23 post-marketing natalizumab-related PML cases

The EMEA announced, in a press-release, on the 23 October that there are now 23 post-marketing natalizumab-related PML cases:
Review of benefits and risks for Tysabri started -The Committee started a review of the benefits and risks of Tysabri, in view of reports of 23 cases of progressive multifocal leukoencephalopathy (PML) worldwide since Tysabri has been on the market. This review is initiated to discuss any additional measures necessary to ensure the safe use of Tysabri and how to balance the risks to the patients against the benefits of the treatment. Tysabri is indicated for patients suffering from highly active relapsing remitting multiple sclerosis with high disease activity despite treatment with a beta-interferon and for patients with rapidly evolving severe relapsing-remitting multiple sclerosis.” EMEA

You need to more vigilant than ever regarding possible symptoms of PML if you have been on Natalizumab (Tysabri) more than 12 months.

Genetics of MS update post-ECTRIMS 2009

Studies of family members of MS patients has shown that the more closely related you are to an MS patient the higher your risk of the disease. For example, if you are a sibling or child of an MS patient your risk is about 3%. This shows that genes play a role in MS.
Studies over the last 30 years has shown that a region of DNA on chromosome 6 is the main genetic locus in MS. The main gene involved is called HLA-DRB1 and this gene has an immune function. HLA-DRB1 comes in over 400 different forms (or alleles). A common form in Europe, named 15, increases the risk of MS by 3-fold. Other alleles of this gene also play a role in the disease. For example, 14 protects individuals from getting the disease. As each person has two copies of all genes (one from your mother and one from your father), it is important as to which two copies of HLA-DRB1 you have. For example, 14 completely cancels the risk increasing effect of 15 when they are inherited together. This may explain, in part, why MS is rare in Asia; there, the 14 allele is common.
More recently, large scale studies have identified a number of other genes involved in MS, including the interleukin 7 receptor alpha (IL7RA), interleukin 2 receptor alpha (IL2RA), the c type lectin 16 a gene (CLEC16A) and interferon response factor 8 (IRF8) genes. These genes increase disease risk by a substantially smaller amount compared to HLA-DRB1, but due to their role in the immune response highlight that the key mechanism of the disease appears to be immune dysfunction.
Dr Sreeram Ramagopalan, post-doctoral scientist

Novel disease modifying therapies: data presented at ECTRIMS 2009

The 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Dusseldorf in September 2009 brought together leading international experts in MS to share and discuss recent advances in MS research. We were presented very promising new treatments evaluated in phase II and III trials.
Oral therapies have reached an advanced phase of development, with some of the molecules having completed phase III trials. Data from the cladribine and fingolimod phase III trials were presented at the congress, as well as the phase II trial with teriflunomide and new data illustrating the mechanism of action of laquinimod. Prof. Giovannoni (London, UK) presented the findings of CLARITY, the phase III trial comparing two doses of cladribine and placebo in relapsing remitting MS patients. The study showed that a short course of cladribine tablets significantly increased the proportion of patients without disease activity after two years. Prof. Barkhof (Amsterdam, The Netherlands) presented TRANSFORMS, the phase III trial of oral fingolimod compared with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis. Twelve months of fingolimod therapy significantly reduced MRI inflammatory activity and cerebral volume reduction. The results of the phase II trial with two different doses of oral teriflunomide or placebo added to interferon beta for 6 months in patients with relapsing remitting multiple sclerosis were presented by Prof. Freedman (Ottawa, Canada). Both doses of teriflunomide were shown to decrease the inflammatory activity seen in MRI. Prof. Brück (Gottingen, Germany ) and Comi (Milano, Italy) summarized the studies evaluating laquinimod’s mechanism of action and the current data of efficacy and safety of laquinimod. They suggested dual neuroprotective and immunomodulatory properties, and promising efficacy data.
Alemtuzumab is a monoclonal antibody to CD52, a surface receptor of lymphocytes. We already know that alemtuzumab is superior over subcutaneous interferon beta 1-a (Rebif-44) in reducing relapse rate and accumulation of disability in treatment-naive relapsing-remitting MS patients for three years. In this Congress, Dr. Coles (Cambridge, UK) presented the primary efficacy outcomes of CAMMS223 at 4 years, which showed that alemtuzumab maintains its superiority to SC IFNB-1a.
Two trials with secondary-progressive MS patients were presented. Unfortunately, intravenous dirucotide failed to delay disease progression compared to placebo in a phase III study with 612 patients, as shown by Prof. Freedman.  Likewise, lamotrigine did not show any benefit in decreasing rate of cerebral atrophy and slowing disease progression in a placebo-controlled phase II trial in 120 people with secondary progressive MS, as was shown by Dr. Kapoor (London, UK).
Finally, Prof. Freedman disclosed the consensus of the mesenchymal stem cell transplantation (MSCT) experts held in Paris earlier this year. MSCT might be an important and exciting new modality for the treatment of MS. The formation of the International MSCT Study Group and the conception of a common protocol to be used worldwide will help advance this promising therapeutic line.
Overall, some new therapies seem to be clinically beneficial for MS patients. However, ongoing trials are underway to evaluate clinical benefit and safety data before these new drugs may be widely administered.
Dr Isabel Bosca, Visiting Neurologist Barts and The London

Panel recommends that FDA approves Fampridine for increasing walking speed in PwMS

Aminopyridines, a family of compounds to which Fampridine belongs, works by lowering the requirements for axons (the electrical cabling of nerves) by blocking a specific group of proteins on their surface called voltage-gated potassium channels. This makes it more likely for an electrical impulse or action potential to be transmitted across a demyelinated segment of an axon. Although this will improve motor function the effect on sensory and other pathways may make some problems worse, for example exacerbation of pain and increase in the frequency and severity of MS-related positive symptoms (pins & needles, muscle spasms and seizures).
Aminopyridines will almost certainly increase the energy requirements of damaged, vulnerable, demyelinated axons as they will require more energy for repolarization the process by which they get ready to transmit another electrical signal. There is now good evidence that increasing the energy requirements of axons may result in further axonal injury and loss. Essentially this is the theory underlying the use of sodium channel blockers, such as phenytoin or lamotrigine, as neuroprotective compounds in MS; by reducing transmission you reduce the energy requirements and hence protect vulnerable axons.
For these reasons I am wary about the long-term use of Fampridine in MS-related motor fatigue. I am worried that Fampridine may speed up the rate of disability progression. I stand to be proved incorrect on this; we will only find this out by doing clinical trials and following up patients with progressive MS on these medications for long periods of time using standardised methods.
I have posted Hugh Bostock’s videos, from Queen Square, on conduction in a normal nerve and a demyelinated nerve, on YouTube, to illustrate how slow and difficult it is to transmit an electrical impulse down a demyelinated nerve. When you watch the videos please try and imagine how much more effort/energy is required for conduction in demyelinated axons; aminopyridines are the chemical whips that keeps these axons firing.
Prof G