Wednesday, 22 February 2017

HSCT activity in Progressive MS

Paolo A. Muraro, et al.Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol 2017

Question:  What are the long-term outcomes after autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis?

Findings:  In this multicenter cohort study of 281 patients with predominantly progressive forms of multiple sclerosis who underwent autologous hematopoietic stem cell transplant between 1995 and 2006, transplant-related mortality was 2.8% within 100 days of transplant, and neurological progression-free survival was 46% at 5 years. Younger age, relapsing form of multiple sclerosis, fewer prior immunotherapies, and lower neurological disability score were significantly associated with better outcomes.

Meaning:  The results support the rationale for further randomized clinical trials of autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis.


Importance:  Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.

Objective:  To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

Design, Setting, and Participants:  Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

Exposures:  Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

Main Outcomes and Measures:  The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

Results:  Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

Conclusions and Relevance:  In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

If you cared to read the paper by ProfG and others members of TeamG on length dependent axonopathy (we hope that it will be open access soon) it suggests that it is not too late to benefit people with progressive MS, even with immunosupression. 

Therfore just as well wee havn't given in progressive MS.

This study offers some support when analysis of people with MS undertaking HSCT was done. In this 80% of people had progressive MS and disability progression was stoped in about 50% of 5 people up to 5 years of analysis. It will take longer follow-up to see if this is sustained but based on the data below people continue to fail so at 10 years the progression free cohort only makes up about 30 percent. As you can see if you were relapsing verses progressive you were about two-three times as likely to see benefit.

So it says 50% of people progressed and tells me we need more than peripheral immunosuppression. I suspect you need to deal with inflammation in the brain. It also says that nearly 3% of people didnt make it, so it is not something you should do with your eyes closed. However in more recent studies this risk of mortality has reduced. 

You need to be clear what the risks are and the competence and success of centres where you may undergo this . The types of HSCT was not all the same and (17.4% [49 of 281] low intensity, 63.7% [179 of 281] intermediate intensity, and 18.9% [53 of 281] high intensity treatment regimes. 

The data raise the possibility that AHSCT may have reduced the risk of disease progression in the treated patients, yet demonstration is lacking in the absence of a control group. 

The incidence of new autoimmune disease was 5.0% (14 of 281), but considerably lower than after lymphocyte-depleting treatment with alemtuzumab, which approaches a risk of 50%.,

It is open access so have a read.

#NeuroSpeak & #ClinicSpeak: treating PML-related IRIS

A new treatment for PML-related IRIS based on hard science and anecdote #NeuroSpeak #ClinicSpeak #MSBlog

Substituting one disease for another. A large number of you argue that by treating MS, a disabling disease, with immunosuppressive therapies we simply create another ticking time bomb and swap one disease, MS, for another disease, immunosuppression. The difference between these two diseases is that MS-related disability is in general irreversible and associated with loss of quality of life. Immunosuppression on the other hand can be derisked to some extent and its consequences, in particular the opportunistic infections, treated.

The poster-child for derisking opportunistic infections must be natalizumab-associated PML. We now know that pwMS who are JCV-seropositive need to come off natalizumab because of the risk of PML. In high-risk subjects who decide to stay on natalizumab, against our advice, we offer them 3-monthly MRI studies to look for asymptomatic PML, which has a better prognosis than symptomatic PML. The problem with PML is that you need immune reconstitution to clear the virus from the brain and herein lies the problem. When you wash out natalizumab with either plasma exchange, or by waiting for it to wash-out spontaneously, when your immune cells start re-trafficking into the brain you develop and encephalitis. This is called IRIS (immune reconstitution inflammatory syndrome). IRIS in itself is very dangerous. Therefore in patients with a large PML burden, or PML in strategic brain areas such as the brainstem, we tend to give steroids to try and dampen down the damage associated with IRIS. Anecdotal experience suggests steroids work. Is there another strategy we can try?

Two case reports below describe the anti-HIV drug, maviroc, which blocks a particular chemokine receptor CCR5 on lymphocytes, may help prevent or dampen down IRIS. T-cells, including cytotoxic CD8+ T-cells, use CCR5 to cross the blood-brain-barrier. Blocking CCR5 dampens down IRIS and appeared to prevent IRIS-related damage in these two cases. Clearly maviroc as a monotherapy is not enough to stop the immune system clearing the JC virus from the CNS. The question that arises is whether or not maviroc is better than steroids in achieving this? The latter will require a clinical trial. 

In reality I hope the number of cases of natalizumab-associated PML drops to become a very rare complication of this treatment. Now that we have derisking strategies, and other highly-effective DMTs which are safer do we really need to continue to put pwMS at such a high risk of PML? 

Please note that until we get a drug  that clears JCV from the body we will never derisk the PML problem completely. As you are aware PML is a complication of immunosuppression and therefore it will remain a very rare complication of our MS treatments. 

Steiner & Benninger. Maraviroc in PML-IRIS: A separate ball game under HIV infection and natalizumab? Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e331. doi: 10.1212/NXI.0000000000000331. 

Progressive multifocal leukoencephalpathy (PML) is a severe, often fatal, opportunistic infection of the CNS. First reported in 1958 as a white matter disorder in 3 patients with lymphoproliferative disorders, subsequent studies revealed a polyomavirus, named John Cunningham (JC) virus from the initials of the patient from whose brain it was initially isolated, as the causative agent.

The pathogen is a ubiquitous DNA virus that infects only humans. Subclinical infection often takes place within the first decade of life. 

PML became strikingly prevalent, observed in 4%–5% of all patients with HIV prior to the availability of highly active anti-retroviral therapy (HAART). 

The era of monoclonal antibodies for immune-mediated conditions such as natalizumab (Tysabri) for MS and Crohns disease and efalizumab (Raptiva) for psoriasis heralded another context for PML. 

As of November 30, 2016, there have been 698 reported cases of PML under natalizumab.

While HAART has a significant beneficial impact on the prognosis of PML in patients with HIV, it remains one of the 4 most common CNS opportunistic infections affecting patients with AIDS.

The institution of screening patients with MS for seropositivity for JC virus has decreased the prevalence of PML in natalizumab-treated patients with MS. The termination of this therapy and using plasma exchange to remove the monoclonal antibody from the circulation when PML is diagnosed has a beneficial effect on prognosis.

However, the introduction of HAART and the discontinuation of natalizumab led to the recognition of the immune reconstitution inflammatory syndrome (IRIS), an entity that is not unique to PML and has been observed also with mycobacterial diseases, leprosy, fungal infections, and herpes viruses. 

IRIS is the consequence of rapid entry of immune cells into the brain at the time of immune restoration. IRIS has occurred in the majority of patients with natalizumab-associated PML following withdrawal of natalizumab and plasma exchange. The diagnosis of CNS-IRIS in patients with MS with natalizumab-associated PML can be challenging because the deterioration might be attributed to PML, MS, or some other opportunistic infection.

Thus, diagnosis of PML in an immune-compromised patient is associated with a 2-edge challenge and risk: clearing the JC virus from the brain, which requires normalisation of the immune state, and reconstitution of immune surveillance while minimising infiltration of the brain with activated T cells that attempt to control an underlying CNS opportunistic infection.

Maraviroc is drug developed to protect against HIV. HIV infects human T cells via recognition of the CD4 and notably the chemokine receptor CCR5. Maraviroc blocks CCR5.

It has been reported that the CD8 T cells that target the JC-virus infected cells express CCR5, and maraviroc can inhibit the accumulation of CD8 T cells. 

It is also evident that maraviroc use can have serious side effects, including liver problems.

There are two case reports concerning the treatment of IRIS.

Hodecker et al. Maraviroc as possible treatment for PML-IRIS in natalizumab-treated patients with MS. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e325. doi: 10.1212/NXI.0000000000000325.

Serial axial postcontrast T1-weighted magnetic resonance images of the brain of case 1 (A–C) and case 2 (D–F). (A) In February 2015, a T1-weighted image showed right subcortical occipital lesion (hyperintense in T2-weighted images) with subtle contrast enhancement suggestive of progressive multifocal leukoencephalopathy (PML) in a clinically asymptomatic patient. (B) Four months later, MRI showed progression of the contrast-enhancing occipital lesion, and maraviroc treatment was initiated. (C) Six months after start of maraviroc, MRI shows regression of PML–immune reconstitution inflammatory syndrome (IRIS) with no detectable contrast enhancement. (D) A routine MRI in February 2015 showed disseminated contrast-enhancing lesions in the cerebellum suggestive of PML in a clinically asymptomatic patient. (E) In May 2015, a T1-weighted image showed extensive IRIS after discontinuation of maraviroc. (F) Eleven months after the initial diagnosis of PML and after 8 months of maraviroc treatment, multiple disseminated contrast-enhancing lesions in the cerebellum are still detectable.

Bsteh et al. Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e323.

(A, B) MRIs at admission show a lesion in the right central region without Gadolinium (Gd)-enhancement suspect of progressive multifocal leukoencephalopathy (PML). (C, D) MRIs after plasmapheresis show a markedly increased PML lesion size on T2 sequences but no Gd-enhancement. (E, F) Eight days after maraviroc initiation, MRIs reveal stable PML lesion size with inhomogenous spotty Gd-enhancement, consistent with moderate localized immune reconstitution inflammatory syndrome. (G, H) MRIs obtained 6 months after maraviroc initiation showed regression of PML lesion size in T2 without Gd-enhancement but a demarcated substance defect in T1 sequences.
CoI: multiple

Tuesday, 21 February 2017

Guest Post MSBaseGold: Comparisons of DMT

Today we are delighted to have another Guest post from Tomas Kalincik from University of Melbourne, Australia, please see his Biography on his previous post.

Kalincik et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017 Feb 10. pii: S1474-4422(17)30007-8.

BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years.

METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models.

FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006).

INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.

FUNDING: National Health and Medical Research Council, and the University of Melbourne.

Tomas Kalincik

"This large collaborative study brought together investigators from MSBase and clinicians from six academic MS centres in Cambridge, Cardiff, Swansea, Bristol, Dublin and Dresden. We have used propensity score matching, pairwise censoring and weighting in order to create a composite cohort of sufficient size to enable conclusive comparisons of alemtuzumab (a monoclonal antibody depleting circulating B and T lymphocytes, which was approved in multiple countries for use in relapsing-remitting MS in 2015) and three other commonly used therapies - interferon beta, fingolimod and natalizumab.

The comparison of alemtuzumab with interferon beta allowed us to replicate the results of the pivotal phase 3 trials of alemtuzumab (CARE-MS 1 and CARE-MS 2), anchoring our study in the existing evidence. It showed that the effect of alemtuzumab on suppressing relapses was superior to that of interferon beta. In patients with previously highly active disease, alemtuzumab was also more likely to prevent worsening of disability and even lead to some disability reversal. We have used this replication of the previous studies as a validation of our methodology before applying it to a new scenario - the comparison with fingolimod and natalizumab.

Alemtuzumab was superior to fingolimod in decreasing relapse incidence. However, its effect on disability (whether disability accrual or its resolution) was similar to that of fingolimod. On the other hand, alemtuzumab and natalizumab had very similar effects on suppressing MS relapses and worsening of disability. However, natalizumab was more often associated with improvement in disability early after patients commenced therapy. This difference in treatment effect was mostly seen during the first year of treatment.

Our study focused on comparing clinical efficacy of alemtuzumab and the three therapies. It did not compare the effect of the therapies on brain MRI, neither did it answer the question of its relative treatment safety."

CoITK reports grants from National Health and Medical Research Council (Australia), and Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; grants, personal fees, and non-financial support from Biogen; personal fees from Roche, Teva, and BioCSL; and personal fees and non-financial support from Sanofi Genzyme, Merck, Novartis; and personal fees from WebMD Global.

MouseDoctor says:

As we are looking at MS drugs in the Real World today, we would like to thank Tomas for discussing his recent work. If you can spare a minute and can understand Australian:-). 

You can have a view of  Dr.Kalincik in the News (Click here)

Drug companies generally only do head to head studies when they know their product will win. Therefore it is great that registries exist, to allow comparisons of effects to be undertaken. This study confirms what we suspect in terms of drug hierarchies. 

Real world data on efficacy or #alternativefact

Neurol Ther. 2017 Feb 16. doi: 10.1007/s40120-017-0064-x. [Epub ahead of print]

Comparative Effectiveness Research of Disease-Modifying Therapies for the Management of Multiple Sclerosis: Analysis of a Large Health Insurance Claims Database.

Boster A, Nicholas J, Wu N, Yeh WS, Fay M, Edwards M, Huang MY, Lee A.



Limited data are available on the real-world effectiveness of newer oral disease-modifying therapies (DMTs) in multiple sclerosis. The purpose of this study was to retrospectively compare the real-world effectiveness of dimethyl fumarate (DMF), fingolimod, teriflunomide, and injectable DMTs in routine clinical practice based on US claims data.


Patients newly-initiating DMF, interferon beta (IFNβ), glatiramer acetate (GA), teriflunomide, or fingolimod in 2013 were identified in the Truven MarketScan Commercial Claims Databases (N = 6372). Relapse episodes were identified based on a published claim-based algorithm and used to determine the annualized relapse rate (ARR) for the year before and after initiating therapy. Poisson and negative binomial regression was used to determine the adjusted incidence rate ratio (IRR) for each therapy relative to DMF.


Significant ARR reductions in the year after initiating therapy were reported for DMF and fingolimod (P < 0.0001). Compared with DMF, the adjusted IRR (95% CI) for relapse in the year after initiating therapy was 1.27 (1.10-1.46) for IFNβ, 1.34 (1.17-1.53) for GA, 1.23 (1.05-1.45) for teriflunomide, and 1.03 (0.88-1.21) for fingolimod. Results were consistent across subgroup and sensitivity analyses.


These real-world data suggest DMF and fingolimod have similar effectiveness and demonstrate superior effectiveness to IFNβ, GA, and teriflunomide.


Biogen, Cambridge, MA, USA.

In the way that social media has changed the face of news distribution once and for all, open access journals are steadfastly changing the face of science - for better or worse is a matter open to debate. Their 'free at point of access' policy means that their readership naturally increases with time compared to traditional paid journals. Open access journals may therefore become the modern-day equivalent of the unwitting accomplice for here-sayers and nay-sayers.

In MS therapeutics, as we have no head to head studies against the different disease-modifying therapies in MS, we are left with retrospective analysis of recorded data. In the case of the US, this would be the 'Commercial claims' insurance databases. Boster et al. (in a study funded by Biogen) claim that DMF (tecfidera) has similar effectiveness to fingolimod, but is SUPERIOR to the other first-line therapies (alemtuzumab and natalizumab were not included) (see Figure below). They justifiably point out that this can be explained by the non-compliance to therapy on injectables, but even controlling for this it would appear that DMF still comes out on top. The accuracy of data keeping and truthfulness of accounts is barely just touched upon.

The market size of DMF is sizable and that is food for thought. The fact that I have posted on this today will increase the altametrics of this article (Multiple Sclerosis BlogSpot averages on ~5000 page views/day). The alternative oral drug, Novartis's fingolimod (gilenya) is it's main competitor.

The authors conclude: "These data should assist in treatment decisions regarding the choice of DMT and enable clinicians to consider both real-world effectiveness and route of administration in consultations with their patients". In an attempt to be equally provocative I might add that biosimilars demonstrating equivalent efficacy are the poor man's alternative! It would be therefore reasonable to assume that in the current day #alternativefact, that almost nobody is flush with aces.

Figure: Unadjusted annualized relapse rates for 1 year before and 1 year after DMT initiation. DMT disease-modifying therapy

Monday, 20 February 2017

#OffLabel & #ClinicSpeak: nabilone instead of street cannabis

Off label Nabilone is a treatment option for MS-related spasticity #OffLabel #ClinicSpeak #MSBlog

I grew up in apartheid South Africa and recall the sweet smell of 'dagga' (SA street lingo for cannabis), that wafted from the workers, or gardeners, quarters at my primary school. The workers, who were all black at that time, generally used cannabis in large amounts to survive the drudgery of their apartheid existence. They were all migrant workers with families who tragically lived far away. They barely survived on a minimum wage, doing menial unskilled labour. Their bloodshot eyes, clouded awareness and sweet bodily aroma made me aware  at a very young age, that the torpor due to their excessive cannabis use could not be good for either their physical or mental health. Apartheid has many wrongs to answer for; the mental and physical health of the majority comes close to the top of the list.  

It would be decades later as a MS researcher that I would discover, from the MouseDoctors, that cannabis could have real benefits for pwMS. Our research led to the development of THC as a symptomatic treatment for pwMS and should also have led to the development of THC as an add-on neuroprotective drug for people with more advanced MS. Unfortunately, the phase 2 neuroprotective trial we were involved in was done at a time when we did not have the insights we now have about the EDSS (not fit for purpose), asynchronous progressive MS, nor that MS is a length-dependent axonopathy. I am confident that if we had the opportunity to do a trial of THC as an add-on neuroprotective agent in more advanced MS we would design the trial very differently and have more than a fighting chance of getting a positive result. 

Although we do have a licensed cannabinoid for the treatment of MS-related spasticity we can't prescribe it under the NHS. Sativex, which contains the active ingredients of cannabis (THC and CBD), cannot be prescribed as it has not been 'NICEd'. Sativex has not bee shown to be cost-effective. This is very frustrating as so many of our patients would benefit from this drug. This very unfortunate situation forces many pwMS in the UK to buy street cannabis. As a neurologist I can't sanction this; cannabis is illegal in the UK and I would be putting myself at risk if I prescribed, or even recommended, street cannabis. I am aware that in other parts of the world, where cannabis has been legalised for medicinal use, neurologists can prescribe cannabis. 

How to get around this problem in the UK? I have recently started prescribing nabilone, a licensed small molecule drug that works on the CB1 receptor. CB1 is the cannabinoid receptor responsible for THC's anti-spastic effects. Nabilone is licensed in the UK for the control of nausea and vomiting, caused by chemotherapeutic agents and used in the treatment of cancer. I have recently had two patients who were using excessive street cannabis to control their spasticity and nocturnal leg spasms. Nabilone at a dose of 2 mg twice of day has allowed both these patients to stop smoking street cannabis and both have noted improved control of their spasticity. On the plus side both these patients have stopped smoking cannabis, which in itself has health benefits in that they are not exposing their lungs to smoke. 

Please be aware that the use of off-label nabilone is not ideal and in a perfect world we would have unfettered access to Sativex. What is galling is that Sativex was developed, and made, in the UK by a small start-up Pharma company. If the NHS does not support its own, UK-based, Pharma industry what hope is there for Pharma UK? This is in distinct contrast to France and Germany, where the politicians go out of their way to make sure their national healthcare systems support their own, home-grown, Pharma Companies. Is this nepotism? Is this the reason Trumpster's want to the UK to shutdown NICE?  

Please note that some patients are prescribed Sativex in the UK under the IFR (individual funding request) system, via patient access schemes paid for by individual NHS Trust's and not NHS England, or via the private prescription route. 

CoI: multiple