Wednesday, 28 June 2017

#ClinicSpeak & #PoliticalSpeak: why should people with primary progressive MS be treated as 2nd-class citizens?

Will pwPPMS be forced to pay for ocrelizumab privately? #ClinicSpeak #PoliticalSpeak

My blog post yesterday regarding equitable access to healthcare and HSCT generated some lively discussion. One reader asked: 'Any idea when ocrelizumab will be available in Europe for PPMS? It isn't fair that the FDA has approved the drug and we are still waiting and losing brain'. Interestingly, I was asked the same question at the EAN meeting after one of my talks and one of the Roche delegates at the meeting was able to answer the question for me and said it will be available soon.

Even if it ocrelizumab gets licensed 'soon' there will still be many hurdles to get over before it can be used in clinical practice. In the UK it will need to go via NICE and then it has to be vetted by NHS England. I have major concerns that the cost-effective model that will be used for PPMS will not be the same as RRMS, where the comparator is current DMTs and the model is based on incremental costs. For PPMS ocrelizumab will be compared to best supportive care. I therefore anticipate ocrelizumab being available for PPMS in other countries and not the UK. The latter worries me even more; why should English patients be disadvantaged? This discussion also raises the possibility of the worst case scenario, i.e. the EMA deciding not to license ocrelizumab for PPMS. What will happen then? This will mean the the product will be on the market for RRMS and pwPPMS who can afford to pay for it; i.e. the wealthy will get ocrelizumab privately and those who can't afford to pay for it won't be treated. The latter already happens in the NHS with some of the high-cost cancer drugs that have not been NICE-approved. Most HCPs, patients and even politicians find this sort of healthcare inequity abhorrent. This is why the NHS and other socialist healthcare systems are meant to exist; to stop a healthcare lottery based on wealth. 



One of my patients with PPMS who was in the fingolimod PPMS trial has already said to me he can't wait any longer. He asked me about starting rituximab and paying for it privately. He had no idea of the cost of rituximab and so we are now having to explore the possibility of using off-label cladribine. The use of cladribine for the treatment of PPMS is not really backed-up with much data, is really a shot in the dark and is based on the scientific principle that suppressing inflammation will help. 

I have also recently become aware that Roche may be launching a compassionate early access programme for PPMS, which is something I will explore for him and other patients in a similar situation. 

What do you think we should do to make sure pwPPMS get access to ocrelizumab ASAP? Can you please complete the following survey to explore some ideas. If you have any suggestions please don't hesitate to contact me. 


CoI: multiple

Blocking NOGO to make nerves

Ineichen BV, Kapitza S, Bleul C, Good N, Plattner PS, Seyedsadr MS, Kaiser J, Schneider MP, Zörner B, Martin R, Linnebank M, Schwab ME.Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology.
Acta Neuropathol. 2017 doi: 10.1007/s00401-017-1745-3


Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution

You may have heard of LINGO-1 which is the target for remyelination that has been tried in MS by Biogen. This is related to NOGO (it was a no go signal, i.e. stop signal for nerve grow in the central nervous system). Block it and nerves grow). NOGO is also known as reticulon 4

NOGO variants are derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. There are three variants: Nogo A, B and C. Nogo-A has two known inhibitory bits including amino-Nogo, at the beginning of the molecule and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in  destruction of  the growth cone from where nerves grow.

LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex.The Nogo receptor complex is formed when Nogo-66 binds to its receptor. LINGO-1 is an essential negative regulator of myelination. It has been implicated in the inhibition of axon regeneration through a ternary complex formed with NgR1/Nogo-66 (ligand-binding subunit) and p75 (signal transducing subunit). NgR1 relies on its co-receptors for transmembrane signalling.The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this receptor complex. 
The inhibitory action is achieved through RhoA-GTP upregulation in response to the presence of MOG, MAG or Nogo-66 in the central nervous system. LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination, by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1.

This paper reports that if you block NOGO-A it can have two effects it supports a nerve sprouting effect and it can speed up remyelination. This is great 

However now to burst the bubble abit. "Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis".

This study shows what I was saying on saturday about trials in progressive MS. It says that if you do not have a trial system that can detect change than it doesn't matter what your drug does, it won't work.

The suggestion that blocking NOGO is new is not true. It was thought about long before anti-LINGO was thought about as NOGO was discovered first,


Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, Murray BM, Barres B, Tessier-Lavigne M, Bernard CC. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci. 2004;7(7):736-44. 

This paper intimates that blockade of NOGO-A can affect the disease course of EAE, we looked at this in EAE in ABH over a decade ago and it did absolutely nothing...why would it the disease episode in EAE has little to do with nerve loss or demyelination it is inflammatory. 

(Why did we not publish this? it was company sponsored and one experiment does not make a paper). 

Anyway, others also eventually reported it was not much or an immune modulator.

Litwak SA, Payne NL, Campanale N, Ozturk E, Lee JY, Petratos S, Siatskas C, Bakhuraysah M, Bernard CC. Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis. PLoS One. 2013;8(12):e82101

So back to the current paper the authors are spinal injury people and so they do their work to show sprouting and so the trial is fit for purpose but if you do EAE a 2-3 week EAE experiment you are looking at three things at once where the immune arm dominates so it is not the right stage of the model to look for repair. So bad trial  design means drug fails.

Away use in spinal injury would be system to test this out. Where is anti-NOGO in development?

Now the real problem anti-LINGO shows us that 99.9% of your drug never gets to the target meaning you load up you subjects with loads of protein, meaning placebo of nothing is flawed. You need a chemical not an antibody.

If blocking the NOGO receptor is going to work wonders, why did this not occur in the anti-LINGO trials in MS? This is because anti-LINGO works on the same cascade and also promotes sprouting in animal models. So let's be realistic. Will anti-NOGO get developed in MS, I think the patent life must be about dead and companies would have done it years ago it they thought it was a winner.

The NOGO system was evolved because it was advantageous not to regrow nerves in the central nervous system. What will be the consequences of blocking the biology? 

I guess you will not have to wait to find out nerve re-growth is being investigated.....but that's another story 

#NewsSpeak: do you want to make a difference?

Do you want to make a difference to world of MS? #NewsSpeak #OffLabel

One of our long running campaigns has been trying to promote access to treatments for pwMS in resource poor environments. For the last 2 years we have been promoting an Essential #OffLabel list of DMTs for resource poor settings. The MS International Federation (MSIF), who represents MS Societies from all over the world, are helping us with this campaign, for example they gave me a platform at their annual CEOs meeting last year to present our campaign.  

The MSIF are now trying to recruit a Head of Research and Access who will lead on the search for improved understanding and treatments for MS and better access to treatments and healthcare. This is global role. So if you are passionate about research, care deeply about MS and feel you have the skills then this may be the job for you. On the plus side it is based in central London; probably the most skilled-up, creative and dynamic city in the world. 


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