Wednesday, 31 August 2016

Progressive MS deja vu

Last year we there was a buzz at ECTRIMS about ocrelizumab and this year it may well be Siponimod and its influence on secondary progressive MS. This is to be presented at the late breaking session at ECTRIMS 2016.

Is this a game changer?

The disruptor for MS pharma, is fingolimod coming-off patent in 2019. With the development of generics the price tumbles (except that MS pharma control a number of generic companies :-)

However, does the success of siponimod mean that people in power are happy that fingolimod failed in PPMS? 

Had it been a success could they have protected the PPMS market, whilst the RRMS fell to generic competitors?

As fingo is second line surely Sipo will get a first line label now. This is because the climate has changed since fingo was approved and got a second line label (It was expensive and had side effects), as alemtuzumab exceeds this on price and side-effects but that has a first line label (in UK).

Siponimod has succeeded in relapsing MS in early trials just like fingo other all other fingo me too's and now with some success in SPMS. Why go for fingo when you could have sipo to cover RR and SP bases? 

Was this the master plan?

However, will this be a game changer? 

First we have to know is whether it is really progression that is being targeted or has the trial been loaded with relapsing people with SPMS? If I was designing a trial I would load it with people with lower levels of EDSS and have as many gadolinium enhancing subjects in the mix. 

We know that relapsing MS/MRI activity contributes to damage and we know that this responses to Spingosine-1-phosphate modulators?

We will have to wait and see the data. It will be the first question everyone asks but I suspect that "the data is still being analysed".

Answers to this may help define the battle ground with ocrelizumab. 

Is Siponimod the first drug to have an effect on progressive MS? However, will we have deja vu and just as oral cladribine stumbled at the last hurdle to be beaten by Fingolimod, will siponimod be pipped or pip ocrelizumab to the  final progressive hurdle? 

Will the regulators buy the idea that ocrelizumab was active for all of progression, rather than just working in active (MRI positive relapsing) progression?  I suspect the data has been collected in such a way that it will be impossible to answer as there were probably not enough scans to work out if lesions occurred after the initial negative scans. I personally think this will be a tough ask, but can the regulators be hood-winked? 

Importantly will the cancers that popped up (nine verses 0 in placebo) in the ocrelizumab progressive trial, do it in just like it did for oral cladribine (three verse 0 in placebo. You say there were more in the original publication but some turned out not to be cancer).  I suspect one pharma may be lobbying hard for the bad view to be upheld.  Maybe the additional RRMS studies will change the view of the regulators, but if the regulators are of the blinkered-phenotype which seems par for the course for reviewers then there will be problems, I suspect. 

I hope not

However, the other issue of a successful progressive MS drug, may mean that trials, like the MS-SMART may not be so smart, because if there is a positive result, pharma will surely insist that any drug that is positive in academic studies undergo the same rigour of the process that pharma are made to do.

The academic trials will not have that level of support and it would be terrible if the studies stalled at the end of phase III. 


Will it now be worth pursuing the simvastatin story which will take many years to complete, because doctors will be encouraged to prescribe the licensed option?

However, we may get some  insight into MS-SMART as results of using prozac in progressive MS are being presented at ECTRIMS 2016.

Anyway, one further nail in the EAE coffin as one more aspect of MS appears to get a solution. But how does it do this ?

CoI None....ProfG may know the answers already and take a different view

Siponimod saving nerves

Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, Piras E, Gargano F, Borsellino G, Battistini L, Schubart A, Mandolesi G, Centonze D. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016;13(1):207.
BACKGROUND:Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1, 5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE.
METHODS: Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells.
RESULTS: Siponimod administration (0.45 μg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission.
CONCLUSIONS:Altogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.

Given the recent news that Siponimod has a beneficial effect in secondary progressive MS to be presented at ECTRIMS 2016 hot topic session is going to be one of the hightlights of the meeting one suspects. This animal study suggests that it may have some benefit in saving nerves

Tuesday, 30 August 2016

ResearchSpeak: low lymphocyte counts in MSers

Do you have a normal lymphocyte count? Do you know your lymphocyte counts? #ResearchSpeak #MSBlog #MSResearch

"The retrospective study below found that 1 in 10 DMT-naive MSers had low lymphocyte counts and in the majority of these no obvious cause could be found. The authors' suggest the lymphopaenia is due to autoimmunity, or is stress-induced through increased cortisol production or Epstein-Barr activation."

"I live and learn something new every day of the week about MS. I had no idea that ~10% of MSers had idiopathic (no apparent cause found) lymphopaenia. What is interesting that in this study low lymphocyte counts at baseline predicted low lymphocyte counts on treatment. Clearly these findings needs to be confirmed and explained. Who knows it may provide interesting insights into the pathogenesis of MS. I like the suggestion that it may be linked to stress and/or EBV reactivation."

"Lymphopaenia is one of the key battlegrounds in the marketing of DMTs. Low lymphocyte counts are an important risk factor for several serious adverse events on DMTs. Understanding MS-related lymphopaenia may help de-risk some of these DMTs. I am interested to know how many of you know what your latest lymphocyte counts are? If you don't you should find out and keep a record of it for yourself."

A lymphocyte: image source Wikipedia


Lim et al. Lymphopenia in treatment-naive relapsing multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016 Aug 12;3(5):e275. doi: 10.1212/NXI.0000000000000275. eCollection 2016.

Background: Lymphopenia accompanies some autoimmune diseases. Several studies, but not others, have suggested that lymphopenia occurs in treatment-naive multiple sclerosis (MS), so the issue remains unresolved.

Methods: Data were collected retrospectively during an institutionally approved service evaluation of blood test monitoring of patients with relapsing MS in a regional MS service in Southampton, UK, over a 2-year period (2012–2014). Control lymphocyte data were derived from preoperative blood counts of age- and sex-matched individuals undergoing septoplasty in the same hospital for structural reasons, excluding neoplastic and infective operative indications.

Results:  Seven hundred sixty-four patients were identified with blood test data (table). Baseline and post-treatment blood tests were available in 466 and 247 patients, respectively. Average blood test frequency was 4 per year. Lymphocyte counts were relatively stable with time, with a coefficient of variation of 7.5%. The mean lymphocyte count in treatment-naive patients with MS was 2.18 × 109/L with an SD of 0.66 × 109. Lymphopenia was present in 10% (48 patients; 46 grade I, one grade II, one grade III). In only 3 cases steroids were administered in the month before lymphopenia. There was no association between pretreatment lymphocyte count and any patient characteristic or month or season. 

Discussion: Since the lymphocyte reference range covers 95% of values in a healthy population, lymphopenia is expected in 2.5%. In our treatment-naive relapsing MS population, we found lymphopenia in 10%. Moreover, lymphopenia was not associated with relapsing activity. Hence, the lymphopenia in patients with MS is unlikely to be related to autoimmunity. A more likely explanation is stress-induced lymphopenia in both cohorts, through cortisol or Epstein-Barr activation.

Metabolic problems in immune cells can cause autoimmunity

Immunol Cell Biol. 2016 Aug 26. doi: 10.1038/icb.2016.77. [Epub ahead of print]

"Immunometabolism and autoimmunity".

Freitag J, Berod L, Kamradt T, Sparwasser T.

Abstract

A continuous increase in the prevalence of autoimmune diseases is to be expected in the aging societies world-wide. Autoimmune disorders not only cause severe disability and chronic pain, but also lead to considerable socio-economic costs. Given that current treatment options are not curative, have substantial side effects and a high percentage of non-responders, innovative options to the existing therapeutic armament against autoimmune diseases are urgently required. Accumulating evidence suggests that changes in the metabolism of immune cells are associated with and contribute to the pathogenesis of autoimmunity. Additionally, some autoimmune diseases share alterations in metabolic pathways, key metabolites or metabolic byproducts such as reactive oxygen species. Other examples for metabolic changes in autoimmune settings include modifications in amino acid and cholesterol levels or glucose catabolism. Thus, the emerging field of immunometabolism may hold the potential to discover new therapeutic targets. Here, we discuss recent findings describing metabolic changes in autoimmune arthritis, multiple sclerosis.


Mounting an immune response requires changes to metabolic processes (i.e. the chemical transformations that are needed for survival). Immune cells have different metabolic requirements depending on their activation state (in order to meet the demands of the activation state) and differentiation state (into effector T cells, which include helper, cytotoxic or regulatory T cells).

Points of metabolic dysregulation in immune function may prove to be therapeutic targets of the future. For example, the natural antioxidant from the green tea plant, EGCG has been shown to promote suppressive Treg cells whilst inhibiting Th1/Th17 formation (proinflammatory cells). This is currently being evaluated in a clinical trial in MS (Sunphenon in progressive forms of multiple sclerosis, NCT00799890).

Leptin is another. Also popularly known as the anti-obesity hormone, leptin has been found to promote CD4 T cell expansion as well as secretion of proinflammatory molecules, such as TNFalpha. Levels of leptin have been sound to be elevated in MS, leading to activation of leptin-mTOR pathway in suppressive Treg cells and as a consequence their impaired expansion. For therapeutic purposes rapamycin-mediated blockade of mTOR activation facilitates Treg expansion and significantly ameliorates EAE (the murine version of MS). Current clinical trials in MS are NCT00228397 (Temsirolimus) and NCT00095329 (Sirolimus).

Statins which lower cholesterol have been proven to be beneficial in MS by inhibiting the formation of proinflammatory Th1 and Th17 responses but favouring Treg responses. In fact the MS-STAT (NCT00647348) showed benefits with regard to brain atrophy measures in SPMS.

These therapeutic targets may therefore prove to be highly attractive options in the near future.

Monday, 29 August 2016

SurveySpeak: Impact, or lack of it

How do you feel about research, or academic, IMPACT? It is a sad fact of life in the modern university. #SurveySpeak #MSBlog 

"One of our successes this year has been our medical school investing in Alison Thomson our designer; she has officially been appointed as a lecturer. This is the first time our University has embedded a designer within a biomedical research environment. As always we need to justify our existence; this means metrics and impact. We now have to build a case for Alison's work having impact. It would help us enormously if you could please complete a short survey (9 questions and ~1 minute of your time) to help show that Alison's work in relation to the Barts-MS Blog is having impact. The survey is not only for people with MS, but anyone who reads this blog. Thank you!"