Tuesday, 28 February 2017

Tabalumab (LY 2127399) Trial in 243 people in 63 Centres. Where you involved? what Happened?

You said 

"I believe patients participating in trials have the right to be informed about the trial results".

I said
"I agree with you...are any of the readers, people who participated in this Eli Lilly MS trial. Were you informed of the results? (NCT00882999)"


However, should we have to be detectives?

In this case, we have not proof that people were harmed, but the possibility is there 

How long after a trial is finished do you believe is enough time for the results to be submitted for publication in a proper paper? 

When should we start searching for the information, or should we not bother trying to find what is not being said?

Hopefully the Promise is the Publication of the Trial Results including the B cell Phenotyping Data.

Does this relate to Disease Activity?


Modifiable risk factors in MS - help yourself

Modifiable Risk Factors in the Progression of Multiple Sclerosis: A Systematic Review of the Epidemiology and Treatment [Internet].


Hempel S, Fu N, Estrada E, Chen A, Miake-Lye I, Beroes J, Miles J, Shanman R, Shekelle P.


Washington (DC): Department of Veterans Affairs (US); 2015 Dec.
VA Evidence-based Synthesis Program Reports.


Multiple sclerosis (MS) is the most common progressive disease of the central nervous system in young adults and the cause of serious physical disability in adults of working age. Epidemiologic data suggest that rates of MS vary with demographic and environmental factors. The disease presentation is very heterogeneous with diverse clinical manifestations. Progression of MS may vary with modifiable risk factors. This systematic review focused on modifiable risk factors and exposures that are associated with MS progression, and interventions that are directed at modifiable risk factors to delay progression.

I keep a close eye out for research publications looking into improving outcomes in MS, it is not all about disease modifying treatments ;) We keep our blog readers appraised of this on a regular basis and I know many of you embrace the freedom it provides to choose.

Here, Hempel and colleagues identified 8,594 articles but only 94 met their criteria (quality not quantity!).

So what were the modifiable risk factors?
1) VITAMIN D - lower vitamin D levels were associated with higher EDSS (disability) scores.
2) SMOKING - increased risk of faster progression in smokers than non-smokers.

What about risk modification treatments?
1) EXERCISE - although the pooled effect of exercise interventions was not significant from control groups, but when using a sensitivity analysis (a way of determining if specific values of an independent variable, i.e. exercise, impact on a dependent variable, i.e. EDSS) the results favored the exercise arm.
2) VITAMIN D - vitamin D supplementation showed a trend for EDSS improvement.

Overall, the evidence for modifiable based on this meta-analysis is moderate at best, as it is difficult to analyze environmental risk factors. The interactions between environmental risk factors are manifold and direct causal inferences cannot be made. That said, they are out there, easy to do and all with minimal side effects.

"Today you are You, that is truer than true.
There is no one alive who is Youer than You"
- Dr Seuss.

Monday, 27 February 2017

What's Happening with the Clinical Trial Data

As soon as rituximab and then Ocrelizumab was found to inhibit relapsing MS, companies began the hunt for "me-toos" to do the same thing.

Ocreliziumab depletes CD20 B cells and blocks relapses, so it gets rid of memory B cells, but not the earliest of B cells or the antibody forming plasma cells.

Unless you know what CD20-B cell depletion is doing, getting rid of the all B cells may not seem unresponable.

Companies thought that they could get rid of B cells by depleting B cell growth factors

A few companies had the same type of idea to make a buck

Merck made a fusion protein to block BAFF and APRIL B cell growth factors called Atacicept.

Eli Lilly made an antibody that blocked BAFF called LY2127399 or tabalumab

There was another one called Belimumab, which never made it into MS.....Luckily.

Rather than selecting a cashcow, looks they got a different beast
In fact Atacicept made things worse in trials!

1. Atacicept in Subjects With Optic Neuritis (NCT00624468)
2.A Phase 2 Study of Atacicept in Subjects With Relapsing Multiple Sclerosis (ATAMS) (NCT00642902)

It said

Sponsor voluntarily decided to prematurely terminate this trial due to an increase in multiple sclerosis (MS) disease activity observed in atacicept arms of both trials as compared to placebo.

Both trials were eventually published 

Sergott RC, Bennett JL, Rieckmann P, Montalban X, Mikol D, Freudensprung U, Plitz T, van Beek J; ATON Trial Group. ATON: results from a Phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis. J Neurol Sci. 2015; 351:174-8.

So is the problem APRIL, BAFF or both?

The answer comes with the result of what happened with tabalumab that blocks only BAFF.

A Study of Patients With Relapsing Remitting Multiple Sclerosis NCT00642902

The company has reported on Clinical tiral. gov that the trial was completed.  

What happened.?

We don't know because the results have not been reported.

Blocking BAFF gets rid of  mature B cells and can even get rid of plasma cells and reduce antibodies, but they appear to have the potential to increase the memory B cell pool, which recently we suggested could be the problem in MS.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017. pii: S2352-3964(17)30045-2.

Therefore both tabalumab and atacicept could make MS worse.

Response to therapy may help elucidate whether the idea has any legs, it may help us understand treatement and may help us personalise this treatment. 

For Merck it may help us to understand how Cladribine actually works

For Lilly it may help with responsible reporting and help determine if BAFF inhibition is what makes MS worse

You prompted us to ask more about access to the data, notably Lilly

The company website (Click) says "..companies must act to earn the trust of the public they serve"

However, as we have no access to data or the result, which one could predict worsened MS,  many years after the trial was completed, how is that going to lead us towards trust?

They say "We have an online portal to facilitate requests from legitimate researchers for clinical trial data there

So when requested it is "out of scope"

"Whether favourable or unfavourable, Lilly posts the results of all Lilly-sponsored Phase II, Phase III and Phase IV clinical trials of Lilly marketed products conducted anywhere in the world that were initiated on or after October 15, 2002"

When asked specifically, it was said that "this standard only applies to marketed compounds".

So as Talabummab was not a marketed we are not getting access to the data, 

"Lilly discloses results of Lilly-sponsored clinical trials for compounds whose development terminates on or after October 1, 2009". 

In response to this question about disclosure the response was "We expect to submit the results of this study to Clinicaltrials.gov in the third quarter of this year following the official termination of the molecule’s development marked by the inactivation of the IND this year". 

This will no doubt say the trial failed, but will it say it worsened disease? 

However, on clinical trials.gov it is unlikely to talk about the immunostaining and disease activity, which is the data that will help us understand what occurs in MS.

If there was an increase in B memory cells? How long did this occur, does it relate to disease activity?

I guess, we will never know.

Companies do preclinical testing to ensure their drugs are relatively safe, so that they can make an IND filing.

IND means an Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug to clinical investigators before a marketing application for the drug has been approved. The IND application is reviewed for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is cleared, the candidate drug usually enters a Phase 1 clinical trial and beyond until they apply for a New Drug Application (NDA) which allows companies to market a product.

  • Is the drug safe and effective (efficacy) in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks?
  • Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?
  • Are the methods used in manufacturing the drug (good manufacturing practice [GMP]) and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?

It seems development of Talabumab is not going to occur, so why hide results from people?

We will have to wait so see if EL actually does anything

Even with providing access data, the publication process would mean that nothing would get published before Q3 (third quarter) 2017.

Is this just another case of Bad Pharma?

#PolticalSpeak & #OffLabel: rituximab and the future of MS treatment

COMBAT-MS = COMparison Between All Treatments for MS #OffLabel #PoliticalSpeak

Ever since coming back from my sabbatical and witnessing the unmet need in resource poor countries for disease-modifying therapies for MS I have been promoting an Essential Off-Label DMT list for the treatment of MS. It has also become clear to me that this is not only a problem in resource-poor countries, but high-income countries as well.

The term flipping the pyramid refers to treating MS with the most active treatments first-line. In most countries the more effective treatments are only available 2nd or 3rd line mainly due to the costs of the treatments. In some countries, particularly in Sweden and the USA, they have overcome this problem by prescribing cheaper off-label options; rituximab and HSCT being the main off-label high-efficacy options available. To be frank rituximab (anti-CD20) is not really a cheap off-label option, but it is significantly cheaper than the licensed high-efficacy MS DMTs.

The issues around off-label prescribing when licensed therapies are available have been debated and discussed on this blog many times (search term OffLabel). These issues are rehearsed in an Editorial in last week's BMJ (see below). Morales & Guthrie make the point '... off-label prescribing may need more explicit justification, the evidence supporting prescribing is actually more important than the presence or absence of a licence in itself...'. How do we get the necessary evidence to support clinicians and patients make the correct decision? One way is to do randomised controlled trials comparing say rituximab with one of the licensed DMTs. Who will pay for this? Fortunately, PCORI (Patient-Centered Outcomes Research Institute) has funded a pragmatic trial to generate evidence on the relative efficacy and safety of rituximab to other licensed DMTs. PCORI as an organisation was established to evaluate the benefit and harm of already existing methods and treatments used in health care in real world populations and where there is a decisional dilemma. PCORI was part of the 2010 Affordable Care Act (“Obamacare”) and is an independent non-profit trust-fund.

In July 2016 PCORI announced a $8.5 million study comparing the effectiveness of rituximab, a biologic drug, to other commonly used disease-modifying therapies in individuals with the relapsing-remitting form of the disease. The study will be based at Karolinska Institute in Sweden and conducted in collaboration with Kaiser Permanente Southern California. In particular, it will assess the comparative safety outcomes of medications.

I am privileged to have been invited to be a stakeholder on this important study. My role is advisory and to help with keeping the wider MS community engaged and up-to-date on the progress and the aims of the study. The good news is that we had our first meeting on the 9th February and have made good progress. It seems as if we have found an appropriate name for the study COMBAT-MS (COMparison Between All Treatments for MS). The term may be appropriate in that the results of this study may be very disruptive. Could these results be what is required to start and off-label prescribing revolution? I sincerely hope it does in resource poor environments where so many pwMS are being left without any DMTs and MS is simply allowed to run its natural course. In high-income countries the battle between off-label prescribing and licensed therapies will be more nuanced. On the one hand the politicians and the EMA want to support Pharma, and their innovation machines, and on the other cash-strapped healthcare systems will be looking to reduce their drug costs. Who will win? I sincerely hope our patients win; surely they deserve the choice of a flipped pyramid? I would therefore like to thank the COMBAT-MS team for trying to make a difference and generate the real-life evidence we need to assess the efficacy and safety of rituximab in the management of MS. 

The other good news is that rituximab is coming off patent and we can expect several, hopefully cheaper, biosimilars to emerge on the market in the next year or so. Some concerns remain about the future of PCORI under the new Trump administration. However, we all expect funded projects, such as COMBAT-MS, to be completed.

What this study highlights is the need to explore how to optimise the use of off-label rituximab in MS. What dose should be used? Could it be used as a PIRT (pulsed immune reconstitution therapy)? Will a response marker emerge that will allow us to use anti-CD20 therapies more intelligently? How will rituximab do in a head-2-head study against ocrelizumab? Will the fact that anti-drug antibodies are higher with rituximab, than ocrelizumab, make a difference long-term?

Morales & Guthrie. Off-label prescribing of antidepressants. BMJ 2017;356:j849 (Editorial)


..... Strength of evidence matters more than presence or absence of a specific licence

..... In most countries, medicines have a product licence that describes how they should be used. Licensing is intended to ensure that medicines meet acceptable standards of efficacy, safety, and quality for a particular indication in a particular group of patients.

..... “Off-label” use occurs when a drug is prescribed for an unlicensed indication, to an unlicensed patient group (such as children), and/or as an unlicensed dosage or formulation.

.... Clinicians can legally prescribe off-label, and professional licensing agencies recognise that off-label use is necessary if licensed medicines are ineffective, if they are associated with adverse effects, or if the licensed dose or formulation does not meet the patient’s needs.

..... Professional responsibility in these circumstances is fundamentally the same as for on-label prescribing. As the UK medical regulator says, “We expect you to carefully consider any treatment that you prescribe, and we expect you to be able to justify your decisions and actions when prescribing, administering and managing medicines regardless of whether they are licensed or unlicensed.”

.... Although off-label prescribing may need more explicit justification, the evidence supporting prescribing is actually more important than the presence or absence of a licence in itself.

..... These mismatches between licensing, evidence, and guidelines within countries complicate clinical and shared decision making, and variations in licensing and guidelines between countries add further confusion.

..... For all prescribing, patients (or their parents or carers) should be given enough information to allow them to make an informed decision whether to take a medicine. This should include whether the intended use is off-label, but more importantly prescribers should discuss the strength of the evidence base underlying their recommendation.

..... Off-label prescribing matters because it is usually (but not always) associated with substantial uncertainty about the balance of benefit and harm. Prescribers should therefore be cautious when they prescribe an off-label medicine on the basis of an extrapolation of evidence for a different indication, in a different patient group, or for a substantially different dose or formulation.

..... Equally, however, on-label prescribing also often involves extrapolation, most commonly because the patient needing treatment is very different from the patients included in trials.

CoI: multiple

Sunday, 26 February 2017

#ClinicSpeak: pressure ulcers in MS

If you have a pressure ulcer you need to do something about it. #ClinicSpeak #MSBlog 

Dogs are increasingly being used as diagnosticians in medicine to help sniff out cancers and other metabolic conditions by using their ultra-sensitive sense of smell and their ability to learn and be trained. One condition that doesn't require a dog's nose are pressure ulcers. Patients with pressure ulcers have a characteristic smell; the bacteria and organisms that live in the ulcer produce odorants that is hard for the trained clinician to miss. 

Two week's ago when I collected one of my patients from the waiting room her odour told me that she had developed a pressure sore. My heart sank; the time and effort that goes into treating a pressure ulcer is enormous. Not to mention preventing it from reoccurring in the future. 

When I was training to be a neurologist pressure ulcers were the norm in patients with more advanced MS. Over the last two decades it is now unusual to see pressure ulcers. I say that, but in the last two years they are beginning to be more common. Why? I suspect like any other healthcare problem they are an indicator of austerity Britain; cut health and social care spending and you will see pressure sores becoming a problem again. In MS pressure ulcers are at the vanguard of a failing healthcare system

The paper below finds that pressure ulcers have a major impact on QoL for pwMS and they are strongly linked to problems with mobility. 

We are in the process of developing a C-QUIT (continuous quality improvement tool) with the idea of it being the 'carrot' and 'stick' to help drive adoption of the policies in the 'Brain Health: Time Matters' document. One metric that may get into the final tool is the proportion of pwMS with advanced disease who develop pressure ulcers. Pressure ulcers, or the lack of pressure ulcers, are a very good index of the quality care of care someone who is immobile is receiving. Do you agree? Keeping someone who is wheelchair, or bed, bound healthy and free of pressure sores takes resources and effort, not to mention love and compassion.  

If you are a carer, or a family member, of someone with advanced MS and they have a pressure ulcer or early skin changes suggestive of an early pressure ulcer, don't ignore the problem. Early intervention, or prevention, of pressure ulcers is better than having to wait until they are a problem. 

Please note that pressure ulcers are typically confined to people with advanced MS; if we can prevent, or delay, people getting advanced MS we should reduce this problem substantially. This is another reminder for us to treat MS early and effectively.

PaperpileMcGinnis et al. What is different for people with MS who have pressure ulcers: A reflective study of the impact upon people's quality of life? J Tissue Viability. 2015 Aug;24(3):83-90.

BACKGROUND: Multiple Sclerosis (MS) is a progressive, degenerative disease of the central nervous system. People with advanced disease who have compromised mobility, activity, sensory and/or cognitive abilities are at risk of pressure ulcers. Having a pressure ulcer has a substantial impact on a person's quality of life; a generic pressure ulcer Health Related Quality of Life (HRQL) framework has been used in this study.

AIM: To explore the views and opinions of patients with MS who have a pressure ulcer using a thematic framework and compare these to the general pressure ulcer population.

METHODS: Data for six MS patients was obtained through secondary analysis of transcripts from semi-structured interviews conducted during two studies which were part of a programme of HRQL Research.

FINDINGS: Patients with MS reported that their pressure ulcer affected their lives physically, psychologically and socially. All were confined to bed (as part of their pressure ulcer treatment) and therefore unable to participate in activities. Difficulties with movement and activity were partially attributed to the MS. Patients with MS did not report feeling ill with their pressure ulcer and expressed positive emotions and optimism. Pain or discomfort was a feature of the pressure ulcer for most patients.

CONCLUSIONS: Pressure ulcers have a major impact on QOL for all patients. Problems with mobility and activity associated with the pressure ulcer were confounded by the MS.

ACTRIMS 2017 further points to Memory B cells

This week ACTRIMS has been going. The academics have been microbioming and even got salt in the act as salt affects gut bacteria, but in terms of pharma news this is a poor companion to ECTRIMS and the AAN.

However, a couple of weeks ago we suggested that drugs that inhibit MS, target memory B cells. 

Have a read (click on the link below)

The data published with dimethyl fumarate was not so great, but it is nice to see data replicated and so more evidence to support the idea comes from ACTRIMS. The effect on B cells was not dependent on whether DMF was associated with leucopaenia and not related to antibody levels. However we know leucopaenia puts you at extra risk from infection.

Dimethyl fumarate effects on circulating B-cell phenotype
Erin E. Longbrake, Claudia Cantoni, Francesca Cignarella, Anne H. Cross MD, & Laura Piccio. ACTRIMS 2017.

Background: The efficacy of anti-CD20 monoclonal antibodies in clinical trials of relapsing multiple sclerosis (MS) confirmed that B-cells play an important role. Little is known about how dimethyl fumarate (DMF) affects B-cells. Objectives: To determine how the composition and function of circulating B-cell populations is affected by exposure to DMF.

Methods: Peripheral blood mononuclear cells (PBMC) and serum were collected from MS patients stably treated with DMF, patients on no immunomodulatory therapy and healthy volunteers. B-cell subpopulations were analyzed by flow cytometry.

Results: The proportions of circulating class-switched memory B-cells (CD20+ IgD- CD27+), non-class-switched memory B-cells (CD20+, IgD+ CD27+) and double negative memory B-cells (CD20+ IgD- CD27-) were significantly decreased among patients taking DMF relative to healthy and untreated MS controls. Concurrently, there was an increase in the proportion of circulating naïve B-cells (CD20+ IgD+ CD27-). Expression of the activation marker CD80 was also reduced on circulating B-cells from DMF-treated patients. Quantitative serum immunoglobulins did not change with DMF treatment.

Conclusions: DMF reduced the expression of circulating memory B-cells. A similar pattern has been observed among other disease modifying therapies, and this may underlie some of the drugs’ efficacy against relapsing MS. More study is needed to determine whether changes in B-cell phenotypic markers are paralleled by changes in B-cell function

Animals in Research

Why do we talk about Animal Research on the Blog?
Signatories (including Queen Mary and 111 other signatories) to the Concordat of animals in research (Click here) have agreed to be more open about their use of animals in research, and to abide by the following four commitments.
Commitment 1: We will be clear about when, how and why we use animals in research

Commitment 2: We will enhance our communications with the media and the public about our research using animals

Commitment 3: We will be proactive in providing opportunities for the public to find out about research using animals

Commitment 4: We will report on progress annually and share our experiences
All signatories agree that they will work to fulfil the four Commitments, initiating projects and strategies that are relevant and appropriate to their organisations to be more open about their use of animals in research. The signatories will be asked to report on their progress in taking these steps

Saturday, 25 February 2017

#ClinicSpeak & #ResearchSpeak: chubby, female and young are not a good mix

Can you reduce the chances of your children getting MS? #ClinicSpeak #ResearchSpeak #MSBlog

Obesity, in particular adolescent obesity, is a risk factor for developing MS. The study below shows that this risk, not surprisingly, extends into childhood or paediatric MS. 

Is obesity simply associated with MS due to another factor or does obesity act in the MS causal pathway? An example of an association would be that its actually low vD levels, or lack of outdoor activity and less sun exposure, that is the causal factor. People who have less outdoor activity tend to be more sedentary and hence more likely to be obese. The risk factor here is less outdoor activity and not the associated obesity. 

Obesity could be causal if some part of adipose tissue biology interacts with the MS causal pathway. An example of this is could be one of pro-inflammatory mediators that adipose tissue produces, and there are many such mediators, prime the immune system to develop autoimmunity. In other words if there was less adipose tissue, and as a result less adipose tissue induced systemic inflammation, then the risk of autoimmunity will drop.

Another way adipose tissue may interfere with the causal pathway is actually via vD metabolism. Adipose tissue may lower systemic vD levels by consuming vD as part of its metabolism. The low vitamin D level, and not the obesity, that is the risk factor here.

The only way to answer the association vs. causation question is to do a randomised controlled trial of a dietary, or pharmacological intervention, which reverses or prevents adolescent obesity, and to see if the intervention reduces the risk of developing MS. This type of trial would be very difficult to do and in my opinion is not feasible now. It may become feasible when we have a pharmaceutical that effectively treats obesity; with drugs it is easier to do randomised controlled trials. With lifestyle interventions, particularly weight loss and obesity, this is even more difficult when the outcome needs to be looked at a population level.

A cheaper, and cleverer, way to do randomised-controlled trial to prove causation is to use the Mendelian randomization method and to see if the genetic variants that are linked to obesity are risk factors for developing MS. 

An earlier study using people from California registered with the Kaiser Permanente HMO and a replication sample from Sweden showed just this. The investigators constructed a weighted genetic risk score using genetic variants previously established to predict obesity. Subjects with higher genetically-induced obesity scores had a higher risk of developing MS. Although the investigators controlled for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS they clearly couldn't control for other important con-founders that are very relevant to this analysis, for example dietary factors, exercise - in particular out-door activity - and vD levels. Despite this that study suggested that obesity is probably part of the MS causal pathway and that if we want to reduce the incidence of MS in the population we need to tackle the problem of adolescent obesity. 

Tackling adolescent obesity is much easier said than done! However, if you have MS and you children are already at higher risk of developing MS you may want to think about this more seriously. 

In high prevalence areas such as Western Europe the lifetime risk of a woman developing MS is ~ 1 in 500 (background population risk). If you are a woman with MS and have children you need o be aware that the chance of your daughter(s) getting the disease is ~ 1 in 40 and your son(s) ~1 in 80. Would you want to do everything you can to lower that risk? 

Chitnis et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol. 2016 Nov 4;3(12):897-907.

OBJECTIVE: The aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.

METHODS: Case-control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex- and age-stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex-stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity.

RESULTS: Only 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001).

INTERPRETATION: Higher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.

Secondary Progressive EAE. Is it the astrocyte?

Some body asked me to comment on this paper.

Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A, Blain M, Healy L, Antel J, Quintana FJ. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A. 2017;114(8):2012-2017.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.

I said that I was reluctant to do this.....The human data is out there for every one to see.

However, it did reach the news and so here is my take, which you asked for.

I've been told I have been abit grumpy. Maybe I should enthuse more, but research is about questioning

If you are not interested in understanding science papers and their problems, then this is not for you.

If you think every thing in science is clear cut then read on... as we make black and white become grey.

For science readers it is food for thought.

In the above paper they say "Following immunization......NOD (non-obese diabetic) mice initially develop an acute neurological event, which is followed by a chronic progressive phase that starts at approximately day 25"

When they looked in the CNS of animals treated for ages with fingolimod they found reduced activation of the innate immune system 

Then the study looks at the effect of the drug on isolated astrocytes and importantly human astrocytes and finds a number of pro-inflammatory genes down regulated, some are upregulated like IL-10 and neurotoxicity goes down, through blockade of one of the central transcription factors controlling inflammatory signalling. 
So they suggest that fingolimod is going to protect nerves and fingolimod will stop secondary progressive MS. 

It is however pointed out that fingolimod actually failed to affect primary progressive MS, but there was some effect in secondary progressive MS with siponimod. This study sponsored by Novartis, makes it look promising. Maybe Siponimod works via blocking astrocytes

However, whilst the message in the paper is crystal clear, the supporting EAE is perhaps not quite as clear cut as it seems.

We have a read round the subject because if this study highlights a quick way to find treatments for progressive MS, we need to be doing this.

However, NOD mice develop diabetes and so are classed as a harmful mutants, creating more problems to use them. Generally however the adjuvants used to cause EAE, block NOD mice from becoming diabetic. Anyway back to the study.

First thing to be said, in contrast to the suggestion tin the paper, there were studies looking at chronic EAE, years before this current report.

It was not mentioned...wonder why I get grumpy:-)

Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler. 2011;17(8):939-48

In a similar experiment in ABH mice treated with fingolimod, there was a marked effect on disease with treated animals. So the results look the similar but perhaps the treatment effect was much more marked.

There was less nerve damage and less myelin loss, however              the interpretation was somewhat different. 

It was not that this was about astrocytes, they were not looked at, but it was that fingolimod was blocking relapses.

This is because the model in relapsing progressive, where relapses occur but animals recover with increasing deficit. The relapses burn out after 3-4 attacks and you get a very slow worsening of disease (secondary progression starting months after disease onset) that does not respond to T cell inhibition and incidentally did not respond to fingolimod treatment, so suggesting that fingolimod may fail in progressive MS, which it was subsequently shown to do.

ProfG has mentioned the importance of "Thinkhand" as a treatment option and has reported that ocrelizumab and natalizumab have protected hand function in the none hole peg test. However the trials with S1P1 modulators have not reported effects on hand function. Why not?

It must tell us something but what?

Anyway in the first study (above) the beasties were treated from day 40 and "FTY720 ameliorated progressive NOD EAE without significant effects on the peripheral T-cell response".  So we have a difference in World View.

However, this was measured by monitoring T cell responses from the spleen. However, as the response of the drug is to keep cells in lymphoid organs, would we be expecting a decrease in T cell function..maybe if we looked at the blood there may had been an effect. However the inference is clear this is workig via blockade of astrocytes and not T cells  

However, we need to look at the history of the generation of the progressive model.

We studied EAE in NOD mice many years ago, where it was clear that this was a low-EAE susceptibly strain
Genetic analysis of experimental allergic encephalomyelitis in mice. Baker D, Rosenwasser OA, O'Neill JK, Turk JL. J Immunol. 1995;155(8):4046-51.

We also showed that the mice would respond to MOG.

Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu JM, Baker D. J Immunol. 1994;153(10):4349-56.

The NOD mice and ABH mice share a transplantation antigen called H-2Ag7 that is used to recognise the myelin oligodendrocyte glycoprotein. The MOG 35-55 epitope is a minor disease causing epitope. Similar it may not be the major target in C57BL/6 mice (type of mouse) either.

Delarasse C, Smith P, Baker D, Amor S.Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunology. 2013;140(4):456-64.

Yes I know I'm just gettin gthe altmetrics up:-)

Anyway back to NOD mouse EAE and the suggestion that is a progressive EAE model.

Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, Monsonego A, Bar-Shir A, Engel Y, Gozin M, Weiner HL. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest. 2008;118:1532-4
They said when 10-week-old NOD mice were immunized with MOG35–55 ..., the first signs of disease appeared at days 11–12 (peaking at days 16–18), and after partial recovery from this initial acute attack, there was a progressively worsening relapse without full remission. This was then followed by a secondary progressive course characterized by chronic clinical impairment. 

The implication is that the worsening occurs progressively from day 25 onwards.

This was also reported in another study. But in this case, disease was treated with myelin (MOG) to block the T cell immune response.

Levy Barazany H, Barazany D, Puckett L, Blanga-Kanfi S, Borenstein-Auerbach N, Yang K, Peron JP, Weiner HL, Frenkel D. Brain MRI of nasal MOG therapeutic effect in relapsing-progressive EAE. Exp Neurol. 2014;255:63-70.

However, remember secondary progressive MS doesn't respond too well to immunosuppression. So if this works in the secondary progressive model then it perhaps lacks predicitve value to that occuring after treatment of MS.

Now let's look at the line graph. Here's one of ours (below)

An attack and then it goes progressive?

Actually it does, but not at day 25 as the line graph suggests.

The above is all caused by relapsing-remitting disease driven by T cells. The relapses show increasingly poor recovery and so deficits accumulate with time. They are also asynchronous so they are not occurring at the same time and if you only look at the "line" you think the disease is secondary progressive. It is not.

We seldom get to see the individual data. I have repeated said people should publish the number of animals that get disease, the maximal severity of disease and timing of onset so it may allow you interpret these lines.

However, there appears to be one example, when the same people reporting the secondary progressive model, report in another paper and show individual scores. It suggests that EAE in NOD mice, is if fact not really an instant secondary progressive model starting at day 25 but it is in fact a relapsing-remitting disease with poor recovery, like the ABH mouse. This accumulates deficits related to relapsing attacks.

This is not a slow insidious progressive disease as implicated by looking at the line,which is an average of a number of animals

Levy H, Assaf Y, Frenkel D. Characterization of brain lesions in a mouse model of progressive multiple sclerosis.Exp Neurol. 2010 Nov;226(1):148-58.

So if disease is really relapsing in NOD mice it will respond to FTY720 by their suppression, causing less demyelination, nerve loss and cytokine X or Y and less astrocyte activation. 

What was found?

Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A, Blain M, Healy L, Antel J, Quintana FJ. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A. 2017;114(8):2012-2017.

Why is this important because, if it is a true secondary progressive model with validity it would not respond to peripheral immunosuppression very well as occurs in MS and maybe we can use this (taking a couple of months) rather than our current model (Taking 6 months) to test agents.

You can make your own conclusions,

If we had the raw data we could see in an instant what is really going on.

If we did, there would be time to eat humble pie or is this a case of MD-investigative reporter?

We have been talking about animal work this week. We had the suggestion of multi-centre animal studies. However, for EAE research raw data files would be the type of data that would be worth more for drug development than consortia doing multi-centre studies.

Could blocking astrocytes result in blockade of progressive EAE and MS ...absolutely.

P.S. Dear "Headmaster" hope this style of walking you through data is informative..rather than giving a sound bite. This will be important when we do the clinical posts soon.

Friday, 24 February 2017

Dodgy EAE experiments means more wasted animals

Yesterday we say that there was a desire to do multi centre animal studies.

We said if you do rubbishy animal experiments, you get rubbish.
A well planned and undertaken experiment can mean more than ten rubbish experiments.

The funny thing is that the suggestion of mutli-centre animal trails was published in the Journal Nature .

This is a bit rich, because whilst we want to get our papers published, this it is also one of the homes of unreproducible pop science. 

A while ago it was suggested that salt intake makes autoimmunity worse. This got one of the biggest altmetrics on the plantet. It was covered by loads of media and every one lapped it up.

MD2 said hang on what are they saying and worked out the doses of animals and humans and the conclusion was what a load of.......

To MD2's credit they posted a comment on the Nature website that you should take it with a pinch. Nature removed the comment twice and MD2 complained and on the third time it is still there. 

The authors were livid. How dare MD2 question this?

Because it sounded dodgey?

However dissecting the science and looking at the dose of salt used to induce the issues you are looking at the dose equivalent to half a kilo of salt a day.

This will kill the average human and make people vomit. About 8g makes you puke. However, mice & rats can't vomit and so what was the equivalent 600g must have felt like I don't know.

So you get a paper in Nature and it spawns another ten or so experiments.

So something that you should take with a pinch.. means you are wasting loads of animals.

So what happens in EAE? 

It has been repeated and the original study was shown partially reproduced and shown to be weak. Here we have another paper in a different disease, we will have loads more.

Read the abstract if you want

High salt intake does not exacerbate murine autoimmune thyroiditis. Kolypetri P, Randell E, Van Vliet BN, Carayanniotis G.
Clin Exp Immunol. 2014;176(3):336-40.

#PoliticalSpeak: the not so BigPharma Alternative - sorry we have let you down

We do not have enough hours, or energy, to reignite our BigPharma Alternative. #PoliticalSpeak #MSBlog

Impact when you don't expect, or deserve, to have one. I received the following email from a PhD researcher earlier this week:

Dear Prof. Giovannoni,

Your article about repurposing in ‘Multiple Sclerosis and Related Disorders’ has caught my attention.

I am a ..... researcher at the ....... and I am doing research about drug repurposing in oncology. More specifically, I am focusing on the regulation, the intellectual property right strategies, and the economic implications of drug repurposing.

I am working in close collaboration with the Anticancer Fund, a Belgian non-profit organization that is currently funding several clinical trials investigating off-patent repurposed drugs in cancer patients.

Similar as to what is described in your article, we have encountered several hurdles in getting the repurposed drugs to the patients. Please find attached our policy brief listing these hurdles and proposed action items for regulators and policy makers.
I think the proposed movement to support the “Big Pharma Alternative” as described in your article is inspiring and I was wondering whether there is any progress in the field of multiple sclerosis with regard to drug repurposing?

Thank you for your time, I look forward to hearing from you....

Sadly, I have to respond to him that the BigPharma Alternative has floundered. We have only so many hours in a day and when the repurposing, or off-patent, drug bill was filibustered out of the house of commons and we we received a stern response from George Freeman, the then Parliamentary Undersecretary of State for Life Sciences, stating that there were no hurdles for prescribing off-label we lost steam. What George Freeman was saying that Pharma, in particular Big Pharma, is such a big part of or knowledge economy that we don't want to kill the goose that lays the golden eggs. In other words let Pharma innovate and make money, we will pay them, tax them and we will all live happily ever after. What this attitude doesn't address is the difficulty people have when they live in resource-poor environments, or are part of healthcare systems that require individuals to co-pay. Two thirds of personal bankruptcies in the US are triggered by ill-health. The article below from an American lawyer highlights the other side of the story, or the underbelly of Big Pharma; i.e. their predatory behaviour to milk the system. This is something we can't ignore and it is very prevalent in the MS space. 

Can we revive our BigPharma Alternative? I am not so sure. We will continue to promote our Barts-MS Essential Off-Label DMT list for use in resource-poor environments and will provide our off-label treatment protocols to anybody who wants to use them. However, we don't have the energy or resources to take these big issue on by ourselves; the sad thing is the politicians and lobbyists seem to have won. Just may be if the health policy unit at our University had supported us we would have had a chance of building some momentum, but Professor Allyson Pollock, who has now left our University, was adamant that she thought what we were doing was wrong. The good news is that the MS International Federation, or MSIF, has agreed to carry the baton when it comes to promoting off-label DMTs in resource poor environments; at least we have some help on this front. This is the battle we are prepared to fight, with a little, or a lot of, help from our friends. 

Giovannoni et al. The problem with repurposing: Is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? Mult Scler Relat Disord. 2015 Jan;4(1):3-5.

If it is not feasible to develop licensed drugs to the stage that they can actually be prescribed for a new indication, can we justify, either ethically or economically, the undertaking of proof-of-concept studies using off-patent medications? Without a financial incentive it is very difficult to repurpose off patent drugs for a new indication. Therefore, we need a political solution to allow the repurposing of off-patent drugs by other stakeholders or Big Pharma.

Levy MS. Big Pharma Monopoly: Why Consumers Keep Landing on "Park Place" and How the Game is Rigged. Am Univ Law Rev. 2016;66(1):247-303.

Now, more than ever before, pharmacologists are contributing medical advances to confront ravaging disease. They are developing drugs to mitigate the effects of Alzheimer’s, HIV, multiple sclerosis, and various forms of cancer. To capitalize on the opportunity, brand-name pharmaceutical firms are patenting these drugs, consequently guarding formulas and, with it, profits. Patents grant brand-name firms market exclusivity, which essentially allows them to set their own prices. Even though brand-name firms are investing some of their capital to cultivate new drugs, they also are enjoying gigantic revenue streams, absurd profit margins, and seemingly unfettered control of their respective markets. Consequently, sick patients are unable to afford their medication; high prices are bankrupting consumers in the absence of reasonably-priced generic alternatives. Despite the fact that generic drugs contain identical ingredients, cure the same symptoms, and cost 70% less, brand-name drugs persistently dominate their generic counterparts. Indeed, brand-name firms are improperly preventing generic market entry. Without generic competition, no watchdog exists to curb big pharma’s prohibitive prices. Despite the Supreme Court’s fleeting fix in FTC v. Actavis, which condemned reverse payment settlements that precluded competition, brand-name firms are employing other tactics predatorily to extend their market exclusivity and charge consumers unaffordable prices. To prevent brand-name abuse and help infirm patients afford their medication, this Comment proposes that courts apply federal antitrust law to brand-name firms that attempt to monopolize a pharmaceutical market through anticompetitive means, particularly by abusing Risk Evaluation & Mitigation Strategies (REMS) and by "product hopping." To combat exclusionary conduct, courts should mirror the “rule of reason” framework set forth in Actavis and apply an "enhanced" version specifically tailored to the pharmaceutical industry, giving stronger credence to generic challengers. In addition to finding brand-name tactics exclusionary, this Comment also proposes that courts adopt a bright-line rule prohibiting brand-name firms from exploiting the "legitimate business" defense to immunize their destructive conduct. The current framework perpetuates abuse and grants brand-name firms ostensibly indefinite monopolies. Analyzing brand-name defensive tactics under federal antitrust law would facilitate generic market entry and consequently moderate drug prices. Even after sacrificing their entire financial portfolios, patients are still unable to afford their medication. This Comment interprets Actavis as prohibiting the “legitimate business” defense and provides a remedy to deserving consumers by preventing REMS abuse and product hopping, fostering generic competition, and tempering excessive drug prices.

Thursday, 23 February 2017

#ResearchSpeak & #ThinkHand: MS outcomes - are we closer to the holy grail

Are we closer to doing defining a new battery of outcome measures for progressive MS? #ThinkHand #ResearchSpeak #MSBlog

Those of you who follow this blog will realise that we are gradually developing an online suite of apps to help you self-monitor your disease. Why? To empower you to ask the right questions about your prognosis and treatments.

It is clear that when DMTs for progressive MS are licensed you will need to show that your disability is worsening. There is no way that the payers will allow all-comers access to DMTs for progressive MS. Access to treatments will be based on the inclusion criteria for the clinical trials. Most trials have required 'objective evidence' of worsening disability. 

We are also aware that most neurologists, at least in the UK, don't have time in routine clinical practice to do an EDSS, or a battery of other tests, to monitor worsening disability. The solution is to get you to monitor your own disease. We have therefore developed an online web-EDSS that we think is pretty good. We have also produced an affordable, environmentally-friendly 9-HPT and will be adding walking-distance and the self-measured 25-FTW to the battery. We are also developing visual function tests and potentially other outcome measures in the future. What we are lacking is an engaging, responsive cognitive test. The current online cognitive tests are very boring and simply not engaging enough to bring people back to repeat them over time. If you have any suggestions for creating a good online cognitive screening and monitoring tool that can be used to assess MS-related cognitive impairment please let us know.

We have chosen our self-monitoring tests carefully to map onto what is acceptable by the field. The MS Outcome Assessments Consortium (MSOAC) is an initiative that has come together to put together a battery of tests that will be acceptable to the regulators as an outcome for progressive trials. MSOAC now report on their work in a series of very well written papers in the MSJ. It is clear that the four assessments they have evaluated will now become the new 'gold-standard' for progressive trials. One thing that is not clear is how this battery will be used for assessing disease improvement. The 20% threshold for disability-worsening may be too high a bar for disability improvement.

Don't you think it is incredible that the field is now asking the community to design trials to assess improvement in disability and not just worsening disability? This just shows you how far the field has come and where it is going in the not too distant future.

The MS Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organisations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful

Feys et al. The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Mult Scler. 2017 :1352458517690824. doi: 10.1177/1352458517690824.

Impaired manual dexterity is a frequently reported disability in people with multiple sclerosis (MS) and is increasingly prevalent with worsening disease. While various tests and patient-reported outcome measures are available, the Nine-Hole Peg Test (NHPT) is considered as a gold standard measure of manual dexterity and most frequently used in MS research and clinical practice. We find that the NHPT is reliable within and between test sessions, discriminates between healthy subjects and MS patients with different levels of upper limb impairment, and shows high convergent validity with other manual dexterity as well as more comprehensive upper limb measures. Ecological validity is established by its relation to perceived upper limb use in daily life and perceived difficulty in performing activities of daily living. The NHPT is responsive to deterioration in longitudinal studies, and research suggests that a 20% change in test score is commonly used to define clinically meaningful worsening, a definition that needs further validation in all stages of the disease.

Benedict et al. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017:1352458517690821. doi: 10.1177/1352458517690821. [Epub ahead of print]

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

Balcer et al. Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis. Mult Scler. 2017:1352458517690822. doi: 10.1177/1352458517690822. [Epub ahead of print]

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Motl et al. Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. Mult Scler. 2017 :1352458517690823. doi: 10.1177/1352458517690823. [Epub ahead of print}

The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient's real environment.