What’s this all about? I wonder if we will get the Pulitzer prize for this?
I suspect we will get a lot of grief. You have said what have you been up to?
I have asked you to tweet. #isitoK that Pharma do trials on disabled people, but do not publish the results if they are not advantageous to the company?
Today, we move from ocrelizumab and Roche, back to alemtuzumab and Sanofi-Genzyme.
This is part I and Part II of the story to bring you up to speed so that you can see part III tomorrow (what have we done in 2019?) and then get you ready for part IV, part V, (very soon…as the papers are accepted and formatted and ready to publish), part VI (doing the rounds) and then part VII, which is this years efforts.
If you spotted my mega cock-up on Saturday, as I launched a post written in November, to support our student’s work presented at the Charcot Foundation, by mistake.. Sorry. You know where this story is going as you got part I to VI.
However to understand the story I need to cast your mind back a few years
As you know, we got hold of the oral cladribine phase III trial data set and started publishing stuff from it.
Both cladribine and alemtuzumab may effect MS via B-cell depletion. Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e360.
This helped bring back oral cladribine from the dead, after it was withdrawn in 2010 and has told us how it probably works.
Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, Lock H, Longhurst HJ, Giovannoni G, Schmierer K. J Neurol. 2018;265(5):1199-1209.
This is good as it gives you another option as of 2017/2018 and it should also tell pharma how to make a new set of even safer B cell therapies.
The other plus point is that over 250 people in our care got an extra option when there was none and it also helped ProfK get ChariotMS off the drawing board.
However, this encouraged us to do it again and this time we got the phase III data package of alemtuzumab done by Sanofi Genzyme. This came in dribs and drabs over about two years from 2016-2018 before we said “stop” otherwise they would be still sending it. They redacted every page of thousands and thousands of pages to removed names etc.. But there were a few things that caught our attention.
One of them put us on the hunt for activities of B cells, which I see as a positive element, and another one on the trail of anti-drug responses, where you generate an immune response against the drug. This is the same as an anti-drug allergy. I also see this as a positive element, as it speaks to safety
This was the Irony of Humanization Part I
Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. JAMA Neurol. 2017;74(8):961-969.
Although the action on B cells to tackle MS has been had its difficulties because of the “T cell mafia” are not ready to accept an alternative view, the suggestions about the causes and consequences of B cell repopulation responses in the generation of secondary autoimmune side effects has caused more of a stir.
Indeed, some people, with company support, have gone to some lengths to discredit the view that B cell repopulation in the absense of T cell regulation is important. This in part relates to the finding that in contrast to what was originally proposed by Cambridge and the Company (in the Europen label) that T regulatory cells are enhanced i.e. as a means to control MS…it is really an artifact of data handling. Such that it was a problem of working in percentages rather than absolute numbers as such a 13% increase was actually a 85-90% decrease. Whilst this debate rumbles on, I am happy with the suggestion as it may help focus on ways to stop the the secondary autoimmunity that occurs in about 50% of pwMS treated with alemtuzumb.
However, there was also something else going on with the B cells and this was the production of anti-drug antibodies. I think if we can understand that, it will help us to understand why B cell autoimmunity occurs.
The first monoclonal antibodies were made in mice and rats this lead to a Nobel Prize for Doctors Kohler and Milstein. This innovation made in Cambridge University has revolutionised medicine. However, it was soon realised that mouse or rat proteins are rejected by the human immune system and so the drugs stop working.
Therefore, the next invention from the bods at Cambridge was the development of “humanisation” of the rodent antibodies. In this case all but the target binding amino acids of the original rodent antibody are replaced by human proteins and so the idea is that by humanisation of alemtuzumab from the orignal rat IgG2a antibody to a human IgG1 antibody that its immunogenicity is reduced.
The World’s first humanised antibody termed CAMPATH-1H (Cambridge pathology-one) was made by Geoff Hale and Herman Waldmann, with Greg Winters). This removed most of the rodent bits of the parent antibody and replaces it with human protein. This is called alemtuzumab . The rat bits were the amino acids that bound specifically to CD52 on T and B cells.
This was designed to reduce human rejection of the rodent protein in the original antibodies, but keep the specificity of the target. This has spawned alot of useful therapeutics.
The next bit of innovation from Cambridge was to use CAMPAH-1H in MS
However, the irony, as found in part I, is that alemtuzumab is probably the worse humanised antibody on the planet and when used in MS with regards to anti drug responses, virtually everybody that gets it makes an antibody response againt it. There are binding antibodies (Babs) which bind and there are neutralizing antibodies (NAbs) which are Babs that bind to the functionally active site and so can stop the drug working. Therefore, we want to avoid the production of NAbs . In the first publication the company called them “inhibitory antibodies” and were left to go unnoticed
Irony of Humanization Part II.
Having established that neutralizing anibodies occur, the next question is are they functionally important?.
It was shown that they are important.
Alemtuzumab depletion failure can occur in multiple sclerosis. Dubuisson N, Baker D, Kang AS, Pryce G, Marta M, Visser LH, Hofmann WE, Gnanapavan S, Giovannoni G, Schmierer K. Immunology. 2018 Jun;154(2):253-260 .
Although this showed that one infusion was OK, about 0.6% had neutralizing agents prior to the second cycle and about 30% of people at the end of 23 months had neutralizing antibodies and about 75% had binding antibodies and could mean that drugs may stop working.
We found evidence that this (Part II) occurred. We could work out the response of a few people and one person who made high amounts of neutralizing antibodies did not appear to deplete their white blood cells. If the drug is not depleting it is probably not working. So this made us concerned for the people in our care. This caused us to do Part III (published later today), which We’ll discuss tomorrow.
What did the company do in response?.
The manufacturers do not think it is a big issue. Indeed, it isn’t unless you are one of the affected individuals and then it’s a big issue. In response to queries I made, the manufacturers have not provided access to the data which they have. I have been fobbed-off and my ideas have been discredited in print. You can select to do the analysis in such a way as to minimise the issue we were asking about. This is marketing and not safety. Think about the post I did about the exploding car.
The company have data on individual pre-and post dose lymphocyte numbers and pre and post- dose binding and neutralizing antibody responses. In the CARE-MS trials there were about 800 people and about 250 people from the CARE-MS EXTENSION study where people got repeated doses of alemtuzumab. No data on the individual effects of neutralizing (inhibitory) antibodies was yet presented that know of. By publishing the data themselves, they could have accepted the limited occurrence of treatment failure, made neurologists aware of the potential for treatment failure, given people a screen and managed this aspect.
One would say it’s a protein, of course you will get a neutralizing response, all proteins make them! However, evasions push one to make a mountain from a molehill.
The mountain has been built and tomorrow you can see what we have done to try and help you to avoid these issues.
Anti-drug antibodies can stop the drug working or they can give you an allergic response and can be dangerous than if not dealt with.
Nye CJS, Wagner A, Kousin-Ezewu O, Jones JL, Coles AJ. A case of anaphylaxis to alemtuzumab. J Neurol. 2019; 266(3):780-781. doi: 10.1007/s00415-019-09214-2.
This person developed an allergic response. After the first cycle they made IgE, which is an immunoglobulin made after IgG. This gets captured by mast cells that line the gut and the lungs and so when the person got alemtuzumab, it caused the mast cells to degranulate releasing histamine. This is what causes the itch after a mosquito bite. In extreme cases it stops you being able to breathe out and you can die without medical attention. Thank fully the nurses have been well trained and can deal with his. I’ve seen this in action when my mum conked-out due to allergy be my eyes. In the case of he.alemtuzumab allergy this occured despite treatment to stop this happening, which is standard for alemtuzumab treatment. If they had been screened before the infusion it may have been possible to predict it.
How could you test for this….tomorrows post.
The floor is over to you Dr.Angry.