Thursday, 27 April 2017

#PoliticalSpeak & #BrainHealth: can we shame MEPs?

The European Parliament sucks! #PoliticalSpeak #BrainHealth #MSBlog

The following is the EMSP report from our recent meeting at the European Parliament. The meeting was hosted by Cristian Busoi, an MEP from Romania, who was the only, and I really mean the only, MEP to attend. No other MEPs bothered to attend despite them being aware of the meeting and having many constituents in their countries with the disease. I wish we could name and shame them.


The report: 



My presentation:


The peogramme:

Wednesday, 26 April 2017

AAN Targeting EBV with CD8 specific T cells

Symptomatic and Objective Clinical Improvement in Progressive Multiple Sclerosis Patients Treated with Autologous Epstein-Barr Virus-specific T Cell Therapy: Interim Results of a Phase I Trial

Michael Pender, MD, PhD; Peter Csurhes; Corey Smith; Nanette Douglas; Michelle Neller, PhD; Leone Beagley, PhD; Sweera Rehan, PhD; Tracey Hopkins, PhD; Kate Thompson, PhD; Stefan Blum, MD; Kerryn Green, MBBS; Zara Ioannides, MD; Alan Coulthard, PhD; Kaye Hooper, PhD; Scott Burrows, PhD; Rajiv Khanna, PhD

Objective: To determine the safety of treating progressive multiple sclerosis (MS) patients with autologous Epstein–Barr virus (EBV)-specific T cells. Background: Mounting evidence indicates a role for EBV in MS pathogenesis. EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T-cell immunity.
Design/Methods: In this trial we administer autologous EBV-specific T cells to patients with progressive MS (EDSS 5.0–8.0). Each patient receives their own T cells stimulated ex vivo to enhance reactivity to EBV nuclear antigen-1, latent membrane protein 1 (LMP1) and LMP2A, and is followed through 26 weeks. Four escalating dose infusions are administered biweekly.
Results: To date, four SPMS patients and one PPMS patient have been treated. No significant adverse events have been observed. Three patients experienced symptomatic and objective clinical improvement, which commenced 2–8 weeks after the first infusion and was most marked in the two patients receiving T cells with the highest EBV reactivity. Striking improvement occurred in one SPMS patient, with normalization of lower extremity tone and plantar (Babinski) responses for the first time in 16 years, increased walking distance with walker from 100 metres at baseline and for the previous 5 years to 1200 metres, marked reduction in fatigue, increased manual dexterity, and improvements in lower extremity power, reflexes and sensation. A second SPMS patient had reduced fatigue, increased productivity and improved balance. The third responder (PPMS) had improved colour vision, visual acuity and manual dexterity and reduced fatigue, lower extremity spasms and urinary urgency. These data are consistent with prior data from the first patient ever treated (SPMS compassionate use) who experienced reduced fatigue and lower extremity spasms, and improved cognition, hand function and productivity.
Conclusions: This is the first report of clinical improvement in a prospective trial of autologous EBV-specific T cells to treat progressive MS patients. Further studies are planned.

Study Supported By: Multiple Sclerosis Society of Queensland, Multiple Sclerosis Research Australia and Perpetual Trustee Company Limited


This isa safety study designed to test whether vaccination against EBV could impact on MS. They have made viral reactive CD8 T cells and transfer them in to kill the EBV infected (B) cells. This will be of interest, so maybe ProfG may have time to tweet or report on the presentation.


In the AAN press release it said the trial was designed to look at ten people and have found it should have been five with PPMS and five with SPMS. In the trial, the volunteers received four escalating doses of cytotoxic CD8 T cells over six weeks and were followed for an additional twenty weeks after the last dose. 

Here the abstract above it says five people were looked but in the press release from the AAN, it says six. These results are encouraging, but the study is seemingly unblinded and is reporting symptomatic improvements and this is not what a trial in progression may go for. But being a phase I it is designed to say it is safe. 

This study used autologous cells, so they were generated from the same people who they were later received the cells back after they were expanded. 

However, this data is now being reported as company data. It appears the company has got some rights from the University in Queensland. 

Anyway according to the company website. They are planning to use their product as allogenic cells, i.e. made in one person to be used in another person. Whilst this will help in production of a standardised cell this, without more data on the technology, makes little immunological sense as to get proper engagement of cells you need your antigen presenting cells to present to your own T cells.

An allogenic cell may not recognize the B cells infected with EBV in another person, but they can recognize a large percentage of other peoples major histocompatibility complexes (transplantation antigens) as a target, so you could be injecting cells that that can potential kill every cell in the recipient. I hope not. 

More likely the injected cells will last about 5 days and then the recipient will destroy them as being invaders.  

#NeuroSpeak & #ClinicSpeak: fingolimod rebound is a yellow-carder

Another thing for HCPs to lookout for: rebound post-fingolimod. #ClinicSpeak #NeuroSpeak 

An emerging and very important differentiator in the MS space is rebound activity that occurs when stopping a therapy. The MHRA have now made this a reportable, or yellow-card, event. It is good to see the regulators taking such a keen interest in such an important issue. Maybe they are begging to flex their muscles before the EMA departs after Brexit. 


MHRA: Multiple sclerosis therapies: signal of rebound effect after stopping or switching therapy. April 2017.

Healthcare professionals should report any suspected adverse effects relating to fingolimod (Gilenya▼) or other treatments for multiple sclerosis, including suspected adverse effects occurring after discontinuation, via the Yellow Card Scheme.

We are aware of two recently published articles1 2 describing a suspected rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected for that patient prior to discontinuation or treatment change) in patients with multiple sclerosis after treatment with fingolimod (Gilenya▼) was stopped, some of whom were switched to other treatments.

In conjunction with other European national regulatory authorities and the European Medicines Agency, we are evaluating all available evidence on this safety signal. Further information on the outcome of the review and any relevant new guidance will be issued as soon as it is available.

Healthcare professionals are reminded to be vigilant for such events and report any suspected adverse effects relating to fingolimod or other treatments for multiple sclerosis via the Yellow Card Scheme.

For any reports of suspected rebound effect, please provide as much detail as possible. This could include any clinical, imaging and other test details; along with a description of disease activity prior to and during therapy.

Article citation: Drug Safety Update volume 10, issue 9, April 2017: 3.

Hatcher SE et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol 2016; 73: 790–94.

Willis M et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2017; 4: e320. 

CoI: multiple

Tuesday, 25 April 2017

#ThinkSpeak & #AAN2017: burnout

Did you know neurologists are the specialists that are most likely to suffer burnout? #ThinkSpeak #AAN2017


I went to the opening, or plenary, session of the AAN meeting and heard Terrence Cascino, the President of the AAN, present the data from a national survey of US neurologists on well-being, burnout and career satisfaction. It was flabbergasted to hear that neurology is the speciality most likely to be affected by burnout and that ~60% of  respondents had at least one symptom of burnout. As this impacts negatively on their work, I wonder how it is affecting the management of their patients with MS?

When Terrence Cascino presented the list of symptoms of burnout I realised that I, and a lot of my colleagues, suffer from burnout; i.e. emotional exhaustion, feelings of cynicism and detachment (depersonalization), and a sense of ineffectiveness at work (low personal accomplishment). I realise that I need to do something about it, but what?   


Busis et al. Burnout, career satisfaction, and well-being among US neurologists in 2016. Neurology. 2017 Feb 21;88(8):797-808.

OBJECTIVE: To study prevalence of and factors that contribute to burnout, career satisfaction, and well-being in US neurologists.


METHODS: A total of 4,127 US American Academy of Neurology member neurologists who had finished training were surveyed using validated measures of burnout, career satisfaction, and well-being from January 19 to March 21, 2016.

RESULTS: Response rate was 40.5% (1,671 of 4,127). Average age of participants was 51 years, with 65.3% male and nearly equal representation across US geographic regions. Approximately 60% of respondents had at least one symptom of burnout. Hours worked/week, nights on call/week, number of outpatients seen/week, and amount of clerical work were associated with greater burnout risk. Effective support staff, job autonomy, meaningful work, age, and subspecializing in epilepsy were associated with lower risk. Academic practice (AP) neurologists had a lower burnout rate and higher rates of career satisfaction and quality of life than clinical practice (CP) neurologists. Some factors contributing to burnout were shared between AP and CP, but some risks were unique to practice setting. Factors independently associated with profession satisfaction included meaningfulness of work, job autonomy, effectiveness of support staff, age, practicing sleep medicine (inverse relationship), and percent time in clinical practice (inverse relationship). Burnout was strongly associated with decreased career satisfaction.

CONCLUSIONS: Burnout is common in all neurology practice settings and subspecialties. The largest driver of career satisfaction is the meaning neurologists find in their work. The results from this survey will inform approaches needed to reduce burnout and promote career satisfaction and well-being in US neurologists.

AAN Siponimod Phase III positive in Secondary Progressive MS

Safety and Tolerability of Siponimod in Patients with Secondary Progressive Multiple Sclerosis: Robert Fox , Ludwig Kappos , Amit Bar-Or , Bruce Cree , Gavin Giovannoni , Ralf Gold, Patrick Vermersch , Harold Pohlmann, Christian Wolf , Frank Dahlke , Erik Wallström , Tatiana Sidorenko

Objective: To present safety and tolerability results of the randomized, double-blind, placebo-controlled, Phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). 
Background: Siponimod, a selective sphingosine 1-phosphate (S1P) receptor-1/-5 modulator with peripheral and central effects was investigated in SPMS, a condition driven by neurodegeneration and inflammation in the central nervous system, where treatment options are limited. Efficacy results are reported separately. 
Design/Methods: In EXPAND siponimod significantly reduced the risk of 3-month confirmed disability progression. Safety and tolerability based on the safety analysis set for the double blind treatment period are reported. Patients were randomized (2:1) to receive once-daily siponimod 2mg or placebo (with a 6-day initial dose titration). 
Results: Of 1651 randomized patients, 1645 comprised the safety population (siponimod, N=1099; placebo, N=546). Mean age was 48 years (SD 7.87), median EDSS 6.0. At least one treatment-emergent adverse event (TEAE) was reported for 88.7% and 81.5% of siponimod and placebo patients; in 7.6% and 5.1% of patients, these led to treatment discontinuation. Most common TEAEs (>10% in any group) were headache, nasopharyngitis, urinary tract infection, falls and hypertension. Serious TEAEs were reported in 17.9% and 15.2%, including four deaths in each treatment group (0.4% and 0.7%). Incidence of infections and malignancies were similar (49.0% vs. 49.1%, 1.9% vs. 2.6%, respectively). Lymphopenia below 0.2x10˄9/uL was observed in 2.7% vs. 0.2% of patients and Liver Function Test elevations ≥3xULN – in 5.6% vs. 1.5%. The incidence of other AEs of interest were: bradyarrhythmias, 3.5% vs. 2.4%; hypertension, 12.6% vs. 9.3%; and macular oedema, 1.8% vs. 0.2%, respectively. With dose titration (during treatment initiation) there were only few bradyarrhythmic events. No cases of Mobitz II or higher degree AV-blocks were reported. Conclusions: The safety profile of siponimod appears to be in line with other S1P receptor modulators. 

Efficacy of Siponimod in Secondary Progressive Multiple Sclerosis: Results of the Phase 3 Study Ludwig Kappos , Amit Bar-Or , Bruce Cree , Robert Fox , Gavin Giovannoni , Ralf Gold , Patrick Vermersch , Sophie Arnould , Tatiana Sidorenko , Christian Wolf , Erik Wallström , Frank Dahlke

Objective: To present the efficacy results of the randomized, double-blind, placebo-controlled, phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). 
Background: Siponimod, a selective sphingosine 1-phosphate receptor-1 and -5 modulator with peripheral and central effects was investigated in SPMS, a condition for which treatment options are limited. 
Design/Methods: Patients were randomized (2:1) to once-daily siponimod 2mg or placebo. The primary endpoint of this event- and exposure-driven study was time to 3-month confirmed disability progression (CDP), assessed by the Expanded Disability Status Scale (EDSS). Key secondary endpoints were time to confirmed worsening of ≥20% from baseline in the Timed 25-Foot Walk test (T25FW) and T2 lesion volume (T2LV) change from baseline. Other secondary endpoints were 6-month CDP, annualized relapse rate (ARR), 12-item Multiple Sclerosis Walking Scale (MSWS-12), number of T1-Gd+ and T2 lesions and percent brain volume change (PBVC). For other secondary endpoints p-values are nominal (not corrected for multiplicity). Safety and tolerability are presented separately. 
Results: Overall, 1651 patients were randomized. Siponimod reduced the risk of 3-month CDP by 21% versus placebo (HR [95% CI]: 0.79 [0.65, 0.95]; p=0.013). Point estimates in favor of siponimod were consistently observed across predefined subgroups, including patients with no relapses in the 2 years prior to study and those without gadolinium-enhancing lesions at baseline. The risk reduction observed for T25FW was 6.2% and not statistically significant (p=0.440). Siponimod reduced the risk of 6-month CDP by 26% (p=0.006), ARR by 55.5% (p<0.0001), T1 Gd+ lesion number by 86.6% (p<0.0001), and new T2 lesion number by 81% (p<0.0001). Relative difference in change from baseline in T2LV, MSWS-12 and PBVC were 79.1% (p<0.0001), 39.7% (p=0.057) and 23.4% (p=0.0002), respectively, versus placebo. 
Conclusions: Siponimod had a robust positive effect on disability progression and other relevant outcomes in SPMS. 
So good news for secondary progressive MS. At last a **imod that does something so why did fingolimod not work in primary progressive. It is clear that it blocks the same targets. Points in favour was found in people without relapses or gadolinium enhancing diseased. ProfG is a co-author so can fill you in on that score

CoI Multiple