Saturday, 30 April 2016

ClinicSpeak & NeuroSpeak: sequencing DMTs switching from natalizumab to alemtuzumab

Can you switch from natalizumab to alemtuzumab safely? #ClinicSpeak #Neurospeak #MSBlog

"Finally, our algorithm for switching patients at high-risk of PML to other DMTs, in particular alemtuzumab, is in print. We originally published this algorithm on the blog way back in 2014 so why publish it in a journal now? Firstly, it is always good practice to get your work peer-reviewed and secondly it is not accepted practice to quote a blog."

"It is ironic that the day after the EMA announces a positive opinion on daclizumab as a treatment for relapsing forms of MS our paper comes out in print. Ironic in that I have being making the case for daclizumab being the agent of choice post-natalizumab. This means our recommendations will be out of date very soon. In anticipation of this I have already updated the recommendations by including both daclizumab and rituximab as potential switch agents. The daclizumab recommendation is based on scientific principles. Let's hope Biogen and Abbvie do a switch study to produce the necessary data to support this recommendation. In comparison the rituximab recommendation is based on real-life data from Sweden. Despite the latter, NHS England have already said no to rituximab off-label. However, the fact that we can't use rituximab in the NHS in England and Wales doesn't mean other neurologists reading this blog can't. So may be the blog is the best platform for keeping up-to-date with our thinking on this issue?"

Figure: adapted from Giovannoni et al. 

Giovannoni et al. Neurological dilemmas: Switching patients at high risk of PML from natalizumab to another disease-modifying therapy. Pract Neurol doi:10.1136/practneurol-2015-001355

There are several options for switching people with multiple sclerosis (MS) who are at high risk of developing progressive multifocal leukoencephalopathy (PML) from natalizumab to alemtuzumab. However, some of these have risks that need to be managed, for example, the risks of carrying over asymptomatic PML from natalizumab on to the new therapy, and the risk of rebound disease activity associated with a prolonged washout after starting natalizumab. We propose a pragmatic bridging strategy, using another disease-modifying therapy (DMT), to reduce the risk of switching from natalizumab to alemtuzumab. We also discuss the caveats and subtleties associated with sequencing DMTs in MS and the complex decision making involved.

CoI: multiple

Neural Stem Cells

Results from the AAN 2016 on neural stem cells 


(http://aan16.posterview.com/nosl/i/P3_042 (Click)

Here are results from neural stem cell study.

EMA Panel Backs Daclizumab (Zinbryta) for Multiple Sclerosis

Daclizumab is given by self-administered subcutaneous injection once a month.
The humanized monoclonal antibody selectively binds to the high-affinity interleukin-2 receptor subunit (CD25) expressed at abnormally high levels on T cells in patients with MS. Daclizumab offers a targeted mechanism of action that does not cause broad and prolonged immune cell depletion, the company notes in a news release.
According to the CHMP opinion, the benefits of daclizumab include its ability to reduce the annualized relapse rate and risk for disability progression.
The positive CHMP opinion is based on results from two clinical trials. In the DECIDE study, daclizumab 150 mg administered subcutaneously every 4 weeks showed a reduced relapse rate and fewer new lesions on MRI compared with interferon β-1a (Avonex, Biogen) injected intramuscularly weekly.
In the placebo-controlled SELECT study, daclizumab reduced relapse rates and had positive effects on key measures of MS disease activity relative to placebo.
The most common side effects with daclizumab seen in clinical trials are elevations of liver enzymes and hepatic injury, cutaneous events, infections, gastrointestinal disorders, and depression. The CHMP recommends that daclizumab be prescribed by physicians experienced in the management of MS.
For more information on the mechanism of action of daclizumab check Gavin's post ~6 months ago. Personally, I am concerned about yet another drug with a potentially significant secondary autoimmunity problem, however the EMA was happy with daclizumab's risk:benefit profile.

Friday, 29 April 2016

What Does DrK think....Practice what you Preach!

Yesterday's drug delivery, giving six people options where there maybe none...and saving the NHS up to £600,000.
                  Can't wait for the EMA...Cladribine Ready to Go 

For those Health Care professionals and People with MS who may be interested. 

We have updated our Information concerning off-label cladribine use at BartsHealth.


Barts ms clinical guidance for cladribine from BartsMSBlog

There is also information concerning the subcutaneous Administration of Cladribine



Furthermore people enrolling must sign a consent form and be very clear why they are willing to try cladribine. 



We want the best choices for people in our care. 

These may well be the current MS Pharma produced DMT.

However, at BartsMS we are at least willing to try some thing different when these avenues may not be available. 

The documents above show we are prepared to consider Cladribine as an off-label treatment (as we have done it on a similar individual basis, for example, with Rituximab) in situations where (i) eligibility for licensed DMTs cannot be established, or (ii) pwMS, together with the BartsMS team, make an informed decision in favour of off-label treatment rather than a licensed DMT. 

ClinicSpeak: suicide in Swedish MSers

Are you depressed? Please download the Beck Depression Inventory and assess yourself. #ClinicSpeak #MSBlog #MSResearch

"The article below complements my post yesterday on loneliness and social isolation; it confirms that pwMS are at increased risk of both attempted suicide and completed suicide. Men are more successful at committing suicide than women. These are rather depressing figures, but as MS is strongly associated with depression they are not surprising. What can be done about it? All pwMS should be screened for depression and suicidal ideation, or suicidal thoughts, and if they are found to be at risk they should be offered help. Easier said than done? In a recent audit of our service a glaring omission was the patchy screening for depression in our MS clinics. I have included the Beck Depression inventory that you can download and score yourself. If you find you are depressed please see your GP, neurologist or MS CNS."



BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients.

METHODS: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period.

RESULTS: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting  suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60-2.04).

CONCLUSION: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients. 

Thursday, 28 April 2016

Competition for Canbex




As you may know we are trying to develop a treatment for spasticity. Baclofen is the usual go to drug, but it is not without its problems. One is the Zombie effect because it is very sedating because it is sedative, because it inhibits nerve function making muscle weakness and having cognitive effects. 

It also has a low binding affinity for its target the GABA B receptor. So you need high blood/brain levels for it to work. 

Next the other problem it has a short half life = the time taken for half of the drug to disappear. This means that the drug is gone within 8hours.

This means that it can't get you through the night. Therefore you have to wake up. to dose in the night or you are going to wake up with stiffies...yet stiff legs and hands. 

So you have a peak and a trough in drug levels meaning cogfog to maintain therapy or if you try avoid the cogfog it is an "on" and "off" with the drug working. 

In this study presented at the AAN they have taken baclofen and re-formulated it to give a slow release to avoid the peaks and the troughs but to create a longer half life, so you can have a twice a day pill. In this study they show that the long-life pill is better than placebo but no different from baclofen and it drops the levels of side effects.

So if this drug makes it it this creates competition for our drug, if our drug every makes it. 

Our claim is not that it will work better than current drugs, it is that that it will avoid the side-effects e.g. sedation of current drugs. 

How does it do this? ....Magic?.....You will soon find out.

If you fit the profile and are interested in participating in our trial of VSN16R and can get to...or are willing to go to London (UCL or Barts), Liverpool or Sheffield, you can contact one of the centres (CLICK).

The study will last less than 1 month.


ClinicSpeak: calling on researchers to take on social isolation

Are you lonely and socially isolated? What can we do about it? #ClinicSpeak #MSBlog #MSResearch

"If you have MS and are disabled there is a reasonable chance that you have become unemployed, split from your partner and have noticed your social group shrinking. In short you may be lonely and socially isolated. Social isolation is a big problem in chronic diseases, in particular multiple sclerosis. I see both loneliness and social isolation in almost every clinic I do; it is one of the reasons I go home emotionally drained and exhausted after my MS clinics. Sometimes the best I can do is offer talk therapy to my patients; simply talking to them and asking them about what they do each day and taking an interest in their lives helps. The good news is that the NIHR have just put out a funding call to study loneliness and  social isolation. If there are any social scientists out there interested in putting in a bid around MS please drop me a note. Barts-MS and our partners under the MS@UCLP umbrella look after about 10,000 MSers in Central and North East London and the adjacent home counties. This issue is a big problem and needs addressing."


"As I am writing this it makes me realise that as loneliness and social isolation are linked to disability then treatments that prevent disability should reduce both these phenomena. I am not sure if anyone has looked into this in more detail. Preventing loneliness and social isolation could be another argument to support early effective treatment."

Wednesday, 27 April 2016

Alemtuzumab 10 years on

P2.086 - Incidence and Timing of Thyroid Adverse Events in Patients with RRMS Treated with Alemtuzumab through 5 Years of the CARE-MS Studies


P.A senior et al.

OBJECTIVE:
To summarize 5-year incidence and timing of thyroid adverse events following alemtuzumab treatment in the ongoing CARE-MS extension study.
BACKGROUND:
In the phase 3 CARE-MS studies, patients with active relapsing-remitting MS showed greater improvements in efficacy outcomes with alemtuzumab versus SC IFNB-1a over 2 years; efficacy was durable through 5 years in the extension study. Alemtuzumab’s consistent safety profile across the clinical trial program includes an identified risk of predominantly nonserious autoimmune thyroid disorders.
DESIGN/METHODS:
In the 2-year CARE-MS I and II (NCT00530348; NCT00548405) core studies, alemtuzumab-treated patients received 2 annual courses at Months 0 and 12. Patients could enter the extension study (NCT00930553) for ongoing follow-up and as-needed retreatment for relapse or radiological activity. As part of a comprehensive monitoring program, thyroid function testing was performed at baseline and quarterly thereafter. Thyroid monitoring is recommended for 4 years following last dose of alemtuzumab.
RESULTS:
During Years 0-5, thyroid events were reported in 39% (317/811) of patients; 4.4% had serious thyroid events. Most thyroid events were mild or moderate in severity. The proportion of patients with thyroid events peaked at Year 3 and subsequently declined (Year 1: 5.7%; Year 2: 10.7%; Year 3: 20.9%; Year 4: 12.6%; Year 5: 10.0%). No thyroid events resulted in study discontinuation. Most events were managed with first-line, conventional therapy; 3.2% of patients underwent thyroidectomy.
CONCLUSIONS:
The annual incidence of thyroid events following alemtuzumab treatment is consistent with previous reports, peaking in Year 3 and declining thereafter. Ongoing patient education and laboratory monitoring continue to enable timely detection and treatment of alemtuzumab-associated thyroid events.

Based on the CARE I/CARE II data on which Alemtuzumab was licenced the rate of autoimmunities was about 20% but based on follow-up we know this is closer to 50% and indeed in this study 40% of people treated developed thyroid problems by 5 years and one cannot believe it is going to go from 10% down to 0% in year 6 so more to come. Neuros perhaps are accepting about this because, thyroid problems are generally treatable.....which in 4% of cases is having your thyroid removed surgically. However some of these autoimmunities can be very serious if not picked up and the the original phase II was halted because of deaths due to ITP. We have to be ever vigilant for this as another poster at AAN points out


P2.103 Fatal Autoimmune Haemolytic Anemia Associated with Alemtuzumab in a MS Patient with Severe Relapsing Remitting Disease Course and Prior Immune Therapies —Peter Rieckmann, Arne Lenz, Markus Hoffmann, Udo Poske, Karin Behr, Boris Kallmann

Is this frightening neuros and pwMS from taking this drug? 


Ocrelizumab and now oral cladribine are coming from behind and do not have this problem. Is the clock ticking?

Yet the efficacy is good

ProfG has already shown you
P3.054 - Long-Term Responders from the CARE-MS I Study: No Evidence of Disease Activity for 4 Years Following 2 Courses of Alemtuzumab and No Further Treatment
Gavin Giovannoni



P3.022 - Patients with Active RRMS and an Inadequate Response to Prior Therapy Demonstrate Durable Improvements in Relapse and Disability Following Treatment with Alemtuzumab: 5-Year Follow-Up of the CARE-MS II Study
Coles AJ et al.

OBJECTIVE:To examine 5-year clinical efficacy and safety in CARE-MS II alemtuzumab-treated patients.
BACKGROUND: In CARE-MS II (NCT00548405), active relapsing-remitting MS (RRMS) patients with an inadequate response (≥1 relapse) to prior therapy at baseline, alemtuzumab showed superior efficacy versus SC IFNB-1a over 2 years. Efficacy was durable through 4 years.
DESIGN/METHODS: In the CARE-MS II core study, alemtuzumab patients received 2 annual treatment courses at Months 0 and 12. Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or radiological activity. Endpoints included annualized relapse rate (ARR), 6-month sustained accumulation of disability (SAD)/confirmed disability progression (≥1-point EDSS increase [≥1.5-point if baseline EDSS=0] confirmed at 6 months), 6-month sustained reduction in disability (SRD; ≥1-point EDSS decrease [baseline score ≥2.0]), and no evidence of clinical disease activity (absence of relapse and 6-month SAD).
RESULTS: 393 (93%) alemtuzumab-treated patients completing CARE-MS II enrolled in extension. Through 5 years, 91% remained on study, 60% received no alemtuzumab since the initial 2 courses, and 8% received another disease-modifying therapy. Low ARR (0.21) was maintained over Years 3-5. Through Years 0-5, 76% of patients were free from 6-month SAD, 77% had stable or improved EDSS, and 43% achieved 6-month SRD. More than half of patients (52%) had no evidence of clinical disease activity over Years 3-5. Incidences of infusion-associated reactions and infections during extension decreased versus core study; serious adverse event (AE) incidence was low. Thyroid AE incidence peaked at Year 3, declining thereafter.
CONCLUSIONS: Alemtuzumab demonstrated durable improvements in clinical efficacy over 5 years despite most patients not receiving alemtuzumab for 4 years. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continued treatment for RRMS patients.

P3.053 - Durable Efficacy of Alemtuzumab Over 10 Years: Long-Term Follow-Up of Patients with RRMS from the CAMMS223 Study

OBJECTIVE:Evaluate 10-year efficacy and safety in treatment-naive patients who received alemtuzumab 12 mg in phase 2 CAMMS223, and enrolled in the ongoing CARE-MS extension study.

BACKGROUND: In CAMMS223, in patients with active relapsing-remitting MS (RRMS), alemtuzumab showed superior efficacy versus SC IFNB-1a. During 3 randomized studies, efficacy was durable through 5 years, with most patients not receiving retreatment for 4 years.
DESIGN/METHODS: In the CAMMS223 core study (NCT00050778), patients were randomized to receive 2 annual courses of alemtuzumab with a possible third course based on T-cell counts. Patients could enter the extension (NCT00930553) for additional follow-up and as-needed retreatment. Endpoints included annualized relapse rate (ARR) and 6-month sustained accumulation of disability (SAD)/confirmed disability progression (≥1-point Expanded Disability Status Scale [EDSS] increase [≥1.5-point if baseline EDSS=0]).
RESULTS: Of 108 alemtuzumab 12-mg-treated patients in CAMMS223, 60 entered the extension; based on rising T-cell counts, 39 received a third course (25 after Year 3). 57 (95%) of extension patients were followed through Year 10; of these, 12% and 10% received 4 or 5 alemtuzumab courses, respectively. Through Year 10, low ARR was maintained (0.07), 76% were free from 6-month SAD, and 78% had stable or ≥1-point improved EDSS versus baseline. Serious adverse event (AE) incidence was low. Incidence of infusion-associated reactions decreased after first treatment course (98%). Annual incidence of infections decreased after Year 1 (55%). Incidence of thyroid AEs peaked in Year 3 (17%) and declined thereafter.
CONCLUSIONS: Alemtuzumab demonstrated durable clinical efficacy through Year 10 despite most patients receiving ≤3 treatment courses. Safety findings were consistent with those of other alemtuzumab clinical trials. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continued treatment for patients with RRMS.

You asked for the ten year data and there you have it the 10 year data. More of the same compared to that already published by Tuohy et al. but as you can see it is not simply two doses and that's it, as many people need another dose. So is it really pulsed immune reconstitution therapy (PIRT) as suggested by profG or pulsed immune ablation therapy (PIAT), where by the pathogenic cells are wiped away for years and if and when they regenerate they need another dose of medicine. 

However what you want to know is what is the number of converters to secondary progression?

Based on the original 10 year Cambridge data it was about 4%

COI None relevant

ClinicSpeak & BrainHealth: are you up for routine cognitive testing?

Can we afford not to screen MSers for cognitive impairment? Have your say. #ClinicSpeak #BrainHealth #MSBlog

"You are all aware that I ran a longish social media campaign to get MS rebranded a preventable dementia. My motivation was to get regulators to realise that early disability in MS is driven by cognitive impairment that occurs long before physical disability is noted. The hope was to get highly-effective therapies licensed first-line to allow informed pwMS to make active decisions about trying to prevent irreversible damage to their brains and acquiring irreversible cognitive deficits. Whether or not the 'MS Preventable Dementia' campaign made a difference I don't know, but alemtuzumab got a 1st-line license and the rest is history."

"I remember presenting the 'MS Preventable Dementia' campaign at the EMA MS Workshop on the 17th October 2013 (see below). I recall taking a pasting from both the regulators and some of my colleagues at this meeting. One regulator categorically denied that MS is a preventable dementia and thought classifying it as such was wrong. This particular regulator, as most neurologists, see dementia as a disease mainly of the elderly and limited to so called classic neurodegenerative diseases, e.g. Alzheimer's disease. I have in past suggested to some of these deniers that they study the philosophy of medicine and the classification of diseases. They would then see that MS ticks all the boxes for being a potentially dementing disease. The difference between MS and say Alzheimer's disease is that we have effective treatments for MS and if we use these treatments early and effectively we could at least delay, and hopefully, prevent irreversible cognitive impairment."

"The reason why 50% of pwMS are unemployed on average 10 years after initial diagnosis at an EDSS of 3.0-3.5 (no overt physical disability) is almost certainly due to cognitive impairment. The cognitive impairment in early MS doesn't cause obvious symptoms and signs because of compensatory mechanisms. The cost however of compensating for cognitive impairment is cognitive fatigue, depression and anxiety. The early burden of MS is massively under reported and because neurologists and MS nurse specialists don't routinely screen for cognitive impairment it goes undiagnosed and under recognised. Would you like this to change? Would you want routine cognitive testing? A recent debate that was played out in the Multiple Sclerosis Journal goes through the arguments for and against routine cognitive testing; I think Dawn Langdon one the argument. In support of Dawn, NICE have suggested in their MS Guidelines that pwMS should have annual cognitive screening done. I am all for it, because if we detect cognitive impairments early we may be able to proactively manage patients and this information would almost certainly affect treatment decisions. We also know that identifying patients with cognitive impairments, albeit subtle impairments, means we could watch these patients more closely and help them address potential issues before they arise. There also many cognitive rehabilitation programmes that patients may find helpful. I am also personally in favour of patients being informed about their disease; patients not knowing about cognition is against this management philosophy."

"The problem, however, with routine cognitive assessments in NHS practice is resources; we simply don't have the physical manpower to do routine testing. We are however, hoping to get a pilot off the ground to do cognitive testing at Barts Health. The question is would you as a person with MS want to know about your cognition? We know cognitive impairment is closely linked to accelerated brain volume loss and poorer long-term outcomes. Knowing you are in a poor prognostic group may be the trigger for choosing more effective treatment or for making difficult decisions about your life. I would appreciate it if you could complete the short survey below about routine cognitive testing; it will help us get an idea if there is an appetite out there for routine cognitive testing."





Langdon D. A useful annual review of cognition in relapsing MS is beyond most neurologists - NO. Mult Scler. 2016 Apr 5. pii: 1352458516640610.

McNicholas & McGuigan. A useful annual review of cognition in relapsing MS is beyond most neurologists - YES. Mult Scler. 2016 Apr 5. pii: 1352458516639385.

Hutchinson M. A useful annual review of cognition in relapsing MS is beyond most neurologists - Commentary. Mult Scler. 2016 Apr 5. pii: 1352458516642624.


CoI: multiple

Tuesday, 26 April 2016

ClinicSpeak & BrainHealth: wellness

What does wellness mean to you? #AAN2016 #BrainHealth #MSBlog

"A key theme of the AAN 2016 was brain health and wellness. What does wellness mean to you? Can we define wellness and make it a therapeutic target in MS?"


"We at Barts-MS continue to promote the holistic management of MS and brain health is simply one way of framing this strategy in relation to MS. However, wellness goes beyond the brain and includes many other aspects of your life. I am increasingly buying into wellness as a therapeutic target and continue to challenge my colleagues to do so as well. Can you really tell your patients to go on diet and exercise when you are overweight yourself and don't exercise? One of my academic colleagues who is a very high profile oncologist continues to smoke, albeit secretively. How can this individual get on a public platform, which he does frequently, to promote non-smoking as a core cancer prevention strategy?"

"I am aware that wellness means different things to different people, which means if we make this a therapeutic target in MS we will truly have to personalise it. I want you to reflect on these issues so that we can discuss them over the next few weeks."




CoI: multiple

The resources debacle

Lancet. 2016 Apr 5. pii: S0140-6736(16)00620-6. doi: 10.1016/S0140-6736(16)00620-6. [Epub ahead of print]

Clinical workload in UK primary care: a retrospective analysis of 100 million consultations in England, 2007-14.

Hobbs FD, Bankhead C, Mukhtar T, Stevens S, Perera-Salazar R, Holt T, Salisbury C; National Institute for Health Research School for Primary CareResearch.

Abstract

BACKGROUND:

Primary care is the main source of health care in many health systems, including the UK National Health Service (NHS), but few objective data exist for the volume and nature of primary care activity. With rising concerns that NHS primary care workload has increased substantially, we aimed to assess the direct clinical workload of general practitioners (GPs) and practice nurses in primary care in the UK.

METHODS:

We did a retrospective analysis of GP and nurse consultations of non-temporary patients registered at 398 English general practices between April, 2007, and March, 2014. We used data from electronic health records routinely entered in the Clinical Practice Research Datalink, and linked CPRD data to national datasets. Trends in age-standardised and sex-standardised consultation rates were modelled with joinpoint regression analysis.

FINDINGS:

The dataset comprised 101 818 352 consultations and 20 626 297 person-years of observation. The crude annual consultation rate per person increased by 10·51%, from 4·67 in 2007-08, to 5·16 in 2013-14. Consultation rates were highest in infants (age 0-4 years) and elderly people (≥85 years), and were higher for female patients than for male patients of all ages. The greatest increases in age-standardised and sex-standardised rates were in GPs, with a rise of 12·36% per 10 000 person-years, compared with 0·9% for practice nurses. GP telephone consultation rates doubled, compared with a 5·20% rise in surgery consultations, which accounted for 90% of all consultations. The mean duration of GP surgery consultations increased by 6·7%, from 8·65 min (95% CI 8·64-8·65) to 9·22 min (9·22-9·23), and overall workload increased by 16%.

INTERPRETATION:

Our findings show a substantial increase in practice consultation rates, average consultation duration, and total patient-facing clinical workload in English general practice. These results suggest that English primary care as currently delivered could be reaching saturation point. Notably, our data only explore direct clinical workload and not indirect activities and professional duties, which have probably also increased. This and additional research questions, including the outcomes of workload changes on other sectors of health care, need urgent answers for primary care provision internationally.

Image: Overcrowded train in Bangladesh of devotees returning from the World Moslem Congregation.

Figure: Population of the UK 64.1 million (2013), life expectancy 81.5 years.

The debate on population dynamics is not mere verbal wrangling, or 'the second coming' caused by migration as the politicians would have you believe, but a realistic and tangible threat for every nation over the next +10 years. We are fast approaching a point where the amount of resources needed to sustain the worlds population exceeds the available resources, and healthcare availability plays a major role in this (have you wondered why in the US with a population size of 318.9 million the Obama healthcare reform is being strongly opposed?). I'm not sure containment is the answer here, or better still waiting for the zombie apocalypse.

In the UK the primary care is central to the provision of Healthcare, a model followed by many countries, and is likely to demonstrate the first signs of weakening as it is overwhelmed by unsustainable increases in workload. It is also the gatekeeper for secondary healthcare and failings here lead to deficits in the latter. Based on the findings from this study, the number of consultations per patient per year in UK rose by roughly 10% between 2007/8 and 2013/4. Most were face-to-face contacts with GPs (rather than the practice nurse). The rate of rise in consultations were linked to demand from extremes of the age spectrum - infants (the birth rate debacle) and the elderly (the Damocles of successful advancements in the field medicine debacle). And to consultation duration (12.4% increase in GP consultation rates linked to 4% rise in mean consultation duration). A common strategy advocated to cope with the rising workload has been to utilise the telephone triaging, but with a doubling in the telephone consulting rates over time and in about a third also resulting in a subsequent surgery consultation, has meant that it does not reduce workload in the long run.

So the pressure felt by many practices is well founded, and the whole system is fast approaching saturation point. It's probably not the time for austerity/efficiency savings, but the exact opposite. Now where did I put my piggy bank?

Monday, 25 April 2016

Remyelination to Neuroprotection at the AAN

Neuroprotective and oligodendrocyte precursor cell differentiation promoting activities of the RXR nuclear receptor agonist IRX4204 are potentiated by thyroid hormone 

Authors: Martin Sanders, MD; Robin Avila, PhD; Bruce Trapp, PhD; Satish Medicetty, PhD; Rosh Chandraratna, PhD 

Objective: (1) determine if the RXR nuclear receptor agonist IRX4204 is effective in an in vivo neuroprotection (NP) model; (2) evaluate the effects of combination treatment with thyroid hormone and IRX4204 in this model; (3) determine if adding thyroid hormone increases the previously reported stimulatory effect of IRX4204 on in vitro differentiation of oligodendrocyte precursor cells (OPC) into oligodendrocytes (OL). 
Background: IRX4204 is a potent, highly selective RXR agonist compound being developed for treatment of multiple sclerosis (MS) and other neurologic diseases. Central hypothyroidism is a documented side effect of treatment with RXR agonists, including IRX4204. Since thyroid hormone is critical for CNS functions, we studied the effects of combination treatment with IRX4204 and thyroid hormone in an in vivo model of NP, and on OPC differentiation in vitro. 
Design/Methods: Mice were administered cuprizone to induce demyelination; and rapamycin to prevent remyelination. NP was assessed by quantitation of SMI-32 immunostained axonal ovoids (transected axons) in the corpus callosum. Quantitation of OPC differentiation was performed by high-content screening of OPCs, which express PLP-EGFP when differentiated into OL; and by MBP immunostaining. 
Results: Combination treatment with thyroid hormone and IRX4204 in the NP model resulted in reduction in axonal transection compared to vehicle, and approximately three-fold greater, statistically significant reduction compared to IRX4204 alone (-38.3% vs -13.6%). Addition of thyroid hormone with IRX4204 to OPC cultures resulted in statistically significant additive increase in myelin producing OL versus IRX4204 alone. 
Conclusions: IRX4204 demonstrated neuroprotective effects in vivo; and OPC differentiation promoting effects in vitro; both of which were potentiated by thyroid hormone. RXR agonists should be co-administered with thyroid hormone, not only to maintain euthyroid status, but also to obtain improved efficacy in MS and other neurologic diseases patients treated with these agents. 
Study Supported By: Supported by The National Multiple Sclerosis Society Fast Forward Program

Researchers at Cambridge and Edinburgh discovered that RXR agonists could promote remyelination. Whilst they struggled to get a trial in MS off the ground using a generic compound, and pharma companies with such drugs weren't interested in MS, Cambridge has apparently been funded by NHS England, and they will use Bexarotene an anti-cancer drug. RXR is a ubititous molecule expressed all over the place and so you must expect side-effects and this does induce rashes and itchiness, low white cell count and notably thyroid problems due to down regulation of thyroid hormones. Even if it is positive will bexarotene go anywhere?. It will be hard without company support. So in contrast to the UK, try a generic and fail to get it approved approach, our US colleagues aim to devlop a new drug. IRX4204 is also an XRX antagonist that has been used in human cancer treatment. It is highly brain penetrant, and promoted differentiation of OPCs into oligodendrocytes. They realise there is a problem with the thyroid hormone depression so in this animal study they add IRX4204 and supplement with thyroid hormone and find improved efficacy in saving nerves. This is yet more evidence that having demyelinated nerves leaves them vulnerable to death. Promote remyelination and it should be neuroprotective which is what is found here.

However it is not only demyelination that occurs ans as we have been anticipating the is immunosuppressive. You can see the poster presentated at the AAN (click)
This means it does every thing which could mean that trials could be uninterpretable if they are not done carefully.

ResearchSpeak: will you be able to choose your PIRT?

Choose your PIRT (pulsed immune reconstitution therapy)? #AAN2016 #ResearchSpeak #MSBlog #MSResearch

"The following are the two posters I presented on PIRTs at the AAN in Vancouver."

"There were many posters and presentations on the durability of the treatment response of MSers to alemtuzumab. The data just gets better, and better with each year of follow-up. What people don’t seem to realise is that the majority of MSers are flat-lining (NEDA) with only two cycles of treatment. In fact a significant proportion of treated subjects have actually improved. Our world-view of MS doesn’t really take into account improvement in fixed disability. The 5-year alemtuzumab data brain volume demonstrates brain atrophy rates well within the range of what we see in normal subjects. This data is almost too good to be true and I have hypothesised that the average data may be contaminated by a subgroup of subjects with reversal of pseudoatrophy.

What is reversal of pseudoatrophy? When you have inflammation in your brain it swells from the effects of inflammation. When you switch off this inflammation the brain shrinks; this is typically seen within the first 6 months after starting an anti-inflammatory therapy. It is likely that when inflammation returns the brain will swell again and increase in volume. We know that a proportion of subjects who receive alemtuzumab will have recrudescence of their disease activity and if their brains swell this may bias the brain atrophy data towards being supranormal, i.e. better than normal. 

Another possibility is that alemtuzumab causes disability improvement in pwMS. Could subjects who improve post-alemtuzumab rewire, or expand, their brain sizes due to axonal sprouting, synaptogenesis (new synapses) and plasticity? I have put in a request to the statisticians at Sanofi-Genzyme to analyse the data to look for reversal of pseudoatrophy and/or brain recovery. The latter may not be that far fetched, in a very early MRI follow-up study on alemtuzumab-treated patients from Cambridge using MTR (magnetization ratios) a marker of structural integrity showed improvement in the MTR suggesting recovery of brain function.

The other poster is on the CLARITY extension study and the durability of cladribine as a PIRT. MSers in the phase 3 trial who were randomised to placebo in years 3 and 4 of the extension study did very well with very low levels of recurrent disease activity. Unfortunately, we don't have as rich a data set with cladribine, as we do with alemtuzumab, to see how these MSers do over the long-term. If cladribine tablets get licensed by the EMA, as I hope they do, maybe the NHS will allow us to do a randomised head-2-head study to compare alemtuzumab with cladribine? An even better study would be to include a HSCT arm to test three PIRTs in parallel. 

The billion dollar question is whether or not you the NHS will allow you to choose between PIRT 1 and PIRT 2?"






CoI: multiple

ClinicSpeak: MS Awareness Week 25 April - 1st May

Did you know today is the beginning of the 2016 MS awareness week? #ClinicSpeak #MSTrust #MSAwareness

"The MS Trust one of the UK charities that Barts-MS supports. They are raising awareness about the inequality of MS Services provision across the UK. Please make a noise and spread the word."


Click on image to visit MS Trust Site and learn about the activities this week.

"If you use the MS Trust's services, and information resources, you will realise just how good they are in helping pwMS manage their disease. As always in this time of austerity the MS Trust needs our help more than ever to keep itself running."

"To help the MS Trust we will be running as a team in the annual 2016 London Vitality 10km run on the 10th July. As always we would appreciate your generous support. Can you imagine a MS World without the MS Trust? We can't! Thank you."

Click on image to make a donation!

Sunday, 24 April 2016

When Trials Go Wrong

This is taken from Neurosens and reports on the disasterous trial that led to one person death aand others brain damaged. It has nothing whatso ever to do with MS but some of you may be interested. It is about the drug trial that went wrong.

Serious toxicities occurred with the experimental drug BIA 10‐2474, “as if something gave way or swung suddenly at a specific dose or concentration threshold which is typical of an on-off effect,”

BIA 10-2427 is a fatty acid amide hydrolase (FAAH) inhibitor that was undergoing testing in a first-in-man phase I trial in Rennes, France. A total of 64 healthy volunteers aged 18-55 years participated in a single ascending dose stage to test eight doses (0.25 to 100 mg) versus placebo. This phase of the study ran from July 9 to October 9, 2015, with no significant toxicities reported. For the multiple ascending dose study that began on October 6, 48 healthy volunteers were scheduled to receive either placebo or 2.5 mg, 5 mg, 10 mg, 20 mg, 50 mg or 100 mg for 10 days. The next dose level was initiated only if no toxicities were observed with the lower doses. The 2.5-mg dose was estimated to be 1/40th of the highest dose with no observable adverse effect level based on pharmacokinetic testing.

The six volunteers on active drug in cohort 5 (50 mg) received the first dose on January 6, 2016 (two others received placebo). On the evening of January 10 (day 5), one volunteer who had received five consecutive 50-mg doses was hospitalized after presenting with signs and symptoms resembling a stroke. Biotrial, the clinical research organization conducting the study, did not consider the acute symptoms to be related to the study drug and the remaining five volunteers received their sixth dose the next morning. The trial was suspended on January 11. The remaining five subjects were hospitalized between January 13 and 15, 2016.

In five of six volunteers, there was rapid onset of neurological symptoms of varying clinical and radiological severity. One subject died. MRIs in the six volunteers showed consistent evidence of microcerebral tissue damage, described as highly variable in severity, with unusual topography, and primarily affecting the hippocampus and pons. Cerebral haemorrhaage and brain necrosis were reported in some study participants. There were no seizures or peripheral neurological symptoms. No biological, metabolic or immunological abnormalities were observed.

No neurological toxicities were observed in subjects in the prior dosing cohorts. In the single-dose study there were 18 adverse events, such as orthostatic hypotension, reflex tachycardia, PR or QT interval prolongation, mild dizziness and headache. Two adverse events of possible significance (diplopia, blurred vision) were considered to be not relevant by trial investigators. Subjects exposed to BIA 10-2427 in the earlier stages of the study have since been investigated and no clinical or MRI anomalies have been detected.

In addition, no neurological toxicity was reported in a phase II trial of PF-04457845, an FAAH inhibitor that was in development as a treatment for pain due to osteoarthritis (Huggins et al. Pain 2012;153:1837-1846).

Among its findings, it was noted that several volunteers were included in the study despite having risk factors for treatment-related adverse effects. One volunteer had a history of severe head injury with loss of consciousness; and another had a prolonged PR interval (>240 msec) on ECG and blood pressure >140/90 mmHg on four pre-dose readings. Other problems with the trial included too rapid escalation from 20 to 50 mg/day, and a lack of neuropsychological assessment.

The committee found that toxicology studies in four species were conducted properly and no neurological toxicities were found despite the use of high doses administered for prolonged periods. However, there were reports of cerebral damage, especially in the hippocampus with gliosis and inflammatory cell infiltration, in rodents receiving high doses (150-500 mg/kg over four weeks). Such damage was considered by the committee to be common in rodents and did not constitute a safety signal.

(MD says I have not heard of this).

The TSSC noted that pharmacokinetic studies demonstrated that complete inhibition of FAAH could be achieved at doses from 1.25 to 5.0 mg, and questioned the need to escalate to 80-100 times higher than this if FAAH inhibition was the putative mechanism of action of the drug. Moreover, studies of the single-dose cohorts had demonstrated non-linear pharmacokinetics, with the area under the curve (AUC) increasing more rapidly than dosing. The committee speculated that this was due to a slowing of elimination at doses >40 mg/day. BIA 10-2427 has at least four active metabolites, of which two reach measurable plasma concentrations. Pharmacokinetic variability has been shown to be higher for these metabolites, but little is known about their clinical effects or toxicity. The committee noted that there is a potential for intracerebral metabolism, which could have resulted in CNS effects if one or more of the metabolites was highly reactive or toxic at low concentrations.

The TSSC considered several hypotheses for explaining the observed toxicity. Administration error was considered to be unlikely. A pharmacodynamic interaction was also rejected since the five patients affected were unlikely to have consumed the same foods (e.g. chocolate) or medications, blood tests ruled out the use of narcotics, cannabis and alcohol, and a common genetic factor that might alter FAAH inhibitor response was statistically implausible.

The more likely mechanism, according to the committee, was an off-target effect that has not been identified. BIA 10-2427 is an irreversible FAAH inhibitor with relatively poor specificity for FAAH, so there may have been interactions with other CNS hydrolases. This proposed effect might be augmented due to the non-linear pharmacokinetics at doses >40 mg.

Alternative mechanisms were also suggested. FAAH is a hydrolase that degrades anandamide, which preferentially interacts with the CB1 receptor. However, anandamide’s effects are not limited to the endocannabinoid system. It affects ion channels by activating TRPV1 (transient receptor potential vanilloid 1); is an agonist of PPAR (peroxisome proliferator-activated receptor), which is involved in inflammation; interacts with NMDA (N-methyl D-aspartate) glutamate receptors; and can activate transcription pathways (e.g. MAPK) involved in apoptosis. Stimulation of endocannabinoid receptors by anandamide is not known to result in the toxicities that occurred. If FAAH is inhibited, anandamide is degraded via the cyclooxygenase pathway, resulting in leukotrienes and prostanoids. The committee noted that these have known vasomotor effects that might be compatible with some of the lesions observed in the affected subjects.

The TSSC investigation is ongoing and the committee plans to produce comprehensive good-practice recommendations on first-in-man trials.

For a free download of the minutes, 07 March 2016:

English: http://ansm.sante.fr/content/download/86439/1089765/version/1/file/CR_CSST-FAAH_15-02-2016_Version-Anglaise.pdf

You may be also interested in this the views of a Doctor on a trial that went wrong (CLICK)

ClinicSpeak: rebranding induction therapies PIRTs

Is it time to ditch the term induction therapy? #ClinicSpeak #MSBlog #MSResearch

Are you up for a PIRT or pulsed immune reconstitution therapy?  #ClinicSpeak #MSBlog #MSResearch

"It is time to ditch the term induction therapy and invent a new one? The term ‘induction’ is not a very useful term when describing the mode of action of alemtuzumab, cladribine and HSCT, because it comes with baggage and is often misrepresented. I am now beginning to realise that most people in the field equate the term ‘induction’ with the use of high-efficacy treatment early on in the course disease. For example, at the AAN I heard several people refer to the use of natalizumab as a first-line therapy as an induction strategy. Similarly, the use of mitoxantrone before interferon-beta or glatiramer acetate is frequently referred to as induction strategy (see below). Therefore, I think it is time to rebrand ‘induction’ therapies with a term that describes their mode of action and usage more clearly. Dare I suggest the term ‘pulsed immune-reconstitution therapy/ies’ or 'PIRT(s)'. The term pulsed gets across the concepts of short intermittent courses and immune reconstitution explains how these drugs probably work.

PIRTs have many advantages over maintenance therapies, which I have highlighted in the past. The main advantage is that PIRTs (1) they tend to be on average highly-effective treatments, (2) they only remain in the body for a short period of time, which is a very useful attribute if you are a woman who is thinking about falling pregnant, (3) they induce long term remission in some patients, which may turn out to be a cure in the future and (4) they frontload risk. Most of the adverse events associated with PIRTs occur early in the treatment hence the term frontloading. In comparison with maintenance therapies the risks accumulate over time. The latter point is not a trivial point; with immunosuppressive drugs the risks of opportunistic infections and treatment-related malignancies increases with time."


Edan et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1344-50.

OBJECTIVES: The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients.

METHODS: In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months.

RESULTS: The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point.

CONCLUSIONS: Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.


Ramtahal et al. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. J Neurol. 2006 Sep;253(9):1160-4. Epub 2006 Sep 21.

Background: Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. 

Objectives and methods: We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. 

Results: Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. 

Conclusions: Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.


CoI: multiple

Saturday, 23 April 2016

ThinkSpeak & ResearchSpeak: my top highlight from the AAN 2016 meeting in Vancouver

The ASCEND SPMS trial demonstrates that SPMS is not an intractable problem #ThinkSpeak #ResearchSpeak #MSBlog #MSResearch #AAN2016

People with SPMS now have hope #ThinkSpeak #ResearchSpeak #MSBlog #MSResearch #AAN2016

My top highlight for the AAN 2016 are the ASCEND Trial results #AAN2016



"Most commentators have dismissed the natalizumab in SPMS trial, or ASCEND trial, as being negative and have simply moved on. 

One person said to me: 'SPMS is an intractable problem and it is best to prevent it by early effective treatment’. Another said: 'What did you expect, the ASCEND is just another negative SPMS trial, which could easily have been predicted from our experience with the interferon trials.' How cynical and sad? These attitudes entrench the concept of the therapeutic window in MS and perpetuate the concept that it is futile to try and develop treatments for SPMS. I disagree with both of these positions and prepared to go out on a limb and hypothesise that the therapeutic window remains open throughout the course of MS and it is not futile to try an develop treatments for SPMS. We have to give people with MS hope. In my opinion the ASCEND Trial was clearly positive; although the study did not hit the desired primary outcome natalizumab did show an effect in virtually flattening loss of upper limb function. Surely a treatment that protects upper limb function in people with SPMS is worth exploring further? To quote one SPMSer: 'Now that I am in a wheelchair my hands and arms have become my legs’.

Click here to see and download PDF

What is galling is the ORATORIO trial of ocrelizumab in PPMS was positive. Is ocrelizumab really superior to natalizumab? Is PPMS that different to SPMS? I would argue no on both accounts. The differences between the ASCEND and ORATORIO trials can be explained on differences in the study populations. The ASCEND SPMS population was older and more disabled; over 60% of study subjects had an EDSS of 6.0 or 6.5. In other words they had lost most meaningful reserve capacity in the motor system to their legs. We know from other studies that at a disability level of EDSS of 6.0 (unilateral support) or 6.5 (bilateral support) the EDSS is not a very good outcome measure over 2 years; most MSers with this level of disability spend many years at these levels before progressing to a higher level of disability. In measurement speak we refer to this as the ceiling effect of the EDSS. In comparison over 60% of PPMSers in the ORATORIO study had an EDSS of less than 6.0 and hence were at a level of disability on the EDSS scale that is more likely to move. In addition, with a disability below EDSS 6.0 there is more reserve capacity in the motor system to allow recovery of function and get a read-out in a two year period. In other words at lower levels of disability there is less therapeutic lag.

For the last 2-3 years I have been discussing two concepts, or hypotheses, on this blog, i.e. therapeutic lag and the length-dependency. The results of these two studies, with other evidence - new and old - strongly support both these related hypotheses. Therapeutic lag states that the more reserve that is lost in a specific pathway the longer it will take to see a treatment effect in relation to therapies that are targeting MS specific mechanisms. This is why the ORATORIO trial was positive on both the EDSS and timed-25-foot walk (T25FW), and the ASCEND trial was negative on both these outcome measures. I would predict that if the ASCEND trial had been longer in duration then it may have been positive on both of these outcomes, in particular the T25FW which is more sensitive to change than the EDSS. Unfortunately, the ASCEND trial did not allow for therapeutic lag. If these hypotheses are correct the treatment effect of ocrelizumab should be greatest in comparison to placebo in the ORATORIO trial in relation to upper limb function, which is assessed using the 9-hole peg test. We will have to wait for more detailed analyses from the ORATORIO trial to be published to see if this is the case.

So what have we learnt from the ASCEND trial?

  1. That non-relapsing SPMS is a tractable problem; if we focus on the relevant outcomes, i.e. neuronal systems that have sufficient reserve capacity to demonstrate a treatment effect using responsive outcome measures such as the 9HPT and the ABILHAND we have a chance of a positive trial. The ABILHAND is a validated patient-related outcome measure of hand and upper limb function. 
  2. If we are going to continue to have to use the EDSS as an outcome measure we are either going to have to study an earlier population, similar to the ORATORIO study population, or do longer studies to allow for therapeutic lag. 
  3. In my opinion we need to ditch the EDSS as a primary outcome measure in progressive MS trials. For those of us old enough to remember we have seen evidence for these arguments in relation to the interferon in SPMS trials. The European interferon-beta-1b SPMS trial was positive when the North American study was negative; the former was in a younger less disabled population, whereas the latter was older and more disabled. 
  4. If we are going to do studies in more advanced MS then we need to focus our attention on neuronal systems with functional reserve, for example upper limb and bulbar function (speech and swallowing). For this to occur we will need to bring the regulators (EMA and FDA) on board. I think this is possible and is now urgent. 
  5. I suspect that to have a realistic chance to modify the non-relapsing progressive phase of MS we will need to use highly-effective DMTs. I am not surprised that both ocrelizumab and natalizumab have produced positive trial results in these populations; please note my emphasis on positive.  Because of this I have been lobbing Pharma to do trials in advanced progressive MS (both PPMS and SPMS combined) with the highly effective DMTs, i.e. alemtuzumab, ocrelizumab, daclizumab, ofatumumab and cladribine. Let's see who is brave enough to take on the challenge. If Pharma won't do it we will. 


Some caveats. The cynic in me worries more about the payers than the regulators. The cost effectiveness calculations in relation to DMTs are based on the cost of the treatment versus the savings to the individual and society. Once a person with MS has lost their mobility they have already accrued a large amount of personal and societal costs. These include both direct medical cost and indirect costs for example loss of employment. The sad thing once a person becomes unemployment their worth to society drops. If this is the case then the payers, for example NICE, may judge the cost-effectiveness of DMTs in more advanced MS to be less favourable; in other words expensive high-cost drugs such as natalizumab and ocrelizumab may not be cost-effective in more advanced MS compared to early MS when preservation of function will save society more money. This is one reason why Pharma are reluctant to take on the risk and develop drugs for more advanced progressive MS. A potential way to counter this is to allow Pharma and payers to agree to a differential payment scale; the more disabled a person with MS is the less the company is able to charge for their drug. This may sound crazy but it makes a lot of sense to me; it would force pharma to move to an outcomes based remuneration system. Under this system payers will get better value for money and pwMS will get treatments that work. This will allow us to move away from a fixed-pricing system to a value-based pricing system. We seem to be getting used this in many other sectors, surge pricing systems are used by the airlines, software industry and Uber. If you have used Uber you will know all about surge pricing. I can see a world where the same agent is more expensive when used in early MS and as the patient becomes more disabled the price for the drug is less. The question is the NHS and the Pharmaceutical sector ready for valued-based pricing? I think so this is already being explored in oncology. Why should the NHS, or individual, pay for something that doesn’t work? On the other hand why should we deny people with progressive MS drug X because it is considered to be not cost-effective at their stage of the disease ?

You can see that I am all fired-up from the AAN with as many ideas whizzing around my head as minutes in the day! Attending conferences provides thinking, talking, networking and downtime. This AAN was no exception. I would like to conclude this post with a huge thank you to Biogen for having the balls to do the ASCEND study and for the SPMSers for volunteering to take part in the study. Without this study we wouldn't have these insights.

Finally, a appreciative thank you to a well-meaning and generous Pharma executive who gave up his first-class upgrade to try and help me get a good nights sleep. When I was sitting in the BA lounge waiting to board my return flight from Vancouver a senior Pharma Executive, who I know well, came over to chat to me. When he heard I was flying economy+ back to London he tried to get me a business class upgrade. He was called to the BA desk for a first-class upgrade and turned it down by asking BA if they could upgrade me instead. They said they would try. However, when we got to board we both had our originally allocated seats. I am grateful that someone would try give up the comfort of a first class upgrade to try help me get a good nights sleep. However, I would prefer him to lobby his company to do a SPMS trial based on the insights of the ASCEND study."

CoI: multiple