Thursday, 6 October 2016

Alemtuzumab and the forgotten little details

Last week ProfG got a surprise because of NHS England's tight-fisted approach to funding Alemtuzumab use. 

Some neuros think this is causing unnecessary alarm

Based on the Pivotal Phase III trial data it is clear that about 40-50% of people do not need further antibody infusions following the first two cycles. 

This is great news for the people that go NEDA.

However, it was surely clear from the get-go that some people will need to receive a further treatment cycle or try something else. 

What is the advantage of further treatment cycles? 

The best way to look is through analysis of the long-term data.

People in the phase II studies have been followed for some time and this gives us important clues of what to expect.

Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, May K, Button T, Azzopardi L, Kousin-Ezewu O, Fahey MT, Jones J, Compston DA, Coles A. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy.
J Neurol Neurosurg Psychiatry. 2015; 86:208-15


Number of People requiring the two cycles:    = 52%

Number of People requiring three cycles          = 36%

Number of People requiring four cycles           =  8%

Number of People requiring five cycles            =  1%

Therefore by allowing a third set of injections about 90% of people will be effectively be treated. So for an extra 3 injections of alemtuzumab (3 x £7045 = £21,135 + the infusion costs and dealing with the autoimmune issues occurring (50% in 5 years) in people, about an extra 35% of people treated may shed their MS, at least for a significant amount of time

Giving people two infusions and then switching to a lower cost DMT (but which do you switch too?) means that by the 5 year mark the drug costs (3 x £7,000) will be the same except that you will now be treating people yearly from year 3 onwards and you have exposed people to the risk without allowing them to get full benefit.

Surely the extra infusion has to be cost-effective in the long term, but it appears NICE have thrown a narrow-minded spanner in the works, or perhaps the manufacturers did not do their health economics in a way to approve this extra set of injections.

Some people have activity breakthrough and require additional treatment. Maybe their relapses have been brought from 4 a year down to one a year. Still a success but seen as a failure from a NEDA perspective. 

Extra infusions appear to be worthwhile while the antibody is still depleting, but if there is disease breakthough and lack of effective depletion of white cells then one has to ask whether there is any neutralizing antibody response that block, or partially inhibit the action of alemtuzumab.

I was once told by a pharma person that there were no neutralizing antibody responses, and that is maybe because they have read the pivotal phase III papers that does no highlight this issue. 

It was mentioned in the phase III trial data published that at the end of cycle on about 30% of people have binding antibodies and this goes up to over 80% after the second infusion. It is said that this does not affect the depletion.

However, such responses must have a consequence, whether this can contribute to infusion reactions which occur in about 90% of people. One must suspect that with each cycle of alemtuzumab the anti-alemtuzumab response is boosted.

Although alemtuzumab is a humanised antibody it is amazing that about 75% of people develop neutralizating anti-alemtuzumab antibodies contrasting to only about 1-9% with other humanised antibodies in MS. 

Wow! 

How do I work this figure out?

Tucked away in ECTRIMS 2013 open access multiple sclerosis journal supplement some of the details were reported.

P523
Ziemssen et al. Immunogenicity of alemtuzumab does not impact safety and efficacy in relapsing remitting multiple sclerosis patients in the CARE-MS I study

Anti-alemtuzumab antibodies were detected in 87.0% of
alemtuzumab-treated patients. Titers increased at Months 1 and 3
of the first course, declining by Month 12, when 29.2% of patients
remained antibody-positive. Among patients with binding antibodies, 93.3% tested positive also for inhibitory anti-alemtuzumab antibodies. Development of both binding and inhibitory antibodieswas further increased after the second course, with titers peaking at Month 13 and declining thereafter. Antibody status did not affect clinical efficacy (6-month SAD or annualized relapse rate), magnetic resonance imaging outcomes (T2-hyperintense lesion volume; T1-hypointense, T2-hyperintense, or gadolinium-enhancing lesion counts), overall incidence of adverse events, or the incidence of infusion-associated reactions. Through 2 courses of treatment, the presence and titer of binding or inhibitory antibodies had no discernible effect on T- or B-lymphocyte depletion or recovery.

Therefore 87% of people in care-MS I made binding antibodies and of those it states that 93.3% have neutralizing antibodies. 

Yep neutralizing antibodies also known as inhibitory antibodies

Furthermore, they were there after one month of the first infusion, which is amazing considering alemtuzumab is a T and B cell depleting antibody.  We have a fair idea why this happens.

Therefore do people, who don't respond to alemtuzumab have very active disease that is requiring 4 or 5 infusions or do they have neutralizing antibodies that stops the drug working properly (depletion not as good, or lasts for a shorter period of time=currently argued not to occur at least after two infusions)?

Maybe this aspect should be considered if you have active disease on alemtuzumab but it is evident that most people have them. 

18 comments:

  1. Can you test for these neutralizing antibodies?

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    1. I could do it as I can get the reagents from the chemical supply company but it wouldnt be to the correct lab standards required.
      However, I think that the people with the test are Genzyme, however based on the abstract it would seem that most people with the treatment can have the antibodies but I guess we want to know who have titres of a few million which can happen for the binding antibodies:-(

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  2. In the case someone fails Alemtuzumab, 5 out 10 if you consider retreating >2 a bad strategy as NICE says, what can you go for? it makes no sense to go for a drug with less efficaccy, and HSCT its not an aproved treatment. I guess people will have to sell the house in order to pay for retreatment, or do HSCT tourism...sigh, it makes me so mad, what are they thinking? MS societys need to fight this NICE offensive this past week.

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    1. I do not think it a bad strategy the data says it is not a bad strategy.

      If this NICE strategy is true it needs to be fought tooth and nail

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  3. How can they fail to publish this important information what else is being buried?

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  4. As an Alemtuzumab recipient (under the direct care of Dr Coles's team in Cambridge) I don't like the inference from the title of this post of deception / hiding of important information. What you are posting above isn't new. I was involved in a study (which has been published) which Cambridge ran which tested whether a drug given just prior to the Alemtuzumab infusion could ensure that the drug retains its effectiveness i.e. doesn't become less effective with additional rounds of infusions because of neutralising anti-bodies. There appears to be two types of research teams - those who identify new treatments and work with pharma to make them available to patients and those who just snipe at the work / research of these successful teams. I'd be very surprised if Dr Coles or his team were involved in suppressing "forgotten little details". Team G have yet to deliver any treatment to patients - there are many thousands of alemtuzumab recipients who are living lives relapse free many years after receiving treatment. Any news from Team G on the progress with your anti-spasticity drug, neuro-protective drugs? This post has annoyed me. Cambridge have made the real strides / breakthroughs in MS research and actually changed the future of many people with MS. Experiments on Lewis Mice, Shiver Rats, Intoxicated gerbils haven't helped me one iota.

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    1. Alemtuzumab is a very good drug, but it can be made better/safer.

      So first thing.

      If it had not been for Lewis rats, little mice etc. there may not have been any CAMPATH, it was made in a rat after all and the concept of T and B cells may not have happened when it did,etc,etc, etc.

      Next point: Indeed Cambridge have published on many aspects of the use of CAMPATH and the influences of cycles of drugs, but the neutralizing antibody data from the phase III studies has not been published in paper form to the best of my knowledge.

      Importantly as to content, I doubt this is under total control of the Cambridge group as it is not their data to publish but the data is that of the company producing drug who paid for the trials. I suspect they have most influence on content and not Cambridge, so defend the company as much as you like!

      So whilst you can take a swipe at us, it does not mask the fact that this data was not reported, you obviously don't think it is important, but what about the person who has had the drug many,many times and they are still relapsing or one of the people who have serious infusions reactions. Should the neurologists be aware of this aspect?

      To say where are your drugs? Then you might as well have a swipe at most of the World. Stanford, Harvard etc, etc. as few people have taken a drug from invention to people and without companies it wouldn't happen.

      CAMPATH was invented by Waldmann/Winters and Co. but yes Compston & Coles pushed it along the MS path and congrats to them for doing this. However, you may be interested to know that ProfG contributed to the licencing process of alemtuzmab as Dr. Coles was on sabbatical at the time.

      However, will your blood boil again...better get some paracetomol...as I do believe there is other stuff surprsingly missing from the reports that is of interest. Can the information be found elsewhere? Yes it can!. But should Neurologists have to look?

      Maybe those mouse experiments may help to understand the autoimmunity problems of Campathers...we shall see.

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    2. We will agree to differ. This drug gave me my life back. You're a very nice Prof Mouse, but bad-mouthing Alemtuzumab is as bad as bad-mouthing my elderly mother. When you publish your anti-spasticity drug trial results I will employ Inspector Morse to check every cross reference and Stephen Hawking to test every scientific claim.

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    3. It's not bad-mouthing, Alemtuzumab is undoubtedly a good drug. There is however missing data that may well explain how secondary autoimmunity may develop in many of those treated with alemtuzumab and also the development of neutralising antibodies that may also have an influence over time such as on treatment resistance.
      Surely the more data we have the better, so MSers and clinicians can better make an informed choice?

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    4. As a happy Campather/ Lemmie (seems like the war veterans club nowadays), and as a scientist I couldn't agree more with MouseDoc, data is power... give it to us, make it accessible, its the only way to move forward.

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    5. As a Pre Campather/Lemmie (not a scientist) I can see that Alemtuzumab was in no way being bad mouthed. What is being discussed is the omission of data that could influence decisions regarding recommendations and funding.
      The use of the word Team does make it seem like there's an invisible battle going on though. The only battle that is be happening is one against MS. Oh and maybe NICE and NHS England.
      Be nice.

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  5. Just add it to the list of hidden. ~ 200 cases of listeria meningitis I hear after treatment with Lemmie. Ouch

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    1. Where is the evidence presented otherwise it is hear say, however I am aware that some place prescribe pregnancy diets to stay clear of unpasteurised cheese etc. and with alemtuzumab we need to be vigilant for infections

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    2. Re: listeria meningitis

      Yes, we are aware of this. I am only aware of two cases of listeria meningitis post alemtuzumab. We inform patients about this complication and put them on a pregnancy diet for 3 months post treatment.

      Where do you get 200 cases from? This figure is incorrect. I get safety updates regularly on alemtuzumab and we would have been informed about a signal this big.

      Based on current data the risk of listeria meningitis post-alemtuzumab is well-described and would be classified as a rare adverse event with a risk between 1:1,000 and 1:10,000 (WHO classification).

      It is important for alemtuzumab-treated patients to be aware of the risk of infections and be extra-vigilant whilst you are waiting for your immune system to reconstitute.

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    3. Rau et al. Listeria Meningitis Complicating Alemtuzumab Treatment in Multiple Sclerosis--Report of Two Cases. Int J Mol Sci. 2015 Jun 29;16(7):14669-76. doi: 10.3390/ijms160714669.

      Alemtuzumab, a humanized monoclonal antibody targeting the surface molecule CD52, leads to a rapid depletion of immune cells in the innate and adaptive immune system. In phase 2 and 3 trials in multiple sclerosis (MS), infections have been reported more frequently in alemtuzumab than in interferon beta treated patients. Here we report two patients treated with alemtuzumab for MS developing Listeria
      meningitis few days after the first infusion cycle. Both patients recovered completely after prompt diagnosis and adequate treatment. Physicians and patients should be aware of this serious, but treatable complication.

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