If you are using, taking or thinking of taking alemtuzumab you need to read all of this post. At the very least the bottom bit.Tweet, Retweet and Facebook or whatever to your circle of friends
To continue explaining our recent paper and the last bit for Detective Week, so MD is back in his Civvies next week.
Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab David Baker, Samuel S. Herrod; Cesar Alvarez-Gonzalez,Gavin Giovannoni; Klaus Schmierer
JAMA Neurol. Published online June 12, 2017. doi:10.1001/jamaneurol.2017.0676
- Alemtuzumab induces binding (could cause allergic infusion reactions and could stop drug having optimum effect) and neutralizing (could stop drug working) antibodies in most people.
- These issues were known, but not reported clearly in pivotal trial results
- They are a problem for some people and the drug does not work
- The neutralizing antibodies increase with time and the third/forth injection cycle may be more problematical
- Should there be a test be repeat infusions?
- Some people do not respond to alemtuzumab.
It only takes about 6 days to make an antibody response, with 3-4 days to sensitize a T cell so within a day of finishing the 5 day infusion you could have an anti-drug response because all the immune system is seeing in those first few days is loads of alemtuzumab
We knew that there is an anti-globulin response as it had been reported, as had ways to reduce them.
Somerfield J, Hill-Cawthorne GA, Lin A, Zandi MS, McCarthy C, Jones JL, Willcox M, Shaw D, Thompson SA, Compston AS, Hale G, Waldmann H, Coles AJ.A novel strategy to reduce the immunogenicity of biological therapies.J Immunol. 2010185(1):763-8.
Those studies talked about the high incidence of antibodies that bound to alemtuzumab. This did not specifically mention neutralizing antibodies that would block alemtuzumab function,
Normally this type of information is published in pivotal phase III antibody trials.
However, anti-alemtuzumab antibodies only received cursory mention in the pivotal trial reports, save to say they were of no importance. Neutralizing antibodies other than those to beta interferon (control group) where not mentioned
So it made us do more digging
The Prof Coles had done an open access paper that you can all read.(CLICK ON ME) Alasdair J. Coles. Alemtuzumab Therapy for Multiple Sclerosis Neurotherapeutics. 2013; 10(1): 29–33.There is a section:
These were not mentioned in the pivotal trial report. Why not?
So 30% after 1 month. Is this right?
Well let’s look at the data.
You don’t have to do a freedom of Information to find the information it can be found here.
CLICK HERE) Turn to page 34/35
pooled Phase 3 studies tested positive for anti-alemtuzumab antibodies. Of the 85.2% of
patients who tested positive for anti-alemtuzumab antibodies at any time-point during the
course of the study, 92.2% (637/691) tested positive for inhibitory antibodies”.
Coles A. J., D. A. Compston, K. W. Selmaj, S. L. Lake, S. Moran,
D. H. Margolin, K. Norris,P. K. Tandon,CAMMS223 Trial Investigators. 2008. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359: 1786–1801
So sounds like not much of a problem but reports in rheumatoid arthritis indicated there was over 60% of people making antibodies within twelve months, so is this a fudge by the phase II investigators to downplay the antibody response?
Now, you may argue that the data is there for all to read…but it is clearly not well known otherwise I would have not been told that neutralizing antibodies don’t exist.
A humanized antibody creating neutralizing antibodies in about 70-80% of people, tells you there is something weird going on. Alemtuzumab was the first humanised antibody and this was designed to reduce immunogenicity., but it must be a relative effect as it is clearly immunogenic.
We thought it was surprising that this information has been omitted from the phase III write up.
But the information could be found.
Why the name change of a very well-defined term?
If you look at the table above. What does a titre of 6.5 million mean?
In the table we can see levels of antibody at up to 6.5 million
for life and may be boosted each time you get a new course.
McCarthy CL, Tuohy O, Compston DA, Kumararatne DS, Coles AJ, Jones JL.Immune competence after alemtuzumab treatment of multiple sclerosis. Neurology. 2013;81(10):872-6
In the CARE-MS documents we received, some effort is made to show that the presence of binding or neutralizing antibodies do not influence depletion, efficacy or infusion responses, we didn’t get to see information presented on the individual responses. However not surprising as only 5/789 had pre-existing neutralizing antibodies and so not enough to make a conclusion.
So the influence of binding antibodies and anaphylaxis potential is masked.
However 75 % of people will have circulating antibodies at the end of second infusion cycle and 30% have neutralizing antibodies, so the risks of not depleting on the third cycle is increased.
Based on what we know this is not a reported problem for the treated population but at the individual level it would be important to see.
This is the important point
But what about the people needing 4 or 5 cycles?
Is the antibody depleting?
So are neutralising antibodies important?
Let’s go back to the paper at the top and see what was said in the rest of the immunogenicity section.
Am I being a DramaQueen? If you know the about information above I am a DramaQueen, if not an Investigative Journalist.
Now you can say, look at the label
Go to the EMA and you get
Best get your info from the FDA
You just have to look
Why do this? I could and perhaps should wait and publish it first.
I do this because I think, you need to know now and shouldn’t wait until I publish it (or someone else publishes it). As it may be relevant to you. I know there are people in the World, where this is indeed relevant and the neuros will have a dilema of what to do next.
Are the Anti-Drug responses Important at the Individual level? Simple answer is Yes.
At the population level, I agree these antibodies have no effect within the trial, however back to the data, I can see two things.
(a) There are people who do not deplete well , independent of anti-drug antibodies
(b) There are people who do not deplete well because they make anti-drug antibodies.
So £28,000 (in the UK) for something that does nothing
Below is a graph found on the internet that told me to look at the data and told be where to look in the thousands of pages within an EMA document.
Only the first thirty days are the important period when the cells are being deleted. We did not see it in the EMA stuff we looked at, but this is from the EMA website. (Check it in the document below)
Lemtrada, INN-alemtuzumab – European Medicines Agency
When you are looking for a needle in a haystack. Graphs are what you need. But raw data is what we need. I have drawn some boxes to help you focus on the points I’m making.
You only look at the first 30-40 days because repopulating B cells skew the data after that.
Is the blue above the red? If it is, does it mean being having anti-drug antibody is important to individuals? They are not depleting as well as those without antibody.
Are there non-depletors?, If there are, is it one in a blue moon?
The graph above suggests there are non-depleters. You can see it is not common.
I’m not much of a human genome mapper, but there are people out there who are and one could easily look to see how common polymorphisms are to CD52, and other gene products that affect lymphocyte depletion.
There are no obvious loss of function mutations (i.e. knockouts) when I looked through over 60,000 genomes from the Broad Institute data base. The polymorphisms above are reasonably common meaning about 30-40% of people would be homozygous for these variants. If it truly affects response to alemtuzumab it will be affecting a lot of people. Is this why the blue dots above are higher than the red dots?
However, there is only one other relatively common polymorphism besides the two above, that occur as homozgotes and this occurs in Latinos. Do they deplete different from the Europeans. A 5 minute bit of data analysis if you have the raw data
Is it something else I suspect. We know some gene variants affect, how well you deplete. Do they influence responses to Rituximab, ocrelizumab, etc?
Boyko AN et al. Lymphocyte depletion and repopulation is consistent across alemtuzumab treatment courses in patients with relapsing-remitting multiple sclerosis: 6-year analysis of patients from the CARE-MS studies . Mult Scler J 2016
In patients who received only the original 2 courses of alemtuzumab, mean CD4+, CD8+ and CD19+ counts at the start of Course 2 were 0.28, 0.24 and 0.34 x 10*9/L, respectively. Both T and B lymphocytes were depleted after the second course of alemtuzumab (N=369), reaching their lowest levels at 1 month after Course 2 (mean CD4+: 0.05; mean CD8+: 0.06; mean CD19+: 0.03 x 10*9/L). CD19+ counts repopulated quickly and reached the lower limit of normal (LLN; 0.1 x 10*9/L) by 3 months. T cells repopulated more slowly; CD8+ counts reached LLN (0.2 x 10*9/L) by about 6 months, and CD4+ counts reached LLN (0.5 x 10*9/L) at Month 24. Once reaching plateau (CD19+, 15 months; CD8+, 30 months; CD4+, 24 months), cell counts were stable through 48 months and remained above LLN. Depletion and repopulation of T and B cells were similar after 1 or 2 alemtuzumab retreatments (Course 3: n=79; Course 4: n=10).
(see it takes 2 years for CD4 levels to return to the lower normal limit so this may be why it takes 2 years for the secondary autoimmunities to occur and you can see the CD8 cells (regulatory cells) are back quicker so the pathogenic cells return in a regulated environment.)
Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J.Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.
Neurology. 2014 Jun 17;82(24):2158-64
An omission or does it simply not happen, that there are no people who do not respond well to treatment? I suspect the occurance of this is low.
However, some people do stop responding to alemtuzumab and the logical reason is due to antibody neutralisation, it happens with all protein therapeutics. Again we have to go no further than the internet and do some digging and some data interpretation.
We can go back to published data that was used to say that it is safe to go onto fingolimod after alemtuzumab. The lymphocyte number was shown for 13 individuals who failed alemtuzumab and went onto fingolimod. Six people had three cycles and it is clear that the two people in the bottom panels I selected stopped depleting. Probably because of neutralizing antibodies.
These people need to be changed, together they got about £60,000 worth of antibody to do nothing.
Importantly, it gets even more complicated because after alemtuzumab, it can cause white blood cells to become CD52 negative and so unresponsive to drug.
Brett SJ, Baxter G, Cooper H, Rowan W, Regan T, Tite J, Rapson N.Emergence of CD52-, glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-1H treatment. Int Immunol. 1996;8(3):325-34.
CD52 is a glycosylphosphatidyl-inositol (GPI)-linked glycoprotein expressed at high levels on normal T and B lymphocytes and at lower levels on monocytes, while being absent on granulocytes and bone marrow stem cell precursors. The emergence of CD52- lymphocytes of both T and B cell lineages was observed in three out of 25 rheumatoid arthritis patients treated with the humanized antibody Campath-1H in phase II clinical trial.
Whereas the majority of CD52- B cells had disappeared from the peripheral blood by 3 months post-treatment, both CD52- CD4+ and CD8+ T cells persisted in the circulation for at least 20 months. In the two patients that were tested, the GPI-anchored surface molecules CD55 and CD59 were also absent on the CD52- cells, although expression of other cell surface transmembrane, proteins (CD3, CD4 and CD2) was unaffected. The CD52- cells maintained a stable phenotype in vitro despite repeated re-stimulation in culture. Both CD52- and C52+ clones, established from one of the patients, responded to a similar extent to several T cell mitogens, as assessed by proliferation, suggesting that a general defect in expression of GPI-linked molecules does not impair T cell activation. These data show that an immune attack against a GPI-anchored surface molecule can result in the selection of a GPI-anchor-deficient cell population. Despite the persistence of CD52- T cells in the peripheral blood, no adverse reactions associated with the presence of these cells were noted in any of the patients; in fact they responded with longer remission times after Campath-1H treatment than the other patients in the trial.
So if MS is a problem of B cells then they will still be dealt with..phew? If it is a T cell issue then 12% of people may not deplete as well as they could. Does this happen in MS?.
I could have kept this last bit of detective work quiet, so I could publish it first.
But if you are using/recieving alemtuzumab I think you should know and monitor your depletion. If you are not depleting, are you neutralizing the response? and do you need to think about a switch?
Now that the existence of neutralizing antibodies is in the open in the academic literature in a searchable way, there will be a race to publish the first case that neutralizing antibodies actually impact MS at the individual level.
I guess you realise there are probably two places with a head start if they trawl their data, but as you can see it is all there already if you know where to look. (However in the cases above you don’t know if they had neutralizing antibodies), but I know it happens.
If you are a non-depletors (on first infusion) maybe get you neuro to give ProfG an email, so we can try work out why, if this not known already, depletion may not be that good. I will volunteer to do this, we have the technology, but we don’t have the cash:-(.
It may determine whether you can switch to another IgG1, as we know certain genes determine whether you deplete with rituximab too, or whether you need an non-antibody treatment.
Is this an issue for ocrelizumab?
Maybe it is time to Publish the data, so that we don’t have to dig to find the information. The answer is there.
CoI: None. DrK, ProfG multiple