Prof G's MS Blog Archive

The 25^th 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

http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2239

Concerns:

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