How mice helped develop a new drug for MS

In the news today there have been reports that laquinimod, a new drug developed to treat multiple sclerosis (MS), has performed well in an early (Phase IIb) (1). An MS patient’s immune system attacks their central nervous system, leading to impaired communication in the nervous system and finally to physical and cognitive disability. A key feature of MS are the lesions where the myelin sheath that protects nerve cells is damaged, and in this trial patients who took a 0.6 mg per day dose of laquinimod showed a 40% decrease in the number of lesions. Few patients suffered side effects, and those side effects were relatively mild and disappeared when treatment was stopped.

http://www.washingtonpost.com/wp-dyn/content/article/2008/06/20/AR2008062000981.html
http://www.mssociety.org.uk/research/potential_therapies/laquinimod.html

This is good news since at present there are only a few treatments available to block progression of MS and they have serious drawbacks. Current reatments need to be injected and can have cause serious side effects, and some have a general immunosuppressive effect and can leave the patient more vulnerable to infection or cancer.

The team at Active biotech who developed laquinimod knew that they needed a drug that could be given orally and reduced damage caused by the malfunctioning immune system in MS without suppressing the immune system more generally. Their starting point was a drug called linomide (roquinimex) which had shown promising effects against MS before the clinical trials were halted due to severe side effects in some patients. Subsequent studies in beagle dogs indicated that these side effects were, rather ironically, due to the fact that linomide can cause severe inflammation in some circumstances. By making a series of modifications to the chemical groups at different positions on the molecule the Active Biotech team generated numerous chemical derivatives of linomide (2)*. The next step was to determine structure–activity relationship of these derivatives, in other words to determine the relationship between the different structural changes and the ability of the molecule to inhibit the development of symptoms in an experimental model of MS. Since they needed to determine the effect of the modified compounds on the intact immune system they needed to use a whole animal model, and the model they chose was an acute experimental autoimmune encephalomyelitis (aEAE) mouse that reproduces some of the characteristics on MS but develops much more quickly. The new compounds that showed the greatest activity against aEAE were then tested for proinflammatory responses in beagles. These studies resulted in the identification of laquinimod, which has more potent anti-aEAE activity than linomide but a far lower tendency to induce inflammation.

Laquinimod was then evaluated against chronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice and rats (3) and found to be effective. This was an important result since crEAE is considered to be a more accurate model of MS than aEAE, though it takes longer to develop and is therefor not as suitable for large scale screening of drug candidates. Furthermore it was observed that unlike some current MS treatments laquinimod does not have a more general immunosuppressive effect.

On the basis of these results in animal studies and additional safety and pharmacokinetic data Laquinimod went into clinical trials in MS patients, the early results of which were announced today. A phase III trial involving over a thousand patients is now underway and will with luck confirm these results and demonstrate an effect on the progression of the disease over a longer time period.

Cheers

Paul Browne

* Although this paper was published in 2004 the work it describes was undertaken several years earlier and predates the work described in the 2002 paper by Brunmark G. et al.

1) Comi G. et al. “Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study” The Lancet, Volume 371, Pages 2085-2092 (2008), DOI:10.1016/S0140-6736(08

)60918-62) Jönsson S. et al. “Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3 -quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship.” J. Med. Chem., Volume 47(8), Pages 2075-2088 (2004). PubMed 15056005

3) Brunmark G. et al. “The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis.” J Neuroimmunol., Volume130(1-2), Pages 163-172 (2002). PubMed 12225898

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