Sunday, 19 February 2017

The SPMS trial that never was.

Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.Brochet B, Deloire MS, Perez P, Loock T, Baschet L, Debouverie M, Pittion S, Ouallet JC, Clavelou P, de Sèze J, Collongues N, Vermersch P, Zéphir H, Castelnovo G, Labauge P, Lebrun C, Cohen M, Ruet A; PROMESS study investigators..
PLoS One. 2017 Jan 3;12(1):e0168834. doi: 10.1371/journal.pone.0168834.

BACKGROUND:Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far.
OBJECTIVE:To compare CPM to methylprednisolone (MP) in SPMS.
METHODS:Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
RESULTS:Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
CONCLUSION:Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
TRIAL REGISTRATION:Clinicaltrials.gov NCT00241254.

So more not good news for SPMS, here is another trial that has failed. Cyclophophamide forms an metabolite that is active and entrers the CNS and can kill B cells as well as any other cell that is dividing including hairs in the follicles. There was a hint of activity but the trial was terminated because there were not enough volunteers.

Saturday, 18 February 2017

#ResearchSpeak: when best practice clinical guidelines our out of date

Is your neurologist a sheep or a wolf, a herder or an independent thinker? #ResearchSpeak #MSBlog

The following study looks at decision-making by neurologists in relation to a simple case scenario. The researchers come to the conclusion that neurologists display herd behaviour, i.e. they follow the crowd rather deciding independently. The study is based on a simple case scenario of a 40-year-old woman with MS who has been stable for 3 years on subcutaneous interferon and developed a self-limited neurological event. I assume this was a relapse. There were no new magnetic resonance imaging (MRI) lesions. Her neurological examination and disability scores were unchanged. She was advised by her MS neurologist to switch from interferon to fingolimod against best practice guidelines

What this scenario doesn't explore is that we all know the EDSS is not fit for purpose and the fact that it was unchanged is neither here nor there. You can still have a relapse despite an unchanged EDSS. Similarly, the there were no new lesions on the MRI. The scenario doesn't mention whether or not a spinal cord MRI was done. May her relapse due to a spinal cord lesion. The researchers assume that if the MRI shows no new lesions then this person has not had a relapse. A significant number of relapses occur without new MRI lesions. The MRI only detects lesions that are ~4mm in size or larger. A small lesion in a critical area can cause a relapse without being detected on MRI.  They also assume that the MRI and EDSS are the disease, when in fact they are not the disease. The disease is biological and hence needs to be thought of as a biological process. They also assume the 'best practice clinical guidelines' are set in stone and to be obeyed at all costs and are current and up-to-date.  Most guidelines take so long to produce and get consensus that when the come out they are usually out-of-date. Guidelines are usually reached by consensus and hence are typically behind the adoption curve and not at the vanguard of new treatment paradigms.  

I assume that the neurologist who read this scenario interpreted the 'self-limited neurological event' as a relapse and advised the patient be switched to a more effective treatment. Unless these investigators can provide evidence that this was not a relapse how can the expect the neurologists they surveyed not to switch treatments? In an era of treat-2-target of NEDA it is clear that the 'best practice clinical guidelines' our out of date. In my opinion this study shows that the neurologists who applied the 'best practice clinical guidelines' were the herders, blindly following guidelines and the ones that elected to switch treatment were the independent thinkers, acting in their patient's best interests. My conclusion on reading this paper is the exact opposite to the researchers' conclusions. 

What do you think? 


Saposnik et al. Herding: a new phenomenon affecting medical decision-making in multiple sclerosis care? Lessons learned from DIScUTIR MS. Patient Prefer Adherence. 2017 Jan 31;11:175-180. doi: 10.2147/PPA.S124192. eCollection 2017.

PURPOSE: Herding is a phenomenon by which individuals follow the behavior of others rather than deciding independently on the basis of their own private information. A herding-like phenomenon can occur in multiple sclerosis (MS) when a neurologist follows a therapeutic recommendation by a colleague even though it is not supported by best practice clinical guidelines. Limited information is currently available on the role of herding in medical care. The objective of this study was to determine the prevalence (and its associated factors) of herding in the management of MS.


METHODS: We conducted a study among neurologists with expertise in MS care throughout Spain. Participants answered questions regarding the management of 20 case scenarios commonly encountered in clinical practice and completed 3 surveys and 4 experimental paradigms based on behavioral economics. The herding experiment consisted of a case scenario of a 40-year-old woman who has been stable for 3 years on subcutaneous interferon and developed a self-limited neurological event. There were no new magnetic resonance imaging (MRI) lesions. Her neurological examination and disability scores were unchanged. She was advised by an MS neurologist to switch from interferon to fingolimod against best practice guidelines. Multivariable logistic regression analysis was conducted to evaluate factors associated with herding.

RESULTS: Out of 161 neurologists who were invited to participate, 96 completed the study (response rate: 60%). Herding was present in 75 (78.1%), having a similar prevalence in MS experts and general neurologists (68.8% vs 82.8%; P=0.12). In multivariate analyses, the number of MS patients seen per week was positively associated with herding (odds ratio [OR] 1.08, 95% CI 1.01-1.14). Conversely, physician's age, gender, years of practice, setting of practice, or risk preferences were not associated with herding.

CONCLUSION: Herding was a common phenomenon affecting nearly 8 out of 10 neurologists caring for MS patients. Herding may affect medical decisions and lead to poorer outcomes in the management of MS.

CoI: multiple

Meta analysis points a finger at a virus.

Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, Gran B.The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2017 ;12(2):e0172415.

BACKGROUND:The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS.
OBJECTIVE: To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients.
METHODS:Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association.
RESULTS: 43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF.
CONCLUSIONS:This systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.



We all have endogenous retroviruses in our genome, it makes up about 5% of our genome. There is a suggestion that these can be reactivated to be a target in MS. This study does a meta analysis of data out there and concludes that HERV-W is associated with MS. However, how many papers are related to the fact that there is commercial development of an anti-HERV-W antibody.

The problem with meta analysis is publication bias, as there is bias towards positive data being published, and if you don't understand the biology then you can't sort out the "wheat from the chaff".

This is why meta analysis of EAE data is largely futile, there is a dearth of negative studies and there is such over-interpretation of results to make them look interesting. 

The number of studies where drug X or compound Y is reported to save nerves, cause remyelination, when the drug never gets into the CNS. So if you see that there is an immunosuppressive action, it will be neuroprotective and stop demyelination and even allow remyelination because inflammation is stopped. You claim your drug to be neuroprotective and pro-remyelination and the person doing the meta analysis buys it. 

Therefore, be careful all sorts stuff can be believed of as fact.

If we did a meta analysis on whether T or B cells are the important target in MS, I bet T cells will win hands down.

Fingolimod works by trapping white blood subsets in lymph glands...if you did a meta analysis on that, we would all agree  that this is so. Are there any decenting ideas or data...I think there is.

Therefore careful understanding of the facts, probably gives us greater insight. We need more thinkers than herders

Friday, 17 February 2017

#ResearchSpeak: are polyunsaturated fatty acids intake a preventable risk factor for MS?

PUFAs supplements may reduce your risk of getting MS. #RsearchSpeak #MSBlog

The study below shows that high intake of polyunsaturated fatty acids (PUFA) reduces your risk of getting MS. This observation is independent of other identifiable risk factors. Is this association or causation; chicken or egg? The only way to do this is by doing a randomised controlled population study to see if PUFA supplementation reduces the risk of getting MS, compared to a suitable control substance (placebo or another fatty acid). Another strategy would be to confirm this finding in another cohort of people, which may be difficult, or to try and test the hypothesis using a genomic approach, i.e. Mendelian randomisation. The problem with the latter is that we will need to know a lot about the biology of PUFAs and how subtle genetic variants affect the metabolism and levels of PUFAs. 

What it does suggest that if you are 'at risk' of getting MS, i.e. are a first, second or even a third degree relative of someone with MS it may be a good idea to look at your diet to make sure you are getting enough PUFAs. If not you can easily supplement your diet. In addition to this you need to make sure you are vitamin D replete, you don't smoke and you keep your weight down. 

As with all dietary interventions PUFAs have an up and a down side. Omega-3 PUFAs can increase your risk of bleeding and may interact with other medications.


Bjørnevik et al. Polyunsaturated fatty acids and the risk of multiple sclerosis. Mult Scler. 2017 Jan 1:1352458517691150.

BACKGROUND: Results from previous studies on polyunsaturated fatty acid (PUFA) intake and multiple sclerosis (MS) risk are conflicting.

OBJECTIVE: To prospectively investigate the association between dietary intake of PUFA and MS risk.


METHODS: We followed 80,920 women from Nurses' Health Study (1984-2004) and 94,511 women from Nurses' Health Study II (1991-2009) who reported on diet using a validated food frequency questionnaire every 4 years and identified 479 incident MS cases during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), for the effect of PUFA intake on MS risk adjusting for age, latitude of residence at age 15, ancestry, cigarette smoking, supplemental vitamin D intake, body mass index, and total energy intake.

RESULTS: Higher intake of total PUFA at baseline was associated with a lower risk of MS (HR top vs bottom quintile: 0.67, 95% CI: 0.49-0.90, p trend = 0.01). Among the specific types of PUFA, only α-linolenic acid (ALA) was inversely associated with MS risk (HR top vs bottom quintile: 0.61, 95% CI: 0.45-0.83, p trend = 0.001). The long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not associated with MS risk.

CONCLUSION: Low dietary PUFA intake may be another modifiable risk factor for MS.

Not in My Name. Time to Stop -. Stem cells

Papers are getting assessed on altmetrics and one of the outputs are blog posts, so anyone who has clicked on the altmetric link to get here you are in for a shock....read on

Jiang H et al. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells.Sci Rep 2017 Feb 10;7:41837. doi: 10.1038/srep41837.

Placental derived mesenchymal stem cells (PMSCs) have been suggested as a possible source of cells to treat multiple sclerosis (MS) due to their immunomodulatory functions, lack of ethical concerns, and potential to differentiate into neurons and oligodendrocytes. To investigate whether PMSCs share similar characteristics with embryonic mesenchymal stem cells (EMSCs), and if transplanted PMSCs have the ability to integrate and replace degenerated neural cells, we transplanted rat PMSCs and EMSCs into the central nervous system (CNS) of Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our findings demonstrated that transplanted PMSCs, similar to EMSCs, were effective in decreasing infiltrating inflammatory cells, preserving axons, and ameliorating demyelination, thereby improving the neurological functions of animals. Moreover, both PMSCs and EMSCs had the ability to migrate into inflamed tissues and express neural-glial lineage markers. These findings suggest that PMSCs may replace EMSCs as a source of cells in MS stem cell therapy.


The blog is a site that allows us to talk about research, and some of it is good news and some is bad news. We hope some of the readers are scientists and neurologists as we feel it has educational content for all..but also we need to educate the public about the type of things scientists do.

We can do the rose-coloured tinted glasses approach, which you get in most Science websites where every thing is great. But if every thing was great, we would have cured something by now.

As a card carrying vivisectionist,  we have to take the flank from parts of Society that do not like or want animal experiments. However, the UK Government want us to be open about working with animals, and this is why we post on animal studies.

I have decided against doing "cure of the week" which happens every week as I realize many animal studies are years away from offering something of use. 

Anyway back to the post

If you poll pwMS about where we should be putting their research resources?. I bet high on the list will be people wanting stem cell trials. 

This is because science has promised that we can reverse the effects of time, and the media and public have bought into this view, so you rightly say trials, trials, trials!

Indeed the MS Societies listen and put their resource behind their members wishes. Trials have been initiated and everybody's hopes are high. The hope you are being sold is that the stems cells turn into myelinating cells and new nerves and then we can turn back time.

Mesenchymal stem cells, or MSCs, are multipotent stromal cells that can differentiate into a variety of cell types. Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into haematopoietic and connective tissue, whereas MSCs do not differentiate into haematopoietic cells.

Everyone gets on the band wagon, and even we dipped our toe in the stem-cell waters. 


I know you like to hear about this stuff, but I need to put this into perspective, because if the stem cells trials don't work you will be blaming the animals.....Don't!

So to describe the paper in this study creates mesencyhmal stem cells from embryos and placenta and show that they inhibit EAE and stop demyelination and nerve loss when transplanted into the brain.

Yeah we say.

However, how many more of these studies are we going to see? 

MSC made from this or that cell. 

I wonder whether we should call time? 

Are we going to want to use stem cells from embryos or someone else's placenta, when one can make stem cells from yourself.  
Technology has moved on

There have been endless studies of mesenchymal stem cells and EAE. The results are remarkedly consistent (As seen below, from this study).


The effects are pretty uninspiring.

The benefit is a small diminution, and sometimes a delay, due to a small inhibitory effect. Perhaps much of the benefit of demyelination and nerve loss reported can be then be downstream of this, because the damaging inflammatory response has not arrived in the CNS to cause damage. 

It is often impossible to work out if it was in fact a diminution of the severity of disease or was it because a few animals in the experiment didn't get disease. 

I maintain that we need to see this data. 

However, this minor effect in the most optimum of conditions can easily be bettered by most current DMT. 

If this is good as it gets, then the chances of this being useful in MS is really rather dubious. 

If all they really do is have an immunosuppressive action then is this the way to go?. 

I'm yet to be convinced.

However, do we need these types of study? Mesenchymal trials in humans are well underway. 

Therefore, do we need more animal experiments for the  time being? Perhaps the time for these types of animal experiments has passed.

The success or failure of trials in humans will determine whether this approach is developed or not. 

It will probably be safe, but will it work?....I suspect something towards a failure or something wishy-washy as the trials are based on data made of quick-sand.

Remember this is an opinion and I could be wrong.

Trials in humans are done due to opportunity and public pressure, where we are running before we can walk. How do we guide the mesencymal cells to become oligodedrocytes etc, can they do anything when given systemically? Do they really convert into useful cells? (answer in animals is generally no), there are so many unknowns. This means that the chance of success are slim.

I am there to be proved wrong and then I will eat humble pie when I am.. I don't mean to dash hopes. Stem cells do have potentials 

Am I wrong to be a cynic? and burst some bubbles or should I have a rant and say "Not in my name"

I have to justify what I do, but I am not going to defend all the work of others and this paper happened to come into my firing line.

Am I sorry for doing this in public...No. 

The 3Rs of animal use is supposed to a core principle of working with animals in Europe.

In the experiment above, there is a group where experiment healthy animals are followed and show nothing. They,
 are sometimes injected with adjuvants that serve essentially no useful function excepts it wastes animals. It is no longer an experiment, we know it is not going to induce neurological signs...stop it!

Next up, For anyone reading this study, the method of disease induction and method of killing are no longer allowed in the UK. 

To kill animals they chop their heads off. 

This is not worse thing...a Japanese person once said they throw rats into liquid nitrogen to freeze the brain quickly....non-sense it would not be the quickest way of doing it!- This was stupidity and animal abuse

Anyway "This technique should only be used in rare circumstances and where there is exceptional scientific justification" The animals must be dead before being decapitated. (https://www.nc3rs.org.uk/rat-schedule-1-stunning-followed-decapitation-terminal).

However, if you call people on things does it make them hide the truth.

In the study they only state they inject the adjuvant subcutaneoulsly, but where is this? 

I guessed they have been rejected for saying where, so they don't say it. However, they give a reference  which says the same thing and gives a reference from the yesteryear and it states that the adjuvant is put subcutaneous in the feet.

This practice was likewise outlawed in the UK over twenty-25 years ago as being inhumane, as putting the adjuvant into the feet you get swelling and so pain and the animal has problems walking. This can be put under lose skin and this does not seem to cause the animals the same problem. Therefore, the foot pad injection has no place in science, at least in EAE science. Maybe they did not do this, they selected the wrong references

I personally refuse to accept this work if they do use injection in feet, it is bad science.This is the way to make people change practise..maybe not they just hide things:-). 

It is obvious there are some people that do not care about this and they are based in prominent countries that should know better! 

This is perhaps what happens when you move your research to places, where they do not give a stuff about the beasties they work with. Remember this,  as UK science based on animals closes down

Perhaps it is about time that Journals state producing a list of procedures that they will not accept on ethical grounds.

Yes, EAE will eventually end up there, but if we continue to undertake bad practices then we will hasten this process and so a good reason to speak out...the animals can't 

However, killing off animal work in the UK is going to mean that you get more of this guff.



Some people out there will be saying shut you whining minnie, 
"This is why we move out of the UK you are too Regulated"

Thursday, 16 February 2017

#DigitalHealth: Using VR headset to self-monitor vision


First of all, a bit about myself, my name is Nicolas Dubuisson. I completed my medical training in Belgium and so far I am 3 years through my Neurology training, so well on the way to becoming a Neurologist. I joined BartsMS as an ECTRIMS Clinical Training Fellow to ProfG four months ago. I plan to stay with Barts team until October 2017.


Currently, I’m working with Alison and the team in order to develop new self-monitoring tools for people with MS. One of these projects involves working with a team of designers to develop two smartphone applications that will be able to evaluate visual field and colour vision. The ultimate aim is to embed these into the web-EDSS calculator to improve it as an outcome measure. At the moment people with MS have to rely on their neurologist to tell them if there eyes are affected by MS, or not.

The first function of the APP will be to develop the Humphrey test, currently conducted by a optometrist, into an engaging resource for people to use. Its first objective is mainly to evaluate deficits in the visual fields, which could occur following a lesion along the visual pathway.
This function of the APP is not specifically for people with MS, but rather we hope the resource can be used to help diagnose and monitor other ophthalmological problems as well.
In the existing humphrey test, the optometrist asks the patient to look at a white dot with one eye at a time. Other bright dots will appear on the screen in different places and the patient must press a button each time the signal is caught by their eye.


Existing Humphrey Test in ophtalmology clinic.

The final result is displayed as two circles (one for each eye) with different shades of grey. The light grey represents a perfect vision and the black an absence of vision.


Humphrey result showing a right superior quadrantanopia (black zone).


The application we are developing takes exactly the same principle but the machine is replaced by the virtual headset and a smartphone.



We are developing software to conduct the same test from the phone and a headset.

The second function of the APP will be to test the colour vision. In clinical practice, the current test is called the Ishihara test. We are working to develop an APP in the form of a 3D game. The first prototype that we have shows a wall with 16 coloured squares in front of you. You then have to point out (moving your head) which box is a different colour. Once the correct box has been identified, the wall rises and the player move towards the next wall.




The first step in our project (which will start next week) will be to invite patients from neuro-ophthalmology clinic to compare our tests with those used in routine practice (Humphrey and Ishihara). Once validated (we know that our tests work the same as the current tests), we will look into making these test more engaging and ultimately enable these tests to be made available for others to use at home.

We plan to share updates on this project on the blog. We’d be interested to hear about your experiences of eye tests in relation to your MS. Have you completed any of these tests or have you tried any eye testing APPs?

NB: This will not replace your appointments with the ophthalmologist but on the contrary will be complementary to it and hopefully empower you and other people with MS to monitor their own disease.

Compound in cannabis does not look Dope

van Amerongen et al. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clin Ther. 2017 Feb 9. pii: S0149-2918(17)30054-1

PURPOSE: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).


METHODS: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements.


FINDINGS: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.


This study looks at oral THC in spasticity and pain and the simple answer is it failed?

Why because the outcomes will have been self-assessed; the sativex study says that it did not work on the scientific outcomes, but on how people were feeling. 

In this study people were obviously not feeling good enough.

They say it is of value..... because it is well tolerated, so is a glass of water, but is that going to treat your pain and spasticity? 

The only thing it worked on was when the people were in clinic.

Was the study big enough to be of value, I suspect not.

CoI: I'm a competitor

Wednesday, 15 February 2017

#ClinicSpeak & #NeuroSpeak: alternative facts and PML

Pharma vs. the EMA: whose PML figures are more reliable? #ClinicSpeak #NeuroSpeak #MSBlog

A person with MS from Spain emailed me last week asking for advice. I assume he is on natalizumab and is JCV seropositive and is at risk of developing PML (progressive multifocal leukoencephalopathy) as a complication of his treatment. His neurologist has offered him a choice of dimethyl fumarate (DMF, Tecfidera) or fingolimod (Gilenya). He is however very concerned about the risk of PML on both of these options; the PML figures his neurologist gave him in relation to the number of cases of PML on both of these DMTs are very different to figures he found when searching online. He emailed me to find out which figures are correct. 


Biogen informed me a few weeks ago that a 5th case of PML had been reported on Tecfidera and that last case had had lymphopaenia with only one total lymphocyte count below 500/mm3 (0.5x109/L). Similarly, in December Novartis informed the MS community of the 9th case of PML on Gilenya unrelated to previous natalizumab exposure. I was therefore surprised when this patient referred me to the European database of suspected adverse drug reaction reports.





It is clear that in this database, as at 31st January 2017, there are at least 19 cases of PML reported on Tecfidera and at least 56 cases of PML on Gilenya. Which figures do we believe? I have asked both Biogen and Novartis to clarify, which figures are correct, i.e. their official figures of 5 and 9 cases of PML, respectively, or the EudraVigilance figures of 19 or 56 cases of PML, respectively. 

Please note that European database of suspected adverse drug reaction reports is an official website. All the data displayed in the web reports is taken from EudraVigilance, a system designed for collecting reports of suspected side effects, used for evaluating the benefits and risks of medicines during their development and monitoring their safety following their authorisation in the European Economic Area (EEA).

The following is a list of important facts about the source of the data you can view on this website for each web report:
  1. Each individual case in EudraVigilance refers generally to a single patient; an individual case is composed of at least one report, called the initial report, which might be complemented by follow-up reports.
  2. A web report shows serious spontaneous cases held in EudraVigilance since the medicine or active substance was authorised for use in the EEA. A case is classified as 'serious' by the reporter when a side effect is one that (i) results in death, (ii) is life-threatening, (iii) requires hospitalisation or prolongation of existing hospitalisation, (iv) results in persistent or significant disability/incapacity (as per reporter's opinion), (v) is a congenital anomaly/birth defect, or (vi) results in some other medically important conditions.
  3. A web report shows serious spontaneous cases where an authorised medicine or active substance is suspected by the reporter to have caused or contributed (e.g. by interacting with one or more other medicines) to a serious side effect. Reports where an authorised medicine or active substance is reported as a concomitant medicine are excluded. 
  4. The figure displayed is always the running total of serious spontaneous cases reported up to the end of the previous month. The figures are updated online on the 15th of the current month.
  5. Pharmaceutical companies that hold the marketing authorisation of a medicine, as well as national medicines regulatory authorities, are legally required to submit reports of suspected side effects that occurred in the EEA to EudraVigilance. This includes reports received from healthcare professionals and patients.
  6. Pharmaceutical companies that hold the marketing authorisation for a medicine in the EEA are also legally required to submit to EudraVigilance all reports of suspected unexpected adverse reactions that are serious and that occurred in a third country (non-EEA) where they hold a marketing authorisation.
  7. The web report does not include reports from studies (e.g. clinical trial, non-interventional study) or other types of reports (i.e. only spontaneous reports).
I was as confused as this Spanish person with MS who simply wanted to know the risk of PML on DMF and/or Fingolimod. The clarifications below are very helpful. The EudraVigilance figures are a crude indicator of an adverse event on a particular drug, but the numbers cannot be used to calculate incidences. 

Addendum Added 16h20, GMT, 15-Feb-2017:

I have now had a formal response from Novartis. The EMA, or EudraVigilance, figures are essentially from two sources. One from EU members states and the other from Novartis. The Novartis figures are global figures. The numbers in the 
EudraVigilance database are both suspected, and confirmed, cases of PML and as expected some of them will turn-out not to have PML and some will be duplicate entries. Novartis provide the EMA with information about whether or not the cases are associated with, or without, the previous use of natalizumab. 

The following are Novartis’ official and latest figures:

The overall rate of PML under fingolimod therapy not attributed to previous natalizumab treatment is very rare and estimated to be less than 1:10,000 patients.

10 PML cases in ~184,000 fingolimod treated patients (~397,000 patient-years) as of November 2016.

(Estimated risk (95% CI) is 0.054 (0.026, 0.1)/1,000 patients and incidence rate (95% CI) is 2.52 (1.21, 4.63)/100,000 patient-years exposure.)

Two cases presented with confounding factors, 1 case had previous natalizumab exposure for 10 months (3 years 9 months before PML diagnosis).

One additional case, PML occurred during 3-month natalizumab exposure, after 4.5 years fingolimod treatment, history of recent exposure to steroids.

Nine patients were within the age range of 49 to 63 years, while one patient was 32 years old.

In nine cases, fingolimod exposure ranged between 30 and 54 months, while one received fingolimod for 18 months.

None of the patients had sustained grade 4 lymphopenia.


Addendum Added 16h36, GMT, 15-Feb-2017:

The Biogen figures are 5 confirmed PML cases in ~230,000 dimethylfumarate treated patients (~330,000 patient-years of exposure) as of October 2016. 


CoI: multiple

Metabolomics in MS

Metabolomic signatures associated with disease severity in multiple sclerosis.Villoslada P, Alonso C, Agirrezabal I, Kotelnikova E, Zubizarreta I, Pulido-Valdeolivas I, Saiz A, Comabella M, Montalban X, Villar L, Alvarez-Cermeño JC, Fernández O, Alvarez-Lafuente R, Arroyo R, Castro A. Neurol Neuroimmunol Neuroinflamm. 2017 Jan 27;4(2):e321.

OBJECTIVE:To identify differences in the metabolomic profile in the serum of patients with multiple sclerosis (MS) compared to controls and to identify biomarkers of disease severity.
METHODS:We studied 2 cohorts of patients with MS: a retrospective longitudinal cohort of 238 patients and 74 controls and a prospective cohort of 61 patients and 41 controls with serial serum samples. Patients were stratified into active or stable disease based on 2 years of prospective assessment accounting for presence of clinical relapses or changes in disability measured with the Expanded Disability Status Scale (EDSS). Metabolomic profiling (lipids and amino acids) was performed by ultra-high-performance liquid chromatography coupled to mass spectrometry in serum samples. Data analysis was performed using parametric methods, principal component analysis, and partial least square discriminant analysis for assessing the differences between cases and controls and for subgroups based on disease severity.
RESULTS:We identified metabolomics signatures with high accuracy for classifying patients vs controls as well as for classifying patients with medium to high disability (EDSS >3.0). Among them, sphingomyelin and lysophosphatidylethanolamine were the metabolites that showed a more robust pattern in the time series analysis for discriminating between patients and controls. Moreover, levels of hydrocortisone, glutamic acid, tryptophan, eicosapentaenoic acid, 13S-hydroxyoctadecadienoic acid, lysophosphatidylcholines, and lysophosphatidylethanolamines were associated with more severe disease (non-relapse-free or increase in EDSS).
CONCLUSIONS:We identified metabolomic signatures composed of hormones, lipids, and amino acids associated with MS and with a more severe course.

Last week we had metabolomics telling us what type of MS you were getting so it is interesting that a look-see study reported a week later did not get excited about the trypophan metabolomics but they did report that tryptophan is associated with EDSS not sure if it increased or decreased like the study from Australia

Tuesday, 14 February 2017

#ThinkHand: viewing disability through art

Could the state of your toenails allow us to determine how disabled you are? #ThinkHand #MSBlog

It has come clear me to me over the last week that the ability to cut your toenails, or not, may be a very good integrator of MS disability. To raise awareness over this issue I want to launch an 'art project'. The aim of the project is to continue to raise awareness, as part of our #ThinkHand campaign, about the importance of arm and hand function for pwMS. I want to collate a series of pictures of the toenails of pwMS and to relate it levels of physical disability. 



To participate please send us a picture of your toes, with some brief details about your MS and yourself. The pictures will be anonymised and only used as part of our #ThinkHand campaign. 



Please send  the following information with your picture to bartsmsblog@gmail.com

Sex: M/F
Age:
Disease duration:
EDSS:    (if you don't know your EDSS you can estimate it using our online calculator)
Country
Are you able to cut your own toenails?:
   5 - Yes, easily without help
    4 - Yes, independently, but it takes longer than in the past 
    3 - Yes, independently, but it takes too long so I often get them cut by someone else
    2 - Yes, but I need help
    1 - No, I can't cut my in toenails
    0 - N/A, I have always had someone else cut my own toenails
Biography:  (this is optional please keep this brief)

Thank you

ProfG, the Cheerleader for #ThinkHand

Rebound on fingolimod, let's move away from the hive mind

Mult Scler Relat Disord. 2017 Jan;11:1-3. doi: 10.1016/j.msard.2016.11.003. Epub 2016 Nov 11.

Severe rebound after withdrawal of fingolimod treatment in patients with multiple sclerosis.

Gündüz T, Kürtüncü M, Eraksoy M.

Ther Adv Neurol Disord. 2015 Sep;8(5):233-8. doi: 10.1177/1756285615594575.

Tumefactive multiple sclerosis lesions in two patients after cessation of fingolimod treatment.

Faissner S, Hoepner R, Lukas C, Chan A, Gold R, Ellrichmann G.

Abstract

BACKGROUND:

Fingolimod (FTY) is the first oral medication approved for multiple sclerosis therapy. Until now, little has been known about the effects of FTY withdrawal regarding disease activity and development of tumefactive demyelinating lesions (TDLs), as already described in patients who discontinue natalizumab.

METHODS:

In this study we present the clinical and radiological findings of two patients who had a severe rebound after FTY withdrawal and compare these with patients identified by a PubMed data bank analysis using the search term 'fingolimod rebound'. In total, 10 patients, of whom three developed TDLs, are presented.

RESULTS:

Patients suffering from TDLs were free of clinical and radiological signs of disease activity under FTY therapy (100% versus 57%, compared with patients without TDLs) and had rebounds after a mean of 14.6 weeks (standard deviation 11.5) [patients without TDLs 11.7 (standard deviation 3.4)].

CONCLUSION:

We propose that a good therapeutic response to FTY might be predisposing for a severe rebound after withdrawal. Consequently, therapy switches should be planned carefully with a short therapy free interval.


Figure 1: From Gunduz et al. Note the relapses after cessation of fingolimod treatment.

In a rush to get therapies licensed, the collective 'we' have overlooked potentially devastating side effects of treatments, assimilating resistance by repetitive preeching. Can we ever get this right?

In this case, rebound of MS disease activity on treatment withdrawal, and in some cases the end result is worse than the original disease. Not only this, you are also then committed to buying into possibly life-long immunosuppression in order to avoid the possibility of rebound (and one with a "short therapy free interval"). En face, rebound doesn't sound as serious as say PML, but it can still result in great disability, even if your disability score states that you have progressive MS and may not benefit immunomodulatory treatment (see Figure 1)!

I've been pondering this for a while...

Both natalizumab and fingolimod are gating mechanisms; one holding back the immune system from entering the brain (natalizumab), the other sequestering them in lymph nodes (fingolimod). In the same way that there is flooding during extreme river flows, the release in the tight hold on the immune system leads to rebound. With fingolimod, animal data suggests that there is a rapid increase in the receptor number (sphingosine 1 phosphate) that is blocked by fingolimod on T cells after stopping treatment. This is then followed by an immediate efflux of self-reactive T cells from the lymph nodes that quickly enter the brain.

It may therefore not be wise to cycle from natalizumab to fingolimod, or to be on fingolimod for too long. The key may be to cycle through treatments over short periods, i.e. keep the immune system guessing. As far as I'm aware this has not been suggested before, and as such have no evidence to support this statement. But, we may in the future, start writing treatment plans for the next five years for PwMS if this is demonstrated to work!

Monday, 13 February 2017

#ClinicSpeak: opportunistic infections are to be expected on fingolimod

Opportunistic infections are to be expected on immunosuppressive therapies. #ClinicSpeak #MSBlog

The abstract below described a case of cryptococcal fungal infection of the skin in a pwMS on fingolimod. This is not a new observation. The latest summary of product characteristics for fingolimod includes cryptococcal fungal infection as an identifiable complication of fingolimod. The risk of fungal infection is very low, in fact it is rare, when you consider how many pwMS are on fingolimod worldwide (>180,000). The problem with fingolimod is that you can't derisk the drug. Almost all the opportunistic infections have occurred in pwMS who have a lymphocyte count above 200/mm3 (0.2 x 109/L) a level that is expected as part of the mode of action of the drug. Therefore you need to be vigilant on the drug and look-out for symptoms suggestive of infections and/or malignancies. Yes, the malignancies are a problem with fingolimod and all immunosuppressive therapies. The reporter malignancy with fingolimod is basal cell carcinoma of the skin; fingolimoders have at least double the risk of developing basal cell skin cancer compared to the general population.  

The title of this case report suggest they are the first to identify an opportunistic infection on fingolimod. If only the reviewed the literature they will have come up with many reports of cryptococcal infection, and other opportunistic infections, in pwMS. 


Carpenter et al. Cutaneous cryptococcosis in a patient taking fingolimod for multiple sclerosis: Here come the opportunistic infections? Mult Scler. 2017 Feb;23(2):297-299. doi: 10.1177/1352458516670732.

BACKGROUND: Fingolimod is an oral disease-modifying therapy for relapsing forms of multiple sclerosis, which acts by sequestering lymphocytes within lymph nodes.

OBJECTIVE: To describe a case of extrapulmonary cryptococcosis in a patient taking fingolimod.

METHODS: Case report.

RESULTS: A 47-year-old man developed a non-healing skin lesion approximately 16 months after starting treatment with fingolimod. Biopsy revealed cryptococcosis. Fingolimod was discontinued and the lesion resolved with antifungal therapy.

CONCLUSION: Despite few reported opportunistic infections in the pivotal clinical trials and first few years post-marketing, there has been a recent increase in reported AIDS-defining illnesses in patients taking fingolimod. Neurologists should be alert for opportunistic infections in their patients using this medication.

CoI: multiple

Sunday, 12 February 2017

#ResearchSpeak: restoring walking - stimulators vs. exoskeletons

Are exoskeletons the solution to MS-related walking impairment? #ResearchSpeak #MSBlog

The case study below describes a man with MS who lost the ability to walk, but with the clever use of implanted nerve stimulators they were able to restore his ability to walk. Use of nerve stimulation is only possible because MS is a disease of the central nervous system and leaves the so called peripheral nerves, or peripheral wiring, intact. This is why FES (functional electric nerve stimulation) works. The technique use here is invasive and expensive; it requires the implantation of electrodes and expensive hardware. I personally think this is not the solution to walking-related MS disability. In an ideal world we would want to prevent walking impairment from happening in the first place; we are trying to do that with our treat early and effectively (treat-2-target of NEDA with zero tolerance) paradigm. If this does work then we need a more pragmatic approach. I suspect this will end-up being the commercialisation of exoskeletons that have already been shown to work. At the moment they are too expensive for broad use, but as with all technologies the price will plummet with time. At the moment they are not available for pwMS under the NHS. 


If you are pwMS who is unable to walk or are finding it increasingly difficult to walk, would you use an exoskeleton or at least want to try one? 

Selkirk et al. Feasibility of Restoring Walking in Multiple Sclerosis with Multichannel Implanted Electrical Stimulation. Am J Phys Med Rehabil. 2017 Feb 1. doi: 10.1097/PHM.0000000000000692.

A patient with multiple sclerosis-related gait dysfunction was followed over the course of his disease. Despite aggressive treatment, he developed significant weakness in ankle dorsiflexors and hip and knee flexors and was no longer capable of consistently taking a step on his own. With electrical stimulation of hip and knee flexors and ankle dorsiflexors using implanted electrodes, he was able to consistently walk short distances as far as 30 m, thus significantly improving his Expanded Disability Status Scale score. This case study supports further exploration into the potential benefits of an implanted pulse generator to ameliorate gait dysfunction and improve quality of life for people with multiple sclerosis.

The Missing Data

Atacicept blocks BAFF and APRIL B cell growth factors and Makes MS Worse

Tabalumab (LY 2127399) is an anti-B-cell activating factor (BAFF) blocking (not APRIL) human monoclonal antibody designed for the treatment of autoimmune diseases and B cell malignancies.Tabalumab was developed by Eli Lilly and Company.

A phase III clinical trial for rheumatoid arthritis was halted in Feb 2013.In September 2014, a second phase III trial focussing on treating systemic lupus erythematosus, was terminated early as the study failed to meet its primary endpoint.

What happened in MS?

A Study of Patients With Relapsing Remitting Multiple NCT00882999 involving 245 people in 63 centres in USA and Europe.

They say the Study was Completed what happened?

Was it like atacicept and it made things worse? or did it not do nothing? It can't of worked or surely we would of heard.

Was it completed as said in June 2012 by the company or was it "Aborted" (the rest was written in German..does it mean completed) as linked to a comment by Norman Putzki (Biogen & Now Novartis).

FYI Qunitiles is a contract research organisation that monitors and co-ordinates trials
You sent a link to the Lily site that states

Lilly believes companies must act to earn the trust of the public they serve. To support this, Lilly supports responsible sharing of clinical study data and will continue to be an engaged partner in ongoing industry-wide discussions toward this goal.

Here are 7 ways in which we are committed to responsibly disclose our clinical trial data results for the benefit of patients and future research:

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. I GUESS UNFAVOURABLE OR IT WOULD BE TALKED ABOUT......WAS IT MARKETED?

Results from all Phase III clinical trials and any clinical trial results of significant medical importance are submitted for publication. 

We don’t just do this for medicines that have met their clinical goals and been approved for use – we also disclose results for investigational medicines whose development have been discontinued.

We register all Lilly-sponsored Phase II, Phase III and Phase IV clinical studies, conducted anywhere in the world, that were initiated on or after October 15, 2002, on www.clinicaltrials.gov.

Lilly also registers all Phase I clinical studies commencing on or after October 1, 2010 on www.clinicaltrials.gov.

Lilly, along with the industry as a whole, has started posting results to the European database www.clinicaltrialsregister.eu. Our first results were submitted on 21 July 2015. We are updating results for trials conducted in the EU on our marketed products back to trials from 2004. This is a 2 year process and will be completed in 2016.

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

This includes Lilly-sponsored Phase I clinical trials in patients that initiated on or after October 1, 2009 and Lilly-sponsored Phase I clinical trials in healthy volunteers that initiated on or after October 1, 2010.

We have an online portal to facilitate requests from legitimate researchers for clinical trial data here:www.clinicalstudydatarequest.com

HAD A GO ON THIS 
Enquiry 1683 - Tabalumab (LY2127399) in multiple sclerosis - Feasibility of providing data from studies of interest

Lilly is sharing data from clinical and interventional studies in patients for medicines and indications approved in the United States and the European Union. This study is not in scope for data sharing as tabalumab has not been approved as a treatment for any indication.
Kind Regards,
Data Sharing Team


*****************************************************************************
So went direct-Response
I received your request for the anonymized tabalumab data, and your request was discussed with a number of my Lilly colleagues. At this time, we have decided not to support the proposal. Please feel free to reach out to me if you have any questions.

Senior Medical Director, Biomedicines Core Team
Eli Lilly and Company


************************************************
245 people were reported to be involved in this trial. 

Don't they deserve to know what has happened?

There are over 60 sites across Europe and USA, somebody knows if it did nothing (maybe APRIL is what we need to focus on) or WORSE (then its BAFF).

I've reached out again



Measuring Progression...Does it bode well for the future?

Kuhle J, Nourbakhsh B, Grant D, Morant S, Barro C, Yaldizli Ö, Pelletier D, Giovannoni G, Waubant E, Gnanapavan S.Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology.  pii: 10.1212/WNL.0000000000003653.

OBJECTIVE:To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.
METHODS:Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.
RESULTS:Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both).
CONCLUSIONS:Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity.

This is some work by NeuroDocG, but she won't report on it because she thinks she will be accussed of blowing her own trumpet.  So modest:-)

So, I do it. 

I would have to say this paper is disappointing :-)

So NDG should blow her own trumpet because she knows best what it means. 

Furthermore NDG would not pick the points I am about to discuss as a highlight or should I say Lowlight of the work.

Does it tell us that beta interferon saves nerves.

However, why is it disappointing, it is disappointing because it implies that riluzole is a drug that won't work to stop nerve loss. 

Riluzole is a drug that is a sodium channel blocker and a glutamate receptor blocker, so it should be neuroprotective, and block neurofilament release. This study implies that it does not do anything over and above what beta interferon may or may not do. 
This is because with time the neurofilament levels went down. 

Is this a treatment effect? or was it because people entered the trial when they were worse? 

But it says that if you have evidence of disease activity such as lesions then this is associated with damage as we would expect for the inflammatory penumbra.

So the claim that metabolites of tryptophan is the first biomarker of disease worsening, if a bit of a porkie pie. This is yet more evidence that neurofilament can pick up stuff.

However, what NDG would not say is that this study suggests that MS SMART may not be so smart, as this study suggests that it may not work in the secondary progressive trial.

MS SMART is a trial of 3 drugs against one placebo. The original aim was to replace the losers with new drugs in an adaptive design but has the process picked Donkeys and not Racehorses? 

We have no idea what fluoxetine does and how it may work....but it's prozac and an serotonin re-uptake inhibitor and so should at least make people less depressed, but a Dutch trial has failed to show it modifies progressive study since MS SMART started. 

More recently my favourite horse of the trio was reported to failed to inhibit optic neuritis and perhaps made myelination worse. The failing in optic neuritis should have been predicted because drug was started too late to be really useful. But the potential affect on myelination and the extra weeing that this drug may cause, could be disappointing.

We won't have too long to find out as MS SMART is now finishing.

So will MS SMART produce anything? 

I hope it does. The biology is there to support some value 

It will be disappointing if it doesn't. 

But if it doesn't,  

What would it say about the meta analysis to find the neuroprotective drugs? 
(Using Bog-standard EAE experiments to determine Neuroprotective (or repair drugs) is probably a waste of time). 
There is is masive publication bias for positive results and the data is often done in such a way as to make understanding the result in-intelligable. To find neuroprotectives I would look in the stroke and neurodegenerative disease literature.

What would it say about trial design? 
(Neuros killing off basic science ideas again)

or is the idea? 

Oh course I am playing Devil's Advocate...and there are explanations, why the big-SMART-three have not produced the goods in the studies I mentioned.

I'll get a good telling off by NDG next week:-)

Saturday, 11 February 2017

Atacicept Why didn't it work

So to End B memory Cell week (my posts will reduce)

It is all well and dandy coming up with an idea when everything goes the same way, but what happens when things make MS worse  what can this tell us.

Read the paper


http://www.ebiomedicine.com/article/S2352-3964(17)30045-2/pdf

We mentioned the paper


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

We should not forget


Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, Lamarine M, Hyvert Y, Freudensprung U, Plitz T, van Beek J; ATAMS Study Group. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial.
Lancet Neurol. 2014; 13:353-63


BACKGROUND: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production.
METHODS: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT).
FINDINGS: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group
INTERPRETATION: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted.



Top Left. Mature B cells drop after atacicept. Bottom left IgG levels drop after atacicept in MS. Middle-Memory B cells increase in mice given atacicept-like molecule (TACI-Ig). Right top Blockade of BAFF with antibody increase memory B cells but decrease mature and plasma cells in arthritis

Here, the idea was to block B cell growth factors (BAFF), using a fusion protein of a type of BAFF receptor fused to an antibody (atacicept), and indeed that what is does. It makes naive also known as mature B cells go down and it also kills plasma cells and so immunoglobulin levels go down, but memory B cells go up. MS gets worse. 

So is this a T cell- mediated disease? or 

Does it really tells us that it is the memory B cell?

So for the relapsing disease it does not appear to be the plasma cell or mature B cell as a problem.

Another way to do the same thing is to block B cell activating factor (BAFF) with an antibody. The example in the graph you can see Belimumab in arthritis. As you can see mature (naive) and plasma cells go down memory B cells go up. 

I don't think this was used in MS but another study used another antibody to the same target. This was done by Lilly.

The trial was claim to be completed and presumed failed as it was never reported but there is a suggestion it was terminated...this would suggest worsening, but as it was in development in Lupus at the time is this a reason to keep quiet?

I requested and was refused access to the data by the Lilly Team.
Maybe someone from Lilly or someone with influence can ask them to share data as it speaks to safety.
 
So is MS a T cell disease?..You decide


or would you want your therapies to deplete memory B cells? 

Time to get more data to support or refute the idea!