Natalizumab treatment markedly reduces the release of neurofilament into the spinal fluid of people with MS. Neurofilaments are the main structural protein of neurons and axons. This is further evidence that natalizumab treatment reduces the accumulation of nerve injury in MS. Hopefully, this will stimulate pharmaceutical companies to include spinal fluid neurofilament analysis in all of their clinical trials.
Author: Gavin Giovannoni
Pregnancy and foetal outcomes after interferon-β exposure in multiple sclerosis
A report on 88 pregnancies in Italian woman that were exposed to interferon-beta (average exposure 4 to 5 weeks) has demonstrated that exposure to interferon-beta was not associated with an increased risk of spontaneous abortion. However, it was associated with both a lower baby weight and length. No significant fetal complications, malformations, or developmental abnormalities were noted with a follow-up of 2 years. These findings point to the relative safety of IFNβ foetal exposure of up to 4 weeks during pregnancy. These data will assist woman with MS on interferon beta with difficult decisions with regard to pregnancy.
New drug target to promote remyelination
Click here for BBC news coverage
Drugs that target a specific type of retinoid acid receptor (RXR-γ) are a promising target to stimulate remyelination in the damaged central nervous system.
Click here for article by Huang and colleagues, Nature Neuroscience 2010;doi:10.1038/nn.2702
How much vitamin D is too much?
If you interested please read the Institute of Medicine’s 2010 report on vitamin D and calcium intake.
Click here for on-line access to the report
The committee of scientists, convened by the National Academies’ Institute of Medicine, doubled the upper level of vitamin D that people that people between the ages of 9 and 50 can safely take in any given day from 2,000 to 4,000 IU.
MS Endophenotype Study
HELP!
MS is a common, complex neurological disease. Although the precise aetiology of MS is not yet known numerous studies indicate that both genetic and environmental factors are important. It now appears that the environment acts long before MS becomes clinically evident and suggests the existence of a prodromal phase for the disease. The possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring “endophenotypes” that result from associated risk factors. Identifying and studying individuals, for example family members of people with MS, with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.
We are therefore recruiting people with MS who have brothers and/or sisters without MS, and people with MS who are twins (identical and non-identical) to explore the possible cause of MS. Twins will help us understand the cause of disease and the influence of early environmental exposures; identical twins have the same genetic background and twins in general share the same early environment, which can be different when looking at non twins and unrelated individuals.
ECTRIMS 2010 Update: Phase 2 Ocrelizumab Results in RRMS
Ocrelizumab (anti-CD20) that targets B-cells was given as two treatment cycles, 6 months apart, in a phase 2 study in relapsing-remitting MS. It reduced MRI activity by ~90% (median T1 Gd-lesions at wk 24: placebo 1.6, 600mg 0.0, 2000mg 0.0, Avonex 1.0; p<0.0001 vs placebo) and annualised relapse rate by up to 80% (ARR: placebo 0.61, 600mg 0.18 (RRR 80%), 2000mg 0.2 (RRR 72%), Avo 0.4). Importantly the overall adverse event profile looks good (AEs: placebo 70%, 600mg 61%, 2000mg 65%, Avonex 55%). Infusion reactions typically disappeared at the day 15 infusion and there were no opportunistic infections. Worryingly there was one death in the high dose Ocrelizumab group at 14 weeks, from "systemic inflammatory response syndrome". These very impressive results need to be tempered against the death that we must assume is due to Ocrelizumab. Nevertheless this study demonstrates the importance of B cells in the pathogenesis of MS; the latter needs further exploration and may ultimately lead to a safer and even more effective therapy.
Improvement in MS disability after Alemtuzumab
Treatment of early RRMS with Alemtuzumab reduces relapses and the accumulation of disability compared to interferon β. Remarkably PwMS treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years in comparison to those treated with interferon β.
Critics have poopooed this observation as the study was single-blinded and liable to unblinding; i.e. only the evaluating neurologist is blinded to what the study subject received in the study. Due to infusion reactions from Alemtuzumab it is not possible to do double-blinded studies with the agent; i.e. studies in which the evaluating neurologist and study subjects do no know what they have received.
In an additional analysis of the phase 2 trial data it appears that the participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity during the study trial, were noted to improve after Alemtuzumab but not following interferon β treatment. This would suggest that disability improvement after Alemtuzumab may not simply be due to its anti-inflammatory effects.
This statement is subject to the same criticisms levelled at the whole study; but despite these criticisms this would be the first treatment in MS to offer such a benefit. No wonder PwMS are so excited about the prospect of receiving this therapy.
Preliminary experiments hint that Alemtuzumab stimulates white blood cells to produce growth factors that promote survival of nerve cells and enhanced oligodendrocyte (cells that produce myelin) function. This data will need to be replicated and shown to be relevant in patients treated with Alemtuzumab.
The implications of this research for PwMS cannot be overemphasised; at last a possible treatment with the potential to promote recovery.
Jones et al Brain. 2010 Aug;133(Pt 8):2232-47. Epub 2010 Jul 21.
Oral Cladribine turned down by the European Medicines Agency
Despite evidence that oral cladribine is effective in relapsing-remitting MS the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a negative opinion regarding the marketing authorization for Cladribine Tablets. The CHMP have concerns about the long-term safety of Cladribine.
In my opinion, long-term safety data can only be obtained from post-marketing surveillance studies and the extension study of the pivotal clinical trial. Unfortunately, there are probably not enough patients in the latter study to answer this question. It is a good thing that the drug is licensed in Russia and Australia.
Click here for press release from Merck-Serono
Fingolimod – first oral drug for MS in the United States
The FDA has licensed Fingolimod as a first-line therapy for people with relapsing-remitting MS. Let’s hope it passes through the European Medicine Agency (EMA) with the same ease as the FDA and NICE gives it the thumbs up in the UK; the pessimist in me expects not. I predict that its use will be handcuffed in Europe for patients with highly-active disease (similar to Natalizumab) and for patients intolerant of first-line injectable therapies. I also suspect NICE will make it second-line; however this will depend on how much Novartis charge for the drug.
Click here for Bloomberg’s Statement
To see how the drug works please see the following YouTube video:
Click here for YouTube video on Fingolimod’s mechanism of action
Vince Cable’s “Science, Research and Innovation” Speech
Apologies about politicising this blog, but what happens to investment in science in the UK will eventually impact on the lives of people with MS and their families. The only way to limit the impact of this devastating disease is through scientific research. The unmet need in MS is massive:
1. We have yet to optimise disease-modifying therapies. Is expecting a cure too much?
2. What about restorative therapies?
3. Symptomatic MS therapies are dismal; too many side effects and limited or suboptimal efficacy.
4. What about prevention? Preventative strategies are just beginning to emerge as potential option.
Without investment in research how are we going to address these needs?
You may find Vince Cable’s speech interesting.