Prescrire International is the concise, English language version of la revue Prescrire. Prescrire International is a unique source of independent comparative information on drugs and other therapeutic interventions. The New Drugs section provides you with comparative assessments of new drugs and news indications. The Reviews section gives you assessments of therapeutic interventions as well as treatment guidelines that will help you to offer your patients effective care based on the best availabe evidence. The Adverse Effects section gives you a balanced view of the latest suspected or confirmed adverse drug reaction data collected from the many published and unpublished data sources all over the world.
So “sacre bleu” what do they say
Alemtuzumab (LEMTRADA) and multiple sclerosis. Biased evaluation, evidence of serious risks. Prescrire Int. 2015 Mar;24(158):69.
As of late 2014, interferon beta injection was the standard “disease-modifying” treatment for patients with relapsing-remitting multiple sclerosis, in the absence of a better alternative. Alemtuzumab (Lemtrada), an anti-lymphocyte monoclonal antibody first used in some types of leukaemia, is authorised in the European Union, at a different dosage, for patients with multiple sclerosis. Clinical evaluation in multiple sclerosis is based on three unblinded trials comparing alemtuzumab with interferon beta-1a. These trials were all biased in favour of alemtuzumab and thus fail to establish the potential value of this immunosuppressant. Overall, adverse effects, including the most severe, were more frequent with alemtuzumab than with interferon beta-1a. The adverse effects of alemtuzumab reported in these trials had already been observed in cancer patients. They included potentially severe reactions to the infusion, as well as a risk of infections and cancer due to profound and prolonged immunosuppression. At the dosage authorised in multiple sclerosis, autoimmune disorders such as thyroid disorders and immune thrombocytopenic purpura are particularly frequent and serious. In practice, patients with multiple sclerosis already have difficulty coping with the troublesome consequences of their underlying disease. They should not be subjected to the serious adverse effects of alemtuzumab, especially given the absence of any proven benefit.
Having looked how to blind a trial to Alemtuzumab, to include dummy infusions, steroids, anti-virals and the reviewers said they did not believe it was possible to blind an alemtuzumab trial
The standard disease-modifying treatment for patients with relapsing-remitting multiple sclerosis is interferon beta injection, in the absence of a better alternative. In 2007, natalizumab had an unfavourable harm-benefit balance in patients with severe multiple sclerosis in whom interferon beta was ineffective, due to insufficient evidence of efficacy and a risk of life-threatening progressive multifocal leucoencephalopathy. In 2014, we found no new comparative trials focusing on the efficacy of natalizumab monotherapy in its authorised indications in the EU. Post-marketing data confirm the adverse effects identified in clinical trials, including serious and life-threatening opportunistic infections, particularly progressive multifocal leucoencephalopathy in about two per thousand treated patients (an incidence twice as high as initially estimated), and potentially severe hypersensitivity reactions. An increased risk of cancer in the long term cannot be ruled out. Post-marketing data also show that natalizumab can cause severe liver damage. In addition, natalizumab withdrawal because of progressive multifocal leucoencephalopathy almost always triggers an immune reconstitution syndrome that can lead to neurological complications or even death. In practice, regardless of the severity of multiple sclerosis, it does not seem reasonable to expose patients to the many serious adverse effects of natalizumab for such an uncertain benefit.
It is true that when PML first reared its head the risk of PML was thought to be about 1 in 1000 and according to Biogen it has indeed crept down to about 1 in 100. Some people may argue that because people are switching off Natalizumab the denominator has been removed and so the risk is even higher.
There is no question that tysabri is a very active drug, especially if you are JC virus negative, but the issue is how to stop and switch to something else. ProfG has done many many posts on this but it is the case for a JC virus positive person taking Tysabri that they have to think about the risk of PML which kills about 20-25% of people affected and leaves the others with a lot more disability.
So next up we have Aubagio:
Teriflunomide (AUBAGIO). Multiple sclerosis: just a metabolite of leflunomide.Prescrire Int. 2015;24:61-4.
In mid-2014, subcutaneous or intramuscular interferon beta injection is the standard disease-modifying treatment for patients with relapsing-remitting multiple sclerosis, in the absence of a better alternative. Teriflunomide, the main active metabolite of leflunomide, has been approved as an oral treatment in this setting. Both substances have immunosuppressive effects. Clinical evaluation of teriflunomide is based on a comparative trial versus interferon beta-1a in 324 patients and on two placebo-controlled trials in a total of about 2300 patients lasting 1 to 2 years. In these trials, oral teriflunomide at a dose of 14 mg per day led to a statistically significant decrease in the average annual number of relapses compared to placebo, but teriflunomide may be less effective than interferon beta. No impact on the progression of disability has been shown during less than 2 years of follow-up. The burdensome adverse effect profile of teriflunomide is similar to that of leflunomide and includes hepatotoxicity, infections, leucopaenia, arterial hypertension, peripheral neuropathy and alopecia. The long half-life of teriflunomide (about 19 days) complicates the management of its adverse effects and multiple drug interactions, and has important implications for patients wishing to have children. Teriflunomide is teratogenic in animals and should not be used by pregnant women. Foetal toxicity via semen cannot be ruled out. In practice, the adverse effects of teriflunomide in multiple sclerosis are disproportionate to its efficacy. It is better to choose interferon beta, despite its limitations
It is true that all MS drugs have side-effects, some more than others and different levels of efficacy, some more than others. So more reason why it is time for a rethink about cladribine. Is it’s side-effect issue a real problem that puts it at as much riskier than these current drugs.
However, it is wrong to suggest that MS drugs are all bad. They are not, it has put MS on the map and Pharma interest in MS has brought enormous benefit.
So a set of three posts by anonymous, I wonder if this is really Dr.Dre. If this was not anonymous, would it be Doc Dead in a ditch:-).