Monday, 31 March 2014

Politics: How will the benefits cap affect the health of MSers in the UK?

George Osborne’s recent benefit cap will limit the amount of money that the Government spends on welfare in relation to people with MS living England, Wales and Northern Ireland. Scotland has some flexibility in relation social spending. Welfare spending, excluding the state pension and some unemployment benefits, will be capped next year at £119.5billion.

In this context the caps seem short-sighted, since they have failed to identify the reasons for high social spending (roughly 4% of GDP for benefit spending, compared to 5 % as a mean for other EU Countries) e.g. poor health, social exclusion and low level mental health problems, which can all be bundled up into the general effects of low socio-economic positioning - making the benefit cap self defeating.

There are different problems concerning society which are more intractable. These problems, such as an aging population, require something other than a simple welfare cap. Higher spending on disability benefits is becoming necessary for the elderly. Thankfully ATOS Healthcare the 'cruel monster' whose job it was to determine which people with MS are eligible for disability benefits have been banished from the sanctity of State capitalism.

In my opinion, the disappearance of ATOS is a necessary spectacle, i.e. PR stunt. ATOS will surely be replaced by a fiercer company, more determined to feed off a declining NHS and the Welfare State. All the while cheered on by Government, finally able to deal with those sick, entitled people.

The good news is that our social spending (funds governments set aside for social programs. Many of these programs are designed to offer assistance to the poor or needy, and may include allotments for housing, food, and medical care. Depending on the needs of the individual, these programs could offer either permanent or temporary assistance.The ultimate goal of most government social spending programs is the eventual elimination of poverty) isn't that high, that welfare spending can bring down social spending overall, such as by targeting poor health, and that amount of money spent on social matters correlates to growth only in so far as those that spend more have grown faster. Take the cases of Finland and the US. The USA spends 19.2% on social spending whereas Finland spends 29.4%, however since the 1970s Finland's economy has outgrown America 3.8 times over.

Labours, or the oppositions, collaboration (all bar a hand-full of backbench rebels) with the coalition government (con-dems) over the benefit cap is, then, strongly ideological. This is good and once more illustrates the need for Labour to abandon any pretensions to Social Justice. I think neo-liberalism and its form of 'structural adjustments' makes more of the population sick, both physically and mentally, whilst evidently reducing parliamentary democracies to one-party states

I would be interested to hear from MSers living in this country what the think about the benefits cap and how it may affect them? Are any of you prepared to discuss your ATOS assessment with the other readers?

MS Life 2014

Are you coming to MS Life 2014

There's still time to Register. 
Come see Members of TeamG and Friends

26 Apr 2014 10:00AM - 27 Apr 2014 5:00PM
Location:Manchester Central

Risky therapies and the Hippocratic Oath

Is the Hippocratic Oath relevant today? You decide. #MSBlog #MSResearch

Re: A comment about the "Hippocratic Oath" and prescribing "risky" therapies? 

"This is a reposting from October 2011; on that occasion it was in relation to the Hippocratic Oath and assisted suicide. In my opinion the modern version of the Hippocratic oath is not at odds with prescribing risky therapies and with Society adopting assisted suicide. The decision to use a risky therapy in MS always needs to be balanced against the risk of not treating the MS. You need to remember that untreated MS is a bad disease. If you don't think so please look at my infographic at the bottom of this page on 'Why Gray Matter matters'."

The following is a modern version of the Hippocratic oath; written in 1964 by Dr. Louis Lasagna:

I swear to fulfill, to the best of my ability and judgment, this covenant:

I will respect the hard-won scientific gains of those physicians in whose steps I walk, and gladly share such knowledge as is mine with those who are to follow.

I will apply, for the benefit of the sick, all measures [that] are required, avoiding those twin traps of overtreatment and therapeutic nihilism.

I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon's knife or the chemist's drug.

I will not be ashamed to say "I know not", nor will I fail to call in my colleagues when the skills of another are needed for a patient's recovery.

I will respect the privacy of my patients, for their problems are not disclosed to me that the world may know. Most especially must I tread with care in matters of life and death. If it is given to me to save a life, all thanks. But it may also be within my power to take a life; this awesome responsibility must be faced with great humbleness and awareness of my own frailty. Above all, I must not play at God.

I will remember that I do not treat a fever chart, a cancerous growth, but a sick human being, whose illness may affect the person's family and economic stability. My responsibility includes these related problems, if I am to care adequately for the sick.

I will prevent disease whenever I can, for prevention is preferable to cure.

I will remember that I remain a member of society with special obligations to all my fellow human beings, those sound of mind and body as well as the infirm.

If I do not violate this oath, may I enjoy life and art, respected while I live and remembered with affection thereafter. May I always act so as to preserve the finest traditions of my calling and may I long experience the joy of healing those who seek my help.

What should we do about complementary medicine?

Where to next with complementary medicines? #MSBlog #MSResearch

"We have posted on complementary and alternative medicine (CAM) in the past and have debated whether or not it works. I don't have a problem with CAM provided it can be shown to be safe and the motivation about its use is not to make some quack wealthy. Modern medicine has it roots in CAM; i.e. a large number of classes of medicines come from herbal extracts that were shown to work in the past by trial and error. What is lacking however with CAM is the rigorous science that is underpinned by hypothesis testing and the class of evidence regulatory bodies need to show a treatment is safe and effective."

"Primum non nocere; first do no harm. This is one of the maxims that underpins the modern Hippocratic oath. If something does harm it needs to be effective and on average the efficacy must outweigh the harm. The following is an evidence-based guideline produced by the American Academy of Neurology (AAN) to guide neurologists regarding CAM. Interesting a large section of the guideline refers to cannabis and nabiximols (aka cabinnoids), when there is pretty good evidence of their effectiveness in pain, spasticity and cancer-associated anorexia. May be the AAN are trying to detoxify cannabis for US-based clinicians. The take-home message is that if you want the medical community to accept CAM you need to  get them interested enough to do  the necessary research to show they are safe and effective. This is easier said than done and takes time and resource. It may take as long as 15 years to have enough evidence to show a treatment works and that it is safe to administer to MSers. The costs associated with this latter are only worth it if you can make money from the CAM. This is why CAM are unlikely to gain mainstream traction anytime soon. What do you think?"

OBJECTIVE: To develop evidence-based recommendations for complementary and alternative medicine (CAM) in MS.

METHODS: We searched the literature (1970-March 2011; March 2011-September 2013 MEDLINE search), classified articles, and linked recommendations to evidence.

  1. Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain) (Level A). 
  2. Clinicians might offer tetrahydrocannabinol for spasticity symptoms and pain (excluding central neuropathic pain) (Level B). 
  3. Clinicians should counsel MSers that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term) (Level C). 
  4. Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols) for spasticity symptoms, pain, and urinary frequency (Level B). 
  5. Clinicians should counsel MSers that these agents are probably ineffective for objective spasticity/urinary incontinence (Level B). 
  6. Clinicians might choose not to offer these agents for tremor (Level C). 
  7. Clinicians might counsel MSers that magnetic therapy is probably effective for fatigue and probably ineffective for depression (Level B).
  8. Fish oil is probably ineffective for relapses, disability, fatigue, MRI lesions, and quality of life (QOL) (Level B).
  9. Ginkgo biloba is ineffective for cognition (Level A) and possibly effective for fatigue (Level C). 
  10. Reflexology is possibly effective for paresthesia (Level C).
  11. Cari Loder regimen is possibly ineffective for disability, symptoms, depression, and fatigue (Level C).
  12. Bee sting therapy is possibly ineffective for relapses, disability, fatigue, lesion burden/volume, and health-related QOL (Level C). 
  13. Cannabinoids may cause adverse effects. Clinicians should exercise caution regarding standardized vs nonstandardized cannabis extracts and overall CAM quality control/nonregulation. 
  14. Safety/efficacy of other CAM/CAM interaction with MS disease-modifying therapies is unknown.
Conclusions: Although it is sometimes hard to define, complementary and alternative medicine (CAM) refers to health care approaches that are developed outside of mainstream and conventional medicine. "Complementary" and "alternative" are often used interchangeably, but there are some differences. "Complementary medicine" generally refers to using a non-mainstream approach together with conventional medicine. "Alternative medicine" refers to using a non-mainstream approach in place of conventional medicine. The boundaries between complementary and conventional medicine can overlap and even change with time. Most CAM therapies are not regulated by the US Food and Drug Administration, which means the quality and purity of CAM therapies may vary significantly.

In guidelines and other publications, recommendation for a clinical service is classified by the balance of risk versus benefit of the service and the level of evidence on which this information is based. The U.S. Preventive Services Task Force uses:

Level A: Good scientific evidence suggests that the benefits of the clinical service substantially outweigh the potential risks. Clinicians should discuss the service with eligible patients.

Level B: At least fair scientific evidence suggests that the benefits of the clinical service outweighs the potential risks. Clinicians should discuss the service with eligible patients.

Level C: At least fair scientific evidence suggests that there are benefits provided by the clinical service, but the balance between benefits and risks are too close for making general recommendations. Clinicians need not offer it unless there are individual considerations.
Level D: At least fair scientific evidence suggests that the risks of the clinical service outweighs 
potential benefits. Clinicians should not routinely offer the service to asymptomatic patients.

Level I: Scientific evidence is lacking, of poor quality, or conflicting, such that the risk versus benefit balance cannot be assessed. Clinicians should help patients understand the uncertainty surrounding the clinical service.

Should Primary Progresssive MS be an Orphan Disease

We are discussing how we get treatments to progressive MSers. We need the Big Pharma Alternative and a change in view

Currently there are no approved DMT for progressive MS and when trials are done, most times the trials are done in Secondary Progressive MS. This is because there are more people with SPMS than PPMS and so trials are easier to recruit and do.

However, as we all know PPMSers feel alienated and let down by the medical profession. Could we make an incentive to do studies in PPMSers.

In the United States, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically "any disease or condition that affects less than 200,000 persons in the United States, or about 1 in 1,500 people. This definition is essentially like that of the Orphan Drug Act of 1983, a federal law that was written to encourage research into rare diseases and possible cures. In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2,500 people. The European Commission on Public Health defines rare diseases as "life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them. The term low prevalence is later defined as generally meaning fewer than 1 in 2,000 people.

MS is no longer going to get orphan status in the US with 250,000 affected and a multi-billion dollar market. I
f a case could be made for progressive MS there would be less than 200,000 people affected and there is no available treatment. 

Can you lobby for this status because it lowers the bar for getting drugs to you. Only one major trial is needed so those academic led studies become more feasible, one trial cuts cost so pharma will be more willing to take a punt. 

Should the MS Community have another go at this?

Neuroprotection on top of immunosuppression is required.

Narayanan D, Cheng H, Bonem KN, Saenz R, Tang RA, Frishman LJ. Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis. Mult Scler. 2014 Mar. [Epub ahead of print]

BACKGROUND: Neurodegeneration plays an important role in permanent disability in multiple sclerosis.

OBJECTIVE:The objective of this paper is to determine whether progressive neurodegeneration occurs in MS eyes without clinically evident inflammation.
METHODS: Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing-remitting MS (RRMS) patients (149 non-optic neuritis (ON), 97 ON eyes, last ON ≥6 months). Ninety-three patients were scanned at two visits. Percentages of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed.
RESULTS: GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p = 0.004 in non-ON, 82% vs 72% p = 0.007 in ON). RNFLT and GCIPT decreased with MS duration by -0.49 µm/yr (p = 0.0001) and -0.36 (p = 0.005) for non-ON; -0.52 (p = 0.003) and -0.41 (p = 0.007) for ON. RNFLT and GCIPT decreased with follow-up time by -1.49 µm/yr (p < 0.0001) and -0.53 (p = 0.004) for non-ON, -1.27 (p = 0.002) and -0.49 (p = 0.04) for ON.
CONCLUSIONS: In RRMS eyes without clinically evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of autoimmune responses and inflammation.

In this study they looked in the eye and found changes suggestive of nerve damage irrespective of whether there was inflammation. This is not new and supports other studies. Changes in the eye are in part correlated with events in the brain. This study suggests that you therefore need to put neuroprotection on top of immunosuppressives so not one but two expensive drugs. 

One question not addressed properly yet is, if the immunosuppression is good enough do you need the neuroprotection? 

In some cases it may be a good thing to do both. 

This will be a basis of the PROXIMUS trial of ProfG which will add a neuroprotective on top of a DMT and has now got the green light. Are you going to have to wait 10 years whilst these trials are done and has ProfG mapped out the pathway to get his drug of choice licenced?

Could pharma deliver quicker?

It they went straight to phase III... certainly. Would they do this? 

Teva has been patenting Laquinimod as a neuroprotective left right and centre. It is not much of an immunosuppressive at the doses used in MS, so it may be doomed as a stand alone immunomodulator. But the effect on disability appeared better than its immune modulating effect on relapse rate. Could this be the drug we are waiting for, it has been through phase III and has reasonable safety profile? 

They (Teva) could mix it with another more active DMT...and have been patenting the combinations DMF, GA, Beta interferons, fingolimod etc......They have forgotten a few! such as CD52, maybe they are yet to surface. It takes a year for filed patents to become visible 

The claims are usually based on EAE data....Who would have thought of MS as a GABA-mediated/cannabinoid receptor-mediated disease and Fampridine as an immunosuppressive compound, when it is used to affect walking speed.....If you read the patents these are the claims. Maybe Teva could not get their hands on CD20, CD52 antibodies, maybe Genzyme could get their hands on laquinimod and file the patent....Ooops I have I just invented that and put it in the public domain. 

Claims in patents well that's another story.....but the accepted sort of logic is the Sun causes Ice cream consumption and the Sun causes Sweating, therefore Ice Cream consumption causes Sweating or is that blocking sweating stops you eating ice cream or blocking sweating stops the sun. All true in the words of lawyers :-)

Adding a weak immunomoduator onto a potent immunomodulator could increase efficacy, but it could also increase side-effects. 
Will these studies be done. I hope so, because of the potential benefits.

Sunday, 30 March 2014


Mancini M, Lanzillo R, Liuzzi R, Di Donato O, Ragucci M, Monti S, Salvatore E, Morra VB, Salvatore M. Internal jugular vein blood flow in multiple sclerosis patients and matched controls. PLoS One. 2014 Mar 27;9(3):e92730. doi: 10.1371/journal.pone.0092730. eCollection 2014.

The aim of the study was to investigate the Internal Jugular Veins dynamics using contrast enhanced ultrasonography in Multiple Sclerosis patients, clinically isolated syndrome patients and healthy controls. Contrast enhanced ultrasonography imaging of the Internal Jugular Vein was performed in fifty-eight patients with Multiple Sclerosis, seven clinically isolated syndrome patients and in thirteen healthy controls. Time-intensity curves were quantified using a semi-automated method and compared with clinical disease outcomes. Wash-out parameters were calculated and six Time-intensity curves shapes were created. Significantly reduction of wash-out rate in Internal Jugular Veins was detected in Multiple Sclerosis patients compared to healthy controls [22.2% (2.7%-65.9%) vs. 33.4% (16.2%-76.8%); P<0.005]. Internal Jugular Vein enhancement was heterogeneous in patients with Multiple Sclerosis and consisted of slow wash-out Time-intensity curves shapes, compared with almost only one type of Time-intensity curves shape in control subjects that correspond to fast enhancement and fast wash-out. The vein wash-in parameters were similar in Multiple Sclerosis group compared with controls. A significant correlation was found between Internal Jugular Vein wash-out and level of disability (R = -0.402, p<0.05). Contrast enhanced ultrasonography of the Internal Jugular Vein with time intensity curve analysis revealed alterations of cerebral venous outflow in Multiple Sclerosis patients, however mechanisms that determine this condition remains unclear.

Beta interferon neutralizing antibodies determined by your genes

Link J, Lundkvist Ryner M, Fink K, Hermanrud C, Lima I, Brynedal B, Kockum I, Hillert J, Fogdell-Hahn A. Human leucocyte antigen genes and interferon Beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis. PLoS One. 2014 Mar 7;9(3):e90479. doi: 10.1371/journal.pone.0090479. eCollection 2014.

A significant proportion of patients with multiple sclerosis who receive interferon beta (IFNβ) therapy develop neutralizing antibodies (NAbs) that reduce drug efficacy. To investigate if HLA class I and II alleles are associated with development of NAbs against IFNβ we analyzed whether NAb status and development of NAb titres high enough to be biologically relevant (>150 tenfold reduction units/ml) correlated with the HLA allele group carriage in a cohort of 903 Swedish patients with multiple sclerosis treated with either intramuscular IFNβ-1a, subcutaneous IFNβ-1a or subcutaneous IFNβ-1b. 

Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titres. After stratification based on type of IFNβ preparation, HLA-DRB1*15 carriage was observed to increase the risk of developing NAbs as well as high NAb titres against both subcutaneous and intramuscular IFNβ-1a. Furthermore, in patients receiving subcutaneous IFNβ-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titres. In IFNβ-1b treated patients, HLA-DRB1*04 increased the risk of developing high NAb titres, and in a subgroup analysis of DRB1*04 alleles the risk for NAbs was increased in DRB1*04:01 carriers. In conclusion, there is a preparation-specific genetically determined risk to develop NAbs against IFNβ high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFNβ preparation still remains the single most significant determinant for the risk of developing NAbs.

If you develop neutralizing antibodies to the beta interferons stop working. The risk for high NAb titres overall was 1.6-fold in people carrying the MS risk haplotype DRB1*15, and for people receiving IFNβ-1a the risk was increased up to 8-fold.

This shows that for the two different types of recombinant IFNβ molecules, DRB1*15 for IFNβ-1a and DRB1*04 for IFNβ-1b, indicating an IFNβ molecule dependent genetically determined risk to develop NAbs against IFNβ. There are several possible explanations that could account for differences in immunogenic potential. Sequence alterations, different formulation contents with a potential to evoke the immunological response, and different propensities to form aggregates  are all factors that might have a higher impact on NAb development. The different HLA associations found here might be explained by different binding affinities to the two types of IFNβ molecules to different HLA alleles.  However this study suggests that dependent on your genes expressed it may determine how good your drugs work. This is called "pharmacogenomics".

Although HLA alleles influence the risk of NAbs within the treatment groups it is clear that NAb development in people with MS treated with IFNβ-1a is also influenced by several additional factors. Thus, IFNβ-1a injected intramuscularly is still the least immunogenic way of receiving IFNβ even for HLADRB1*15 carriers and none of the analyzed HLA allele groups lowered the risk of subcutaneously injected IFNβ to the level of intramuscularly injected IFNβ-1a. The skin harbours a high frequency of dendritic cells efficient in presenting antigens, easily provoked by repeated injections of IFNβ and potentially explaining higher immunogenicity of the subcutaneously administrated IFNβ products compared to the intramuscularly administered product.

Approximately 20% of IFNβ-treated patients develop NAb titres high enough to block treatment bio-efficacy. Since up to 60% of people with MS carry DRB1*15 and some 30% carry DRB1*04, and since the risk of high titre NAbs is increased several times (ORs 3–4) in carriers of respective risk alleles, it may well be relevant to base treatment decisions on HLA genotype. For example empirical data suggest that DRB1*15 carriers would have a 35% risk of losing efficacy of s.c. IFNβ-1a but less than 10% on IFNβ-1b (provided they did not carry DRB1*04 on their other chromosome). The reverse risks would be seen for a DRB1*15-negative carrier, who carries DRB1*04, on IFNβ-1b.

Maybe more work in needed to firm-up these risks, but it shows how your genes could help you decide in making treatment choices. This is working towards "personalised medicine".  

Have you been typed?

Saturday, 29 March 2014

Digesting Science Did You Miss the Research Day Today?

Today was one of the Research Days held by UCLP at Great Ormond Street the Home of the World Famous Children's Hospital.

We have been doing Digesting Science for Children of MSers, if you have not seen it, check it out but today some members of TeamG did Digesting Science for Children with MS.  This was organised by Alison and thanks for all her hard work. 
                 ProfB was showing off his brain and eyeballs
Dr M&M strolled through the Treatment Options, Annie kindly took time out from her holiday and what was DrMark doing with a rubber policeman?
Remember the next Research Day is 14 June 2014

Male Sexual Problems

Lew-Starowicz M, Rola R. Sexual Dysfunctions and Sexual Quality of Life in Men with Multiple Sclerosis. J Sex Med. 2014 Feb. doi: 10.1111/jsm.12474. [Epub ahead of print]
INTRODUCTION: Multiple sclerosis (MS) is one of the most frequent diseases of the central nervous system and usually occurs at the age when people would be expected to be in the prime of their sexual lives. Clinicians working in this field commonly concentrate on the classical neurological deficits and often overlook symptoms that seriously affect the quality of life, such as sexual dysfunction (SD). Sexual functioning of MS patients remains poorly understood.
AIM: The aim of this study was to assess the prevalence of SDs, their relationship with demographic factors, and sexual quality of life in men with multiple sclerosis (MS).
METHODS: Sixty-seven patients from the National Multiple Sclerosis Center were interviewed, completed the questionnaires, and underwent neurological assessment.
MAIN OUTCOME MEASURES: Primary outcome measures included the International Index of Erectile Function (IIEF), the Sexual Quality of Life Questionnaire (SQoL), and the Expanded Disability Status Scale (EDSS).
RESULTS: The most common complaints were erectile dysfunction (52.9%), decreased sexual desire (26.8%), and difficulties in reaching orgasm (23.1%) or ejaculation (17.9%). The severity of SD had a clear impact on sexual quality of life, especially in the domains of erectile function and intercourse satisfaction. However, neither IIEF nor SQoL scores were correlated with age, time since onset of MS symptoms, or EDSS scores. Only 6% of the patients had ever discussed their concerns with a medical professional or undergone sexual therapy.
CONCLUSIONS: SD is highly prevalent but commonly overlooked in MS patients and has a significant impact on their sexual quality of life. The data support a multifactorial etiology of SD in MS. More focus on SD and use of appropriate screening tools in clinical practice with MS patients are recommended. 
Remember if you are having any Sexual problems (a) You are not alone and (b) there are some solutions s speak to your MS professional about this

Friday, 28 March 2014

Now the COP wars

#MS Research #MSBlog Cop wars on the way as Teva get competition

We recent post on the MOD wars as alternatives are in development for FingoliMOD, now the COP wars
Copaxone also originally known as COP-1 and now know as glaterimer acetate, the biggest grossing MS drug has competitors. This was the first drug  generated out of EAE..and has spawned the development of COP-2 another random mix of amino acids by a University, which is being developed by Big Pharma.

The patents protecting COP-1 are running out and Teva upped the price in the US to eerk out that last bit of gratuitous profit before the generics waiting in the vanguard can get a slice of the action. 

However, because it is a random mix of amino acids and not just a straight chemical Teva and the competitors have been locked into legal battles. It has been argued that because these products are not the same the competitors will need to do their own phase III trials, adding cost and delaying things.....This of courses help the generics company justify their high price

So one of the pack Synthon (a Dutch company) have just announced that their phase III trial showed equivalence to that of Glaterimer acetate, and is that just as good.

So competition is coming.....a price war or a love-in? 

I predict a Love-in, maybe it will be a little cheaper like the difference between Betaseron and Extavia. However, this example only goes to show that you are happy to pay the price for the cardboard as reported previously as there is no difference between the two and there apparently is no difference between Synthon acetate. Brand loyalty.

Clinic Speak: predicting response to treatments

Is it time to incorporate brain atrophy into clinical practice? #MSBlog #MSResearch #ClinicSpeak

"The following two studies provide data to support treating-2-target of NEDA with zero tolerance. The first study generates a score called the Rio score and shows that those with higher Rio scores on GA do worse than those with low scores. The problem with the Rio scoring system is that it allows some disease activity; in other words it entrenches the practice of allowing some disease activity. This to me is a no-go area; you either buy into the concept that inflammation is bad or not. You can't allow MSers who have smouldering MS to think their disease is being controlled by whichever drug they are on, but it is not really being controlled. ZeTo or zero  tolerance means you will migrate upwards to higher efficacy drugs sooner rather than later. Some argue that everyone will then end-up on natalizumab or alemtuzumab as so many MSers breakthrough on the lower tiers of efficacy. This is not true! It is horses for courses all DMTs have a proportion of MSers who respond, that proportion gets bigger as you move up the efficacy ladder. The real question is do you want to waste time, and brain, waiting to see if you are a responder on the lower tier? I suspect you may want to try one lower efficacy drug, but do you want to try three, four or five? Please remember it takes 6, 12, 18 or even 24 months to assess whether or not you are responder or not. Twenty-four months is a long-time in the life of a brain of an MSer."

"The second study below adds the first study and shows that brain atrophy, or brain volume loss, is also a poor prognostic marker and predicts disease progression. This supports other emerging data sets. Brain atrophy is an integrator of end-organ damage and our ultimate aim in treating MS is to switch off inflammation and normalise brain volume loss. Can we do this? We may be able to do this. If you look at a hierarchy of DMTs that affect brain atrophy you can see that the more potent the drug the better the impact on brain atrophy. To do this comparison you need to focus on year 2 brain atrophy rates; brain atrophy in year 1 is complex and confounded by pseudoatrophy in which the brain shrinks when inflammation is switched off."
"Hierarchy of year-2 brain atrophy rates for RRMS on licensed DMTs i s: (1) bone marrow transplantation, alemtuzumab and natalizumab are top of the pile and reduce brain atrophy rates to within the range we see in normal people, i.e. ~0.20 to 0.25%; (2) fingolimod reduced brain atrophy rates to ~0.4% per; on the boundary of what can be accepted as normal brain atrophy rates. (3) Dimethyl fumarate may have an impact on brain atrophy but the results from the two trials are inconsistent. When you combine the results of the the two phase 3 trials it did slow brain atrophy in the twice daily dose group, but not the three times a day group. I need more data to be convinced of its effect. Brain atrophy rates in year 2 on twice daily DMF was 0.46% per annum. (4) The other drugs, i.e. interferon-beta, glatiramer acetate and teriflunomide don't have an impact on brain atrophy rates in year 2 with the possible exception of once weekly intramuscular IFNbeta-1a (Avonex). The slowing of brain atrophy in year 2 on Avonex and not on Rebif and Betaseron/Betaferon/Extavia is an interesting observation and suggests a difference between low and high-frequency administration of interferons. This is why the emergence of long-acting interferon-beta may not be such a good idea."

"If you were serious about ZeTo and wanted to protect your brain in the long-term you may argue we should start on  the upper-tiers of efficacy and ignore the lower tiers. This is exactly what is happening in countries without limitations on prescribing, such as Australia, Switzerland and the US. When I presented my NEDA trial design to Australian neurologists earlier this month they thought the trial was unethical. Why would anyone randomise someone to a trial that would allow their disease to sub-optimally controlled? However, in the UK and a lot of other European countries the highly-effective therapies are typically limited to second-line use. I would therefore say we have equipoise and the trial would therefore be considered ethical. The following is the trial design."

"Have your say; do you thing it is ethical do the T2T-NEDA study outlined above?"

"To conclude  this post and to stop myself from rambling there is a problem of using brain atrophy in clinical practice. The methods used for measuring brain atrophy are highly variable and are best to look at group data rather than individual data. Saying this some centres in the world use brain atrophy in clinical practice. For example, I visited the MS Centre in Prague last week and was amazed at the system  they are using. I saw a few case studies were brain atrophy measurements were being used to make clinical decisions. Now  that we have drugs that impact on brain atrophy we should be using brain atrophy in clinical practice. Wouldn't you want your neurologist to protect your brain and normalise your brain volume loss? If I had MS I would."

Epub: Río et al. Evaluating the response to glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) patients. Mult Scler. 2014 Mar.

Background: In RRMSers, a scoring system based on new MRI active lesions, relapses and sustained disability progression after a 1-year treatment with IFNβ predicted MSers disability progression over time; however, this score had not been tested in MSers receiving glatiramer acetate (GA).

Objective: The objective of this study was to evaluate whether this previous scoring system can also be applied to MSers treated with GA.

Methods: This was a prospective, longitudinal study of 151 RRMSers treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables.

Results: The total possible score range was 0-3. MSers with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively).

Conclusions: In RRMSers treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.

EpubRojas JI et al. Brain atrophy as a non-response predictor to interferon-beta in relapsing-remitting multiple sclerosis. Neurol Res. 2013 Dec 19:1743132813Y0000000304.

Background: Several predictors for treatment failure to FN-beta have been proposed; however, brain atrophy has not been well studied.

Methods: In this prospective and longitudinal study, all consecutive RRMSers treated with sc IFN-beta-1a were included. Confirmed disability progression or a new relapse between weeks 48 and 144 after beginning with IFN-beta was considered as treatment non-response. EDSS progression, relapses, number of active lesions at 1 year (new or enlarging T2-weighted plus gadolinium-enhancing lesions, categorized in > 2 or ≤ 2), and brain parenchymal fraction (%BVC) volume change within the initial year of treatment were used as predictive factors.

Results: Seventy-one RRMSer were included (71·8% female) with a follow-up of 144 weeks. Thirty-four (48%) fulfilled criteria of non-response to IFN-beta treatment. The model showed: (1) relapses+disability progression: HR  =  4·6, 95% IC: 3·1-6·7 (P < 0·001); (2) relapses+BVC decrease: HR  =  4·1, 95% IC: 3·2-7·3 (P  =  0·001); (3) relapses+disability progression+new active lesions: HR  =  10·1, 95% IC: 7·1-15·2 (P < 0·001); and (4) relapses+disability progression+new active lesions+BVC decrease: HR  =  14·4, 95% IC: 11·4-21·2 (P < 0·001).

Conclusions: Adding BVC measures to previously described predictive failure factors may increase sensitivity to early identify non-responder patients to IFN-beta-1a in the second and third years of therapy.

CoI: multiple

The cost of MS is black and white

Smith W, McCrone P, Goddard C, Gao W, Burman R, Jackson D, Higginson I, Silber E, Koffman J. Comparisons of Costs between Black Caribbean and White British Patients with Advanced Multiple Sclerosis in the UK. Mult Scler Int. 2014;2014:613701. doi: 10.1155/2014/613701. Epub 2014 Feb 5
Background. Multiple sclerosis (MS) is now more common among black and minority ethnic groups in the UK but little is known about the costs of care amongst different ethnic groups.
Objective. This study examined and compared service use and costs for people severely affected with MS from Black Caribbean (BC) and White British (WB) backgrounds in the UK and identified predictors of cost for both groups. 
Method. Population-based cross-sectional study of 43 BC and 43 WB patients with MS (EDSS ≥ 6) and their informal caregivers recruited from an MS service in south east London. Interviews collected data on health and social service use and informal care support. Costs were calculated using UK unit cost data.We compared costs between the ethnic groups and identified possible predictors of cost.
Results. The mean (SD) costs for the WB and BC groups were £ 25,778 ( £ 39,387) and £ 23,186 ( £ 30,433), respectively. Results identified no significant difference in total cost between the two ethnic groups. The EDSS score alone was a significant predictor of cost.
Conclusion. Similar costs between ethnic groups indicate that with regard to this MS service and geographical area, access to care was not affected by ethnicity.

It would have been disturbing if the cost of MS was determined by skin colour. However, the disease courses may be different between the different demographics, which can affect costs e.g. progressive MS would not attract the cost of DMT.....yet.

Koffman J, Goddard C, Silber E, Burman R, Shaw P, Barnes F, Speck P, Higginson I. Comprehending the inexplicable: qualitative accounts of black Caribbean and white british people severely affected by multiple sclerosis. BMJ Support Palliat Care. 2014 Mar;4 Suppl 1:A20. doi: 10.1136/bmjspcare-2014-000654.54

BACKGROUND: Multiple sclerosis is now more common among minority ethnic groups in the UK but little known little is known about how they attribute meanings to their illness and to what extent they are culturally shaped; meanings may influence adjustment outcomes and attitudes to service use.
AIM: To explore the cognitive organisation and meanings of MS among black Caribbean (BC) and white British (WB) people severely affected by their illness and to understand how these may be culturally constructed.
METHOD: Semi-structured qualitative interviews were conducted among Black Caribbean (BC) and White British (WB) people with MS (PwMS) with an EDSS of ≥6.0 (severe disease). Data were analysed using the framework approach.
RESULTS: 15 BC and 15 WB PwMS were interviewed with mean ages of 46.6 and 56.9 years respectively. Attributions were complex, with most PwMS reporting multiple explanations. Uncertainty, represents the first theme surrounding the aetiology of MS where participants constantly rehearsed "why me?" question in relation to their illness, a number citing considerable frustration. The second main theme, 'logical and scientific', was voiced more often by WB PwMS and accounts for arrange of genetic/viral influences, stress, environmental and lifestyle factors. Third, the 'supernatural' illness attribution theme departs from a biomedical perspective and was reported more frequently among BC PwMS. This theme included the sub-categories of religious challenge and divine punishment, a view although exclusive to BC participants was sometimes in conflict with their notions of modernity.
CONCLUSION: We identify causal attributions play important roles in determining emotional responses to MS. Taken together these findings suggest not only considerable cultural diversity in relation to MS causation but also diversity within groups. This highlights the need for health professionals to investigate such beliefs, particularly if supernatural causes are considered inherently uncontrollable. This has important implications for help-seeking and symptom-reporting behaviours.
So more soft science and with a "n" so low to draw any firm conclusions, however with regard to "the supernatural and MS", I must admit I think it it is more "whodo" than "voodoo"...just because we do not understand the biology fully, does not mean it is not caused by biology..because it is.

Cheap Drugs can we afford to develop them? or Can we afford not to develop them?

#MSResearch Do we want cheap drugs?

We have been talking about the cost of drugs in the US, but we can also bring it back to the UK. 

The occasion is a recent trial of Simvastatin in progressive MS, which costs £1-2 per month; that's £12-24 per year for an MS treatment!  The nearest ‘big pharma’ kid on the block with regard to treating progressive MS is Gilenya, whose trial finishes in 2014. This drug costs £14,000 per year give or take a few thousand quid. In the States multiply this by two (yep, ProfG is right about the US paying more for their drugs).

So if we say 10% of MSers have progressive MS, okay it will be more, then with 10,000 progressive MSers in the UK, drug costs would be about £200,000 p.a. (statins) versus about £140,000,000 (big pharma) per year. 

Lets say 30 years on drug is £4,200,000,000 (pharma) versus £6,000,000 (Simvastatin).

So for the government to fund an academic clinical trial costs say £1,500,000 (it costs pharma a lot more because their staff are being paid), that means about £3,000,000 for two trials, plus a few hundred thousand for the licensing. Even if we add £100,000 p.a. for keeping the licence there is considerable saving to the NHS – spend about £15 million to save over £4 billion. 

Maybe George Osborne, Ed Balls, and the other Cronies need to digest these figures and then maybe they will do something about them?  Maybe GPs in charge of the money will see the value of prescribing something that does not cost the earth. 

Now, we don't know whether Gilenya will work, and also we don't know how well it could work compared to Simvastatin. If Gilenya is much better, the cost savings go out of the window based on efficacy, so let's hope it's great.  However, we don't really know yet whether Simvastatin will work either as no more then phase II studies have been done.  More studies are needed. 

Will they be done? 

Big Pharma assume, and they’re probably right, that academia will not come through with the goods......after all they haven't so far and big pharma don't see any "disruptive Influences" (common board room language) on the horizon to inhibit their 20+ billion dollar market.

If simvastatin does come to the market at a cost of £2 a month, there will be no more investment by big pharma developing better drugs for progressive MS. Because if they can only charge £2 a month there will be no interest.  If the drugs work better they still will only be able to charge an increment.  
This is called Pharmacoeconomics.
Putting progressive MS to one side for the moment, what about a case where we know of cheap drugs that work in people with RRMS as well as anything that Big Pharma have to offer?  

Which drugs are we talking about?  There are a number, some could be developed quicker than others.

For one example you (or the NHS) would have to spend about £2,000 a life time (in fact more likely close to £1,000 only) per person compared to £320,000 - £560,000 (£8-14,000 p.a. for current DMT x 40 years).  

So now doing the sums with 100,000 MSers and every one of DMT that is £56,000,000,000 versus £200,000,000 for a £1-3 million outlay to get the drug licensed.

Is there a will to take on Big Pharma? Or are all Neuros in the pockets of Big Pharma?

What effect would this have on Big Pharma’s interest in MS?  

But what would be the effect on all of us if we don’t do it?  Will the NHS survive? Unfortunately, I think this one may be easier to answer!

Thursday, 27 March 2014

Turning off the immune response

If MS is an autoimmune disease then the ultimate way forward is to specifically shut down the parts of the immune system causing the disease....This is the Holy Grail of Autoimmunity read here for some approaches in the offing, some for MS.
Its amazing how Journals (i.e. in this case Nature) can be high- jacked for advertising companies and their desire for cash..... too can blog sites (Ha, Ha but Larry is a mate and it is Diabetes). To some it is news, but it is really a request for if there are any sugar daddies out know where we are:-)

Anyway I posted this, because there is interest in antigen-specific therapies (See Top posts of the month). So there is hope for the future. 

I wish they would consider bringing a transient depletion into their protocols, I think it may make the difference between success and being the main course for Thanksgiving. However I, suspect there may be a few Turkeys in the list..let's hope not. 

Politics: have the US politicians woken-up to the drug pricing issue?

Drug pricing: the politicians have had enough. I predicted this years ago. #MSBlog #MSResearch

"I have been saying for awhile that the current drug pricing climate in the USA is unsustainable and it will only be a matter of time before politicians realise that the US is subsidising drug costs for the rest of the world. The following is a letter from 3 members of the House of Representatives (Henry Waxman, Frank Pallone and Diana DeGette) summoning John Martin, the CEO of Gilead to attend a briefing to explain their pricing of their new anti-hepatitis C drug. The letter is dated the 20th March and they want to be briefed by no later than the 3rd April. The urgency and tone of the letter implies they are pissed off with Gilead for abusing their position, i.e. Gilead have a very effective drug that may cure people of hepatitis and they want to charge $84,000 per treatment. When the this is added to other treatments this could potentially bring the cost up to $150,000 which will be out of reach of most Americans. They also seemed upset that the drug was given a Priority Review by the FDA and assessed within 6 months; this allows the drug to come to market earlier and hence more profits for Gilead. In the briefing they want the CEO to answer some seriously difficult questions about their methodology for pricing the drug."

" I wonder when the CEO is squirming in the hot seat whether or not he will be brave enough to tell them that European countries will be driving a hard bargain and getting the drug for anything down to a third, or less, of the US price. Why? When socialist healthcare systems negotiate they drive a hard bargain and get drug prices down. For example, glatiramer acetate costs the NHS about one-seventh of the cost in the US. May this grilling of Gilead will be the beginning of the end of very high drug prices in the US compared to Europe?"

"I will not be surprised if John Martins' compensation package is discussed? His received $90 million in 2012. Can any Pharma company justify paying its CEO $90M when people are dying from diseases their drugs can cure, but are unable to access them because they cost too much? This is a moral issue and needs debate!"

"After Gilead it is simply a matter of time before a probing flash-light looks into the MS market. It is clear the MS DMT market in the US is not behaving like a true market; whenever a new drug reaches the market the older drugs go up in price. Why? It is clear that there are no mechanisms in place to bring down the prices. It is also strange how narrow the spread of drug prices are; this indicates to me that the MS drug market in the US is functioning like a cartel. One incentive to bring down the prices is the so called co-payment that MSers have to pay. This is incentive is removed by many Pharma companies paying most of the co-payment for MSers so they are not out of pocket. I suspect this is one loophole the politicians will close. It will be bad news for MSers, but it will lower costs."

"If you are interested in reading more about this Gilead story I would recommend the following article in the Wall Street Journal."

ED SILVERMAN. AIDS Group To Pharma CEO: Lower Your Prices Or Lower Your Pay. 21 March 2014. 

MS tissues does not look like animal autoimmune model tissue but looks like virus infection

Schuh C, Wimmer I, Hametner S, Haider L, Van Dam AM, Liblau RS, Smith KJ, Probert L, Binder CJ, Bauer J, Bradl M, Mahad D, Lassmann H. Oxidative tissue injury in multiple sclerosis is only partly reflected in experimental disease models. Acta Neuropathol. 2014 Mar 13. [Epub ahead of print]

Recent data suggest that oxidative injury may play an important role in demyelination and neurodegeneration in multiple sclerosis (MS). We compared the extent of oxidative injury in MS lesions with that in experimental models driven by different inflammatory mechanisms. It was only in a model of coronavirus-induced demyelinating encephalomyelitis that we detected an accumulation of oxidised phospholipids, which was comparable in extent to that in MS. In both, MS and coronavirus-induced encephalomyelitis, this was associated with massive microglial and macrophage activation, accompanied by the expression of the NADPH oxidase subunit p22phox but only sparse expression of inducible nitric oxide synthase (iNOS).  Acute and chronic CD4+ T cell-mediated experimental autoimmune encephalomyelitis lesions showed transient expression of p22phox and iNOS associated with inflammation. Macrophages in chronic lesions of antibody-mediated demyelinating encephalomyelitis showed lysosomal activity but very little p22phox or iNOS expressions. Active inflammatory demyelinating lesions induced by CD8+ T cells or by innate immunity showed macrophage and microglial activation together with the expression of p22phox, but low or absent iNOS reactivity.
We corroborated the differences between acute CD4+T cell-mediated experimental autoimmune encephalomyelitis and acute MS lesions via gene expression studies. Furthermore, age-dependent iron accumulation and lesion-associated iron liberation, as occurring in the human brain, were only minor in rodent brains. Our study shows that oxidative injury and its triggering mechanisms diverge in different models of rodent central nervous system inflammation. The amplification of oxidative injury, which has been suggested in MS, is only reflected to a limited degree in the studied rodent models.
So again animal tissue does not look like MS what's new? Maybe the similarities with a viral infection may be telling 

Wednesday, 26 March 2014

ClinicSpeak: Under-reporting of relapses

Am I so wrong to be promoting ZeTo? #ClinicSpeak #MSBlog #MSResearch

Are you reporting all your relapses? If you don't it could have consequences.  #ClinicSpeak #MSBlog #MSResearch

“The problem of not reporting and documenting relapses is a serious issue for MSers living in the UK. I saw a patient in outpatients yesterday who has had MS for just over 6 years. He was diagnosed as having CIS after presenting with the MS hug (tight constriction band around the chest) and loss of feeling from waist down and weakness in the legs. When he presented he had an abnormal brain MRI and a positive spinal fluid analysis. Anywhere else in the world he would have been put on therapy; in the UK 2008 we weren’t allowed to treat CIS. Over the next 6 years he went onto have mild attacks; patches of sensory loss and tingling in the arms and legs. Although he was seen at clinic on an annual basis these symptoms were dismissed as possibly being due to minor relapses and because they were not documented his diagnosis remained that of CIS. Tragically not repeat MRI studies were done to see what level of activity he had. He was referred to me in mid-February with progressive weakness in the legs since December of last year. He is now using a walking stick. The weakness came on quite suddenly over a few weeks suggesting this was possibly a relapse; but since then he has progressed. He was treated with a course of steroids before Christmas, but this made little difference to his functioning. He has bladder problems, chronic constipation and sexual dysfunction. He is depressed and is anxious about losing his job; he is having increasingly difficulty at work mainly due to memory problems. He tells me he forgets to complete tasks. His latest MRI show a massive lesion load, gross brain atrophy and four gadolinium-enhancing lesions. Although he has focal inflammation on his MRI and a recent history of a disabling relapse I suspect he probably has entered the secondary progressive phase of the disease. To diagnose SPMS you really need to have a history of progressive MS for at least 6 months. When you speak to him about his cognitive problems these have been getting worse for at least 2 years. I have given him the benefit of the doubt and have offered him a DMT with a recommendation for going onto a highly-active treatment (natalizumab).”

"Please note that this gentleman has only had one documented relapse in the last 12 months. The other relapse that 'qualifies' him for treatment was subjective; i.e. a sensory attack with numbness and pins and needles in the feet associated with unsteadiness of gait in June or July of last year. During this relapse he had some difficulties going up and down stairs; he needed a handrail for support. Some of my colleagues would not have classified this as a relapse as he was not examined during the attack and hence it was not documented. Some would say that it was not a disabling attack as he was still able to function normally through it, nor did he require steroids or a hospital admission. This is not just semantics; in the UK we need two documented disabling relapses in a 12 month period to be deemed eligible for natalizumab and we need an active MRI scan as well. It is my policy to give the patient the benefit of the doubt and any relapse that affects normal activities of daily living is disabling. For a Londoner using the underground everyday, not being able to walk down the escalators is disabling."

“I can only wonder what would have happened if this young gentleman (he is only 32 years of age) was started on treatment at the CIS stage and had his MS actively monitored with relatively frequent MRI studies? Would we have prevented him from developing cognitive impairment? Would he be fully mobile? Would we have prevented his brain from shrinking? Would he have normally bladder and bowel function? Would his sex life be normal? Would he be depressed and anxious?"

" I sincerely hope by suppressing the inflammation in his brain and spinal cord his nervous system has enough reserve capacity to recover some function. I am not sure about this; my experience to date with highly-effective treatments in this phase of the disease is that although we suppress relapses and MRI activity progression continues for a few years before plateauing out. I have rarely seen much recovery when there is so much end-organ damage on MRI (atrophy). The plateauing-out observation is a relatively new observation of mine and at present is still anecdotal and needs to be confirmed in prospective follow-up series. I have referred to the hypothesis underlying this observation as the therapeutic lag-effect. I have posted on the therapeutic lag effect in the past. It is not well accepted by my colleagues; some are however supporting my attempts to look for it in existing data sets and to include it in their thinking about progressive MS trial design.”

“The following is a recent slide presentation of mine in which I promote early, highly-effective, therapy in MS. It explains why treat-2-target of NEDA is the rational extension of this approach and why we need a zero-tolerance approach.”

CoImultiple ; please note the specific details of the brief case scenario above have been change to make sure the individual patient is unidentifiable.

The MOD-Wars are coming

Olsson T, Boster A, Fernández O, Freedman MS, Pozzilli C, Bach D, Berkani O, Mueller MS, Sidorenko T, Radue EW, Melanson M. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014 Mar 21. doi: 10.1136/jnnp-2013-307282. [Epub ahead of print]

OBJECTIVE: This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated.
RESULTS: The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema.
CONCLUSIONS: Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RMMS is under consideration.

You already have FingoliMOD and SiphoniMOD, which are spinogosine-1-phosphate modulators, this is being developed by the same company, now you have PonesiMOD and is being developed here. So we may have another cartel member..sorry competitor and maybe you will get some price competition :-). There are plenty of other MODs in the wings. 

Likewise we have a placebo control.....Is this ethical? You have drugs that clearly work in RRMS should people be getting nothing when "Time is Brain"

If you have a sphinogosine-1-phosphate modulator it would be amazingly unusual if it is not going to work. Surely in this day and age the ethical approach should be a non-inferiority trial against an active comparator like Gilenya. 

The MRHA do not give a stuff about the cost of drugs,so maybe it time that Ethical Committees should not give a stuff about commercial sensitivities and insist on an active comparator

Is this marketing suicide if it worse? 

Is it right that companies shift their trials to places were drugs are not readily available so they can push people into volunteering from placebo-controlled trials. A 50-75% chance of something verses 100% chance of nothing if they don't do it. 

Is this a morally corrupt stance by pharma to do this or should they be congratulated for giving some people access to a drug?

Alemtuzumab did not go against placebo and look at the problems it is having. Some people don't think it works, but then again there are people who think the Earth is Flat. 

Politics: Health as a Human Right

Fortunately health is a socially desirable object, which is universally attainable. There are some objects of desire, such as power, which by their very logic are rarities. There are other objects which are desirable because they are materially scarce, for instance gold. However the health of each individual is produced by each individual. There may be barriers such as disease but it is at least possible in theory for everyone in a society to be healthy. 

Unfortunately, as a result of certain systems of economic governance there are additional barriers to the good health of individuals within their groups or in society. These problems are primarily those of the distribution of health. The production and distribution of health maintenance through medicine is an expensive process, and the cost of which has recently been devolved to certain groups in society in the UK (with the health and social care act 2010).

In spite of the economic context of the Attlee government in the 1940’s - the government that established the NHS - the cost of the distribution of health was taken up by the government and the wealthier members of society through general taxation. The system was relatively effective and was proved to be practically sustainable. 

It was shown that within any economic framework all individuals and groups within a society, particularly within prosperous societies such as the UK, it is possible to realize the theoretical niceties of health, and its production and advancement through science. 

Since it has been proven realistic and rendered possible through technological advancement for all individuals to have an equitable chance of sustaining good health, it should be considered a human right. Health should be considered on the same platform as positive human rights, such as Haebeus corpus, freedom of expression (although it is perhaps more fundamental than freedom of expression), and negative human rights, such as the right not to be subjected to physical violence. 

The UK and the USA are self described (and accurately in a sense) economically advanced countries. Through their ‘economic’ and material superiority their conception of human rights should be extended. Most western products of the enlightenment (e.g. democracy) are human rights or relate to the status of human beings and have generally been extended with material and technological advancement. 

However it is clear that health is not regarded as a human right. Beveridge, a liberal and profound child of the enlightenment probably did more than any other to advance the case for health in the 1940s, however its status is currently being rolled back in the UK with NHS privatization. 

ALL state recognized human rights in the west are backed by constitutions and law, and are guaranteed by that state. Health is absent, and it was Beveridge over 60 years ago that  made the strongest case for its inclusion.