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.

To summarize 5-year incidence and timing of thyroid adverse events following alemtuzumab treatment in the ongoing CARE-MS extension study.
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.
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.
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.
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