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."

CoI: multiple and ongoing


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.

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