Saturday, 22 October 2016

#ClinicSpeak & #ResearchSpeak: time to step-up or shut-up

Why did we allow the baby to be thrown-out with the bathwater? Successful, but unsuccessful, treatments for progressive MS. #ClinicSpeak #ResearchSpeak

There are so many killjoys out there who think progressive MS is an intractable problem and that we have no treatments that work. Incorrect! I would like to remind these killjoys of the cyclosporine and methotrexate studies from over 25 years ago in people with chronic progressive MS (SP & PPMS). Both these studies were positive and had an impact on disability progression. Cyclosporine was dropped because of renal toxicity and hypertension and methotrexate was dropped because most people think that protecting the upper limbs in people with progressive MS is not worth doing. 

I suspect, however, if methotrexate had been a innovative compound with a long patent-life it would have been taken forward into larger and more definitive trials. If these trials were done with modern insights we would have had a licensed DMT for progressive MS decades ago. What killed methotrexate as a treatment for MS was that it was a cheap generic drug. It is because of the trial below that I have included methotrexate on our essential off-label list of DMTs. If you had progressive MS would you consider methotrexate?  

The problem is that most pwMS and their families, and some in the neurological community, have unrealistic expectations of what to expect from an effective DMT for progressive MS. An anti-inflammatory therapy is unlikely to stop progression immediately, as this has been primed by previous damage and is destined to run its course over the next few years. What is more likely to occur is the slowing, or flat-lining, of progression over 2-5 year period; this delayed effect is what we refer to as therapeutic lag. The more neuronal reserve you have, i.e. the ability to recover function, the sooner you notice a therapeutic effect. 

With the natalizumab in SPMS, or ASCEND, trial there was no impact on EDSS and T25FW in 2 years, but a significant effect on the 9HPT. I suspect that if the trial went on longer for say 3 years then the EDSS and T25FW curves would have opened-up and we would have had a positive trial. There is a chance we may find-out if this actually happened; a large number of the original ASCEND population got to 3-years in the follow-up study of ASCEND before Biogen stopped the extension study. I predict that the study subjects who received natalizumab throughout the study (2 years of blinded study and one year of extension) will do better than those who were on placebo (2 years placebo and 1 year natalizumab). If I was a betting man I would put money down on this prediction.

The above is water under the bridge, right now we should be celebrating the recent results of ocrelizumab in PPMS and siponimod in SPMS, results. The killjoys say these results are not good enough. What do you want? Please remember a  25% difference in progression rates at 
at 2-3 years of follow-up may be 50% at 5 years and 75% at 10 years. I agree that if you have progressive MS these results are not what you want; you want to get back to normal. However, these drugs are not designed to restore function; for that to occur we need new therapies to add-on to anti-inflammatory therapies. Please be positive and celebrate the recent successes in progressive MS. The tragedy is we had similar successes over 25 years ago and we didn't build on them. This time we need to seize the day; carpe diem!

The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol. 1990 Jun;27(6):591-605.

Methods: Patients with clinically definite multiple sclerosis, mild to moderately severe neurological disability (entry score on the Expanded Disability Status Scale (EDSS) between 3.0 and 7.0), and a progressive course defined by an increase in the EDSS of between 1 and 3 grades in the year prior to entry were randomized to receive either cyclosporine (n = 273) or placebo (n = 274) in a 2-year, double-blinded, multicenter trial. Treatment groups at entry proved balanced for age, gender, duration of illness, and neurological disability. Cyclosporine dosage was adjusted for toxicity and a median trough whole-blood level was maintained between 310 and 430 ng/ml. 

Results: The mean increase in EDSS score was 0.39 +/- 1.07 grades for cyclosporine-treated patients and 0.65 +/- 1.08 grades for placebo-treated patients from entry until the time of early withdrawal or completion of the study (p = 0.002). Of three primary efficacy criteria, cyclosporine delayed the time to becoming wheelchair bound (p = 0.038; relative risk, 0.765), but statistically significant effects were not observed for "time to sustained progression" or on a composite score of "activities of daily living." Active treatment did have a favorable effect on several secondary measures of disease outcome. A large and differential withdrawal rate (44% for cyclosporine-treated patients, 32% for placebo-treated patients) complicated the analysis but did not appear to explain the observed effect of cyclosporine in delaying disease progression. Multivariate analysis did not show institutional effects but did demonstrate substantial effects of baseline neurological disability on outcome. Nephrotoxicity and hypertension were common troublesome toxicities and accounted for most of the excess loss of patients in the cyclosporine arm of the study. 

Conclusion: Thus, chronic cyclosporine therapy was associated with a statistically significant but clinically modest delay of progression of disability in a group of patients with multiple sclerosis selected for moderately severe and progressive disease. Close supervision by physicians familiar with cyclosporine is mandatory to minimize known adverse effects, particularly nephrotoxicity, when considering the use of this immunosuppressant. 

Goodkin et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis.  Ann Neurol. 1995 Jan;37(1):30-40.

Methods: A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. 

Results: Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity

Conclusions: We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

CoI: multiple

Making Cyclosporin More Neuroprotective

Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.Warne J, Pryce G, Hill JM, Shi X, Lennerås F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL.
J Biol Chem. 2016;291(9):4356-73.

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

I draw your attention to some of our research that showed that if we took cyclosporin A we can get the neuroprotective part and reduce the immunosuppressive part of cyclosporin A.

Lead optimization is ongoing

Antigen specific therapy shows nothing

CD206-Targeted Liposomal Myelin Basic Protein Peptides in Patients with Multiple SclerosisResistant to First-Line Disease-Modifying Therapies: A First-in-Human, Proof-of-Concept Dose-Escalation Study.
Belogurov A Jr, Zakharov K, Lomakin Y, Surkov K, Avtushenko S, Kruglyakov P, Smirnov I, Makshakov G, Lockshin C, Gregoriadis G, Genkin D, Gabibov A, Evdoshenko E.

Neurotherapeutics. 2016 Oct;13(4):895-904.Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46-62, MBP124-139 and MBP147-170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.

The mannose receptor (Cluster of Differentiation 206, CD206) is a C-type lectin primarily present on the surface of macrophages and immature dendritic cells. In this study they got a liposome-a spherical vesicle having at least one lipid bilayer. The liposome can be used as a vehicle for administrationof nutrients and pharmaceutical drugs.  In this study they put myelin basic protein peptides into the liposome and it apparently inhibited EAE in rats.

So know they have put it into humans and they put it into relapsing MS and SPMS and  was given to people for 6 weeks and they looked to see what happened...and simply put they got nothing by the end of the study.

What happened in previous trials

Intravenous myelin basic protein failed in SPMS....
Subcutaneous myelin basic protein peptide...failed or made MS worse.

I am not a fan of subcutaneous immune tolerance and not a fan of myelin basic protein as a candidate antigen in MS so best keep my mouth shut,

If you were an investor with this first result in a phase I which is all about safety...encorage you to invest more, because is the therapeutic response going to get better.

Death of an Idea by Twitter

The was a recent paper studying some Canadian families suggesting that the NR1H3 was a genetic factor influencing progressive MS.  

So sooner had the Ink dried than Dan MacArthur...was on twitter saying that the work was mushroom food.
                                Now if paper format

Minikel EV, MacArthur DG.Publicly Available Data Provide Evidence against NR1H3 R415Q Causing Multiple Sclerosis. Neuron. 2016;92(2):336-338. doi: 10.1016/j.neuron.2016.09.054.

It has recently been reported that an NR1H3 missense variant, R415Q, causes a novel familial form of multiple sclerosis (Wang et al., 2016a). 
This claim is at odds with publicly available data from the Exome Aggregation Consortium (ExAC; 

The allele frequency of R415Q is not significantly higher in cases (0.024%-0.049%) than in ExAC population controls (0.031%), whereas if R415Q conferred even 50% lifetime risk of developing MS, it would be hundreds of times more common in cases than in controls. The upper bound of the 95% confidence interval of penetrance for R415Q can be estimated at 2.2% for women and 1.2% for men, indicating that even if this variant is disease associated, individuals harboring the variant would have a lifetime risk of developing MS no higher than a few percent. ExAC data should be considered when evaluating claims of variant pathogenicity. 

NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk.
International Multiple Sclerosis Genetics Consortium. Electronic address:; International Multiple Sclerosis Genetics Consortium

A recent study by Wang et al. (2016a) claims that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause multiple sclerosis in certain individuals and determines a patient's likelihood of primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al. (2016a), but we find no evidence that this variant is associated with either MS or disease subtype. Wang et al. (2016a) also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS-of which no examples exist-can therefore not be substantiated by data. 

Friday, 21 October 2016

ClinicSpeak & ResearchSpeak: to stop, or not to stop, DMTs in SPMS that is the question

Stop DMTs and do the right thing; save the NHS money! #ClinicSpeak #MSResearch #MSBlog #ResearchSpeak

The small French study below concludes that in pwSPMS on DMTs it is safe to stop DMTs because the relapse rate stays relatively constant off, or on, treatment. Please note that 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). What they don't tell you is how massively under-powered their study is (they only had 100 participants in this study) and the study was uncontrolled (no comparator group). When we want to show that a DMT works in progressive MS we take a large number of pwMS and randomise them to active treatment or placebo. The PPMS-ocrelizumab study randomised 732 subjects and the SPMS-siponimod study 1651 subjects; do we really expect 100 pwSPMS to answer the reverse question? 

What we really need is a randomised double-blind study where we randomise pwSPMS on DMT to remain on their active treatment or to placebo and then we wait see what happens in terms of long-term outcomes. A non-blinded study like this is being planned in the US. The best we have is the MS-BASE data below using real-life data and matching of subjects at baseline (propensity scoring). This study included 485 DMT-stoppers and 854 DMT-stayers followed for at least 3-years. Unsurprisingly, time to confirmed disability progression was significantly shorter among DMT stoppers than stayers, implying that the stayers were still deriving benefit from their DMT. Some would argue that this study took all-comers and not just pwSPMS. I would counteract that argument that the progressive pathology that drives both SPMS, and PPMS, is there from the beginning of the disease and that our clinical definition of when SPMS begins is arbitrary. 

Stopping DMTs in pwMS who have transitioned from the relapsing to the clinically-apparent SPMS phase is at present is non-evidence based and flies in the face of recent data showing that DMTs, in particular high-efficacy therapies, are still having an effect on protecting upper limb, and possibly bulbar (speech and swallowing), function in pwMS with more advanced disease. This is why I find it hard to stop DMTs in people who have SPMS. 

Despite the lack of evidence to help us we have strict NHS guidance to stopping DMTs in pwSPMS. The latter is mainly driven by costs; the NHS is on its knees financially and any cost savings are welcomed. Another solution would be to ask the NIHR to fund a randomised DMT stopping trial to see if we can generate the much needed evidence to guide clinical practice?


Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.

METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.

RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).

CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.

Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.

BACKGROUND:  Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.

OBJECTIVES: (1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.

METHODS: Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.

RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.

CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

CoI: multiple