Tuesday, 27 June 2017

Staggeringly profitable business of Science publishing

If you are interested in the publishing process you may want to read this. We have been telling you about the publication process and this article adds to the madness. 

Is the staggeringly profitable business of scientific publishing bad for science? by Stephen Buranyi CLICK Here


In addition to this, the Open access system has turned it all into a bottomless sink. Will it change....not whilst you have things like the REF and Impact factors driving people to publish in these journals. 

The journals have preyed on this so the high impact popular journals have all created open access pay to publish sister journals so when they reject papers they feed them into to the pay to publish journals. 

This has created an open access industry of tripe journals desperate for content......and your cash

Like the saps and Lemmings that we are we have bought into this.
However it is adding millions to the research budget that could be better spent eleswhere.

#EAN2017 & #ClinicSpeak: immune reconstitution therapies

Should access to healthcare, for example HSCT, be equitable? #EAN2017 #ClinicSpeak

As promised the following is my presentation from the Excemed MS Symposium held on Sunday night at the EAN in Amsterdam. I had feedback from several people about how appealing selective immune system depletion followed by reconstitution is as a a treatment strategy for MS. However, the efficacy of all of our licensed DMTs remain a long way off that of what is being reported with HSCT. 

Giovanni Mancardi gave a wonderful meta-analysis in the session on the result of AHSCT and how the safety profile has improved. The most recent mortality is less than 0.3%, i.e. less than 3 in a 1,000 treated patients. I am therefore not surprised that a lot of pwMS who are not concerned about the risks associated AHSCT are frustrated about the lack of access to it as a treatment option. I really hope the NIHR will fund a AHSCT trial in the UK. We need randomised controlled data for AHSCT to become routine; otherwise it will remain a lottery with some pwMS being able to access AHSCT whilst others not being able to access AHSCT. The latter brings up the ethical dilemma about whether of not access to healthcare should be equitable. 


CoI: multiple

Blood NFL as marker of no evidence of disease activity with fingolimod

Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod


Fredrik Piehl, Ingrid Kockum, Mohsen Khademi, Kaj Blennow, Jan Lycke, Henrik Zetterberg, Tomas Olsson

Multiple Sclerosis Journal, First Published 19 Jun 2017.doi: 10.1177/1352458517715132

Abstract

Background:
Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS).

Objective:
To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod.

Methods:
A first cohort consisted of MS patients (n = 39) and neurological disease controls (n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort (n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL).

Results:
Mean NFL pg/mL (standard deviation (SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated (n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod (n = 243), mean NFL pg/mL (SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10−6), and levels remained stable at 24 months (13.2 (6.2)).

Conclusion:
NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.

Yesterday, I spoke at the European Academy of Neurology (EAN) Congress 2017 in Amsterdam about the utility of neurofilament analysis in neurological disorders. My point was to get across to the audience that neurofilaments as a biomarker was here to stay, but also to make it known that as far as MS management is concerned the goal post is shifting. We are looking to a future in which long-term remission (tantamount to a cure) is achievable, and not simply a woefully inadequate hype that recedes at the end of a conference. So how do the current biological fare in slowing down nerve loss?
I know of two therapies that have already demonstrated this; natalizumab (Tysabri) and fingolimod in the cerebrospinal fluid (CSF). Here the authors present more work on fingolimod, but this time looking at blood neurofilament levels (serum/plasma). The question is whether we are able to substitute blood neurofilament measures effectively for CSF neurofilament measures?
When reading through this paper, a couple of things stand out: 1) the levels in the CSF are ~100-fold higher in the CSF than in the blood, whether it be in PwMS or in controls; 2) the relative ratio's of difference between PwMS and controls in the CSF and blood is ~4 and ~2, respectively based on mean results. In a nutshell, there is more room to detect real changes in neurofilament levels in the CSF than in blood. Well big deal you say, but it matters. Maybe not in a clinical trial with 100+ participants, but at an individual level. If I'm a clinician strongly considering using this test in practice, I'll want to know these relative numbers as I may be basing treatment decisions on these numbers. Interestingly, another group (Disanto et al. JNNP 2016; 87:126-129) previously reported a three fold difference between CIS subjects and controls in serum neurofilaments, but using a different platform (mesoscale, as opposed to Simova used in this study). Maybe a more sensitive method is not all that its cracked up to be?!
All is not lost, as far as swapping from interferons or copaxone to fingolimod there appears to be a significant drop in blood NfL levels at 12 months, which is sustained at 24 months (see figure below). Not all subjects demonstrated a reduction in NfL levels after switching to fingolimod, 49 demonstrated a rise in NFL levels. They tended to be older (see figure below) and had a higher age of onset of disease among other factors. 

There are a lot of archived samples sitting in freezers around the world from clinical trials, now may be the time to start analysing them...I say London is open!

Figure: (a) NfL levels in those switching from injectables to fingolimod sampled at time 0, 12 and 24 months. Mean NfL levels reduced by 34% at 12 months; (b) blood NfL levels correlate with age.

Monday, 26 June 2017

Questions for today's Symposium

ProfG is at the European Neurology Meeting in Amsterdam.

Today, there is a SANOFI GENZYME Satellite Symposium: From clinical data to real world experience – similar results, similar benefits for multiple sclerosis patients?

I guess MS CARE extension data will be presented. The message will be alemtuzumab is a very good drug.

The bad news will be that the proportion of people with secondary autoimmunities from the trials, about 20% will have dramatically increased to about 50%.

Here is the programme

Chairperson 
Rogier Q. Hintzen, Rotterdam, The Netherlands

Welcome and Introduction. Rogier Q. Hintzen, Rotterdam, The Netherlands

Mechanism of Action:New Insights into Immunomodulation
Luisa Klotz, , Germany

From Phase 3 controlled trials to extension trials: What do the data tell us? Celia Oreja-Guevara, Madrid, Spain

Daily practice: How does real world evidence reflect clinical data? Tjalf Ziemssen, Dresden, Germany (lead author of ECTRIMS abstract-2013 on binding and neutralizing antibody responses).

Q & A:Rogier Q. Hintzen, Rotterdam, The Netherlands

We can see there is a Q & A session which is great. 

If you are there scratching you head seeking a question, maybe you can ask a few questions.

I wonder what are the new insights? Weren't they publish last week:-)? http://jamanetwork.com/journals/jamaneurology/article-abstract/2630681

What is the mechanism?
Wonder if memory B cells will get a mention? Give us a tweet.

If they don't here's a few questions for the Q&A.

Q. Why do you think MS is a CD4 Th17 T cell mediated disease given that treatments targeting CD4 T cells have typically failed in MS?

Q. Why do you think there is an increase in Treg T cells when their absolute numbers are decreased by over 80%?

Q. Why are you not associating Tregs influences as a major influence on B cell autoimmunities?

Q. Do you think memory B cells are involved in the action of alemtuzumab?

I will guess. Most people don't get a third course, few got 3 or fewer get 4 courses of drug. This indeed impressive.

I guess this is not mentioned that most people develop binding and neutralizing antibodies, which they must do given the levels at cycles one and two (about 80%).

Q. How many people develop binding and neutralizing antibodies on cycle 3 and cycle 4? 
Q. At 12 months after last infusion how many people have persistent anti-drug antibodies and do they affect depletion.

Q. What is the proportion of people who stop depleting or what is the proportion of people who only partially deplete? We already known at the population level there is depletion (Kousin-Ezewu et al. 2014) but at the individual level, are there people who neutralise the alemtuzumab response.
Q. If there are, what is the titre of neutralizing antibodies associated with lack of efficacy.
Q. Are their any non-depleters.
Q. Is there any difference in anaphylaxis/anaphylactoid reactions after third or forth infusion given that most people make binding antibodies and over 70% of people have persistent anti-drug antibodies. Does this relate to pre-existing titres of alemtuzumab binding antibodies?
I suspect if you ask these questions there may be some blank looks .
COI None relevant

More fingolimod rebounds

Forci B, Mariottini A, Mechi C, Massacesi L, Repice A. Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports. Mult Scler Relat Disord. 2017 Jul;15:24-26.
BACKGROUND:
Severe multiple sclerosis reactivation following second line treatment withdrawal, defined "rebound syndrome", is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described.
CASE PRESENTATION: We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment.
CONCLUSIONS: Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome.
When you start treatment you have to consider how you stop treatment if it is not working for you and importantly you need to think about how you transition from a migration inhibitor. These would be natalizumab and fingolimod. We have had a lot of discussion about switching off fingolimod but this is about fingolimod. This is yet another example of an attack shortly after stopping  fingolimod.  So it is important you discuss how disease activation is going to be minimized before you stop fingolimod