Friday, 31 January 2014

January 2014 natalizumab PML Update

February 2014 natalizumab PML update. #MSBlog #MSResearch

"The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; I have been told by Biogen-Idec that if you are not a health professional you should not be reading it. if you are a MSer you should be reading my previous post designed for you."

Headline information

"As of 4th February 2014 there have been 439 cases of natalizumab-associated PML; an increase of 9 cases from last month. The mortality associated with PML in this setting is currently 23%, i.e. 101 MSers have died as result of PML, The majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of over 123,000 MSers have been treated with natalizumab."

"It is becoming increasingly clear that the numbers of MSers developing PML are falling due to the successful risk mitigation strategy that has been implemented Biogen-Idec with JC virus serological testing."

"The following is the most important slide for MSers regarding risks based on the three identified PML risk factors:

  1. JCV serostatus
  2. Duration of treatment
  3. Previous exposure to immunosuppression

In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and this needs to be incorporated into future risk models."

"We have developed a simple infographic to help you intergrate all this information. You can download and print this infographic for your own information."

Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.

"The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch. In those MSers who are high risk and have elected to stay on natalizumab we have started doing 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 above."

CoI: multiple

Lower Cancer Risk in MS

Catalá-López F, Suárez-Pinilla M, Suárez-Pinilla P, Valderas JM, Gómez-Beneyto M, Martinez S, Balanzá-Martínez V, Climent J, Valencia A, McGrath J, Crespo-Facorro B, Sanchez-Moreno J, Vieta E, Tabarés-Seisdedos R. Inverse and Direct Cancer Comorbidity in People with Central Nervous System Disorders: A Meta-Analysis of Cancer Incidence in 577,013 Participants of 50 Observational Studies. Psychother Psychosom. 2014 Jan 22;83(2):89-105. [Epub ahead of print]

Background: There is a lack of scientific consensus about cancer comorbidity in people with central nervous system (CNS) disorders. This study assesses the co-occurrence of cancers in patients with CNS disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorders, Down's syndrome (DS), Huntington's disease (HD), multiple sclerosis (MS), Parkinson's disease (PD) and schizophrenia (SCZ). 
Method: Comprehensive search in PubMed/MEDLINE, Scopus and ISI Web of Knowledge of the literature published before March 2013. We identified 51 relevant articles from 2,229 discrete references, 50 of which contained data suitable for quantitative synthesis (577,013 participants). Pooled effect sizes (ES) were calculated using multiple random-effects meta-analyses. Sources of heterogeneity and uncertainty were explored by means of subgroup and sensitivity analyses, respectively. 
Results: The presence of CNS disorders was associated with a reduced co-occurrence of cancer (ES = 0.92; 95% confidence interval, CI: 0.87-0.98; I2 = 94.5%). A consistently lower overall co-occurrence of cancer was detected in patients with neurodegenerative disorders (ES = 0.80; 95% CI: 0.75- 0.86; I2 = 82.8%), and in those with AD (ES = 0.32; 95% CI: 0.22-0.46; I2 = 0.0%), PD (ES = 0.83; 95% CI: 0.76-0.91; I2 = 80.0%), MS (ES = 0.91; 95% CI: 0.87-0.95; I2 = 30.3%) and HD (ES = 0.53; 95% CI: 0.42-0.67; I2 = 56.4%). Patients with DS had a higher overall co-occurrence of cancer (ES = 1.46; 95% CI: 1.08-1.96; I2 = 87.9%). No association was observed between cancer and ALS (ES = 0.97; 95% CI: 0.76-1.25; I2 = 0.0%) or SCZ (ES = 0.98; 95% CI: 0.90-1.07; I2 = 96.3%). Patients with PD, MS and SCZ showed (a) higher co-occurrence of some specific cancers (e.g. PD with melanoma, MS with brain cancers and SCZ with breast cancer), and (b) lower co-occurrence of other specific cancers (e.g. lung, prostate and colorectal cancers in PD; lung and prostate cancers in MS; and melanoma and prostate cancer in SCZ). Conclusion: Increased and decreased co-occurrence of cancer in patients with CNS disorders represents an opportunity to discover biological and non-biological connections between these complex disorder
People with MS may be have about a 10% reduced risk of cancer however this has to be tempered that some types of cancer may be statistically lower, but others such as is brain cancers may be statistically higher. There have been stories floating round the media concerning an increased breast cancer risk in Taiwan.  As ProfG said let's wait until it is replicated before jumping toconclusions. Remember some treatments may increase this risk. 

I saw similar data on cancer risk else where recently and that will surface in the future no doubt. Cancer is a product of life. There are lots of posts on this subject matter.

Thursday, 30 January 2014

Clinic Speak: pregnancy risks and fingolimod

Did you know highly-effective DMTs increase your chances of falling pregnant? Why? #ClinicSpeak #MSBlog #MSResearch

"I have been saying for sometime that we should consider rebranding MS a pink-ribbon disease. MS is a disease of young woman of child-bearing age; female:male ratio is ~3:1 and climbing, mean age of onset is ~30 years of age with the majority of MSers present between the ages of 16 and 40. Therefore pregnancy is an important consideration when it comes to choosing a DMT. All the current DMTs have issues with pregnancy; woman are not meant  to fall pregnant on DMTs due to risk of teratogenicity (ability of a drug to cause malformations in the developing foetus). The study below highlights emerging data in relation to falling pregnant on fingolimod. Fingolimod is a very fat soluble drug and therefore will cross the placenta and get into the developing foetus' body. The data below of 5 cases, or 7.6%, out of 66 pregnancies with exposure to fingolimod in the womb having congenital abnormalities is sobering. This rate is probably double the back ground risk. I was taught in medical school that between 2-4% of pregnancies in the general population were associated with congenital malformations with  50% of these being minor abnormalities and 50% major malformations. The bottom line is that all woman MSers going onto fingolimod, and other DMTs, need to counselled about contraception and asked whether or not they would be prepared to have a termination of pregnancy if they fell pregnant on a particular drug. The latter question often focuses the mind."

"What is not highlighted in this paper is that in the pivotal trials the rate of pregnancy was higher in woman MSers on fingolimod than placebo. Why? I think this relates to fingolimod improving quality of life and increasing libido and sexual activity. A side of effect, or a wanted effect, of highly-effective DMTs is an improvement in your sex life and an increased chance of falling pregnant. I am not surprised by this finding. Libido and sexual activity is a sign of well-being and if fingolimod and other DMTs do this you would expect more pregnancies in the active treatment arm."

"The paper below highlights the problem with maintenance therapies that is not a problem with induction therapies. Maintenance therapies have to be taken continuously therefore pose the greatest risk to pregnancy and the unborn child. Stopping a maintenance therapy also puts you at risk of rebound MS activity whilst you are waiting to fall pregnant. This is why induction therapies are going to be so appealing to woman wanting to have children. These treatments are given as short courses and the DMT is out of your system within days to weeks after completing the course. The treatment effect of induction therapies last months to years and hence you can fall pregnant without the anxiety about exposing your baby to excessive risks or your MS becoming active. This is why I think induction  therapies are going to change the way we approach treating MS, in particular for woman. It is a great pity that regulators and payers to don't look at the advantage of induction therapies in the same way i do. The table below is a comparison of the two treatment strategies. You can make up your own mind about which one suits you."

"Please note that the issues around pregnancy and DMTs are also relevant to breast feeding and DMTs. Most of the small molecule DMTs will cross into breast milk and hence breast feeding and taking most DMTs are contraindicated. This is less of an issue with some of the biologicals (protein therapies). The breast feeding issue has been covered before on  the blog but will need a separate Clinic Speak post."

Epub: Karlsson et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.Neurology. 2014 Jan.

OBJECTIVE: To report outcomes of pregnancies that occurred during the fingolimod clinical development program.

METHODS: Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception.

RESULTS: As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (MSer lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia (bowed legs) and 1 with acrania (missing skull bones). Elective abortions were performed for 1 case each of tetralogy of Fallot (heart defect), spontaneous intrauterine death (death in the womb), and failure of foetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal foetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, foetal exposure to the drug took place in the first trimester (first three months) of pregnancy.

CONCLUSIONS: The number of MSers becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation.

CoI: multiple

Hope buffering the Impact of MS

The Stress-Buffering Effects of Hope on Adjustment to Multiple Sclerosis.Madan S, Pakenham KI.Int J Behav Med. 2014 Jan 17. [Epub ahead of print]

BACKGROUND:Hope is an important resource for coping with chronic illness; however, the role of hope in adjusting to multiple sclerosis (MS) has been neglected, and the mechanisms by which hope exerts beneficial impacts are not well understood.
PURPOSE:This study aims to examine the direct and stress-moderating effects of dispositional hope and its components (agency and pathways) on adjustment to MS.
METHOD:A total of 296 people with MS completed questionnaires at time 1 at 12 months later and time 2. Focal predictors were stress, hope, agency and pathways, and the adjustment outcomes were anxiety, depression, positive affect, positive states of mind and life satisfaction.
RESULTS:Results of regression analyses showed that as predicted, greater hope was associated with better adjustment after controlling for the effects of time 1 adjustment and relevant demographics and illness variables. However, these direct effects of hope were subsumed by stress-buffering effects. Regarding the hope components, the beneficial impacts of agency emerged via a direct effects mechanism, whereas the effects of pathways were evidenced via a moderating mechanism.
CONCLUSION:Findings highlight hope as an important protective coping resource for coping with MS and accentuate the roles of both agency and pathways thinking and their different modes of influence in this process.
The Charities get criticized about their fund raising Slogans,
but Hope is a Core feature for all our activities.
What should the balance be between Hope and Realistic Expectations? Should Hope be dashed?

Wednesday, 29 January 2014

Another big beast joins the fray: ofatumumab phase 2 trial results

Another big beast arrives on the MS scene. #MSBlog #MSResearch

"MS used to be a orphan disease. Interferon-beta-1a (Avonex) was licensed by the FDA under the orphan drug legislation. What is an orphan disease? Orphan diseases are rare diseases that only affect a small percentage of the population. Orphan drug acts were put in place  to incentivise drug companies to take the risk and develop drugs for these diseases. MS is no longer an orphan disease; sales of DMTs for MS are close to $15billion a year. In the beginning the Pharma companies in the MS space were relatively small, but as the market expanded the big beasts started to arrive; Novartis, Sanofi, Roche and now GSK. GSK is developing ofatumumab for MS; the stunning phase 2 results are presented below."

The Big Beast: GSK joins the fray
"Ofatumumab is a completely humanised monoclonal antibody that depletes B-cells by binding to CD20 on their surface. You will have noted that this is not a unique strategy and ofatumumab follows on the results of rituximab and ocrelizumab. In other words ofatumumab is a me-to drug. Big Pharma like to play it safe; there is little chance of ofatumumab not being effective in MS. In this study ofatumumab suppressed MRI activity by >99%. These results is one of the best results to date in the MS space. The bad news is that at sometime during this study the small Danish biotech, Genmab, who was developing this product decided to partner with GSK. GSK for strategic reasons took the decision that a subcutaneous route would be a better option for this drug and had to repeat the phase 2 development programme. The simple switch from intravenous to a subcutaneous formulation will delay the development of ofatumumab by about 4-5 years. This is a great pity for MSers. Why so long? GSK were simply too slow out of the blocks in getting the repeat phase 2 study designed and done. one of the more nimble smaller competitors would have done this in 18-24 months. Despite the delay ofatumumab offers MSers in the future another very highly-active drug with a side effect profile that looks very promising."

"I predict that the class of monoclonal antibodies that deplete B-cells (anti-CD20 and anti-CD19) will be the real game-changers in the field; they come with very high-efficacy and have a relatively good safety profile. There are, however, several unanswered questions around their use in MS. (1) How should they be used; as maintenance therapies or as induction therapies. A maintenance therapy requires the drug to be given continuously and indefinitely. In comparision, an induction therapy require a treatment period of say 2 years and then a watch and see approach with re-treatment given if MS disease activity reemerges. No prizes for guessing what class of drug Pharma want. The distinction between maintenance and induction is not trivial and affects pricing and reimbursement. In short it gives Pharma executives a big headache. (2) How safe is long-term B cell depletion? Can you survive without any circulating B cells for 30 or 40 years? I suspect you can as there are a large number of hereditary disorders, which affect B cells. We simply treat these patients with immunoglobulin or antibody replacement therapy. (3) Do anti-CD20s work in non-relapsing progressive MS? The Roche ocrelizumab PPMS trial will address this question. (4) How do B cell depleters work? Are they working via an anti-EBV mechanism? As you know EBV resides in B-cells and B-cell depleting agents are very good at suppressing EBV viral loads. In fact Rituximab, which is very effective in MS, is the only licensed anti-EBV drug on the market; it has a license for EBV-associated post-transplant lymphoproliferative disease. (5) Do other drugs and strategies that transiently deplete B cells working in the same way, for example mitoxantrone, cyclophosphamide, alemtuzumab, cladribine, bone marrow transplant, etc.? I love it when science results in more questions be asked than it answers; innovation feeds innovation."

"Let's celebrate these results. Well done to the investigators and MSers for participating in this trial. And thank you Genmab and GSK; it is good to have another kid on the block."

Epub: Sorensen et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study. Neurology. 2014 Jan 22.

OBJECTIVES: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remittingmultiple sclerosis (RRMS).

METHODS: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed.

RESULTS: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19+ expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions.

CONCLUSIONS: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS.

CoI: mutiple

Some older posts of interest regarding CD19 and CD20:

14 Nov 2012
In response to a query re anti-CD19 treatment. Unfortunately, you can't access anti-CD19 treatment at present it is not a licensed therapy. However, we are doing a clinical trial of this agent so if you are interested you can ...

04 Dec 2012
"In response to a comment regarding the safety of rituximab and ocrelizumab in MS. This poster was presented at ECTRIMS. This is very reassuring in that the anti-CD20 look as if they will be in the upper zone of efficacy and if ...
12 Aug 2013
Instead they decided to develop the follow-on compound ocrelizumab. This latter decision will delay the access of an anti-CD20 therapy for MSers by about 4 years. At the time Genentech-Roche made the decision not to ...

04 Jun 2011
Please note that Ocrelizumab is the follow-on compound of Rituximab; both these drugs are monoclonal antibodies that target a protein CD20 that is expressed on B cells. Exactly how these drugs work is not known. However ...
30 Jul 2013
BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. OBJECTIVES:To evaluate the efficacy and safety ...

Cognition problems associated with changes in nerve signalling molecules

Muhlert N, Atzori M, De Vita E, Thomas DL, Samson RS, Wheeler-Kingshott CA, Geurts JJ, Miller DH, Thompson AJ, Ciccarelli O. Memory in multiple sclerosis is linked to glutamate concentration in grey matter regions. J Neurol Neurosurg Psychiatry. 2014 Jan 15

OBJECTIVE: Glutamate is the principal excitatory neurotransmitter and is involved in normal brain function. Cognitive impairment is common in multiple sclerosis (MS), and understanding its mechanisms is crucial for developing effective treatments. We used structural and metabolic brain imaging to test two hypotheses: (i) glutamate levels in grey matter regions are abnormal in MS, and (ii) patients show a relationship between glutamate concentration and memory performance.

METHODS: Eighteen patients with relapsing-remitting MS and 17 healthy controls were cognitively assessed and underwent 1H-magnetic resonance spectroscopy at 3 T to assess glutamate levels in the hippocampus, thalamus, cingulate and parietal cortices. 
RESULTS:Patients had worse visual and verbal memory than controls. A positive relationship between glutamate levels in the hippocampal, thalamic and cingulate regions and visuospatial memory was detected in patients, but not in healthy controls.
CONCLUSIONS:The relationship between memory and glutamate concentration, which is unique to MS patients, suggests the reliance of memory on glutamatergic systems in MS.

The balance of Glutamate (major excitatory nerve signalling molecule) and GABA  (major inhibitory nerve signalling molecule) is important to signs and symptoms because they effect signalling in the nerve circuits. However the interactions between them are complete because it is not simple that  excitation is a postive things because the excitation could stimulate or dis inhibit related excitatory or inhibitory circuits. This study tells us there are cognitive problems in MS and differences in glutamate levels but does not necessarily give easy solutions. Interfering with these essential transmitters is invariably associated with side-effects because they can't target just one circuit in one part of the brain. e.g. the effect of baclofen (GABA stimulator) can give cog fog and floppiness, AMPA/NMDA (Glutamate inhibitors) can be likewise have very unpleasant side effects .

Who are Yer

On the Other Hand
Citizen Dre 

Tuesday, 28 January 2014

Is it morally right to refuse someone a treatment under the NHS because someone else can't afford it?

The morality of private prescribing in the NHS. #MSBlog #MSResearch

"My post yesterday on private prescribing has raised some interesting philosophical questions. An excellent and very though provoking comment today suggest we need to pay more taxes to support the NHS and also questions the morality of a position of principle. Do you agree?"

Private prescribing in the NHS - Multiple Sclerosis Research - Blogger
27 Jan 2014; The coalition has undermined these principles by allowing private prescriptions in the NHS. In the past private prescribing was the remit of the private sector and you needed to have all your care covered privately. Doctors ...

Anonymous Tuesday, January 28, 2014 8:05:00 am

' Unless we are willing to pay more in taxes or radically change the way the NHS works eg you pay for your food and laundry in hospitals, we won't be able to afford it in the future. Most people retired from work and were dead within 10 years. Now we have an aging population who may have 30 years post retirement who will need health care (not taking into account the enormous amount in pensions that will be paid out to NHS workers out of the NHS pot ).

This is such a political issue, but you are dealing with people's lives. How can you say it is morally right to refuse a patient a drug they are willing to pay for that would improve their health on the basis that you can't prescribe it for someone else. Therefore, you would be willing to see that patient's health deteriorate to prove a point. Also if they pay for their drug, surely it is leaving more money in the NHS pot for the other users of the NHS.

We are not talking about the rich here either. A lot of people work very hard for their money, and if they choose to spend it on drugs or healthcare rather than expensive holidays it should be up to them. A dog in the manger attitude helps no one.'

Clinic speak: vitamin D levels as a predictor of MS disease activity

Chicken or egg: low vitamin D levels and MS. #MSBlog #MSResearch #ClinicSpeak

"Chicken or egg? Vitamin D and MS is another conundrum in need of a solution. We know  that low vD levels are a susceptibility factor for MS and  that MS incidence (number of new cases per year) and prevalence (total number of cases in the population) are strongly associated with latitude (distance from the equator) and in particular annual ultraviolet B light exposure (UVB). UVB is the spectrum of light required by your skin to synthesize vD. For  these reasons we believe that low vD levels are part of the causal pathway that leads to the development of MS. However, what happens once you have MS? Will low vD levels increase your chances of having a poor prognosis? Will vD supplements improve your disease course? The study below addresses the former; CISers with low vD levels were more likely to do poorly over the next 5-years than CISers/MSers with high vD levels. This study, however, does not show causation. It is possible that low vD levels are simply a marker of a more active disease. In other words inflammation consumes vD and hence the more inflammation you have the lower your vD levels are. This could be untangled by an adequate double-blind placebo controlled trial of vD supplementation trial in CIS. If vD supplements reduces MS disease activity then vD is a DMT. If on the contrary vD supplements don't reduce MS disease activity then low vD levels are likely to be a consequence of MS disease activity." ]

"The problem with treatment trials is that we in the field have yet to settle on what is an appropriate dose. Most vD experts suggest that you need to take enough vD to raise your blood levels above 100 nmol/L. At the moment this is much higher than the upper limit of the normal range. Why so high? At present the normal range is based on the vD levels in the normal population. If a large number of the normal population are vD deficient, or insufficient, then the normal range will be artificially low. They base their assumption on the vD levels of people living in outdoor environments with unlimited sun exposure, for example hunter-gatherers in Africa, farmers, life-guards, etc. These sorts of people have year round levels above 100 nmol/L. As we evolved as a species in these environments it is likely that these levels are physiological or normal. At present most studies are testing fixed doses of vD levels of 10,000U per day or lower. This may not be enough for MS. Some commentators suggest we need to adjust doses and  treat to a target blood level. Too late. There are several ongoing vD supplementation trials, which to the best of my knowledge are using a fixed-dose. Let's hope they provide answers."

"Should we treat low vD levels in MSers? Yes, I do. Why? Not because I think vD supplements will reduce MS disease activity; we don't have the evidence for this at present. I supplement low vD levels to maximise bone health. MSers are known to have thin bones, aka osteopaenia, and as a result are at increased risk of falls and fractures. Therefore, I recommend vD supplements to all the MSers under my care and I also recommend it to their family members. There is a theoretical possibility that by keeping your children and siblings vD replete that you will reduce their chances of getting MS."

"What now? We need to wait for the Australian CIS vD supplementation trial to report. It may show that vD supplements are disease-modifying. However, we still need to remind MSers that vD may be linked to MS disease activity and therefore there is a good reason to keep yourself vD replete, i.e. with a blood level of >100nmol/L. Do this you need to take more vD than the RDA. We recommend 5,000U vD3 per day for children older than 10 years and adults. This recommendation is based on the guidelines of the Vitamin D Council. For children less than 2 years of age we recommend 600U per day and for children 2-10 years of age 2,000U per day."

"Do I practice what I preach? Yes, I do. I personally take 5,000U per day as well as my family. The problem I have is getting my family to adhere to the supplements. That is the elephant in the room. It is easy to say take this, or do that, it is much more difficult to get people to take your advice and stick to it in the long-term. I hope having MS, or not wanting to have MS, is a big enough incentive not to forget your supplements." 

Epub: Ascherio et al. Vitamin D as an Early Predictor of Multiple Sclerosis Activity and Progression. JAMA Neurol. 2014 Jan.

IMPORTANCE: It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes. 

OBJECTIVES: To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome). 

DESIGN, SETTING, AND PARTICIPANTS: The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome. Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomized had at least 1 25(OH)D measurement, and 334 patients had them at both the 6- and 12-month (seasonally asynchronous) measurements. Patients were followed up for 5 years clinically and by magnetic resonance imaging. 

MAIN OUTCOMES AND MEASURES: New active lesions, increased T2 lesion volume, and brain volume on magnetic resonance imaging, as well as MS relapses and disability (Expanded Disability Status Scale score). 

RESULTS: Higher 25(OH)D levels predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions (P <001), 57% lower relapse rate (P = .03), 25% lower yearly increase in T2 lesion volume (P< .001), and 0.41% lower yearly loss in brain volume (P = .07) from months 12 to 60. Similar associations were found between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses using dichotomous 25(OH)D levels, values greater than or equal to 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability (Expanded Disability Status Scale score, -0.17; P = .004) during the subsequent 4 years. 

CONCLUSIONS AND RELEVANCE: Among patients with MS mainly treated with interferon beta-1b, low 25(OH)D levels early in the disease course are a strong risk factor for long-term MS activity and progression.

Are infections driving T cells to speed progression

Zastepa E, Fitz-Gerald L, Hallett M, Antel J, Bar-Or A, Baranzini S, Lapierre Y, Haegert DG.Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS.Neurology. 2014 Jan. [Epub ahead of print]

OBJECTIVE: Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS).
METHODS: We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS.
RESULTS: Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1-specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression.
CONCLUSIONS: Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.

Many people tell us that CD4 T cells are not important in MS because trials with a depleting CD4 specific antibody failed to affect MS (did it really? or was the trial design flawed?). However any immunologist will tell you that they are in the centre of the immunological universe because they help the other aspects of the immune response to do their thing. In this study they looked   at  T cell function and they found certain proteins at higher level on T cells from progressive MSers that progressed more rapidly. What were they doing. Simple answer is I don't know, but Toll-like receptors are involved in the recognition of microbes, so are infections important to the speed of progression. However blocking CD4 activity does not stop progression, the question is whether it changes the slope, we will get this answer from the SP1and tysabri trials. 

MS in the Media.

#MSResearch. #TheMirror and #Miriam Stoppard gives current MSinformation..Not 

Yesterday MS was in the Rags and wonder what news they had to say. 

Doctor Mirianm Stoppard = celebrity Pop- Doc posted in the Daily Mirror (A British Newspaper)
This story talks about the work presented in Nature by Top Boffins in Cambridge who have found 50 genes..well 57 to be precise and Simon Gillespie from MS Society said “By identifying which genes may trigger the development of MS, we can identify potential risk factors and look at new ways of treating, or even preventing, the condition.”

Hang on.....Is this Hot news or a bit of laboured research by our Celebrity Pop Doc?.

Simon Gillespie left the MS Society to go to the British Heart Foundation about a year ago, was the Nature paper talked about from 2011...seems so

This is hardly hot off the press. 
There have been more genes found in the past few years. 

Was it a mess up and did she mean to post another paper on the discovery of susceptibility arising from analysis of gene pathways published in a Nature publishing group Journal in January 16 involving the guys from Cambridge.

So in about two years time the paper may report that Lemtrada being approved in Europe or it that the time it may take NICE to make up its mind about prescribing in UK:-).

Monday, 27 January 2014

How does NICE measure value for money?

#MS Research how does NIce measure value for money
How NICE measures value for money in relation to public health interventions

Is the National Institute of Clinical Excellence really NICE and an look after the financial purse. Yesterday ProfG was attacked for his views about what is included and what is not.

Cost–utility analysis considers people's quality of life and the length of life they will gain as a result of an intervention. The health benefits are expressed as quality-adjusted life years(QALYs).

Generally, NICE consider that interventions costing the NHS less than £20,000 per QALY gained are cost effective. Those costing between £20,000 and £30,000 per QALY gained may also be deemed cost effective, if certain conditions are satisfied. There may be other significant benefits that are not captured by the QALY. 

So at US costs then no current DMT would pass this test, so this is why we there are price negotiations between pharma and the NHS,
but it means you do not have the choice and it takes so much longer to get access to drugs. 

The reports says Cost–consequences analysis considers all the health and non-health benefits of an intervention across different sectors and reports them in a disaggregated form

The following costs can be included:

Direct costs, including for health care, social services and transportation

Indirect costs, including productivity losses and for criminal justice expenditure

Intangible costs, including those related to quality-of-life and the impact of living with pain.

All impacts and costs are considered (even if the impacts cannot be costed) when deciding which interventions represent the best value. This distinguishes it from cost–benefit analysis. May not provide a good measure of value for money and would not be used as the sole basis for decisions.

Is this something new and NICE have changed the rules from when the Risk Sharing Scheme was set up? I thought it was cost of drugs only?

Do You agree?  Does Prof G agree?

Pharma are out to make a buck and will take whatever they can get. What we clearly need are some cheap alternatives and then the need for NICE disappears. Is that possible? 

ACE inhibitors are not so ACE

Doerner M, Beckmann K, Knappertz V, Kappos L, Hartung HP, Filippi M, O'Connor PW, Arnason B, Cook S, Jeffery D, Comi G, Limmroth V Effects of Inhibitors of the Renin-Angiotensin System on the Efficacy of Interferon beta-1b: A post hoc Analysis of the BEYOND Study. Eur Neurol. 2014 Jan;71(3-4):173-179. [Epub ahead of print]

Background: In experimental autoimmune encephalomyelitis, inhibition of the renin-angiotensin system with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors resulted in a significantly ameliorated disease course. We evaluated the effects of ARBs and ACE inhibitors on the efficacy of interferon beta-1b in patients with relapsing-remitting multiple sclerosis (RRMS). 

Methods: In this post hoc analysis of the BEYOND (Betaferon Efficacy Yielding Outcomes of a New Dose) study, clinical and MRI end points were compared between patients treated with interferon beta-1b 250 or 500 µg and concomitant ARBs or ACE inhibitors and patients treated with interferon beta-1b 250 or 500 µg only (reference group). 
Results: Patients in the ARB group (n = 22) tended to have a higher relapse rate (0.48 vs. 0.23, p = 0.051) and a higher number of new gadolinium-enhancing lesions (0.6 vs. 0.3, p = 0.057) than patients in the reference group. Patients in the ACE inhibitor group (n = 49) also tended to have a higher relapse rate (0.29 vs. 0.22, p = 0.357). No differences were observed for the other end points. Conclusion: In the BEYOND study cohort, a concomitant medication with ARBs or ACE inhibitors did not have a beneficial effect in patients with RRMS treated with interferon beta-1b. As patients appeared to have a higher relapse rate, our results warrant further investigation.

Animal studies may have suggested some use of ACE/ARB inhibitors that are used to control blood pressure can affect EAE. A different set of people, wonder if professional trialists ever talk to the people who made the discovery:-) looked at what happened on a clinical trial to assess the effects of beta interferon, where people were also taking ACE/ARB inhibitors and found no effect. 

The authors suggest there may have been a worsening but let's remember P (probability value) greater than 0.05 means there was no difference. The conclusion should be no affect on relapse rate (P=0.051)  or MRI lesion (P=0.057) for ACR inhibitor and no effect of ARB inhibitors P= (0.357).  So there was no beneficial effect..or significant worsening. 

So time for another meta analysis, but if pharma don't make their trial data open how can we do these retrospective analysis to see if there are drug-drug interactions maybe with access to large data sets you could see a benefit (or not) to aspirin. The authors have made the suggestion of worsening and therefore they need to follow this up get access to all beta interferon trial data and interrogate it. 

However, I hear you say it is that rubbishy animal model (EAE) again, as there was no inhibition of disease in MS. 

So another case of failure to translate from animals to humans!

Em, maybe we need to look at the animal studies and see how this was translated into the human studies. So the animal studies used 10mg/kg lisinopril (and 1mg/kg before disease induction) or enalapril  (ACE inhibitors) and 120mg/kg of Losartan (ARB) and they inhibited the development of EAE. 

However, 10mg dose of lisinopril (about 0.15mg/kg) and 5 mg human dose of enalapril (0.07mg/kg) or 50mg of Losartan (less than 1mg/kg) so about 100 times lower dose and way above the ten times scaling for mice, so what would a comparable does have done in the human, well maybe caused too many side effects because of effects on blood pressure. So maybe a comparable animal and human does would do nothing, because when we look at what 100 times dose did? Well maybe not much, with probably most animals developing EAE with a minor diminution of disease. One would expect Gilenya to flat line the score at about 0 with essentially no disease at all in the same type of experiment. This tells us that you need to look at the data and not just the headline as so often happens in media circles. This is why you hear "Cure of the Week" every week. However, the question has to be put what was the effect of a human dose equivalent as the animal studies were performed along time after the human dosing schedule was known. Guideline 19 of ARRIVE guidelines asks for a report on the relevance to human biology, without proper dose-responses the answer may be "none".

So it may perhaps be a case of overestimation of the drug effect in the EAE papers, on behalf of the neuros. Humans have as much to do in the failure as the animal models.

Private prescribing in the NHS: what is the future of the NHS?

Is socialist healthcare dead? #MSBlog #MSResearch 

"The NHS was founded on two principles that underpin socialist healthcare in the UK. (1) Healthcare will be free at point of service and (2) there will be equity. The coalition has undermined these principles by allowing private prescriptions in the NHS. In the past private prescribing was the remit of the private sector and you needed to have all your care covered privately. Doctors were not allowed to look after the same patient in the private sector and the NHS. Now you can pick and choose. As a neurologist who sees people with MS from all walks of life I am deeply uncomfortable with this change in policy. Why should one patient be denied access to a licensed drug in the NHS simply because they can’t afford it, when another can?"

"Is private prescribing the thin edge of the wedge? Is it the end of the NHS as we know it? We tried to set-up a debate on this last year, but could not get any politicians, from any of the parties, to participate. Why? I am beginning to suspect that there is a cross-party consensus on private prescribing in the NHS and that they would rather not put their heads above the parapet as they have too much to lose. I am very keen to get to the bottom of how, and who, was responsible for this change in NHS policy? I need to know if this is the shape of things to come. Will the NHS increasingly provide a two-tiered system? Should we prepare ourselves for a future of NHS haves and have-nots? I don’t know the answer to these questions, but it needs a public debate. In a world of austerity in which soaring health costs need to be addressed there are no right and wrong answers. Allowing private prescriptions in the NHS may be a subtle way of the government telling the British electorate that we can’t afford the NHS in its current form and we need to top it up with private contributions. If that is the case the Government, or the Whitehall mandarins who thought up this change in policy, should tell us their plans for the future of the NHS."

"I need to know how to deal with issue of private prescribing. I need to rationalise how I am going to deal with this issue in my clinic. At the moment I am referring patients who make a request for a private prescription to my colleagues who don’t have a moral problem with this issue."

"To get more information on this topic we are going to task an intern, or work-experience student, with the job of investigating this issue. As part of his/her job I will ask them to periodically update you on this issue via the blog. If any of you can help please feel free to contact us. The primary objective of this exercise is to get a genuine public debate on this issue that will hopefully lead to some clarity."

"If you are interested in this issue please read some of our previous posts on the topic."

13 May 2013
Fampridine is not being funded by the NHS, but we are allowed to give private prescriptions to individuals who can pay for the medication themselves." "What this practice signifies is the end of socialist medicine in the UK as ...
15 May 2013
"Our post on 'Topping-up the NHS with private prescribing' has generated a healthy debate. In response to a query yesterday I thought I would highlight an example of private prescribing within the NHS in relation to the ...
10 Jul 2013
I have already highlighted the pernicious influence that private prescribing is having on the NHS. Private prescribing has undermined the two founding principles of the NHS: free at point of access and equity. We are planning ...

Sunday, 26 January 2014

Risk sharing scheme: does the DoH deserve to get its money back?

The Big Pharma Exodus. Have we shot ourselves in the foot? #MSBlog #MSResearch

"You will find the paper below interesting. It describes the methodology the next analysis of the UK Department of Health's (DoH) risk-sharing scheme (RSS). The RSS was out in place to allow MSers access to DMTs after NICE (National Institute for Health and Care Excellence) had ruled that interferon-beta and glatiramer acetate were not cost-effective for the NHS."

"The RSS was a political solution to a very tricky problem. NICE was meant to prevent postcode prescribing, i.e. access to medication depending on where in England and Wales you lived. The problem with MS is that the horse had already bolted and there were several thousand MSers on IFN-beta when NICE made its ruling. This created a perverse situation with MSers already on IFN-beta being able to stay on treatment, and nobody else being able to access the drugs. This caused an uproar. A threat of a legal challenge by a few MSers was all it took to get the DoH to change its stance. It was clear that the DoH would have lost its case in either an English court, or on appeal in an EU court. Denying some MSer DMTs when others were on them is against the laws of the EU. The DoH recapitulated and the RSS was born."

"The RSS is a simple idea, but flawed in its implementation. The idea is to see how the drugs work in the real world. The problem is you need to compare the RSS data to something. Initially the plan was to compare it to the London Ontario historical natural history study. This cohort proved unsuitable; rumour has it that the data was imputed and that the EDSS in this database did not behave as it should. For example, you can only get worse on the EDSS in the London, Ontario, database when real-life experience shows the EDSS is a wobbly score with improvements (regressions) as well as progressions. The DoH RSS has now turned to the British Columbia Multiple Sclerosis (BCMS) database as its comparator. This database has been heavily criticized by commentators in the field as MSers in this database behave in a benign way; this database is an outlier. This has problems for the RSS. If you compare how MSers do in the RSS with MSers in  the BCMS database and find no difference is it because the drugs don't work or is it because the MSers in BCMS database have benign disease? Why is this important? It is important to the Pharma companies involved because if they don't show the RSS MSers doing better they are going to have to lower the price of their drugs. It will also create the impression that these drugs don't work. I think we now have enough data from trials, and real-life MS registries, to counteract this argument at an International level, but at a UK level the therapeutic nihilists will use this to say 'we told you so' and to try an extract resources out of the RSS to be used elsewhere. The latter is a potential problem because the RSS has helped MSers enormously. The RSS has been responsible for revolutionising MS services for MSers in the UK, by providing access to specialist care and information which has benefited the whole MS population, whether or not they are on drug therapy. The RSS has created 100s of MS Specialist Nurse posts; a recent estimate puts the numbers of MS specialist MS nurses in the UK at around 270. The RSS has also created a network of over 70 MS specialist treatment centres, which has been responsible for the data collection for the RSS. What will happen to all these gains if the RSS data shows that treatment with IFN-beta or GA is no better than living with benign MS in British Columbia?"

"Are we shooting ourselves in the foot?"

"The paper below sets the scene for how the data will be analysed in the next phase of the RSS. Please don't hold your breath. Most of us are expecting the comparison to reveal no differences. The DoH will then have a new truncheon with which to beat Pharma into a pulp. Pharma will have yet another reason to justify its exodus from the UK and the UK Plc will be poorer for the loss of yet another industry. Politicians are too shortsighted to realise the impact NICE has had on the Pharma industry within the UK."

"In my centre we run an MSc in translational neuroscience; we teach the students about drug development and how to translate basic discoveries into treatments for neurological conditions. Where in the UK are our graduates going to get jobs? Almost all new jobs in Pharma are being created in emerging markets, Switzerland and the USA. Why? Look no further, the RSS is just one of the reasons for the state of affairs."

Palace et al. UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model. BMJ Open. 2014 Jan 17;4(1):e004073. doi: 10.1136/bmjopen-2013-004073

BACKGROUND & OBJECTIVES: In 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-β and glatiramer acetate, were not cost effective over the short term but recognised that reducing disability over the longer term might dramatically improve the cost effectiveness. The UK Risk-sharing Scheme (RSS) was established to ensure cost-effective provision by prospectively collecting disability-related data from UK-treated patients with MS and comparing findings to a natural history (untreated) cohort. However, deficiencies were found in the originally selected untreated cohort and the resulting analytical approach. This study aims to identify a more suitable natural history cohort and to develop a robust analytical approach using the new cohort.

DESIGN: The Scientific Advisory Group, recommended the British Columbia Multiple Sclerosis (BCMS) database, Canada, as providing a more suitable natural history comparator cohort. Transition probabilities were derived and different Markov models (discrete and continuous) with and without baseline covariates were applied.

PARTICIPANTS: From the BCMS database, 898 'untreated' patients with MS considered eligible for drug treatment based on the UK's Association of British Neurologists criteria.

OUTCOME MEASURE: The predicted Expanded Disability Status Scale (EDSS) score was collected and assessed for goodness of fit when compared with actual outcome.

RESULTS: The BCMS untreated cohort contributed 7335 EDSS scores over a median 6.4 years (6357 EDSS 'transitions' recorded at consecutive visits) during the period 1980-1995. A continuous Markov model with 'onset age' as a binary covariate was deemed the most suitable model for future RSS analysis.

CONCLUSIONS: A new untreated MS cohort from British Columbia has been selected and will be modelled using a continuous Markov model with onset age as a baseline covariate. This approach will now be applied to the treated UK RSS MS cohort for future price adjustment calculations.

Lack of blinding in Trials gives bias

Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Rasmussen JV, Hilden J, Boutron I, Ravaud P, Brorson S. Observer bias in randomized clinical trials with time-to-event outcomes: systematic review of trials with both blinded and non-blinded outcome assessors. Int J Epidemiol. 2014 Jan. [Epub ahead of print]

BACKGROUND:We wanted to evaluate the impact of nonblinded outcome assessors on estimated treatment effects in time-to-event trials.
METHODS: Systematic review of randomized clinical trials with both blinded and non-blinded assessors of the same time-to-event outcome. Two authors agreed on inclusion of trials and outcomes. We compared hazard ratios based on nonblinded and blinded assessments. A ratio of hazard ratios (RHR) <1 indicated that nonblinded assessors generated more optimistic effect estimates. We pooled RHRs with inverse variance random-effects meta-analysis.
RESULTS: We included 18 trials. Eleven trials (1969 patients) with subjective outcomes provided hazard ratios, RHR 0.88 (0.69 to 1.12), (I2 = 44%, P = 0.06), but unconditional pooling was problematic because of qualitative heterogeneity. Four atypical cytomegalovirus retinitis trials compared experimental oral administration with control intravenous administration of the same drug, resulting in bias favouring the control intervention, RHR 1.33 (0.98 to 1.82). Seven trials of cytomegalovirus retinitis, tibial fracture and multiple sclerosis compared experimental interventions with standard control interventions, e.g. placebo, no-treatment or active control, resulting in bias favouring the experimental intervention, RHR 0.73 (0.57 to 0.93), indicating an average exaggeration of non-blinded hazard ratios by 27% (7% to 43%).
CONCLUSIONS: Lack of blinded outcome assessors in randomized trials with subjective time-to-event outcomes causes high risk of observer bias. Nonblinded outcome assessors typically favour the experimental intervention, exaggerating the hazard ratio by an average of approximately 27%; but in special situations, non-blinded outcome assessors favour control interventions, inducing a comparable degree of observer bias in the reversed direction.

This is perhaps timely given the recent FDA rejection of Alemtuzumab, Some of the problems high lighted was the fact that the study was not blinded. Without blinding there is a chance an increased chance of bias to report overly positive effects. However, we are getting to a stage where it is not ethical to do placebo trials and you need to compare to an active. So if it is a beta interferon or glaterimer acetate you are going to have to manufacture dummy needles and you then inject nothing for a few years. So if you are a company who don't have an injectable you are going to have to manufacture these? Will this be a barrier to entering into the MS space for any company Novartis, Teva, Merck Serono, Biogen Idec all have injectables...Genzyme-sanofi doesn't.Are they paying the price?  So we will need to get the pills into the forefront to stop this strangle hold of the big four as it is far easier and less costly and certainly less inconvenient to make a dummy pill.

Who are is it more important to blind the MSers or the Neuros