Saturday, 15 November 2014

News: alemtuzumab is licensed in the US

FDA U-turn: alemtuzumab approved in the US #MSBlog #MSResearch

"How and why did the FDA get it so wrong? They have now reversed their decision and licensed alemtuzumab for the treatment of MS. Please see Genzyme's press release below. Good news for MSers in the US is that they now have access to alemtuzumab to treat MS, but only as a 3rd line therapy. This may, or may not, end health tourism from the US to other countries for alemtuzumab induction therapy. I suspect that a lot of MSers in the US will be envious of the European label that allows 1st-line usage that maximises the benefits of alemtuzumab therapy. Once you have failed 1, 2 or 3 other DMTs you will have accumulated a lot of damage, which may limit alemtuzumab's effectiveness. Alemtuzumab is one of the most effective MS therapies we have and the only induction therapy on the table. I rate its clinical efficacy as being in the same zone as natalizumab and bone marrow transplantation (not licensed as a MS treatment). Alemtuzumab offers the advantage of being an induction therapy over natalizumab and it is safer than BMT. However, alemtuzumab comes with its own relatively unique safety profile that makes most neurologists, and the FDA, label it as too risky for 1st-line use. I think we need ask ourselves who should be taking on the risks of alemtuzumab as a treatment for MS; regulators, neurologists or the MSers themselves? I personally believe that if someone with active MS understands their disease and the risks and benefits of the various treatment options on the table, who am I to deny them treatment with alemtuzumab if they want it as a first-line  therapy? Surely, it should be about informed decision making and informed consent."



"Alemtuzumab's putative mode of action is via depleting your immune system and allowing it to recover spontaneously. Alemtuzumab kills or bursts open white blood cells, or leukocytes, by binding to a specific protein CD52 on the surface of the cell. When alemtuzumab binds to the cells it attracts a large number of other proteins, called complement, to the surface of the cells and these proteins pierce a hole in the cell causing it to burst. Complement is the family of proteins the immune system uses to kill damaged or cancerous cells and invading organisms. When the white cells burst they release their contents into the bloodstream; some of these substances are proteins that mediate the effects of inflammation on the body, which is why alemtuzumab causes an infusion reaction with a raised temperature, chills, rigors and a skin rash in most treated patients. To dampen down the infusion reactions we pretreat patients who are about to receive alemtuzumab with steroids, paracetamol and anti-histamines."

"Alemtuzumab is given as short courses on a yearly basis; daily for 5 days in the first year and then daily for 3 days in the second and subsequent years. Subsequent courses are only given if your MS has been shown to reactivate, i.e. you have relapses or develop new or enhancing lesions on MRI. The majority of MSers (two-thirds) only require 2 courses to go into long-term remission. A minority of MSers will require 3, 4 or very rarely 5 courses of alemtuzumab. Please note that reactivation of your MS after alemtuzumab does not mean that you have failed to respond to alemtuzumab it simply means you need another course, this is different to maintenance therapies (give continuously) were disease reactivation is an indication of non or suboptimal response."

"After each course the white cells recover by dividing or proliferating. When the immune system recovers there have been questions about whether or not it is competent to fight infections, cancers and whether or not it can remember the vaccines you have had in the past. A small study has shown that when the immune system recovers post-alemtuzumab it is competent and does remember the vaccinations you have had in the past. Another observation that tells us the immune system post-alemtuzumab is competent, or nearly competent, is the lack of so called opportunistic infections in alemtuzumab-treated MSers."

"There is one major caveat; when the white blood cell counts post-alemtuzumab are very low, or have not yet fully recovered MSers are at risk of herpes virus reactivation. Unfortunately, the lady below had herpes zoster. Once infected with herpes viruses they persist in the body in a dormant state and can reactivate when the immune system is stressed or compromised. To prevent this from occurring we prescribe prophylactic anti-viral drugs for about 6 weeks to prevent herpes virus reactivation. Despite doing this there is an approximately 1 in 50 chance of developing shingles after alemtuzumab treatment. In the clinical trials the majority of shingles cases were mild or moderate. It is also reassuring to know that shingles can be treated with anti-viral drugs."

"Whether or not MSers treated with alemtuzumab are at increased risk of developing secondary cancers is at present unknown. There have been too few MSers treated with alemtuzumab, and the ones who have been treated have been followed for too short a time, to answer this question. Therefore the increased cancer risk is a theoretical risk at present. In my opinion the cancer risk is low as we have not seen many of the so called indicator cancers, i.e. those cancers associated with drugs that target the immune system, in any of the MSers treated with alemtuzumab in the phase 3 trials. But on balance it is too early to make any judgement on this."

"The one risk from being treated with alemtuzumab is the development of secondary antibody-mediated autoimmune diseases that occur months to years after the last course of alemtuzumab. Autoimmune thyroid disease is the commonest disease and occurs in ~30% of treated MSers. The second most common is immune mediated thrombocytopenia, or ITP, that occurs in 2-3% of treated subjects. In ITP the immune system destroys the platelets or cells that help stop bleeding. A much more rare disease is so called Goodpasture's disease when the immune system makes antibodies that can damage the kidney. This last two diseases can be serious, but if detected early and treated most people make a good recovery. These autoimmune complications of alemtuzumab are why MSers who have been treated with the drug need to be monitored with monthly blood and urine tests for at least 4 years after the last course of treatment. Therefore if you are eligible for alemtuzumab and you want to be treated with this drug you are going to have to be adherent to the monitoring programme. If not and MSers die, or have near-death experiences, from these treatable complications the regulatory authorities may restrict alemtuzumab's use in the future. This would be unfair on those MSers who may wish to be treated with the drug in the future."

"The real advantage of alemtuzumab is the fact that it is an induction therapy; i.e. you get treated with the drug and you don't have to have it continuously. This has advantages for MSers who can't tolerate daily injection or oral therapies. Another advantage is the long-term remission that the majority of MSers go into after a two courses. Woman wanting to fall pregnant and start a family will find this attribute of the drug very appealing. What has been played down is that a large number of MSers who have disabilities find that they improve spontaneously after alemtuzumab. I don't think this is because alemtuzumab is a neurorestorative drug, but it simply reflects that when you suppress and stop inflammation in the brain and spinal cord you allow spontaneous recovery to occur. This is why I don't believe we need drugs to promote remyelination in MS; remyelination will occur spontaneously if we suppress inflammation with sufficiently effective therapies early in the disease course; a similar observation occurs with natalizumab or Tysabri. An important point regarding the spontaneous improvement post-alemtuzumab is the observation that it is more likely to occur early in the course of the disease, before the demyelinated axons die and there is sufficient reserve capacity to allow recovery. You can't remyelinate an axon that is not there; and this is why alemtuzumab has not be as effective in MSers in with secondary progressive MS."



CoI: multiple

18 comments:

  1. I think this is a watershed moment. We now have a highly effective treatment across the world (not the developing countries) which addresses relapses. The long term follow up shows that seven years after treatment some 60 per cent of patients have improved or remained stable. This is a big step forward given that the first treatments only became available 20 years ago. Hopefully Alemtuzumab can be made safer i.e the risk of other autoimmune disease reduced. My question to Prof G, what are the likely next big advances (given that the inflammatory stage can be pretty much addressed)? Also, are you writing off remyelination trials? (Several are underway). COI - i'm a recipient of A.

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    1. Just wondering if you had it first, second on third line? Would you take it again given the chance? Did it improve anything for you? Thanks!

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    2. I got it as part of a trial. Was on interferon. I wish I had got it sooner. 8 years since my first infusion and no relapses, mri shows no disease activity, EDSS is stable (saw improvements after first infusion). My remaining deficits are from first 3 years ie before I received Alemtuzumab.

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  2. Prof G the official US indication does allow freedom on the part of neurologists, as it states "...should generally be reserved for (3rd line)...". I think the more active neurologists will be using alemtuzumab 1st-line and I am sure they will attract many of us wanting to first-line. You seem to forget that the US healthcare system is fee-based and if there is money to be made they will make money.

    Do you have any idea how much Lemtrada will cost in the US?

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  3. Bloomberg reported Bill Sibold at Genzyme said, "the drug will cost $158,000 over the two years".

    http://www.bloomberg.com/news/2014-11-15/sanofi-s-lemtrada-wins-u-s-approval-to-treat-ms.html

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    1. Wow. Genzyme is competing with Gilead in the high costs stakes. I wonder if they will get hauled in front of Congress as well?

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    2. Wonder what is the price of a BMT?

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    3. cheaper then Alum.. 20,000 USD to 100,000 USD

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    4. Good question. I have heard of people going from Norway to Moscow and paying for BMT in a private clinic( the price was something like 400000 NOK = ca 38 000 GBP= ca 59 000 USD), but that was a few years ago.
      The price for 2 courses of Lemtrada here in Norway ( just the medicine, not the extra hospital costs): 99 474 USD.

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  4. Anon 1:09 If you're correct, the biggest barrier might be getting it past the insurance company, then.

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  5. Prof G,

    When you mention cancer surveillance, I thought one of the reasons alemtuzumab was previously rejected by the FDA was some supposed increased risk of thyroid cancer. This doesn't seem to get much mention elsewhere - is it an issue, and if so should treated patients be screened for it, eg with regular thyroid ultrasound?

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  6. The price point is always shocking - but a strong argument can be made that $158,000 and the other associated costs with administering and monitoring over several years, is easy to justify compared to a lifetime of the other drugs. Current therapies are running around $60,000/year, and if you live 20 years with MS and remain on therapy, $1,200,000 at today's cost. Then you factor in the cost of people no longer being able to work, the support services and other costs of living with MS in the US and suddenly Lemtrada appears to be a bargain.

    What is a problem to me, though, is the price of alemtuzumab as Campath for leukemia was $60,000/yr and that was for a much longer round of treatment. the MS version of Campath is Lemtrada, and it is a much smaller dose at a reduced strength. In other words, we get a lot less of Lemtrada,, but it will cost a whole lot more. Our system of how medicine is paid for in the US drives this insanity. Fierce Pharma estimated back in 2012 when Campath was pulled so Genzyme could play with these costs, the cost of it as an MS drug should be $6,000 per year. Crazy- can R&D and clinical trial costs justify this difference?

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  7. Dr.G I'm really curious why Alem seems to cause more secondary autoimmunity than Bmt ? Any puslible explanation for that ?

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  8. HSCT US clinical trials is only costing $120,000 at Northwestern. This will perhaps cause insurance companies to start offering HSCT as a standard MS treatment instead of everyone paying through the nose for Big Pharma. HSCT is already FDA approved having been used for years to treat cancer, there's no reason why hospitals shouldn't be providing the treatment!

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    1. HSCT is approved for other indications (mainly malignancies) , not for MS or Autoimmune conditions

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    2. A lot of hospitals and medical centers around the world are doing HSCTs, maybe they know something.

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    3. yes there is compelling evidence that its highly effective , but FDA approval will take time and will depend on the P3 Trial results ..

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