Friday, 19 December 2014

ClinicSpeak: improvement in function occurs when you stop inflammation

Do injectable DMTs have a future in the treatment of MS? #MSBlog #MSResearch #ClinicSpeak

Improvement in walking speed on natalizumab #MSBlog #MSResearch #ClinicSpeak

"The study below shows that MSers on natalizumab, a highly-effective DMT, improve; their walking speed gets better. This supports many others studies demonstrating an improvement in function in a proportion of MSers on natalizumab across several neurological subsystems, i.e. vision, bladder, upper-limb function, fatigue, cognitionm etc. Why natalizumab? It is almost certainly because it is a highly-effective DMT and renders the majority of subjects NEDA once they  have been on the drug for more than 12 months. Is this observation specific for natalizumab? No we also see this result with alemtuzumab and BMT (bone marrow transplantation), i.e. other highly-effective treatments. Why does this not occur on lower efficacy drugs? It does, but a much small number have improvements, because the the responders tend to be hidden in a sea of non-responders. If only we could determine responder status prior to starting a DMT it would allow us to optimise the sequencing of DMTs to derive the maximum benefit with the best safety profile for the treated population. I am  surprised that the Pharma companies that produce, and market interferon-beta, blinked. We have known for a decade or more that a type 1 interferon signature in the peripheral blood at baseline predicts a poor response to interferon beta. This finding has been replicated by several groups. Why didn't Pharma validate it in a controlled trial? If they did we interferon-beta may be with us for decades and beyond."

"I was asked by a neurologist in Hyderabad if I saw injectables surviving the onslaught of the oral DMTs. I said yes, firstly they are safe and some of us are now using them in pregnancy; the orals are too new for us to be confident about their safety in pregnancy and at least two are know to be teratogenic (teriflunomide and fingolimod). Secondly, many markets are price sensitive and as the injectables are cheaper than the newer therapies healthcare payers may insist on someone failing on a cheaper drug before they can access a more expensive one; the emergence of biosimilars should bring the costs of injectables even lower and will entrench this requirement in some markets. Thirdly, if we can confirm and validate predictive response markers the injectables will be here for ever. For example, if I can say that the chances of you being rendered NEDA (no evident disease activity) with a normal brain atrophy rate is greater than 80% on interferon-beta, would you choose that compared to an oral without any validated response marker? Finally, if a black swan moment occurs and we find a viral cause of MS and are able to monitor the viral load, interferon-beta may be the platform therapy on to which we graft on other antivirals; an analogy being hepatitis C. Some people laugh when I talk about finding a viral aetiology, but there are many observations in MS that seriously question the autoimmune hypothesis or dogma. I covered a few of  these observations in my recent talk in Canada."

Epub: Voloshyna et al. Natalizumab improves ambulation in relapsing-remitting multiple sclerosis: results from the prospective TIMER study and a retrospective analysis of AFFIRM.Eur J Neurol. 2014 Dec . doi: 10.1111/ene.12618.

BACKGROUND AND PURPOSE: Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing-remitting multiple sclerosis, could impact ambulation performance was examined. 

METHODS: A prospective open-label study, TIMER, was conducted in natalizumab-naive MSers (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated MSers (n = 627) and placebo control MSers (n = 315) from the AFFIRM study.

RESULTS: In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of MSers showed clinically meaningful increases (≥20%) in walking speed on the T100MW (25%) than on the T25FW (13%) at week 48 (P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with ≥20% confirmed improvement in T25FW speed at year 2 by 78% versus placebo (P = 0.0133).

CONCLUSIONS: Natalizumab increased walking speed in MSers with relapsing-remitting multiple sclerosis. The T100MW may be more sensitive to changes in ambulation capacity than the T25FW, and both tests appear to detect clinically meaningful improvements in ambulatory function.

CoI: multiple

Visual pathway to view MS

Martínez-Lapiscina EH, Fraga-Pumar E, Gabilondo I, Martínez-Heras E, Torres-Torres R, Ortiz-Pérez S, Llufriu S, Tercero A, Andorra M, Roca MF, Lampert E, Zubizarreta I, Saiz A, Sanchez-Dalmau B, Villoslada P. The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS.BMC Res Notes. 2014 Dec;7(1):910. [Epub ahead of print]

BACKGROUND:Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations.
FINDINGS: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and cognitive disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway.
DISCUSSION: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.
The eye is the window to the brain as it is the most accessible nerve of the central nervous system. This can be tested by many different outcome measures.So there are many studies that are looking as the eye to determine whether there is disease in the brain. Whilst there may be correlations because if there is brain disease they may be eye disease, this is not absolute so there can be brain disease without eye involvement and vice versa. 

Advent Calendar-18

So on our journey to drug development we have sailed through animal toxicology testing and we are ready to move towards human testing.
So we need to get clinical experts to oversee the project, so we need Chief Medical Officers who as responsible for the clinical work.
So easy work if you can get it if every thing goes well...a bit like it is easy to be a pilot if it all goes well but if it doesn't they earn their keep.  So you have experts that can see through phase I and others that are good for phase II and beyond. 

However, I bet to be a CMO is one of the most rewarding jobs in the World. Why, because if you get to supervise work that is going to lead to the next useful treatment for people with diseases, what can be be better as  job?

As a scientist you dream of developing something that is useful for humanity but to do this as your day job must be really satisfying.

We had a medic from pharma commenting on the blog about their job and how brilliant it was. They kept themselves in the real work and saw patients as well.   

Anti-transferrin antibodies

Int J Mol Sci. 2014 Dec 15;15(12):23269-23282.
Identification of Biomarkers in Cerebrospinal Fluid and Serum of Multiple Sclerosis Patients by Immunoproteomics Approach.
Colomba P, Fontana S, Salemi G, Barranca M, Sicco CL, Mazzola MA, Ragonese P, Savettieri G, De Leo G, Alessandro R, Duro G.


Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. At present, the molecular mechanisms causing the initiation, development and progression of MS are poorly understood, and no reliable proteinaceous disease markers are available. In this study, we used an immunoproteomics approach to identify autoreactive antibodies in the cerebrospinal fluid of MS patients to use as candidate markers with potential diagnostic value. We identified an autoreactive anti-transferrin antibody that may have a potential link with the development and progression of MS. We found this antibody at high levels also in the serum of MS patients and created an immunoenzymatic assay to detect it. Because of the complexity and heterogeneity of multiple sclerosis, it is difficult to find a single marker for all of the processes involved in the origin and progression of the disease, so the development of a panel of biomarkers is desirable, and anti-transferrin antibody could be one of these.

 2D-proteomic map of MS CSF

There will always great interest in the immune-mediated cause of MS; oligoclonal IgG (OCB) is probably one of the better known ones. But the available technology to study these have exceeded even our capacity to understand the final results.

You may say 'International Journal of Molecular Science', is not a very high impact journal. But the experimental design is interesting to say the least. As with most discovery platforms (in this case proteomics, aka the study of proteins, is one such platform), it is an unbiased study of patterns in a disease. However, interestingly the original base on which you probe using the patient's blood and CSF is also pooled CSF from patients in the first place (see picture above which represents the proteins present in this CSF) - this then becomes a fishing expedition looking for anything which reacts. The end result was that the investigators found a directed autoantibody response to transferrin in blood and CSF of MS patients.

Now, transferrin binds iron in your body. It is responsible for most of the iron delivery in the body, including the brain. Iron is an important factor in energy production and used by brain cells for processes such as growing and dividing, through to nerve transmission. Accumulation of iron has also been noted in a number of neurological disorders and felt to contribute to the abnormal processes taking place in them, in particular neurodegeneration (the process which leads to progression and disability). It is possible that this change in iron load may be directly related to the to and fro delivery of iron from the brain.

This finding maybe something or nothing at all...