In some people this occurs, and could be more of a problem after the the second infusion cycle.
Whats more, some people do not deplete in the first place.
What information do we need to know from the manufacturer?
In this report they show that on first dose, there is marked lymphocyte depletion that is present 6 months after the first infusion. However there is no obvious depletion 6 months after the second or subsequent infusions and when disease activity re-appears. The percentage CD4 positive value does not change in two non-responders.
or the fine print in the FDA reports.
Neutralizing antibodies can stop the drug working.
Dubuisson N, Baker D, Kang AS, Pryce G, Marta M, Visser LH, Hofmann WE, Gnanapavan S, Giovannoni G, Schmierer K. Alemtuzumab depletion failure can occur in multiple sclerosis. Immunology 2017;DOI: 10.1111/imm.12879
Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Whilst these anti-drug responses have been reported to be of no significance, we hypothesised that they will affect the depleting-capacity and treatment-response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population-level there was lack of influence of “ever-positive” alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and side-effects during the two year trial. This was not surprising as no one prior to first-infusion, and only 0.6% of people prior to the second-infusion had pre-infusion, neutralizing antibodies (Nabs). However, at the individual-level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, suggests that problems may occur in people requiring addition alemtuzumab-cycles. In addition, we also identified individuals, following ‘post-marketing’ alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Thus, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete-poorly, probably due to biological-response variation and NAbs and this may lead to treatment failure. Monitoring depletion following infusion and assessment of neutralizing response prior to re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.
In the MS-CARE trials, it was evident that neutralizing antibodies generate quickly. They were there within one month of first infusion, but they may not have caused too much of a problem because they disappear within 12 months. But by 24 months over 30% of people have an existing neutralizing antibody response. Meaning that one will have more concern for the antibody not depleting as well on third cycle.
Neutralizing antibodies have not been mentioned in the pivotal phase II and phase III trials and were even called inhibitory antibodies in the (European Medicines Agency) report.
Has this issue been hidden all along?
(One for the conspiracy theorists)
Is this important. Based on the trial data only 5 people had pre-existing neutralising antibodies before the second cycle.
We could work out the MS-CARE 1 response because the EMA had provided data of the maximum and minimum and the medium response and there were only three people affected. There were also categoriesed in relation to the amount of antibody produced. One person had a higher level of neutralizing antibodies and 1 out of 3 people clearly did not deplete well or did not deplete at all. We could not say what they were before. We did ask but we were not given the raw data.
The manufacturers had made a poster of people switching from alemtuzumab to fingolimod to say it was OK (Click here).
The poster shows the lymphocyte levels in 13 people of which 6 had three or more infusion cycles. Of these 6 people there were two people (a third) who stopped depleting on cycle 3. Was this due to neutralising antibodies? One can only guess.
I should say you would expect that any protein treatment will cause neutralizing antibodies and for most people I am sure treatment will work. However, it would be valuable to know just how likely it is for you to be the person, where it will stop working.
Also in CD52 is down-regulated to make CD52 negative cells cells following alemtuzumab. Does this influence activity?
Importantly we found there are some people where the drug does not appear to work at all. So there is no depletion in the first place, so someone is paying £28,000 or more for something that does not appear to work.
What is the cause?
We have not found people who do not express CD52 (the target for alemtuzumab) having looked in a data base of 60,000 people. There were also no loss of function variants.
However, there are genetic variations that block IgG1 antibodies from depleting properly. If this is the problem what would the effect on ocrelizumab be, maybe the same.
If you are one of those unlucky people who don’t deplete on first infusion and are willing to help us try find a reason, get your neurologist to contact us.
Why bring this up?
Because it is about your safety or the safety of your pwMS.
CoI. We are authors ProfG, NDG, DrK multiple