Friday, 30 June 2017

What's Torsades?

If you read the post below you may, like I, ask what is Torsades de pointes,  We know that fingolimod can cause heart arrhythmias on first dose. Torsades de pointes is another heart problem


Torsades de pointes or torsade depointes (TdP or simply torsade(s)) translated as "twisting of the points"), is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm.



Action potential of cardiac muscles can be broken down into five phases:
  • Phase 4: Exciting triggers (e.g. sinus node) will cause minor depolarization in the cells; this will result in increasing permeability of sodium channels, which trigger the opening of sodium channels.
  • Phase 0: Sodium channels open, resulting in the entrance of Na+ into the cells; this results in the depolarization of the cardiac muscles.
  • Phase 1: Sodium channels close; this stops depolarization. Potassium channels open, leading to an outward current of K+ out of the cells.
  • Phase 2: Potassium channels remain open (outward current of K+), and calcium channels now also open (inward current of Ca++), resulting in a plateau state.
  • Phase 3: Calcium channels close (inward Ca++ stops), but potassium channels are still open (outward K+ current); this persists until the cells gain back normal polarization (depolarization achieved). Please note that phase 0 lead to a net gain of Na+, while phases 1-3 lead to a net loss of K+. This imbalance is corrected by the Na+/K+-ATPase channel that pumps K+ into the cell and sodium out of the cell; this does not change polarization of the cells, but does restore ionic contents to its initial state.
Repolarization of the cardiomyocytes occurs in phases 1-3, and is caused predominantly by the outward movement of potassium ions. In Torsades de pointes, however, the repolarization is prolonged; this can be due to electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia), bradycardia, certain drugs (disopyramide, sotalol, amiodarone, amitriptyline, chlorpromazine, erythromycin) and/or congenital syndromes (LQT1-LQT4 gene defect).
The prolongation of repolarisation may result in subsequent activation of an inward depolarisation current, known as an early after-depolarisation, which may promote triggered activity.Re-entry, due to a dispersion of refractory periods, is also possible; this is because M Cells (found in the mid myocardial layer) show a more prolonged repolarization phase in response to potassium blockage than other cells. In turn, this produces a zone of functional refractoriness (inability to depolarize) in the mid myocardial layer. When new action potential is generated, the mid myocardial layer will remain in a refractory period, but the surrounding tissue will depolarize. As soon as the mid myocardial layer is no longer in a refractory period, excitation from nearby tissue will cause a retrograde current and a reentry circuit that will result in a positive chronotropic cycle, leading to tachycardia.

Most episodes will revert spontaneously to a normal sinus rhythm. If this does not occur, however, possible adverse outcomes include palpitations, dizziness, lightheadedness (during shorter episodes), fainting (during longer episodes), and sudden cardiac death.

#GuestPost & #NeuroSpeak: fingolimod and azole antifungals

If you are on fingolimod be careful about taking antifungal drugs; they may interact with each other #GuestPost #NeuroSpeak

I don't normally post unsolicited guest-posts on this blog. However, the author of the following Facebook post convinced me that what she had to say was important enough for me to reconsider this position and repost verbatim what she sent me. The latter information is relevant all HCPs and pwMS who are on fingolimod and concerns a drug-drug interaction between fingolimod and a class of antifungal drugs called the azoles. What worries me about this is that I have recently recommended ketoconazole to a patient of mine with a fungal skin infection who was on fingolimod. 


Her email to me: 

Dear Gavin

I am writing to you because I recently discovered from Novartis that there is a risk of torsade de points when combining Azole antifungals with Gilenya that is neither mentioned in the prescribing info in the Gilenya packet (at least not in Switzerland) nor in the database most commonly used by Swiss doctors and pharmacists, and not very concretely in the EMA prescribing info. In case this is of any interest to you at all, I include the story that I have posted in the facebook group on Gilenya I co-moderate below.

The Novartis person apparently said to my pharmacist that they would consider including the warning in the prescribing info in the future. I hope they will because I heard from my gynecologist, who prescribed the Fluconazol, that this is a commonly used antifungal, for example for women with persistent yeast infections. So I find it quite worrying that this warning, which Novartis passed on so easily and willingly to my pharmacist, is not easily accessible by other patients and doctors.

Kind regards,


******


Guest Post

Warning: Concurrent use of FINGOLIMOD and FLUCONAZOLE may result in increased risk of QT interval prolongation and torsade de pointes (“ a specific type of abnormal heart rhythm that can lead to sudden cardiac death.” from: https://en.wikipedia.org/wiki/Torsa...

The European Medicines Agency (equivalent of the FDA in the US) states in the Gilenya prescribing info http://www.ema.europa.eu/docs/en_GB... (p. 7, read 30 June 2017): “ Pharmacokinetic interactions of other substances on fingolimod Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to its metabolism. Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC). Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).”

I was recently prescribed 1 tablet of an antifungal called Fluconazole by a doctor (not my gp or neuro). Because I remembered the warning from the European prescribing info, I had a look at the prescribing info in my G packet. Surprisingly, it did not mention any such thing. I brought up the question at the pharmacy when I went to pick up the medication and they got in contact with Novartis to find out more. The medical affairs officer at Novartis provided the following excerpt from micromedexsolutions.com:

Warning: Concurrent use of FINGOLIMOD and FLUCONAZOLE may result in increased risk of QT interval prolongation and torsade de pointes.

Clinical Management: Concomitant use of fingolimod and fluconazole may result in an increased risk of QT interval prolongation and torsade de pointes (Prod Info GILENYA(TM) oral capsules, 2012; Prod Info DIFLUCAN® IV injection oral suspension tablets, 2011). If coadministration is necessary, observe fluconazole-treated patients with continuous ECG monitoring overnight in a medical facility when initiating fingolimod therapy (Prod Info GILENYA(TM) oral capsules, 2012).

Onset: Not Specified

Severity: Major

Documentation: Fair

Probable Mechanism: additive QT interval prolonging effects

Summary: Fingolimod and fluconazole have been associated with an increased risk of QT interval prolongation (Prod Info GILENYA(TM) oral capsules, 2012; Prod Info DIFLUCAN® IV injection oral suspension tablets, 2011), and torsade de pointes (Prod Info DIFLUCAN® IV injection oral suspension tablets, 2011). Initiating fingolimod therapy may decrease heart rate and prolong the QT interval (Prod Info GILENYA(TM) oral capsules, 2012). Drugs that prolong the QT interval, such as fluconazole, may increase the risk of torsade de pointes in patients with bradycardia. Therefore, observe fluconazole-treated patients with continuous ECG monitoring overnight in a medical facility when initiating fingolimod therapy (Prod Info GILENYA(TM) oral capsules, 2012).

Reference(s): Product Information: DIFLUCAN(R) IV injection oral suspension tablets, fluconazole IV injection oral suspension tablets. Roerig (per FDA), New York, NY, Nov, 2011.
Product Information: GILENYA(TM) oral capsules, fingolimod oral capsules. Novartis Pharmaceuticals Corporation (Per Manufacturer), East Hanover , NJ, Apr, 2012.

A similar warning can be found here http://www.webmd.com/drugs/2/drug-1...
The medical affairs officer mentioned to the pharmacy that they would now consider re-introducing the warning in the prescribing info included in the G packet in my country.

CoI: multiple

Liver problem after generic glatiramer acetate: Cop Wars

Sabatino JJ Jr, Mehta NJ, Kakar S, Zamvil SS, Cree BAC. Acute liver injury in a Glatopa-treated patient with MS. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 5;4(4):e368.

Recently ProfG reported on a case of liver problems after daclizumab. This has happened after treatment with CRAB drugs and this is a case report of a new generic copaxone. It was reported that there the problem occurred after a few injections. So if you are using the generic version please be vigilant. 

Teva has been trying to argue that their random mix of amino acids is different (even batches made by Teva are different) from others random mixes, adding to the issues of the Cop Wars. 

As this is the World's leading MS drug in terms of Sales, it is not surprising that other manufacturers want a slice of the pie. No wonder there are so many court cases with the generics companies,

Just think for every few months that production of the generics and sales are held up due to legal actions, how much is made on the sales. 6 months = $2 billion so bung a few million to patent lawyers is good business.


I think it shows safety and ease of monitoring for the neurologist, tops it over higher efficacy.

This event has been reported in the original glatiramer acetate but occurs rarely. Since approval, over 300 cases of Copaxone-associated liver-related abnormalities were reported to the United States Food and Drug Administration (US-FDA). I am sure if there are more we will hear of them

CoI: Some of authors have received funding in numerous ways from Teva...however their patients were using competitor drug

#ThinkHand: can we afford to ignore the importance of hand function to pwMS?

Our #ThinkHand campaign may yet prove useful in making the case for using ocrelizumab to treat PPMS

You may remember our ECTRIMS 2016 #ThinkHand campaign and our handmade cardboard poster, helium balloons and T-shirts.


DrM&M in front of our poster; please note the helium balloons! 




What is important is the results of the survey that clearly shows how important hand function is for people with MS. The campaign was triggered by the results of the ASCEND, or natalizumab in SPMS, trial results and now the ORATORIO, ocrelizumab in PPMS, trial results. However, the literature is strewn with results showing DMTs work better on upper limb compared to lower limb function. It is therefore important to get the message across to regulators and the wider community so that they will invest in trials in people with more advanced MS, including wheelchair users, with the primary outcome being the 9-HPT.

 

The #ThinkHand campaign has become very relevant in relation to our latest campaign to make sure pwPPMS get access to ocrelizumab and to make the case for funding a trial in more advanced MS. 


If you agree with our latest campaign can you please complete the survey below. Thank you.


CoI: multiple. Design, testing and manufacturing of the cardboard 9-HPT and the running of our #ThinkHand stand at ECTRIMS was kindly funded by an unrestricted educational grant from Biogen, UK.

Thursday, 29 June 2017

#ThinkHand: people with PPMS need your help?

We need your help to raise awareness about hand function in MS #ThinkHand

In the last few days I have become increasingly anxious about the regulators, payers and healthcare professional letting down pwPPMS. Despite having the first positive trial of a DMT in PPMS there are many hurdles to overcome to get ocrelizumab to the people who need it, i.e. people with active PPMS.

It seems as if the wider community are fixated with the impact of ocrelizumab on lower limb function, i.e. compared to placebo it reduced EDSS progression and worsening of the Timed-25-Foot by ~25%. However, the elephant in the room is its impact on hand and arm function. In the ORATORIO study ocrelizumab reduced worsening of the 9-hole peg test by 45%, almost double the impact on lower limb function. These findings are entirely compatible with our length-dependent axonopathy hypothesis. In other words systems with shorter axons and more reserve will respond better to anti-inflammatory DMTs and in a shorter period of time. The upper limb findings of ocrelizumab are so important that I have asked Roche to seriously consider doing a trial in more advanced MS, including people in wheelchairs, to see if ocrelizumab can address this massive unmet need. Other surveys done as part of our #ThinkHand campaign have highlighted the importance of hand function for pwMS. When people lose the ability to walk their arms and hands become their legs and upper limb function keeps them independent. 


The consequences for pwPPMS being denied access to the first licensed therapy cannot be underestimated. So if you care about this issue, and if you care about protecting upper limb function in pwPPMS, can you please complete the survey below. Thank you.



CoI: multiple

My drug is better than low hanging fruit. Rituximab better than CRAB

Spelman T, Frisell T, Piehl F, Hillert J.Comparative effectiveness of rituximab relative to IFN-β or glatiramer acetate in relapsing-remitting MS from the Swedish MS registry. Mult Scler. 2017 Jun 1:1352458517713668.

OBJECTIVE:To compare treatment effectiveness and persistence in relapsing-remitting multiple sclerosis patients who initiated rituximab versus glatiramer acetate (GA) or interferon-beta (IFN-β).
METHODS:A total of 461 patients from the Swedish MS registry in the rituximab arm were propensity score matched on a 1:2 basis with 922 patients from the IFN-β/GA comparator, between April 2005 and November 2015. Annualised relapse rate (ARR) was compared using the Poisson method. A marginal Cox model was used to analyse time to first relapse, 3-month confirmed disability progression and treatment discontinuation in the matched sample. A signed-rank test was used to compare Expanded Disability Status Scale (EDSS) change from baseline.
RESULTS:Rituximab was associated with a reduction in ARR (0.003; 95% confidence interval (CI) = 0.001, 0.009) relative to IFN-β/GA (0.026; 95% CI = 0.020, 0.033) ( p < 0.001). Rituximab was associated with an 87% reduction in the relapse rate (hazard ratio (HR) = 0.13; 95% CI = 0.04, 0.41) and an 85% reduction in the discontinuation rate (HR = 0.15; 95% CI = 0.11, 0.20) relative to IFN-β/GA. EDSS regression from baseline was greater in the 

rituximab group at 12 and 24 months.
CONCLUSION:Rituximab appears to be superior to first-generation disease-modifying treatments (DMTs) with respect to relapse control and tolerability, whereas superiority on disability outcomes is less clear.


I tear my hair out when a DMT is tested against a placebo, meaning in this day and age it is oK to give someone nothing, when you have nearly twenty active treatments. 

The next worse thing is that you test your agent against placebo-plus. 

No disrespect to people taking beta interferon or copaxone as they are the Worlds most popular treatments, but we know their level of efficacy. It is not high and to test rituximab against beta interferon or copaxone is a non-contest. 

Howeve,r it may lose if we look at the  side -effects  as the outcome as the CRAB drugs are well tolerated

We can do an off-label assessment against a CRAB, but why not do the rituximab against fingolimod, or alemtuzumab and give the drug a run for its money.

The ethics committees/funders need to get some jajce (eggs) to stop these practice of placebo controlled relapsing MS trials. I know it makes it easier to get a result  

However, if this particular case it was not a trial of one verses the other it was assessing in real life. For every one rituximab pwMS they selected to control it with 2 people taking CRAB

Wednesday, 28 June 2017

#ClinicSpeak & #PoliticalSpeak: why should people with primary progressive MS be treated as 2nd-class citizens?

Will pwPPMS be forced to pay for ocrelizumab privately? #ClinicSpeak #PoliticalSpeak

My blog post yesterday regarding equitable access to healthcare and HSCT generated some lively discussion. One reader asked: 'Any idea when ocrelizumab will be available in Europe for PPMS? It isn't fair that the FDA has approved the drug and we are still waiting and losing brain'. Interestingly, I was asked the same question at the EAN meeting after one of my talks and one of the Roche delegates at the meeting was able to answer the question for me and said it will be available soon.

Even if it ocrelizumab gets licensed 'soon' there will still be many hurdles to get over before it can be used in clinical practice. In the UK it will need to go via NICE and then it has to be vetted by NHS England. I have major concerns that the cost-effective model that will be used for PPMS will not be the same as RRMS, where the comparator is current DMTs and the model is based on incremental costs. For PPMS ocrelizumab will be compared to best supportive care. I therefore anticipate ocrelizumab being available for PPMS in other countries and not the UK. The latter worries me even more; why should English patients be disadvantaged? This discussion also raises the possibility of the worst case scenario, i.e. the EMA deciding not to license ocrelizumab for PPMS. What will happen then? This will mean the the product will be on the market for RRMS and pwPPMS who can afford to pay for it; i.e. the wealthy will get ocrelizumab privately and those who can't afford to pay for it won't be treated. The latter already happens in the NHS with some of the high-cost cancer drugs that have not been NICE-approved. Most HCPs, patients and even politicians find this sort of healthcare inequity abhorrent. This is why the NHS and other socialist healthcare systems are meant to exist; to stop a healthcare lottery based on wealth. 



One of my patients with PPMS who was in the fingolimod PPMS trial has already said to me he can't wait any longer. He asked me about starting rituximab and paying for it privately. He had no idea of the cost of rituximab and so we are now having to explore the possibility of using off-label cladribine. The use of cladribine for the treatment of PPMS is not really backed-up with much data, is really a shot in the dark and is based on the scientific principle that suppressing inflammation will help. 

I have also recently become aware that Roche may be launching a compassionate early access programme for PPMS, which is something I will explore for him and other patients in a similar situation. 

What do you think we should do to make sure pwPPMS get access to ocrelizumab ASAP? Can you please complete the following survey to explore some ideas. If you have any suggestions please don't hesitate to contact me. 


CoI: multiple

Blocking NOGO to make nerves

Ineichen BV, Kapitza S, Bleul C, Good N, Plattner PS, Seyedsadr MS, Kaiser J, Schneider MP, Zörner B, Martin R, Linnebank M, Schwab ME.Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology.
Acta Neuropathol. 2017 doi: 10.1007/s00401-017-1745-3


Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution

You may have heard of LINGO-1 which is the target for remyelination that has been tried in MS by Biogen. This is related to NOGO (it was a no go signal, i.e. stop signal for nerve grow in the central nervous system). Block it and nerves grow). NOGO is also known as reticulon 4

NOGO variants are derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. There are three variants: Nogo A, B and C. Nogo-A has two known inhibitory bits including amino-Nogo, at the beginning of the molecule and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in  destruction of  the growth cone from where nerves grow.

LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex.The Nogo receptor complex is formed when Nogo-66 binds to its receptor. LINGO-1 is an essential negative regulator of myelination. It has been implicated in the inhibition of axon regeneration through a ternary complex formed with NgR1/Nogo-66 (ligand-binding subunit) and p75 (signal transducing subunit). NgR1 relies on its co-receptors for transmembrane signalling.The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this receptor complex. 
The inhibitory action is achieved through RhoA-GTP upregulation in response to the presence of MOG, MAG or Nogo-66 in the central nervous system. LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination, by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1.

This paper reports that if you block NOGO-A it can have two effects it supports a nerve sprouting effect and it can speed up remyelination. This is great 

However now to burst the bubble abit. "Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis".

This study shows what I was saying on saturday about trials in progressive MS. It says that if you do not have a trial system that can detect change than it doesn't matter what your drug does, it won't work.

The suggestion that blocking NOGO is new is not true. It was thought about long before anti-LINGO was thought about as NOGO was discovered first,


Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, Murray BM, Barres B, Tessier-Lavigne M, Bernard CC. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci. 2004;7(7):736-44. 

This paper intimates that blockade of NOGO-A can affect the disease course of EAE, we looked at this in EAE in ABH over a decade ago and it did absolutely nothing...why would it the disease episode in EAE has little to do with nerve loss or demyelination it is inflammatory. 

(Why did we not publish this? it was company sponsored and one experiment does not make a paper). 

Anyway, others also eventually reported it was not much or an immune modulator.

Litwak SA, Payne NL, Campanale N, Ozturk E, Lee JY, Petratos S, Siatskas C, Bakhuraysah M, Bernard CC. Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis. PLoS One. 2013;8(12):e82101

So back to the current paper the authors are spinal injury people and so they do their work to show sprouting and so the trial is fit for purpose but if you do EAE a 2-3 week EAE experiment you are looking at three things at once where the immune arm dominates so it is not the right stage of the model to look for repair. So bad trial  design means drug fails.

Away use in spinal injury would be system to test this out. Where is anti-NOGO in development?

Now the real problem anti-LINGO shows us that 99.9% of your drug never gets to the target meaning you load up you subjects with loads of protein, meaning placebo of nothing is flawed. You need a chemical not an antibody.

If blocking the NOGO receptor is going to work wonders, why did this not occur in the anti-LINGO trials in MS? This is because anti-LINGO works on the same cascade and also promotes sprouting in animal models. So let's be realistic. Will anti-NOGO get developed in MS, I think the patent life must be about dead and companies would have done it years ago it they thought it was a winner.

The NOGO system was evolved because it was advantageous not to regrow nerves in the central nervous system. What will be the consequences of blocking the biology? 

I guess you will not have to wait to find out nerve re-growth is being investigated.....but that's another story 

#NewsSpeak: do you want to make a difference?

Do you want to make a difference to world of MS? #NewsSpeak #OffLabel

One of our long running campaigns has been trying to promote access to treatments for pwMS in resource poor environments. For the last 2 years we have been promoting an Essential #OffLabel list of DMTs for resource poor settings. The MS International Federation (MSIF), who represents MS Societies from all over the world, are helping us with this campaign, for example they gave me a platform at their annual CEOs meeting last year to present our campaign.  

The MSIF are now trying to recruit a Head of Research and Access who will lead on the search for improved understanding and treatments for MS and better access to treatments and healthcare. This is global role. So if you are passionate about research, care deeply about MS and feel you have the skills then this may be the job for you. On the plus side it is based in central London; probably the most skilled-up, creative and dynamic city in the world. 


Tuesday, 27 June 2017

Staggeringly profitable business of Science publishing

If you are interested in the publishing process you may want to read this. We have been telling you about the publication process and this article adds to the madness. 

Is the staggeringly profitable business of scientific publishing bad for science? by Stephen Buranyi CLICK Here


In addition to this, the Open access system has turned it all into a bottomless sink. Will it change....not whilst you have things like the REF and Impact factors driving people to publish in these journals. 

The journals have preyed on this so the high impact popular journals have all created open access pay to publish sister journals so when they reject papers they feed them into to the pay to publish journals. 

This has created an open access industry of tripe journals desperate for content......and your cash

Like the saps and Lemmings that we are we have bought into this.
However it is adding millions to the research budget that could be better spent eleswhere.

#EAN2017 & #ClinicSpeak: immune reconstitution therapies

Should access to healthcare, for example HSCT, be equitable? #EAN2017 #ClinicSpeak

As promised the following is my presentation from the Excemed MS Symposium held on Sunday night at the EAN in Amsterdam. I had feedback from several people about how appealing selective immune system depletion followed by reconstitution is as a a treatment strategy for MS. However, the efficacy of all of our licensed DMTs remain a long way off that of what is being reported with HSCT. 

Giovanni Mancardi gave a wonderful meta-analysis in the session on the result of AHSCT and how the safety profile has improved. The most recent mortality is less than 0.3%, i.e. less than 3 in a 1,000 treated patients. I am therefore not surprised that a lot of pwMS who are not concerned about the risks associated AHSCT are frustrated about the lack of access to it as a treatment option. I really hope the NIHR will fund a AHSCT trial in the UK. We need randomised controlled data for AHSCT to become routine; otherwise it will remain a lottery with some pwMS being able to access AHSCT whilst others not being able to access AHSCT. The latter brings up the ethical dilemma about whether of not access to healthcare should be equitable. 


CoI: multiple

Blood NFL as marker of no evidence of disease activity with fingolimod

Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod


Fredrik Piehl, Ingrid Kockum, Mohsen Khademi, Kaj Blennow, Jan Lycke, Henrik Zetterberg, Tomas Olsson

Multiple Sclerosis Journal, First Published 19 Jun 2017.doi: 10.1177/1352458517715132

Abstract

Background:
Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS).

Objective:
To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod.

Methods:
A first cohort consisted of MS patients (n = 39) and neurological disease controls (n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort (n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL).

Results:
Mean NFL pg/mL (standard deviation (SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated (n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod (n = 243), mean NFL pg/mL (SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10−6), and levels remained stable at 24 months (13.2 (6.2)).

Conclusion:
NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.

Yesterday, I spoke at the European Academy of Neurology (EAN) Congress 2017 in Amsterdam about the utility of neurofilament analysis in neurological disorders. My point was to get across to the audience that neurofilaments as a biomarker was here to stay, but also to make it known that as far as MS management is concerned the goal post is shifting. We are looking to a future in which long-term remission (tantamount to a cure) is achievable, and not simply a woefully inadequate hype that recedes at the end of a conference. So how do the current biological fare in slowing down nerve loss?
I know of two therapies that have already demonstrated this; natalizumab (Tysabri) and fingolimod in the cerebrospinal fluid (CSF). Here the authors present more work on fingolimod, but this time looking at blood neurofilament levels (serum/plasma). The question is whether we are able to substitute blood neurofilament measures effectively for CSF neurofilament measures?
When reading through this paper, a couple of things stand out: 1) the levels in the CSF are ~100-fold higher in the CSF than in the blood, whether it be in PwMS or in controls; 2) the relative ratio's of difference between PwMS and controls in the CSF and blood is ~4 and ~2, respectively based on mean results. In a nutshell, there is more room to detect real changes in neurofilament levels in the CSF than in blood. Well big deal you say, but it matters. Maybe not in a clinical trial with 100+ participants, but at an individual level. If I'm a clinician strongly considering using this test in practice, I'll want to know these relative numbers as I may be basing treatment decisions on these numbers. Interestingly, another group (Disanto et al. JNNP 2016; 87:126-129) previously reported a three fold difference between CIS subjects and controls in serum neurofilaments, but using a different platform (mesoscale, as opposed to Simova used in this study). Maybe a more sensitive method is not all that its cracked up to be?!
All is not lost, as far as swapping from interferons or copaxone to fingolimod there appears to be a significant drop in blood NfL levels at 12 months, which is sustained at 24 months (see figure below). Not all subjects demonstrated a reduction in NfL levels after switching to fingolimod, 49 demonstrated a rise in NFL levels. They tended to be older (see figure below) and had a higher age of onset of disease among other factors. 

There are a lot of archived samples sitting in freezers around the world from clinical trials, now may be the time to start analysing them...I say London is open!

Figure: (a) NfL levels in those switching from injectables to fingolimod sampled at time 0, 12 and 24 months. Mean NfL levels reduced by 34% at 12 months; (b) blood NfL levels correlate with age.

Monday, 26 June 2017

Questions for today's Symposium

ProfG is at the European Neurology Meeting in Amsterdam.

Today, there is a SANOFI GENZYME Satellite Symposium: From clinical data to real world experience – similar results, similar benefits for multiple sclerosis patients?

I guess MS CARE extension data will be presented. The message will be alemtuzumab is a very good drug.

The bad news will be that the proportion of people with secondary autoimmunities from the trials, about 20% will have dramatically increased to about 50%.

Here is the programme

Chairperson 
Rogier Q. Hintzen, Rotterdam, The Netherlands

Welcome and Introduction. Rogier Q. Hintzen, Rotterdam, The Netherlands

Mechanism of Action:New Insights into Immunomodulation
Luisa Klotz, , Germany

From Phase 3 controlled trials to extension trials: What do the data tell us? Celia Oreja-Guevara, Madrid, Spain

Daily practice: How does real world evidence reflect clinical data? Tjalf Ziemssen, Dresden, Germany (lead author of ECTRIMS abstract-2013 on binding and neutralizing antibody responses).

Q & A:Rogier Q. Hintzen, Rotterdam, The Netherlands

We can see there is a Q & A session which is great. 

If you are there scratching you head seeking a question, maybe you can ask a few questions.

I wonder what are the new insights? Weren't they publish last week:-)? http://jamanetwork.com/journals/jamaneurology/article-abstract/2630681

What is the mechanism?
Wonder if memory B cells will get a mention? Give us a tweet.

If they don't here's a few questions for the Q&A.

Q. Why do you think MS is a CD4 Th17 T cell mediated disease given that treatments targeting CD4 T cells have typically failed in MS?

Q. Why do you think there is an increase in Treg T cells when their absolute numbers are decreased by over 80%?

Q. Why are you not associating Tregs influences as a major influence on B cell autoimmunities?

Q. Do you think memory B cells are involved in the action of alemtuzumab?

I will guess. Most people don't get a third course, few got 3 or fewer get 4 courses of drug. This indeed impressive.

I guess this is not mentioned that most people develop binding and neutralizing antibodies, which they must do given the levels at cycles one and two (about 80%).

Q. How many people develop binding and neutralizing antibodies on cycle 3 and cycle 4? 
Q. At 12 months after last infusion how many people have persistent anti-drug antibodies and do they affect depletion.

Q. What is the proportion of people who stop depleting or what is the proportion of people who only partially deplete? We already known at the population level there is depletion (Kousin-Ezewu et al. 2014) but at the individual level, are there people who neutralise the alemtuzumab response.
Q. If there are, what is the titre of neutralizing antibodies associated with lack of efficacy.
Q. Are their any non-depleters.
Q. Is there any difference in anaphylaxis/anaphylactoid reactions after third or forth infusion given that most people make binding antibodies and over 70% of people have persistent anti-drug antibodies. Does this relate to pre-existing titres of alemtuzumab binding antibodies?
I suspect if you ask these questions there may be some blank looks .
COI None relevant

More fingolimod rebounds

Forci B, Mariottini A, Mechi C, Massacesi L, Repice A. Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports. Mult Scler Relat Disord. 2017 Jul;15:24-26.
BACKGROUND:
Severe multiple sclerosis reactivation following second line treatment withdrawal, defined "rebound syndrome", is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described.
CASE PRESENTATION: We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment.
CONCLUSIONS: Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome.
When you start treatment you have to consider how you stop treatment if it is not working for you and importantly you need to think about how you transition from a migration inhibitor. These would be natalizumab and fingolimod. We have had a lot of discussion about switching off fingolimod but this is about fingolimod. This is yet another example of an attack shortly after stopping  fingolimod.  So it is important you discuss how disease activation is going to be minimized before you stop fingolimod

Sunday, 25 June 2017

The Burden of Multiple Sclerosis

This study examines the cost of MS in different European Countries if you go East the amount spent on people with MS is lower. However you can see that the costs are not harmonised across Europe. 

In the UK the cost is low. Is this because of efficiency or are we near the bottom of the pile (yes you could add about 10-20%  to get a fairer view, because I used todays exchange rates).

Switzerland is out in front on the amount it spends

Multiple et al. New insights into the burden and costs of multiple sclerosis in Europe Mult Scler. 2017 Aug;23(2_suppl):4-216

BACKGROUND:To assess the value of management strategies in multiple sclerosis (MS), outcome data have to be combined with cost data. This requires that cost data be regularly updated.

OBJECTIVE AND METHODS: This study is a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity and health-related quality of life (HRQoL). Descriptive analyses are presented by level of severity; costs are estimated in the societal perspective, in 2015

A total of 208 patients (mean age: 38.5 years) participated in the Russian study; 97% were below retirement age, and of these, 49% were employed. MS was reported to affect productivity at work in 63% of patients. Overall, 87% and 41% of patients felt that fatigue and cognition were a problem. The mean utility and costs were 0.769 and 578,000 RUB at Expanded Disability Status Scale (EDSS) 0-3, 0.509 and 826,000 RUB (€12,407) at EDSS 4-6.5, and 0.071 and 1,013,000 RUB (€15,214) at EDSS 7-9. The average cost of a relapse was 33,000 RUB (€496) 

A total of 747 patients (mean age 47 years) participated in the Czech Republic; 86% were below retirement age and of these, 49% were employed. Employment was related to disease severity, and MS affected productivity at work for 82% of those working. Overall, 92% and 66% of patients experienced fatigue and cognitive difficulties as a problem. Mean utility and annual costs were 0.832 and 257,000CZK (€9,776) at Expanded Disability Status Scale (EDSS) 0-3, 0.530 and 425,500CZK (€16,183) at EDSS 4-6.5 and 0.141 and 489,000CZK (€18,606) at EDSS 7-9. The average cost of a relapse was estimated at 12,600CZK (€480)
A total of 521 patients (mean age 47 years) participated in Hungary; 85% were below retirement age, and of these, 47% were employed. Employment was related to disability and MS affected productivity at work for 82% of those working. Overall, 94% and 66% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and annual costs were 0.691 and 3,432,000HUF (€11,0680) at Expanded Disability Status Scale (EDSS) 0-3, 0.491 and 5,262,000HUF (€16,970) at EDSS 4-6.5 and 0.076 and 6,235,000HUF (€20,108) at EDSS 7-9, respectively. The average cost of a relapse was estimated at 240,500HUF (€776).


A total of 779 patients (mean age = 57 years) participated; 72% were below retirement age and of these, 36% were employed. Employment was related to disease severity, and MS affected productivity at work for 84% of patients. Overall, 96% and 72% of the patients experienced fatigue and cognition as a problem. Mean utility and annual costs were 0.735 and 11,400GBP (€12,949) at Expanded Disability Status Scale (EDSS) = 0-3, 0.534 and 22,700GBP (€25,785)at EDSS = 4-6.5, and 0.135 and 36,500GBP  (€41,460) at EDSS = 7-9. The mean cost of a relapse was estimated at 790GBP (€870).

A total of 411 MS patients (mean age = 40 years) participated in Poland; 94% were below retirement age, and of these, 59% were employed. Employment was related to disability, and MS affected productivity for 85% of those working. Overall, 97% and 71% of patients experienced fatigue and cognition as important problems, respectively. Mean utility and total annual costs were 0.686 and 48,700 PLN (€11,523) at Expanded Disability Status Scale (EDSS) 0-3, 0.521 and 59,200 PLN (€14,008) at EDSS 4-6.5 and 0.208 and 81,600 PLN (€19,308) at EDSS 7-9, respectively. The average cost of a relapse was 3,900 PLN.(€924)


A total of 462 patients (mean age 43 years) participated in Spain; 96% were below retirement age and of these, 45% were employed. Employment was related to disability, and MS affected productivity at work for 72% of those working. Overall, 92% and 64% of patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were estimated at 0.772 and €20,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.486 and €48,500 at EDSS 4-6.5 and 0.182 and €68,700 at EDSS 7-9, respectively. The mean cost of a relapse was €2050.
A total of 491 patients (mean age 47 years) participated in France; 82% were below retirement age, and of these 56% were employed. Employment was related to disease severity, and MS affected productivity at work for 90% of patients. Overall, 95% and 67% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.735 and €22,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.500 and €38,100 at EDSS 4-6.5, and 0.337 and €48,100 at EDSS 7-9, respectively. The average cost of a relapse was estimated at €2300.

A total of 5475 patients (mean age 52 years) participated in Germany. In all, 84% were below retirement age, and of these, 51% were employed. Employment was related to disease severity, and MS affected productivity at work for 80% of patients. Overall, 96% and 78% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and total annual costs were 0.786 and 28,200€ at Expanded Disability Status Scale (EDSS) 0-3, 0.586 and €44,000 at EDSS 4-6.5 and 0.273 and €62,700 at EDSS 7-9, respectively. The mean cost of a relapse was estimated at €2500.
A total of 516 patients (mean age, 53 years) participated in Austria; 72% were below retirement age, and of these, 46% were employed. Employment was related to disability, and MS affected productivity at work for 77% of those working. Overall, 94% and 67% of patients experienced fatigue and cognition as a problem. Mean utility and total annual costs were 0.778 and 25,100€ at Expanded Disability Status Scale (EDSS) 0-3, 0.579 and 44,100€ at EDSS 4-6.5, and 0.244 and 73,800€ at EDSS 7-9. The mean cost of a relapse was estimated at 2563€

A total of 1010 patients (mean age = 45 years) participated in Italy. In total, 94% were below retirement age, and of these, 56% were employed. Employment was related to disability, and MS affected productivity at work in 77% of the patients. Overall, 96% and 65% of the patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were 0.735 and €22,900 at Expanded Disability Status Scale (EDSS) of 0-3, 0.534 and €40,100 at EDSS of 4-6.5, and 0.135 and €53,300 at EDSS of 7-9. The mean cost of a relapse was estimated to be €2600.
A total of 535 patients (mean age 48.5 years) participated in Portugal ; 92% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 72% of patients, most often through fatigue. Overall, 98% and 74% of patients felt that fatigue and cognition were a problem. Mean utility and costs were 0.756 and €16,500 at the Expanded Disability Status Scale (EDSS) 0-3, 0.572 and €28,700 at EDSS 4-6.5 and 0.206 and €34,400 at EDSS 7-9. The average cost of a relapse was estimated at €2930.
A total of 1856 patients (mean age: 54 years) participated in Belgium; 66% were below retirement age, and of these, 44% were employed. Employment was related to disease severity, and MS affected productivity at work in 85% of the patients. Overall, 95% and 72% of the patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.703 and €26,400 at Expanded Disability Status Scale (EDSS) 0-3, 0.478 and €45,300 at EDSS 4-6.5, and 0.193 and €62,000 at EDSS 7-9. The mean cost of a relapse was estimated to be €3000.
A total of 382 patients (mean age: 54 years) participated in the Netherlands; 81% were below retirement age and of these, 31% were employed. Employment was inversely related to disease severity, and MS affected productivity at work for 82% of patients. Overall, 96% and 73% of patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.744 and €23,100 at Expanded Disability Status Scale (EDSS) 0-3, 0.595 and €32,300 at EDSS 4-6.5, and 0.297 and €50,500 at EDSS 7-9. The mean cost of a relapse was estimated at €3000.
A total of 1864 patients (mean age 56 years) participated in Sweden; 74% were below retirement age, and of these, 55% were employed. MS was reported to affect productivity at work in 78% of patients. Overall, 94% and 72% of patients felt that fatigue and cognition were a problem, respectively. The mean utility and costs were 0.757 and 244,000SEK (€24953) at Expanded Disability Status Scale (EDSS) 0-3, 0.563 and 384,000SEK (€39,271) at EDSS 4-6.5 and 0.202 and 888,000SEK (€90,814) at EDSS 7-9, respectively. The average cost of a relapse was 36,900SEK (€3774).
A total of 721 patients (mean age 48 years) participated in Switzerland; 90% were below retirement age, and of these, 65% were employed. Employment was related to disease severity, and MS affected productivity at work for 69% of patients. Overall, 93% and 64% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.799 and 29,600CHF (€27,272) at Expanded Disability Status Scale (EDSS) 0-3, 0.614 and 66,800CHF (€61,547) at EDSS 4-6.5 and 0.348 and 110,800CHF (€102,087) at EDSS 7-9, respectively. The mean cost of a relapse was estimated at 7,600CHF. (€7,002)