through the development pipeline as a high-efficacy DMT it is likely to be much safer than alemtuzumab and natalizumab and hence is likely to corner the market. If this occurs then alemtuzumab is likely to remain a very niche drug used is small numbers of MSers. I have actually heard someone say that alemtuzumab has a sell by date on it; the date being the day ocrelizumab gets its license. I don't necessarily agree with this comment, simply because alemtuzumab has better long-term remission data than ocrelizumab and it may offer an MS cure in a proportion of MSers. I think for some MSers the latter may be what is important.

Another way of de-risking alemtuzumab is to open up the secondary autoimmunity problem to the wider immunology community as a human model to study organ specific autoimmune diseases in. MSers treated with alemtuzumab can then be used to test organ-specific immune tolerance strategies. 

Can we re-educate the reconstituting immune system with a cocktail of proteins from the thyroid gland to teach the newly emerging T-cells to ignore the thyroid gland? 

The problem with antigen-specific immune tolerance is that you will need to have a different cocktail of proteins for each autoimmune disease. Starting with thyroid autoimmunity would make the most sense; it is the commonest autoimmune disease post-alemtuzumab and we know quite a lot about the putative autoantigens involved. We are in the process of preparing a grant application to tackle thyroid autoimmunity; however, we need to start in animal model first before we can move into MS.

Getting rid of the secondary autoimmunity problem will not de-risk alemtuzumab completely. Why? The infectious complications when the immune system is depleted for a few weeks, to months, after each course will remain. In addition, there is still the unanswered question about a delayed secondary malignancy risk. The latter will take decades to be answered in the so called post-marketing surveillance programme. Another concern with immune system rebooters is premature ageing of the immune system, or immunosenescence, this is when the immune system loses its memory to many common infections. Why this occurs is debatable, but is associated with a shrinking of the so called immune repertoire. The repertoire becomes dominated by T cell responses to latent viruses for example CMV (cytomegalovirus) and EBV (Epstein Barr virus)."

Perumal et al. Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis. Mult Scler. 2012 Aug;18(8):1197-9.

Alemtuzumab is an anti-CD52 monoclonal antibody with remarkable efficacy in relapsing multiple sclerosis (MS). In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia as IV. Oncology guidelines recommend alemtuzumab subcutaneous (SC) over IV. There is no report of alemtuzumab SC in MS. We report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events. SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events.

CoI: multiple

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