Tuesday, 21 August 2012

More on alemtuzumab: safety

"Yesterday's post on the withdrawal of alemtuzumab to prevent off-license use of the oncology version of alemtuzumab (Mabcampath) resulted in a flurry of discussion and criticism. With some of the latter occurring off-line. I must point out that I had nothing to do with Genzyme's decision; I am simply acting as the messenger and giving you my interpretation of the situation. 

I would like to stress that the safety issues in relation to the use of alemetuzumab in MS are not insignificant and need to be managed properly. In other words the licensing and prescribing of alemtuzumab (Lemtrada) in MS has to be tightly linked to monitoring for the autoimmune complications that occur months to years after treatment. The main adverse event that has emerged in autoimmune thyroid disease that occurs in ~30% of subjects. Autoimmune thyroid disease is rarely life-threatening and can be detected using 3-monthly blood monitoring. The latter usually detects thyroid autoimmunity in the incipient phase, before MSers become aware of the problem. The more worrying adverse event is the development of autoimmune thrombocytopenia; a disease in which your immune system makes antibodies that destroy platelets. This disease increases the risk of bleeding and if severe can be fatal. In fact one MSer in the phase 2 trial died when they had a bleed into the brain. Approximately 2-3% of MSers treated with alemtuzumab will develop this complication. As a result of this Genzyme introduced monthly blood monitoring and an active surveillance programme, with monthly questionnaires, to detect and treat this condition to prevent any further fatalities. Reassuringly, this surveillance programme has worked; all additional cases of immune thrombocytopenia have been detected and treated and there has been no further fatalities. Because of these, and other autoimmune, adverse events it is very important that the regulatory authorities, i.e. the EMA and FDA, are satisfied that the surveillance programme is water-tight and that all MSers treated with alemtuzumab will be monitored. In other words patient safety is paramount. 

The linking of a marketing authorisation with an active surveillance programme is not new. The precedent was set back in 1990, when Sandoz Pharmaceuticals obtained approval from the FDA to market clozapine (a very effective anti-psychotic drug for schizophrenia) in the United States by agreeing to make it available only through Caremark, in collaboration with Roche Laboratories, which organized weekly blood sampling to monitor the white-cell count, the dispensing of weekly supplies of the drug, and record keeping. Clozapine is associated with a life threatening complication called agranulocytosis (absence of a specific group of white blood cells) in approximately 0.5-1% of subjects receiving the drug. At the time this arrangement was unique in pharmaceutical history as a means of minimizing the potentially fatal risk of a toxic effect in a generally available drug, and was partially responsible for the high annual cost of clozapine. At the time the decision to market clozapine in this way generated a lot of controversy, particularly since many schizophrenics who were candidates for a trial of clozapine could not afford to pay for the treatment and were not eligible for publicly supported care. Despite the controversy clozapine, was and continues to be used safely and has truly revolutionised the care of schizophrenia. The impact of clozapine was so great that a friend of mine, who is a psychiatrist, talks about the pre and post-clozapine era of schizophrenia. 

Alemtuzumab is the clozapine of MS!

Therefore, it is very important for alemtuzumab (Lemtrada) to be used responsibly and to be linked to the active surveillance programme. Any irresponsible use could result in deaths and the withdrawal of the drug from the market or a marketing authorisation that limits the drug to a highly selective group of MSers with very active disease. The latter has already happened in Europe with both natalizumab (Tysabri) and fingolimod (Gilenya); both these drugs can only be used in MSers with highly active MS. In my opinion this is wrong, both these drugs should be available to a wider number of MSers for obvious reasons. I also strongly believe that MSers should be in control of decisions that pertain to risk, not the regulatory authorities or neurologists - they don't have the disease. 

It is clear that the sooner Alemtuzumab, and other DMTs, are used the greater their impact. This is the argument that underpins the treatment philosophy that I subscribe to of early aggressive treatment. Any perceived risk to MSers, that is not appropriately managed will therefore affect the regulatory authorities  decision about the type of licensing authorisation they give to alemtuzumab. The only way that Genzyme is able to address this issue is to make sure that no off-license use of the existing, or oncology version, of the drug takes place.

In conclusion, the decision to stop the off-license use of alemtuzumab (Mabcampath) in MS has been taken in the interests of MSers safety and hopefully to allow this drug to be used as early, and in a 
wide group of MSers with active relapsing disease, as possible. The EMA and FDA may not take this view, but controlling the use of alemtuzumab and linking it with active safety monitoring will increase the chance of this happening."



Other posts of interest in relation to Alemtuzumab on this blog:

Discontinuation of licensed supplies of alemtuzumab or ... - blog*spot
20 Aug 2012
This means that alemtuzumab will no longer be available as a licensed product in the UK once existing supplies run out. This action is not being taken for any reasons related to product safety, efficacy or supply, but as part of ...

ENS platform presentation: alemtuzumab vs. IFNbeta-1a
11 Jun 2012
I see that 74% of alemtuzumab treated patients are CDA free at 2 years, but only 51% are MRI activity free. Would you expect this MRI activity to result in CDA at some later stage, or do you think the MRI activity would reduce ...

Multiple Sclerosis Research: CAM-THY a new alemtuzumab ...
24 Jun 2012
When alemtuzumab-treated MSer's immune systems recover or reboot themselves, it begins to attack other parts of their body; most commonly the thyroid gland. Dr Coles, in Cambridge, believes that they can reduce the risk ...

Multiple Sclerosis Research: Research: Alemtuzumab (formerly ...
13 Apr 2012
Conversely, mean magnetization transfer ratio was stable in 20 alemtuzumab-treated patients (grey matter: -0.01 pu/year, p = 0.87; white matter: -0.02 pu/year, p = 0.51). The gradient difference in grey matter was 0.25 pu/year ...

Multiple Sclerosis Research: Alemtuzumab 5 year follow up
26 Mar 2012
OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of ...

Multiple Sclerosis Research: Making alemtuzumab or campath ...
20 Jan 2012
As you know alemtuzumab or campath-1h has remarkable efficacy in relapsing MS. In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic ...

Multiple Sclerosis Research: NICE and the new DMTs
06 Aug 2012
The drugs concerned are teriflunomide, BG12, laquinimod and alemtuzumab. Is this good or bad news ... All in all this is not good news for MSers wanting to access to these oral therapies or alemtuzumab. I can see why NICE ...

Multiple Sclerosis Research: Alemtuzumab results - further analysis
18 Jul 2011
"This was not a negative study; Alemtuzumab is still a very promising disease-modifying therapy! The patients in this trial were less active than previously therefore the trial lacked power to detect a difference in relation to ...

Multiple Sclerosis Research: Immune complications of alemtuzumab
03 Oct 2011
The average times from initial and last alemtuzumab exposure to ITP diagnosis were 24.5 and 10.5 months, respectively. Five patients developed severe thrombocytopenia. Four were symptomatic, including fatal intracranial ...

Multiple Sclerosis Research: News: Alemtuzumab $60,000 per annum
11 Sep 2011
"Based on its superior efficacy Alemtuzumab should command a premium price. However, the cost will affect its cost-effectiveness and its license in the UK under NICE. Ideally we would like to use Alemtuzumab in early MS; ...

Alemtuzumab - risks of developing other autoimmune diseases
30 Jul 2011
"What is alemtuzumab? You may know the drug as Campath-1h. This is a powerful immuno-modulator that is given as a course of intravenous infusions. It depletes the immune system and allows it to recover. I refer to it as an ...

Multiple Sclerosis Research: Alemtuzumab (Lemtrada) misses a ...
11 Jul 2011
The second phase three study for alemtuzumab involves patients who have relapsed on Interferon i.e. more active so I wonder whether the results for that trial will be more encouraging. Monday, July 11, 2011 8:04:00 PM ...

Research: Alemtuzumab treatment of Interferon-Unresponsive MS
09 Sep 2011
This is more of the same (good) news, with regard to Alemtuzumab. This un-controlled and unblinded study indicates that Alemtuzumab (an antibody that kills white blood cells) quells disease activity in MSers who have ...

Multiple Sclerosis Research: More on the Alemtuzumab trial
12 Jul 2011
More on the Alemtuzumab trial. The previous post is simply the headline results; we need to wait for the full results that will be presented at the ECTRIMS/ACTRIMS meeting from the 19 – 22 October 2011, in Amsterdam, The ...

Second successful phase III Results for Alemtuzumab in MS
14 Nov 2011
"Alemtuzumab is the most effective DMT in late stage development. The first MS'er was treated with the drug in 1991 by Prof. Alastair Compston in Cambridge; if or when Alemtuzumab becomes available in the UK it will have ...

Research: White blood cell depletion and Alemtuzumab
10 Nov 2011
Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has marked efficacy for relapsing-remitting multiple sclerosis (MS). One unresolved issue is the duration and significance of the lymphopenia ...

Genzyme details market potential of Alemtuzumab for MS
17 Jan 2011
Genzyme details market potential of Alemtuzumab for MS. Wow! Let's hope it is not too expensive for the NHS. Click here to read the press release! Posted by Gavin Giovannoni at 22:55 · Email ThisBlogThis!Share to ...

Genzyme is bought by Sanofi: what will this mean for people with MS?
16 Feb 2011
Genzyme is the company that is developing Alemtuzumab (formerly known as Campath-1h) for MS. Alemtuzumab is clearly the most effective of the emerging drugs in clinical development. Sanofi on the other hand are ...

Multiple Sclerosis Research: Meta-analysis of randomised ...
28 Mar 2012
In comparing treatments with interferon beta-1b (250μg), the network analysis revealed that no therapy shows better response for all 3 efficacy outcomes and alemtuzumab, 12 and 24 mg, have better response for 2 of the ...

Dr. Alasdair Coles: Guest Spot. Long-term follow up of CAMPATHers
14 Feb 2012
Without the persistance of Alasdair Coles and Alastair Compston, I doubt that CAMPATH-1H, (the worlds first humanised monoclonal antibody)/Alemtuzumab/Lemtrada would be on the MS agenda. This drug has told us a ...

Multiple Sclerosis Research: Do the markets know more than we do?
12 Jul 2011
"Alemtuzumab is a very effective therapy with many advantages, but also some risks. Now that Cladribine is off the scene Alemtuzumab is the only induction therapy, or immune system rebooter, in late stage development.

55 comments:

  1. Do you think there will be additional safety issues for patients with previous immunosuppressant use? I assume they were exluded from the trials.
    What about PML risk: do you think a positive JC status will be a risk factor?

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  2. I agree with all that is said above about early, aggressive treatment etc and the need for proper monitoring also, however surely that is an argument only for ensuring any off-label use is accompanied by proper monitoring, rather than removing it all together - especially as we're probably 2-3 years away from it being available on the NHS (if at all depending on the pricing)? The real reason for it's removal is, in reality, almost entirely down to the pricing issue. I'm not suggesting that is necessarily inappropriate for Lemtrada to command a higher price than Campath (it's right a premium is charged over Campath given the cost of the trials etc - and, frankly, we need Pharma to be able to return a good profit on effective MS drugs for them to keep developing them) but it's definitely the main reason for this removal, not patient safety so we shouldn't pretend otherwise.

    If Alemtuzumab really is such a paradigm changer to be called the 'MS equivalent of clozapine', then shouldn't all newly diagnosed patients be offered it (looking on a medical rather than NHS economic-based decision making basis)? Selecting between mild/not-mild and highly active versus less active to see who should have it is fraught with uncertainty and unreliability and the patient should be allowed to weigh up the risk of not being as mild/inactive as suspected, versus the risk of safety issues with Alemtuzumab shouldn't they?

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  3. I think that as alemtuzumab is administered in 2 goes a year apart, the drug only stays in the system for a matter of months?(although it's effect lasts much longer) whereas tysabri is administered every month and needs to be present to be effective. I don't think there have been any cases of PML with alemtuzumab in MSers so far.
    I hope I haven't been 'shooting the messenger'. I know the risks the trials have shown. It is so frustrating that the drug finished it's phase 3 trials at the end of last year (successfully) and has only just gone before the EMA for consideration, and then it will have to go before NICE, and you blogged about an idea to consider all the new DMTs together rather than individually (last week I think), and a health economics body said this could take upto 2 years. I don't think anyone believes that alemtuzumab will not come onto the market despite it's safety issues, but do you think the time frame of 2 years is right?

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  4. My neuro keeps on saying to me that he believes in the virtue of agressive early treatment. But I have yet to be offered anything that seems efficacious.

    Yes, I went on Avonex for a short while, but taking minocycline has shown to reduce lesions more... so I stopped and went on that.

    As for access...I'd love to take Campath. I'd do it in a heartbeat.

    And what's more - If I was offered HSCT I'd take it right away.

    I don't care that there are risks of death.

    Me: I'd rather be dead than in a wheelchair with someone cleaning me after I'd gone to the loo. That's my philosophy. Others might say that this is an awful thing to say and life is sacred.

    But I'd rather take a 5% chance that I might die taking drugs that might stop this disease than end up having to kill myself because I didn't want to have full time care.

    I think it is curious how the word 'suicide' is so absent from this blog. Everyone with MS I've ever spoken to has thought about it. Some have done it. I weigh up my treatment considerations against this as the alternative.

    I'm not suicidal. I'm just not prepared to live a life without dignity.

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    Replies
    1. Amen, brother Iain O!

      Waste away without any dignity, or die trying? It's plan B for me.

      Delete
    2. Amen, brother Iain O!

      Waste away without any dignity, or die trying? It's plan B for me.

      Delete
  5. "Everyone with MS I've ever spoken to has thought about it."

    Whilst not strictly the purpose of this particular discussion (and I don't want to distract from the discussion re: Alemtuzumab) I think it important to qualify Iain's comments - especially for newly diagnosed people who may be reading this blog thinking a life of being cared for is inevitable or even likely. Many, many people have a relatively mild (sometimes misdescribed, in my view, as benign which wrongly implies of no effect whatsoever, which isn't quite right) disease course. Some never have to deal with more than occasional, annoying tingling. Others have few physical symptoms at all and perhaps only some relatively mild cognitive effects. These people are not a small minority either - population studies frequently show that up to 40% of people have a relatively mild course. Equally, the other 60% are not all 'being cleaned up after going to the loo'. Wheelchair use remains relatively rare in MS. The proportion who reach 'cleaning after the loo' levels of disability - in the DMD era in particular - is very small indeed. I'm all for choice and faced with even the risk of the above - however small - I think Iain should absolutely be able to choose whatever treatment, with whatever risks, he wants; it's his life. To deprive him of that choice is patronising and dangerously paternalistic. But for many other people, they shouldn't rush to take such risk based on a misunderstanding that disability of this kind of severity is inevitable or even likely. For example, in one trial, 82% of people on Copaxone (relatively weak DMD compared with new ones) were still fully ambulatory without assistance after a mean of 22 years post-diagnosis. At 15 years post-diagnosis, less than 25% needed even a cane in a different study (British Columbia). The Olmsted Country study showed an average of 23 years to reach just an EDSS of 3 - relatively quite moderate disability and 52 years from diagnosis to reach the kind of disability described above (EDSS 8) by which point any number of intervening illnesses or unrelated events will probably have occured for most people. In a recent Swedish study, 35% of RRMS had not progressed to SPMS even after 40 years of disease duration. There are many more studies like this showing the great variability of MS. To counter Iain's views, no-one I've ever met with MS, including me, has seriously contemplated suicide - they live full and active lives and adjust for their condition where necessary.

    Anyway, the point of the above (and these studies are all before the newer DMDs or even any DMDs in some cases came onto the scene) is just to provide some balance to the prevailing unfailingly pessimistic views often found online. Yes, MS can be a terrible disease but it can also be relatively without impact in other cases. It is almost as variable in impact as saying 'I have cancer' with a spectrum ranging from neglible impact to devastating.

    Anyway, back to the discussion - Prof G - do you agree that Alemtuzumab should be available to ALL RRMS regardless of the current disease activity on the basis that by the time you've found out how bad/mild it is, it's too late to do very much about it? I guess the key question for those who subscribe to your views on MS treatment is, in 'early agressive' treatment - how early should early be? When is too late?

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  6. Wouldn't Rituxumab be an acceptable, efficious 'off-label' alternative to Alemtuzumab for those patients who wanted a 'high-risk, high potential reward' therapy who now can't access the latter?

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  7. Sorry - Rituximab not Rituxumab.

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  8. Rituximab isn't high risk

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  9. Re: "What about PML risk: do you think a positive JC status will be a risk factor?"

    There have been cases of PML post-alemtuzumab in the oncology literature. This is not surprising as some of cancers that alemtuzumab is licensed for are risk factors for PML. I think there is a risk of post-alemtuzumab PML, but it will be a very low risk. Once the immune system has rebooted post-alemtuzumab it leaves it relatively intact. Opportunistic infections are rare so I would not expect PML to be a major problem except in MSers switching from Natalizumab to Alemtuzumab. For the latter there will need to be an appropriate wash-out period and a clear MRI and spinal fluid analysis to exclude carry-over PML. The latter has already occurred in an MSer who switched from Natalizumab to Fingolimod.

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  10. Re: "If Alemtuzumab really is such a paradigm changer to be called the 'MS equivalent of clozapine', then shouldn't all newly diagnosed patients be offered it (looking on a medical rather than NHS economic-based decision making basis)?"

    We will have to prescribe within the license and NICE guidance. The former is usually based on the inclusion criteria of the clinical trials; i.e. MSers with active relapsing MS, who may or may not have failed a first line DMT.

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  11. Re: "I think it is curious how the word 'suicide' is so absent from this blog. Everyone with MS I've ever spoken to has thought about it."

    Not really; there has been a lot of discussion in the past on the blog about assisted suicide. If you want to read the posts try putting the word "suicide" into the blog search engine an see how many hits you get!

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    Replies
    1. Fair point. The irony is this: I walked into a Maggies Centre the other day - and it was full of optimism and hope in the face of the real possibility of death from cancer. I thought they might be able to offer me a stress management advisor or something. But as I have MS, not cancer, I was told - very politely - that no. They told me to go back to the NHS. The last time I talked suicide with my neuro he just looked as if I was mad and sent me to the acute mental health ward.
      The thing I want is access to drugs that have a real possibility to change my disease course. But I am still waiting... and waiting...
      No wonder I feel as if suicide is an option. It's the only thing available to me right now that really stops disease progression.
      I see my neurologist tomorrow. I bet you I will be given a nice smile and told that the treatment options that Prof G has so brilliantly pushed to the fore are in no way going to be signed off by my trust.
      And then I'll be offered Copaxone.

      Delete
    2. Re "I went on Avonex for a short while, but taking minocycline has shown to reduce lesions more... so I stopped and went on that"

      Was that your own decision?
      Why minocycline instead of subq beta-interferon, perhaps switching to natalizumab later? That works very well for many RRMS patients

      Delete
  12. Re: "... do you agree that Alemtuzumab should be available to ALL RRMS regardless of the current disease activity on the basis that by the time you've found out how bad/mild it is, it's too late to do very much about it?"

    No! I think it should available, as a choice, to all MSers who have active relapsing MS. Activity in this context is defined as relapses in the last 2 years and/or MRI activity. The decision to be treated with alemtuzumab would depend on individual choice after having weighed-up the risks and benefits, the potential inconvenience of monitoring and the fact that if you are JCV seropositive and have been treated with Alemtuzumab you will be at very high-risk of PML from natalizumab, and potentially other drugs, in the future. You may realise that decision-making about what DMT to use is going to get very complex. For example, if you have good prognostic factors you may want to try some of the other "safer" agents before escalating to alemtuzumab if you fail to respond to these.

    There is no easy answer to these questions, except individualised treatment decisions.

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  13. Re: " I guess the key question for those who subscribe to your views on MS treatment is, in 'early agressive' treatment - how early should early be? When is too late?"

    Early is within months of diagnosis and too late is when you already developed secondary progressive MS and have stopped having relapses.

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  14. Re: "Wouldn't Rituximab be an acceptable, efficious 'off-label' alternative to Alemtuzumab for those patients who wanted a 'high-risk, high potential reward' therapy who now can't access the latter?"

    Yes, but it is still an expensive therapy and we would have to convince the payers to allow it to be used off-license.

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  15. Re: "For example, if you have good prognostic factors you may want to try some of the other "safer" agents before escalating to alemtuzumab if you fail to respond to these."

    Doesn't an 'escalation' approach (trying increasing 'strengths' of drugs if the most recent one used 'fails') contradict an 'early, aggressive' approach (don't wait for continued failure, try early with powerful drugs)? Wouldn't you potentially 'lose' the window of opportunity presented by the latter approach by going through the 'weaker' drug motions in the early years? Or is this where MRI monitoring is key (as opposed to purely clinical)? I suppose the key question is, is 'no progression' (clinical or MRI measures) on GA or IFN 'equal' to 'no progression' after Alemtuzumab? Or might the latter be preventing things we can't see on a standard MRI which, in turn, might be better at preventing SPMS? In other words, might you be happily on GA or IFN for years, with no discernable progression/attacks and so never touch Alemtuzumab (or other more aggressive therapies) on an escalation based apprach, only to end up with a disabling SPMS which could (not would, but could) possibly have been prevented if you'd gone for the more aggressive therapy instead? If so, wouldn't that suggest much more widespread use (or, at least, offering) of Alemtuzumab, even amongst those whose RRMS is apparently 'under control' using safer drugs?

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  16. Re: "do you think the time frame of 2 years is right?"

    Yes! Two years is about right to cover the EMA approval process followed by the NICE appraisal and then the rejections and appeals and finally approval under the NHS. To add to this will be the local bargaining that will need to take place with local commissioners; the commissioners, unlike the PCTs, don't have to accept NICE recommendations, but will decide budgets on local priorities and needs. The latter will mean that post-code prescribing is likely to resurface once again.

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  17. Two years... damn. I think that's the "window of opportunity" I have with a relatively recent diagnosis.
    One thing I have learnt about MS.

    It gets your hopes up and then takes you to one side, gives you a sly wink, shows you far too much flesh then spikes your drink. You wake up the next day without a kidney and feeling terrible.

    Or something like that.

    In two years, Prof G, I'll be leaving messages about getting stents done in Poland.

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  18. Iain O are you eligible for Dr Cole's trial in Cambridge?

    http://www.colescambridge.org.uk/trial%20participation.htm

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    Replies
    1. I am asking my neuro about this tomorrow - but I need to have high IL21 levels. Not sure I do.
      Perhaps I could swap some blood with someone who does.... :)

      Delete
  19. I think you also have to be at high risk of getting an autoimmune disease to get on the trial by having high levels of IL-21. Presuamably they'll give you a blood test to check this

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  20. Re: "I suppose the key question is, is 'no progression' (clinical or MRI measures) on GA or IFN 'equal' to 'no progression' after Alemtuzumab?"

    Do you have a view on this Prof? Might we be doing a disservice to those on GA etc who are apparently stable but have unseen (even on a standard MRI) damage that Alem users (or other more aggressive treatments) might not? Eg Atrophy etc? I recall a study on here showing the Magnetisation transfer ratios were stable in Alem users (but presumably are not in IFN/GA) but this wouldn't be picked up on standard clinical and MRI monitoring. Could 'stable' MSers be missing out by sticking with the lesser treatments only to be hit later with SPMS they could have (potentially) prevented?

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  21. Isn't the real point that prognostic indicators in MS are still so unreliable and the outcome therefore so uncertain (and potentially devastating) that is should always be the patients choice whether to risk the safety issues of the more aggressive treamtments - especially when we believe (with some evidential foundation) that the earlier the treatment the more effective? Until a neuro can say with relative certainty (or even real as oppoed to hopeful confidence) "Your MS will be mild" then the choice should always be that of the patient, shouldn't it, who could lose years waiting to find out that his/her MS is serious and those lost years prove to be decisive (in a bad way) in the impact of treatment? How much confidence do you have Professor in predicting a course of MS being sufficiently mild as to not warrant treatment with more aggressive drugs? What does that MS look like in terms of symptoms - i.e. what is 'mild' MS such as to not be worthy of more serious treatment, especially in light of your comments earlier today re: anorectal symptoms being prevalent. If 'mild' MS could include incontinence, then why shouldn't an MSer with currently fairly stable/mild MS be able to take Alemtuzumab to try and prevent this before it is too late?

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  22. Prof G wrote (in another post):

    No. It only takes one strategic spinal cord MS lesion to leave you with anorectal dysfunction. If the spinal cord does not recover the dysfunction is permanent. The point I am trying to make is that it is better to prevent this happening if you can. You can't predict, with any accuracy, where MS will hit next or how severe or benign your disease will be. Benign MS is a retrospective diagnosis; you have to have the disease for at least 15 years with no disability before you can be labelled as having benign disease.

    Doesn't the above completely override the argument for an escalation approach (as opposed to straight to Alemtuzumab or similar upon diagnosis)? If I see you, Prof G, in clinic and you tell me my MS seems quite mild and I've not relapsed very often so I should wait and see or try IFNB first rather than Alemtuzumab and then I get 1 lesion on my spine that leaves me incontinent permanently - don't you think I have a right to be pretty unhappy about that given Alemtuzumab could have prevented it (and I might prefer to take my chances with Thyroid disfunction or even more serious diseases than be permanetly incontinent)?

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  23. Re: "If I see you, Prof G, in clinic and you tell me my MS seems quite mild and I've not relapsed very often so I should wait and see or try IFNB first rather than Alemtuzumab and then I get 1 lesion on my spine that leaves me incontinent permanently - don't you think I have a right to be pretty unhappy about that given Alemtuzumab could have prevented it (and I might prefer to take my chances with Thyroid disfunction or even more serious diseases than be permanetly incontinent)?"

    Yes! But on the other side of the coin is that you may develop immune thromboctopenia or Goodpasture's disease, both life threatening diseases. This is why it is a balance between risks and potential benefits and chance. The chance of having a spinal cord relapse that leaves you with permanent bowel and bladder dysfunction is low. Some of these arguments are moot; we don't have alemtuzumab available and if we did I may only be able to prescribe it under very narrow or strict NICE guidelines. However, in an ideal world, with quick and easy access to alemtuzumab things would be different.

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  24. Just in case any of you were wondering... (we all love a good story)... saw my neurologist today and all of my lesions had disappeared. Five weeks ago I had 2 or 3. Now not one to be seen.
    But my left leg is wobbly and I still have oligoclonal bands.
    The bummer is that... I'm not eligible for the hard drugs (yet).
    So back on the Avonex for me.
    Neuro convinced it is RRMS if it is MS at all (he thinks it is but the absence of lesions makes this a hard one to pin down). I am thinking it might be more progressive.
    What a crap disease, eh?
    Let's hope in a next life I don't come back as a mouse... and end up in the Mouse Doc's laboritorium being given EAE.
    Thanks for the advice above though. Nice to know that this is a community (of sorts) as well as a scientific blog.
    Who'd have thought.


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  25. Yes, I have a similar problem with the lesions. I have not developped anything in almost 2 years but neuro thinks it's great but I am worried that I am in the progressive phase already.

    However, I do tend to have symptoms which get worse and then get better - actually I had a horrible time last year with vertigo, really horrid and now I am comperatively well so no idea.

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  26. Prof G - With all the talk of Alem and, on other posts, Cladribine and Rituxumab, here's a question: if you had MS and had to self-prescribe one, which would you take? All three seem remarkably effective, with the Rituxumab 96 week study, for example, showing almost total sub-clinical disease suppression (0 Gd+ and only 2 of over 200 patients with new T2 lesions). Also, safety of Rituxumab and Clad look (although not formally phase 3 studied) at least as good as Alem. Anyway, back to the question - which would you take? Do all 3 'reboot'? Do you think all 3, early enough in RRMS, could prevent SPMS or just some of them?

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  27. Re: "With all the talk of Alem and, on other posts, Cladribine and Rituxumab, here's a question: if you had MS and had to self-prescribe one, which would you take? All three seem remarkably effective, with the Rituxumab 96 week study, for example, showing almost total sub-clinical disease suppression (0 Gd+ and only 2 of over 200 patients with new T2 lesions)."

    What about fingolimod and natalizumab? They are also very effective! And emerging therapies, such as BG12?

    We don't have enough data about rituximab to know durable its effect is? In RA the rheumatologists tend to retreat.

    In addition, we may yet have markers that predict good responses to interferon-beta or GA, i.e. be able to predict the 20% or so of MSers who will do very well on these drugs.

    The DMT field is going to get very complex and will need some form of algorithm to help decide who is suited to x or y. You also have to remember that the EMA and NICE in the UK will decide who gets these therapies.

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    1. Re Rituximab retreatment:
      Almost 7 months after the first rituximab dose, the doctors (& I) have decided to go ahead with a 2nd dose.

      The CD19 levels are still very low, so the doctors were wondering whether re-treatment will be of any use.
      Then they did some more reading and found that RA patients who were re-treated at 6 months (with CD19 still at 0) did better then those who got a placebo at 6 months. The placebo re-treated patients tended to start deteriorating.

      How does a treatment that works on B-cells have an effect even in the absence of B-cells?

      Delete
    2. Peripheral B cells numbers, i.e. CD19+ cells in the blood, are a poor correlate of tissue B cells. Therefore rituximab may be working by targeting B cell in the end organ.

      Delete
  28. Dear Iain O
    Mice are very happy to be part of Mouse Docs studies

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    1. I'm sure that's just because they like the music you play. Nothing to do with the trials.

      Delete
  29. Prof G - Ok, let me rephrase the question a different way... (and I realise that for the next 10-15 years this is pretty speculative!).

    If your primary treatment aim was, rather than just quell relapses, to prevent/delay/mimisise eventual SPMS in an RRMS'er what would you do then? Early Alem to prevent inflammation on the basis this is the ultimate cause of SPMS? Alem on the basis that is may also prevent atrophy (stable magnetisation transfer ratio study). Or maybe BG12 on the basis that it may be neuroprotective and therefore impact SPMS more than purely inflammatory DMDs? Or both (forgetting, for a moment, cost etc)?

    Do we have any evidence to base this kind of decision on at all or it is all purely gut instinct stuff at the moment? I realise we don't know, is the easy answer, but, of course, MSers need to make those kinds of decisions now based on what we know now and can't afford to wait years to find out!

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  30. Actually - in 4-9 years those who were on CAMS223 will have been 10-15 years post infusion. That will start to tell us a lot about the impact of early, aggressive immunomodulatory treatment on SMPS. Are these people being followed up for this purpose or was 5 years the end of the trial?

    Given it has been proven that relapses in the first 2 years is correlated to ultimate disease course, it is likely, is it not, that these more aggressive treatments will have an impact? Although I suppose one could argue that the relationship is not causitive - it's just a sign of more active disease which in turn means more active SPMS mechanisms which stopping the relapses might do nothing to impact. On balance, however, it seems more likely that there is a causitive relationship doesn't it? I suppose we've nothing else to go on right now so it's either trust in that or give up and wait for SPMS to hit!

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  31. Re: "Actually - in 4-9 years those who were on CAMS223 will have been 10-15 years post infusion. That will start to tell us a lot about the impact of early, aggressive immunomodulatory treatment on SMPS. Are these people being followed up for this purpose or was 5 years the end of the trial?"

    Yes, they are being followed!

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  32. Re: "Do we have any evidence to base this kind of decision on at all or it is all purely gut instinct stuff at the moment?"

    Emerging evidence suggests that MSers treated early and aggressively are doing well; this is based on the compassionate use programme in Cambridge, the long-term follow-up of the phase 2 cohort, the various bone marrow transplant programmes and the follow-up of MSers on natalizumab.

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    1. So, how would you treat if goal was purely to prevent/delay/reduce severity of SPMS?

      Delete
  33. Have any of the above yet got to the time when one would expect SPMS to rear its head? Eg circa 15 years? That is the key time isn't it to truly judge the 'stop inflammation, stop progression' hypothesis (which, for what it is worth, I believe in)?

    It's a rhetorical question but, again, if that is correct surely that is powerful evidence for letting all with MS take this more aggressive course to try and prevent the risk of SPMS?

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    1. Regarding progression after alemtuzumab, look at Dr. Coles guest post of 14th Feb. this year. I don't think he's reported anything yet.

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  34. I doubt Dr Coles will be saying anything until the information is published in the scientific literature

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    1. Presumably, Prof G has some insight into what Dr Coles might say based on his comment re: "emerging evidence"... If the people treated compassionately in the 90's had progressed, by and large, to SPMS one would expect we (or at least the neuro world) would know that by now and Prof G wouldn't be pushing the early, aggressive theory any more/as hard...? For me, it is the only thing we have that gives any hope (except maybe neuroprotection but that is still very embryonic) so I'm going to go along that route as much as EMA/NICE/my doc will allow me.

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  35. This article is interesting http://www.cam.ac.uk/research/features/campath-from-innovation-to-impact/

    QUOTE from Prof Compston:
    "‘Until we used Campath-1H in patients, this separation between inflammation and degeneration was not appreciated,’ says Compston, ‘but its implications were obvious. If this drug was going to be of any use to people with MS, we would have to use it much earlier in the disease process than we had so far.’

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  36. Prof G - what's you view on this? Given that most Campath trials were for 'early' MS - how can we be treating even earlier to make the drug 'of any use'? Should we be using Campath at first onset of symptoms I.e. CIS stage based on what Dr Coles is saying above?

    Do you have insight on the outcome of the earliest treated Campath patients re: SPMS - what is the 'emerging evidence' to which you refer?

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    1. The best results are the ones that are emerging from the phase 2 extension study. Most of these MSers are stable and you would have expected a lot of them to have progressed by this stage.

      Alemtuzumab is effective, but is not necessarily effective in all MSers. The number of MSers rendered disease activity free post-alemtuzumab is disappointingly low. Many MSers need further courses of treatment after the first 2 years. Therefore we need to look for more effective treatments and treatments that prevent progression. For the latter we need neuroprotective treatments.

      Delete
    2. Isn't Alem thought to be be neuroprotective?

      How do the two above statements reconcil: 'most were stable' and 'disease free was was disappointingly low'? Does that mean most were stable but needed more than 2 treatments to achieve this or that most were stable clinically but continued to show sub-clinical disease activity?

      Delete
    3. Disease free means a different thing with induction agents. If you are on maintenance agents disease activity means you are not responding that well to treatment. With an induction agent it means you need more treatment. The fact that the majority of MSers treated with Alemtuzumab are not disease-free at 2 years is an indication that they needed more courses. The real question is how many become disease free after the 2nd, 3rd and possibly 4th course. I would assume this increases, but the data is not known.

      Finally, most of the disease activity is on MRI and not clinically; so you can be clinically stable yet have new MRI lesions in non eloquent areas.

      Delete
    4. What's interesting is how Alem seems to virtually stop clinical relapses (ARR of 0.11 after 5 years) yet be relatively much less effective on sub-clinical measures. If lesions are proportionate to symptoms how is it incredibly effective in the latter and not the former? Is it somehow not stopping the lesions but making them less symptomatic or moving them away from more eloquent areas?! How can an incredible drug for clinical stability not be similarly remarkable for sub-clinical activity where it appears only marginally better than IFN, BG12 etc? Does anyone have any idea why this might be and what it might mean?

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  37. That quote refers to the patients they treated before the formal trials.

    That is why the Campath trials were for early MS

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  38. What's interesting is how Alem seems to virtually stop clinical relapses (ARR of 0.11 after 5 years) yet be relatively much less effective on sub-clinical measures. If lesions are proportionate to symptoms how is it incredibly effective in the latter and not the former? Is it somehow not stopping the lesions but making them less symptomatic or moving them away from more eloquent areas?! How can an incredible drug for clinical stability not be similarly remarkable for sub-clinical activity where it appears only marginally better than IFN, BG12 etc? Does anyone have any idea why this might be and what it might mean?

    Anyone?

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  39. The problem with the Alemtuzumab trials is that they are not blinded, i.e. the MSers know what drug they are on. This will have a major impact on reporting of relapses, but not on MRI. In other words the low relapse rate on alemtuzumab could be under reporting by MSers ignoring or not wanting to report attacks. This is why I put more weight in the MRI data. But again I must remind you that active MRI scans post-alemtuzumab don't mean the drug is not effective all it means is that the MSer needs to be retreated.

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    1. Do we believe that the difference with induction (eg Alem) in terms of MRI is - it might continue and therefore it needs retreating until it stops but once it stops, it stops - whereas with immunosuppression a baseline level of MRI activity continues but at a lesser level than before? Does that make sense?! Put another way, although two trials might show eg 50% reduction in new T2 lesions could it be that in (over-simplifying) in induction therapy, 50% of people have 0 new lesions and 50% continue (needing retreatment) whereas in 'escalation' DMT 100% of people have 50% less T2 lesions; same average possibly but very different effects...?

      Delete

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