Saturday, 30 April 2011

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis.

Cohen & Chun; Ann Neurol. 2011 May;69(5):759-77.

In addition to its immune effects Fingolimod readily penetrates the CNS and may have direct effects on neural cells. This central mechanism of action distinguishes Fingolimod from other immunosuppressive drugs and may explain its positive effects on reducing the rate of brain atrophy.

"Whether Fingolimod is neuroprotective is not a moot point; it's currently being tested in primary progressive MS. We will know the answer in approximately 3 years."

COI: I sit on the steering committee responsible for the phase 4 development of Fingolimod and our group has received grant support to assess Fingolimod in our secondary progressive animal model of MS.

Friday, 29 April 2011

AAN IN11-2.005 Identification of Epstein-Barr Virus Associated Epigenetic Changes and Association with Multiple Sclerosis

Ramagopalan, et al. OBJECTIVE: To investigate whether EBV associated changes to the epigenome are involved in the pathogenesis of MS. BACKGROUND: The epigenome are the chemical changes that happen to the DNA that do not affect the actual coding sequence of the DNA, but rather how the cell reads and processes the information coded in the sequence. As you may know already symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been firmly established as a risk factor for MS, however the mechanism behind this association is unclear. There is now convincing evidence for an epigenetic component to MS, with maternal parent-of-origin, transgenerational (grandparental) and early life (month of birth) effects, as well as the increasing sex ratio of the disease. RESULTS: In this study we found that 4475 locations in the genome were significantly different (methylated) between the pre- and post-EBV infection samples. Importantly, these areas were enriched for genes associated with MS. CONCLUSIONS: This study provides convincing evidence to support the hypothesis that environmental factors in MS act, at least in part, through influences on the epigenome.

"If this data can be confirmed by other groups it suggests that epigenetic changes to the genome play a crucial role in the pathogenesis of MS."

COI: Ram who did this work is a post-doctoral scientist in our laboratory.

Acknowledgement: This research was generously funded by the MRC.

For those of you who are having difficulties with the concept of epigenetics may find the following link and picture helpful. I will also ask Ram to produce and post a Youtube tutorial on this subject for you to view.

Epigenetics in Wikipedia

AAN P05.065: Remote EBV Seropositivity at First Attack in Children Increases MS Risk Independent of Other Common Childhood Viruses

Makhani, et al. AIMS: This study analysed Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), and herpes simplex virus (HSV) in children with a first attack of central nervous system demyelination (ADS). RESULTS: Children diagnosed with MS were more likely than those with monophasic ADS, i.e. non-MS, to be seropositive for remote EBV infection (37/49 vs 82/185, p<0.001) but not for CMV (7/33 vs 37/97, p=0.09), HSV (6/36 vs 26/110, p=0.48) or VZV (30/33 vs 83/97, p=0.55) exposure. CONCLUSIONS: Although the majority of children with MS are seropositive for remote EBV exposure, EBV is not obligatory for MS development in children.

"I am not convinced; the diagnosis of MS in children is not easy. It will be very important to follow the children with MS that are EBV negative to make sure they have typical MS and not another disease. The corollary to this is that if children can develop MS without antecedent EBV infection the association between EBV infection and MS is unlikely to be causal; it will also question the EBV vaccination strategy that is being promoted as a prevention strategy for MS."

Thursday, 28 April 2011

Going Mobile: Smartphones and other mobile devices can provide real‐time information and assistance for people with neurologic problems

Check this article out!

Paturel, Neurology Now: April/May 2011 - Volume 7 - Issue 2 - p 23–26

"I predict that this is how we will be monitoring MS in the future."

COI: I sit on an advisory board that is designing a suite of apps to achieve this aim.

Human herpesvirus 6 and effectiveness of interferon beta 1b in multiple sclerosis patients

Garcia-Montojo et al. Eur J Neurol. 2011 Apr 25.

Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) are associated with MS. Once infected with these viruses you remain infected with them for life. These viruses have a latent or dormant phase, were they hibernate within the body, and an active or lytic phase characterised by viral replication. IFN-beta may work via its antiviral properties suppressing the replication of these viruses within the body. This study evaluated the effects of IFN-beta-1b on the levels of HHV-6 and EBV in the blood of PwMS. Patients with detectable HHV-6 in their blood had a higher risk of severe relapses and a poor response to IFN-beta-1b. HHV-6 was detected in the blood more frequently during relapses than in periods of remission. No association was found between EBV and any of the clinical parameters studied. The authors' concluded that presence of HHV-6 in blood, and not EBV, during IFN-beta treatment could be a potential marker of poor response to IFN-beta-1b.

"The link between detectable HHV-6 in the blood and poor response to IFN-beta may simply be due to an association with another factor, rather than being causal; i.e. whatever is causing the lack of MS response to INFbeta may also be causing the lack of HHV-6 response to the anti-viral effects.

There are some methodological problems with this study.

As always these findings will need to be replicated by independent investigators in other groups of patients. Reproducibility and consistent results is what makes science sticky; something the CCSVI fraternity seem to ignore."

Wednesday, 27 April 2011

Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis

Krupp et al. Neurology. 2011 Apr 26;76(17):1500-7.

The aim of this study was to determine if memory could be improved by donepezil, the drug licensed for memory impairment in Alzheimer's disease, in PwMS. Unfortunately, Donepezil did not improve memory as compared to placebo.

"Memory impairment in MS is one of the hidden disabilities and clearly a difficult one to treat. A further argument to prevent damage rather than to try and treat it."

Adherence to Multiple Sclerosis Disease-Modifying Therapies in Ontario is Low

Wong et al. Can J Neurol Sci. 2011 May;38(3):429-33.

Patient adherence to various disease-modifying drugs (DMDs) in the treatment of MS is a major problem. Cumulative persistence rates for all four injectable DMDs were similar over time and ranged from 73.6-79.1% at six months, 59.1-63.1% at one year and 41.5-47.4% at two years. Adherence to DMDs in adult MS patients is poor, which is consistent with previously reported adherence rates to MS DMDs in other regions.

"This is a major problem and may explain why these drugs are not that effective in routine day-to-day clinical practice. Hopefully, the emerging DMTs and wide adoption of expert patient programmes will improve this dismal situation."

Suicide attempts in multiple sclerosis

Stenager, et al. Mult Scler. 2011 Apr 20.

Aims: (1) to estimate the risk of suicide attempts in PwMS in Denmark and compare the risk to the background population; (2) to estimate the risk of suicide attempts in PwMS receiving immunomodulating therapy compared with untreated patients.

Results: No increased risk for suicide attempts was found in PwMS. No difference in number of suicide attempts in treated and untreated PwMS was found.

"Good news and contrary to previous literature and current dogma."

Tuesday, 26 April 2011

FDA details timeframe of MS drug Tysabri's risks

The potentially fatal infection, known as progressive multiform leukoencephalopathy (PML), occurs in an estimated 1.5 per 1,000 patients treated with Tysabri during months 25 to 36. The PML risk was 0.3 per 1,000 patients during the first two years of treatment. After three years, the rate was 0.9 per 1,000. Limited data is available beyond four years.

For the first time the FDA said it had estimated the chances of PML for specific time intervals rather than providing a cumulative risk over years. The new estimates "will allow prescribers to better assess risk based on duration of treatment", the agency said.

As of the 1st April the total number of PML cases worldwide stands at 111.

Reuters Press Release

COI: I was the UK's Chief Investigator on the pivotal Natalizumab phase 3 trial and have received consulting fees from Biogen-Idec in relation to the development of Natalizumab for treating MS and managing the risk of PML in subjects on Natalizumab.

Patent filings 2010 - future innovation

A good index of future economic activity and innovation, which includes treatments for MS, is patent filings. The UK is not doing as well as it should!

Please see Nature Trend watch 21st April 2011

Monday, 25 April 2011

BG12 phase 3 data

Twice-daily BG-12 significantly reduced the proportion of patients who relapsed at two years by 49% vs. placebo (p<0.0001). On secondary endpoints, BG-12 significantly reduced annualized relapse rate (ARR) and disability progression by 53% and 38%, respectively, vs. placebo at two years. Mode of action: BG12 or dimethyl fumarate activates the NF-E2-related factor 2 (Nrf2) pathway; this pathway is both anti-inflammatory and neuroprotective.

BioCentury Press Release

"Unexpected results for a drug that is not immunosuppressive. The good news is that BG12 comes with a large pedigree of safety from its use in psoriasis. If these results are confirmed this drug is a paradigm changer and will almost certainly have positive effects in a large number of other, neurological and non-neurological, disorders."

COI: I am a member of the phase 3 clinical trial steering committee.

Saturday, 23 April 2011

AAN P05.032 - neuroprotective potential of BG12

AAN = 63rd American Academy of Neurology meeting in Hawaii

Racke et al. Neuroprotective Potential of Fumaric Acid Esters in a Model of Multiple Sclerosis. P05.032.

BG12 = Fumaric Acid Esters or dimethyl fumarate (DMF)

Pretreatment of mice with DMF reduced inflammatory lesion size by 30% and behavioral performance or recovery by 50%.

"In view of the positive phase 3 results and the mode of action of BG12 these results are very exciting. I still believe that BG12 will be an ideal add-on drug to existing anti-inflammatory DMDs."


COI: I sit on the steering committee for the BG12 phase 3 programme and receive consultancy fees for this role.

Wednesday, 20 April 2011

Urinary Diversion/Reconstruction for Cases of Catheter Intolerant Secondary Progressive Multiple Sclerosis With Refractory Urinary Symptoms.

Delong et al. J Urol. 2011 Apr 15. [Epub ahead of print]

Patients with SPMS treated with urinary diversion or reconstruction who cannot tolerate in-dwelling catheters have improved continence and fewer urinary tract infections. However, patients with with preoperative indwelling catheters, diabetes, obesity and significant blood loss were at greatest risk of complications from surgery.

"A reminder that MS can be disabling and lead to severe bladder problems. We try our best to avoid having to refer patients for surgical procedures. This is another reason to support aggressive early treatment to prevent or delay the development of disability."

Efficacy of Botulinum Toxin A Injection for Neurogenic Detrusor Overactivity and Urinary Incontinence: A Randomized, Double-Blind Trial.

Herschorn et al. J Urol. 2011 Apr 15. [Epub ahead of print]

"Confirmation that Botox helps PwMS with refractory bladder problems."

Tuesday, 19 April 2011

Fingolimod: first oral treatment for MS in the UK

Daily mail press release

Relationship of UV exposure to prevalence of multiple sclerosis in England

Ramagopalan et al. Neurology 19th April 2011

Methods: English national Hospital Episode Statistics covering all admissions to NHS hospitals in England from 1998 to 2005 were used to obtain the period prevalences of MS and infectious mononucleosis (IM). NASA's data on ultra violet B radiation (UVB) intensity for England was collected. The relationships among the 3 variables (MS prevalence, IM prevalence, and UVB intensity) were investigated.

Results: The regression of MS against UVB intensity for all seasons had an r2 of 0.61; when including the interaction of IM with seasonal UVB, the r2 rose to 0.72.

Conclusions: UVB exposure and IM together can explain a substantial proportion of the variance of MS. The effect of UVB on generating vitamin D seems the most likely candidate for explaining its relationship with MS. There is a pressing need to investigate the role of vitamin D and EBV and how they might interact to influence MS risk to identify potential prevention strategies.

"At last some integrated thinking to try and link risk factors."

COI: This work was done by Ram who works in our group!

Monday, 18 April 2011

BG12 - the last of the 5 oral MS therapies in phase 3 is positive

The Phase 3 results of another oral agent BG-12 (dimethyl fumarate) in RRMS were reported last week. The top-line results show that 240 mg of BG-12, administered either twice or 3 times daily, met the primary study endpoint, demonstrating a highly statistically significant reduction (P < .0001) in the proportion of patients with RRMS who relapsed at 2 years compared with placebo. Both doses of BG-12 also met all of the secondary study endpoints; (1) reduction in the annualized relapse rate and (2) the number of new or newly enlarging T2 hyperintense lesions, and (3) in new Gd-enhancing lesions on MRI, as well as (4) in the rate of disability progression as measured by the EDSS at 2 years. The overall incidence of adverse events and serious adverse events was similar among the placebo group and both BG-12 treatment groups. Medscape press release

"The mode of action of BG12 is interesting, suggesting that it may be neuroprotective. BG12 may be the ideal drug to use in combination with other anti-inflammatory drugs. Pity about the twice or three times daily dosing regimen."

Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases

Hoevenaren et al. Acta Neurol Scand. 2011 Jun;123(6):430-433.

The authors describe the pregnancy and outcome in two women with MS using natalizumab. The first patient used it in the periconceptional period, and the second patient used it in both the periconceptional period and throughout gestation. The course of the first patient was complicated by an exacerbation of MS. The second patient did not experience MS relapses during pregnancy, while still using natalizumab. Importantly, the newborns did not show any abnormalities postnatal and at 6 weeks' follow-up.

"Reassuring, but not enough data to commit to using Natalizumab throughout pregnancy."

Sunday, 17 April 2011

Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis

PwMS rarely have antibodies against EBV that are produced within the brain and spinal cord. Some antibodies are produced but are part of the general immune response that occurs in MS. Only rarely are anti-EBV antibodies detectable in the spinal fluid in patients with CIS, the earliest stage of MS. These data argue against a direct infection of the brain and spinal cord with EBV in PwMS.

Otto et al. Neurology. 2011 Apr 12;76(15):1316-21.

"May be EBV affects the immune system in MS in the periphery? Or by preventing the immune system producing antibodies against itself within the brain and spinal cord? The evidence that EBV is involved in MS is too compelling. We simply need to find out how it is involved in the disease; this is very important research."

Saturday, 16 April 2011

Laquinimod reduces the number of relapses by 23%

The results of the phase III clinical study were presented as late-breaking presentation at the 63rd AAN meeting, in Honolulu. The study involved 1,106 people with RRMS. Study participants received either a once-daily oral dose of 0.6 mg of laquinimod or placebo for two years. 80% taking laquinimod and 77% taking the placebo finished the two-year study.

Headline results:
1. Laquinimod reduced the annual relapse rate by 23%
2. Laquinimod reduced disability progression by 36%
3. Laquinimod's effect on MRI - 37% reduction Gd-enhancing lesions, 30% reduction in new T2 lesions, 27% reduction in new T1 lesions and a 32% reduction in brain atrophy.
4. Laquinimod was safe and well tolerated; the frequencies of adverse events were low and comparable to those observed in the placebo group.
5. Liver enzyme elevations were higher in laquinimod treated patients; these elevations were temporary, reversible and did not lead to any signs of long-term liver problems.

Source Newswire press release

"It is hard to imagine Laquinimod as a first choice oral monotherapy in RRMS based on these results. Laquinimod appears to have a disproportionate effect on brain atrophy given its very modest impact on relapse rate; this could be a chance finding and will need to be confirmed in the second phase 3 study, or Laquinimod could be "neuroprotective". Unfortunately, without data on the impact of Laquinimod on cognitive impairment in MS it is impossible to relate the effects of Laquinimod on brain atrophy to a clinical meaningful outcome. The study also had a high-drop out rate of 20% in the actively treated arm; we need to know why. Could it be because of lack of efficacy or poor tolerability? On balance, disappointing results."

COI: Barts and The London participated in this study and I was the PI.

Friday, 15 April 2011

Feedback from our 2nd MS Research Day

The following are the headline results from our feedback survey from the 2nd MS Research Day on the 26th March 2011. Thank you for taking the time to complete the survey. Overall the feedback has been very good. There are areas that need improving, which we will take on board for next year. The web-links for the recorded lectures will be ready within the next few weeks; they are still being edited.

The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-1a

Sandberg-Wollheim et al. Mult Scler. 2011 Apr;17(4):431-40.

Analysis of pooled safety data from 12 key clinical trials did not show an increased incidence of malignancy per 1000 patient-years with sc IFN beta-1a (4.0; 95% confidence interval (CI): 2.9-5.5) compared with placebo (6.4; 95% CI: 3.3-11.2).

Conclusion: Safety data from both clinical trial and post-marketing settings suggest that treatment with sc IFN beta-1a does not increase the risk of malignancy in patients with MS.

"Reassuring!"

Thursday, 14 April 2011

CCSVI: no evidence of chronic cerebrospinal venous insufficiency at MS onset.

Baracchini et al. Ann Neurol. 2011 Jan;69(1):90-9. doi: 10.1002/ana.22228.

Fifty consecutive patients presenting with a clinically-isolated syndrome (CIS) underwent extracranial and transcranial venous echo-color Doppler sonography (ECDS-TCDS). Those with results suggestive of CCSVI underwent selective venography (the gold standard for diagnosing diseases of blood vessels). Fifty healthy age- and gender-matched controls were studied. Findings: transcranial venous echo-color Doppler sonography (TCDS) was normal in all PwMS. Selective venography performed in 7 of the patients with abnormal TCDS (1 denied consent) did not show venous anomalies. These findings do not support a cause-effect relationship between CCSVI and pMS.

"One criteria of causation is that the causative factor has to have the correct temporal profile in relation to the onset of the disease that it is meant to be causing, i.e. it has to predate the onset of the disease. These data suggests that CCSVI is not present prior to the onset of MS, as it is not present at the earliest event CIS, therefore it cannot be causing the disease. Again these results will need to be confirmed in ongoing studies."

CCSVI: value of MR venography for detection of internal jugular vein anomalies in MS: a pilot longitudinal study

Zivadinov R, et al. AJNR Am J Neuroradiol. 2011 Apr 7. [Epub ahead of print]

Conclusions: Conventional magnetic resonance venography (MRV), which is non-invasive, has limited value for assessing internal jugular vein anomalies for both diagnostic and post-treatment purposes.

"As always these findings will need to be reproduced!"

Wednesday, 13 April 2011

Determining the value of drugs - the evolving British experience

I don't like politicising this blog, but the issue of prescribing expensive drugs in the NHS is something we need to do if we want to change the natural history of MS. I urge you all to read the policy article in the latest issue of the New England Journal of Medicine on the proposed changes to prescribing in the NHS.

Briefly, the government is proposing a shift to value-based pricing; i.e. there would be a basic price threshold, that will allow the Dept of Health to negotiate prices for new drugs with manufacturers. Final prescribing decisions would be left to individual GPs who will be given a defined budget and need not follow existing decision-making processes, in particular NICE or specialist guidelines, such as the ABN guidelines in the case of MS. The new approach would require GPs to consider; (1) the burden of illness related to the condition to be treated, defined in terms of the unmet need for treatment or the severity of illness; (2) the extent of therapeutic innovation involved; and (3) the “wider societal benefits.”

"Are GPs in a position to make these judgments? Will this lead to post code prescribing? Will the changes lead to greater cost savings or at best reduce the rate of rise in drug costs? Will PwMS have access to the newer more effective emerging therapies? These are all important questions; PLEASE HAVE YOUR SAY IN OUR POLL!"

Faden & Chalkidou. N Engl J Med. 2011 Apr 7;364(14):1289-91.


Dextromethorphan/Quinidine: in pseudobulbar affect

Pseudobulbar affect (a very unfriendly medical term) describes the uncontrollable and inappropriate laughing and/or crying that occurs in some people with advanced MS. The laughing and crying is typically unrelated to, or out of proportion to, the emotions felt. PwMS and their families find this problem very embarrassing and it often leads to social withdrawal.

This publication reviews the evidence of Dextromethorphan and quinidine as treatment for this problem. The top line results: there was a significantly greater decrease in the rate of pseudobulbar affect episodes per day with Dextromethorphan/quinidine 20 mg/10 mg twice daily compared to placebo.

Why the quinidine? Quinidine inhibits the breakdown of Dextromethorphan which results in higher levels and a longer period of exposure to the drug. A potential downside is that the combination may be associated with a rare cardiac side effect, called QTc prolongation (another unfriendly medical term) and therefore use of this combination will require mandatory ECG or EKG monitoring.

"Healthcare professionals usually underestimated the social impact of pseudobulbar affect; having another treatment for this problem will help. Spread the hope is my motto."

Garnock-Jones, CNS Drugs. 2011 May 1;25(5):435-45.

Tuesday, 12 April 2011

GW Pharma gains on Sativex deal

GW Pharmaceuticals plc (LSE:GWP) gained 12.50p (13%) to 108p on Monday after granting Novartis AG (NYSE:NVS; SIX:NOVN) exclusive rights to commercialize Sativex in Australia, New Zealand, Africa, Asia and the Middle East. The territories exclude Japan, China, Hong Kong and Israel/Palestine. The sublingual cannabis extract spray containing tetrahydrocannabinol (THC) and cannabidiol (CBD) is approved in Canada, Spain, New Zealand and the U.K. to treat spasticity due to multiple sclerosis (MS). GW will receive $5 million up front and is eligible to receive $28.8 million in milestones, plus royalties. Bayer AG (Xetra:BAY) has rights to market Sativex in Canada and the U.K. from GW, while Almirall S.A. (Madrid:ALM) has rights in the rest of Europe. Otsuka Pharmaceutical Co. Ltd. (Tokyo, Japan) has exclusive rights in the U.S. and Neopharm Ltd. (Petach-Tiqva, Israel) has rights in Israel/Palestine.

BioCentury Press Release

"At the end of the day MS is big market for the pharma companies."

Smoking and multiple sclerosis: an updated meta-analysis

Smoking is an important risk factor for MS. We therefore did a updated meta-analysis of all studies published on the topic. Our results confirm that smoking is associated with MS susceptibility and increases the risk of getting MS by ~50% (conservative: risk ratio (RR) 1.48, 95% confidence interval (CI) 1.35-1.63, p < 10⁻¹⁵; non-conservative: RR 1.52, 95% CI 1.39-1.66, p < 10⁻¹⁹). We also analysed 4 studies reporting the risk of developing secondary progressive MS; this fell just short of being statistical significance(RR 1.88, 95% CI 0.98-3.61, p = 0.06), but suggests that people with MS should probably stop smoking. "The million dollar question is how does smoking increase susceptibility to MS? We need to answer this to explain the MS causal pathway. We can't leave any stone unturned."

PLEASE COMPLETE THE MINI SMOKING SURVEY ON THE RIGHT, THANKS!

Handel et al. PLoS One. 2011 Jan 13;6(1):e16149.


COI: This work was done by our group.























Monday, 11 April 2011

Can vitamin D(3) supplementation prevent bone loss in persons with MS? A placebo-controlled trial

Osteoporosis (thinning of the bones) is common in MS. In this small study the investigators failed to show that a weekly dose of 20,000 IU of vitamin D3 could prevent the bone loss in PwMS.

"Why did this study fail? 20,000U of vD3 per week is equivalent to less than 3,000U per day. This dose is clearly too low. The investigators should have tried 10,000U per day; which has been shown to be safe in PwMS. My current recommendation is 5,000U per day with active monitoring of blood vD levels; this advice on dose is based on the vD Council's advice (http://www.vitamindcouncil.org/)."

Steffensen et al. J Neurol. 2011 Mar 13. [Epub ahead of print]

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

An important milestone for the potential use of mesenchymal stem cells in MS. This phase 1 study demonstrates that it is feasible to harvest these stems cells from the skin of PwMS, expand them in the laboratory and give them back to patients safely. In addition, the investigators did this in away that could be used to assess their effectiveness in larger, placebo-controlled, double-blinded, phase 2 studies.

"Well done guys!"

Connick et al. Trials. 2011 Mar 2;12:62.

Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study

Any one up for taking a dose of whipworm (Trichuris suis)? It is safe and my yet prove to be effective in ongoing phase 2, and, hopefully, phase 3 studies.

"You have to remember that man evolved in close association with many parasites. The mutual relationship we developed with them in terms of their effects on the maturation and function of of our immune systems cannot be ignored. The science supporting probiotic therapies is very compelling."

Fleming et al. Mult Scler. 2011 Mar 3. [Epub ahead of print]

A close-up view of whipworm or Trichuris suis

Critical appraisal of animal models of multiple sclerosis

If you are interested in the quality of laboratory-based research you should read this article.

Baker et al. Mult Scler. 2011 Mar 3. [Epub ahead of print]

"It is great that the lab-based scientists have started doing their experiments to the same standards of quality required of clinical trials."

COI: David Baker and Sandra Amor are members of our group.

A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis

At last the Sativex study results in print.

"Most neurologists don't like the study design used in this trial, i.e. an enrichment design in which only the responders from the first phase were included in the second comparative phase to show the drug worked. It is important to remember that it is impossible to blind a trial that is testing cannabinoids as they have psycho-active effects. The reality of symptomatic therapies is that we always use them in this way in the clinic; i.e. we give someone a therapeutic trial and if they don't respond or they develop intolerable side effects we stop the drug."

Novotna et al. Eur J Neurol. 2011 Mar 1. doi: 10.1111/j.1468-1331.2010.03328.x. [Epub ahead of print]

Sativex Trial Design

Long-term effect on quality of life of repeat detrusor injections of botulinum neurotoxin-a for detrusor overactivity in patients with multiple sclerosis

This study shows that repeated injections of botulinum toxin into the detrusor muscle* of the bladder in PwMS, who have refractory over-activity of their bladders, leads to a consistent effect on bladder control and, importantly, results in sustained improvement in quality of life.

* "The detrusor muscle is the balloon-like muscle that relaxes when the bladder is filling and contracts when the bladder is emptying. In MS the detrusor muscle is typically overactive leading to a small contracted bladders (low volume or small balloon) that is irritable. The combination of these effects results in patients complaining of urinary frequency and urgency. Multiple botulinum toxin injections into the detrusor muscle relaxes the muscle, which increases the volume of the bladder and reduces the irritability of the bladder. As the injections into the bladder wall have to be done using a flexible scope under direct visual guidance the procedure and treatment are relatively expensive."

Khan & Fowler et al. J Urol. 2011 Apr;185(4):1344-9. Epub 2011 Feb 22.

I used to work with Professor Clare Fowler who led this study; she was a very caring and thoughtful neuro-urologist who pioneered this treatment. One of my MS heroes!

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: An application in multiple sclerosis.

A new trial design for doing neuroprotective MS clinical studies. The investigators propose using an adaptive design in that the trial changes over time so that only the winners (2 out of 4 of the active arms) in the first phase get through the final or definitive arm of the study.

"This study design is very appealing, but unfortunately it may go down poorly in the patient community. The study will take about 7 years to complete; 2 years to recruit, 2 years to do phase 1 and 3 years for the phase 2 arm of the study. In my opinion 7 years is simply too long in the life of someone with progressive MS to get an answer. We clearly need better and quicker trials for testing neuroprotective drugs in progressive MS."

Friede et al. Stat Med. 2011 Feb 22. doi: 10.1002/sim.4202. [Epub ahead of print]


COI: I sit on the steering committee of the UK MS Society's Clinical Trial Network that commissioned the work to design this study.

Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis.

This study shows that in an animal model of advanced secondary progressive MS the drug FTY720 or Fingolimod is not capable of preventing or delaying the progression of disability independently of its effects on inflammation. The investigators allowed the animals to enter the progressive phase of the disease, before shutting down autoimmune driven inflammation by inducing immune tolerance (a fancy word for switching off the immune system's attack on the brain and spinal cord) before starting the therapy.

"Does this mean that Fingolimod is not neuroprotective? No it does not, it only shows that in this particular setting that Fingolimod is not effective. Can I remind you that modifying this phase of the disease course remains the holy grail in MS therapeutics, i.e. modifying the progressive phase of MS after inflammation has been switched off with potent anti-inflammatory therapies. This is why we are concentrating so much of or time and effort on developing neuroprotective treatments."

Al-Izki et al. Mult Scler. 2011 Apr 1. [Epub ahead of print]

Declaration of a conflict of interest: this study was supported by Novartis and it was done by our group.

Interferon-beta and glatiramer acetate effects on permanent black hole evolution on MRI

When MS causes a new lesion in the brain it leaves behind a scar ~80% of the time. The scar may become a black-hole which indicates loss of underlying tissues. The lesions that cause black holes are considered to be more destructive than lesions than don't leave behind black-holes.

"This study shows that interferon-beta, is as likely as glatiramer acetate, to prevent lesions from turning into black holes. This would indicate that both these DMTs affect the evolution of lesions and reduce their effect on brain tissue; this data would support both these drugs as having some neuroprotective effect."


Filippi et al. Neurology. 2011 Apr 5;76(14):1222-8.

The effect of exercise therapy on fatigue in multiple sclerosis

Exercise therapy may have a positive effect on MS-related fatigue, however, the findings of a systematic review show the impact of exercise can be highly variable.

"I think the problem with in the field of fatigue is that we still don't know how to measure fatigue or even characterise it; for example mental/cognitive vs. physical (exercised-induced or temperature-sensitivity) or fatigue related to low mood or sleep deprivation. Sleep-deprivation is a common problem in PwMS and relates to many issues that are often relatively easy to manage, for example nocturnal spasms, pain and nocturia (getting-up to go to the toilet due to bladder problems). I think it is time we sorted this mess out."

Andreasen A, et al. Mult Scler. 2011 Apr 5. [Epub ahead of print]