Open letter to the EMA

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Just back from ECTRIMS 2019 in Stockholm. My highlight was the alemtuzumab 8-year longterm extension data; the brain volume data is quite extraordinary (figure 5). In short, apart from HSCT, there is nothing that comes close to alemtuzumab in radically slowing-down or preventing end-organ damage.

Comi et al. Alemtuzumab improves clinical and MRI disease activity outcomes, including slowing of brain volume loss, in RRMS patients over 8 years: CARE-MS I follow-up (TOPAZ study). ECTRIMS 2019, P1235.

I was also disappointed to hear the rumour that the EMA’s article 20 procedure was not triggered by an EU member country, but by the EMA itself. A colleague told me that the adverse events reporting from Genzyme were so poor that the EMA could not establish whether or not the new adverse events were causally related to alemtuzumab. So to get some clarity on the new adverse events the EMA triggered their own article 20 procedure to simply get Genzyme to do the work they should have done in the first place.

If this is the case it saddens me that people with MS may not be able to access alemtuzumab early in the course of their disease due to poor internal procedures at Genzyme.

If I had MS I would want to have the option of being treated with alemtuzumab. This is why I wrote the following open letter to the European Medicine Agency. I sincerely hope they listened. I have yet to receive a response from them, but I hope someone at the EMA has MS or has a friend or family with MS and understands why treating MS early and effectively is so important.  

Open letter the EMA sent  on the 20th August 2019

European Medicines Agency
Amsterdam 

Dear Sir/Madam

Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe.  Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT. 

At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a  treatment option. 

The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.  

In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS. 

Yours faithfully 

GAVIN GIOVANNONI

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

20 comments

    • Not really. Ofatumumab is a me-too and does what it does; it is very effective at switching off inflammation. I am less convinced about its ability to target the end-organ. I will post much more in this when I get time.

  • Prof G,

    Thanks for all your efforts. Alemtuzumab has been excellent for me (12 years since first infusion) and I want it to be available for others as a first line treatment.

    I thought the EMA were concerned about serious side effects. Given that Barts have treated some 250 patients, would it not be possible to share Barts’ experience with serious side effects with the EMA?

  • Thank u Prof G. Another great article. Agree totally and support your position. As ms patient whose had his 2nd dose of alem. I had slight difficulty in walking. I can now walk at 6km per hour for 1 km. And 5km non stop. Granted taking 1 hr 30mons. My question what is defined as early phase. Everyone is diagnosed at different times. Is it number of lessions? If so what number? Is it number of symptoms? Etc.

    • Genzyme have to submit data on all patients treated with alemtuzumab which includes our patients. Overall the adverse events seen in the UK alemtuzumabers are different from that seen in the US. Due to age and comorbidities.

  • Question regarding a third course.

    Is there a time limit as to when a third course can be given after the second and and is alemtuzumab currently completely unavailable anyway?

    • At present alemtuzumab is available 3rd line. We can give a 3rd course if necessary anytime after year 2. I the extension study ~40% of MSers needs a 3rd course.

      • And how does a neurologist decide if you do need a third?

        If you have a relapse?

        Does your MRI have to show inflammation?

        What if you get worse but have no inflammation is this the smouldering Ms and should that qualify?

        What if your neurologist does not believe in smouldering MS?

    • I do not believe so but I am not a prescriber the EMA suggestion is not to treat people first line but I do not believe that access is prevented

  • As another PwMS who has received Alemtuzumab, it may seem it’s the converted who are all responding positively to your letter to the EMA. My appreciation of you taking this action is based on wanting others who are keen, or who are inclined, towards having Alem, not missing out. Wish numerous other neuros would write their own version of this letter!

  • It’s disappointing to hear that Alem can not be made available to PwMS earlier in the EU due to a failure of the company. That’s appalling and disappointing. It’s one thing if the drug has a true safety issue and then yes, there should be limited used…it’s another thing if the company is sloppy and non-compliant…shame on Genzyme.

  • Thankful to still have access to lemtrada early on in my disease course here in Canada. Trying to jump on the opportunity (1st infusion in several weeks) incase access/regulation changes here also. Feeling grateful. Convincing arguments in your letter. Let’s hope it’s well received.

    • Thank you prof. G. Therefore in more advanced disease (EDSS 6 and SPMS) also this DMT has less efficacy… Do you have patients in these conditions using Alemtuzumab? With positive results? Thank you very much from Italy

      • The problem here is there are no controlled trials. Alemtuzumab was first used in SPMS and it was concluded that it didn’t work (Coles et al.199) but that was based on EDSS as an outcome and it was not controlled. Yes many people got worse, but how worse would they have got if they had not had the drug? I fear the time is running out or more likely has already run out to get that answer.

        Will Genzyme invest in an expensive and now increasingly more difficult trial (given that alternative are arriving) to do as the patent life disappears and there will be many years for these alternatives to become accepted. The safety issue that is currently occuring has surely not helped things.

    • Same here, I was relapsing every few months quite aggressively and quickly failed 2 of the first-line treatments here in Canada (Avonex and Tecfidera). As I’m JC+ I was offered Alem as a second-line treatment and jumped at the offer knowing full well the front-loaded risks of the medication. I’m relieved to have had it within my first 3 years of wicked, noticeable relapses.

      I currently have thyrotoxicosis due to the Lemtrada (I finished my second round 7 months before the hyperthyroid started). It’s pretty extreme, I’m on 100mg Atenolol and 8x5mg Methimazole to get it under control before radio iodine uptake scan and treatment to nuke the thyroid presumably…. and while I wish the company had taken the time to better mitigate the risk of secondary autoimmunity due to the medication, I’m still thankful and relieved to have had the opportunity to get the treatment as I haven’t had a relapse since. I was very quickly headed for a wheelchair with bad leg weakness, chronic vertigo and extreme heat intolerance. The added heat intolerance of the hyperthyroid makes things exponentially worse but I know it’s here for the short-term.

      I’m happy that the risk is front-loaded because I’m still young enough and resilient enough to deal with it (I think). I already lost a good chunk of brain, I need all the remaining time/brain I can get!

  • As I see the long term follow-up of MS Care II is also impressive, and this study suggests, the CDI not really depends on the baseline EDSS:

    https://onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/278382/heinz.wiendl.alemtuzumab.improves.disability.and.quality.of.life.outcomes.over.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1603%2Aot_id%3D21634

    Of course You have definately right! Hit hard and early, but looks alemtuzumab could give a really good chance later too.

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