Monday, 30 May 2016

Is failure of an arm of MS SMART on the cards?

Zhang T, Kingwell E, De Jong HJ, Zhu F, Zhao Y, Carruthers R, Petkau J, Gustafson P, Oger J, Tremlett H. Association between the use of selective serotonin reuptake inhibitors and multiple sclerosis disability progression. Pharmacoepidemiol Drug Saf. 2016 May 23. doi: 10.1002/pds.4031. [Epub ahead of print]

BACKGROUND:Benefits of selective serotonin reuptake inhibitors (SSRIs) in modifying the multiple sclerosis (MS) disease course have been suggested, but their ability to delay disability progression remains unknown. We examined the association between SSRI exposure and MS disability progression.
METHODS: A nested case-control study was conducted using the British Columbia (Canada) Multiple Sclerosis clinical data linked to health administrative data. The primary outcome was a sustained score of 6 (requires a cane to walk) on the Expanded Disability Status Scale (EDSS), and the secondary outcome was the onset of secondary progressive MS (SPMS, an advanced stage of MS). The cases were those who reached a study outcome and were matched with up to four randomly selected controls by sex, age, EDSS and calendar year at study entry using incidence density sampling. The associations between disability worsening and SSRI exposure were assessed with conditional logistic regression models, adjusted for confounders.
RESULTS:A total of 3920 patients were included in the main analyses, of which 272 reached sustained EDSS 6 and 187 reached SPMS. SSRI exposure was significantly different between patients who reached sustained EDSS 6 and controls [adjusted odds ratio (adjOR):1.44; 95% confidence interval (CI):1.03-2.01]. However, SSRI exposure was not significantly different between those who reached SPMS and their controls (adjOR:1.35; 95%CI:0.89-2.04).
CONCLUSION: We found no evidence to suggest that SSRI exposure was associated with a delay in MS disability accumulation or progression.

MS-SMART is a trial of three drugs verses placebo in the hope of slowing secondary progression. This study aimed to study ibudilast but a US group got their hands on it first and so it was dropped in MS-SMART, and replaced with Prozac.

The logic of how this (Fluoxitine) will work in progression has never really been presented by the SMART team.

In this analysis of a cohort of people with MS it indicates that more people with progressive MS take an SSRI (serotonin reuptake inhibitor, so it blocks break-down of serotinin, a neurotransmitter that limits depression). Is it that people take an SSRI to slow progression or is it that more people with progressive MS are depressed, which is more likely. The the data does not support the view that SSRI slows the accumulation for disability. 

Now this is observational rather than a trial and it must be said that the odds ratios of an influence are very large from 0.9 (No effect) to 2 (twice as good). MS-SMART will be the proof in the pudding, but maybe it does not bode well. 

Furthermore, non-use of an SSRI is going to be a condition of participation of MS-SMART, but as the target population is thus more likely to show depression and will be treated, it is going to make it more difficult to recruit to the MS-SMART trial. Therefore fluoxitine may not have been the best third choice.

I don't wish to put you off the trial and if you are eligible you should consider this.


Even if you end up in the fluoxetine arm your mental health may be be improved and by being in a trial you generally do better due to the strong placebo effect.

ClinicSpeak: intermittent fasting

Will intermittent fasting turnout to be an effective DMT? #ClinicSpeak #MSBlog #MSRsearch

"One of our readers pointed me to the paper below on the apparent health benefits of fasting. The animal study suggests fasting promotes resistance to stress and possibly increased life span. They showed that alternating fasting with feasting extended the lifespan of yeast independently of established genetic factors.  In mice, fasting and feeding,  elevated the number of stem cells and their regenerative capacity. Interestingly, in old mice, this strategy promoted the development of new neuronal cells, i.e. it may have neurorestorative capacity. They then discuss a pilot clinical trial, of three cycles of fasting and feasting which decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects. The authors claim their results support the use of cycles of fasting to promote health. The question is how do we test this strategy safely in MS?"

"As you know intermittent fasting and low-carb diets are currently very popular. These include the Atkins Diet (high-protein low-carb), Dukan Diet (French version of the Atkins diet), more recently the Banting Diet (high-fat, high-protein, low-carb) and the paleo diet (high-fat, high-protein, low-processed carb). How do they work? The theory is they starve the body of sugars and change your metabolism by switching off, or lowering, your circulating levels of insulin. Too much insulin is bad for you and drives the so called metabolic syndrome (truncal obesity, fatty liver, insulin resistance, high cholesterol, hypertension, increased cancer risk, etc.). Interestingly these diets, including intermittent starvation, cause you to become ketotic; your body starts making ketones to feed your brain. Ketones may have several benefits to health, including brain health. There is emerging evidence that they may actually reduce your appetite and ketones may be neuroprotective. There is some evidence that ketogenic diets can improve mitochondrial function (see previous post on  this). Neurologists have also known for decades that some forms of epilepsy are ketone responsive and we treat patients with specific epilepsy syndromes using ketogenic diets. The metabolic changes that underlie ketosis include the rapid mobilisation of fats from adipose tissue, which is why these diets are so effective at causing rapid weight loss. Interestingly, the so called 5:2 diet in which you fast for 2 days of the week may also work via intermittent ketosis."

"How is this all relevant to MS? There is some evidence that ketosis may be neuroprotective in an animal model of MS and the hypothesis paper below makes the case for ketogenic diets as a potential treatment of progressive MS. There are currently some dietary studies testing these hypotheses in MS. I have invited Ellen Mowry, the principal investigator on a trial testing the 5:2 diet, to do a guest post on this subject; let's hope she does it soon."

"What all this tells us is that systemic biology, i.e. metabolism, is important for the brain and may impact on MS. What we need is the evidence before making any recommendations. So if you are considering doing one of these diets please make sure you have discussed it with your neurologist, specialist nurse or family doctor."

Brandhorst et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015 Jul 7;22(1):86-99.

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

Sunday, 29 May 2016

NewsSpeak: FDA approves daclizumab

Another milestone for daclizumab in the treatment of relapsing forms of MS. #MSBlog #MSResearch #NewsSpeak

"The FDA has approved daclizumab (Zinbryta) for the treatment of relapsing forms of MS. However, the FDA have recommended it be used second or third line, presumably because of its safety profile and need for monitoring. The US label is very different to the recommendation of the CHMP (Committee for Human use of Medicinal Products, see below), which has recommend daclizumab for relapsing forms of MS, a label not too dissimilar to that of alemtuzumab (Lemtrada) in Europe. It is interesting that the EMA's and FDA's approach to labelling of MS DMTs has flipped. In the past the FDA simply licensed DMTs for relapsing forms of MS and then allowed people with MS, neurologists and payers to sort out how the drug was used in clinical practice. In contrast, the CHMP used to license treatments with a narrow indication, for example natalizumab is licensed for rapidly evolving severe MS and fingolimod for highly-active MS in people with MS who have failed another therapy. The labelling of alemtuzumab, and now daclizumab, shows a change of heart; the FDA have become more conservative and the EMA less conservative, or dare we say liberal? Is this an interesting observation?"

"I am very upbeat about daclizumab because it has an interesting mode of action. Daclizumab is not immunosuppressive, but immunomodulatory. It binds to the so called high affinity IL2 receptor that is mainly expressed on proliferating T cells and T-reg cells; by doing this it diverts IL2 away from these cells to the intermediate IL2 receptor that is expressed on a population of cells called CD56-bright NK or natural killer cells. The expansion of the NK cells is most likely how this drug works. NK-cells are able to regulate T-cells, by killing them, and NK-cells are antiviral. Importantly, daclizumab appears to leave CD4+, CD8+ and B cell function relatively intact. For example, antibody responses to the flu vaccine in daclizumab treated MSers is fine. These latter observations are important as we need both our T and B cells to fight infection. The one downside of blunting the T-cell proliferative responses is that it takes longer to mount an adequate immunological response to common infections. This is probably why we see more infections, and more severe infections, in the daclizumab treated groups of study subjects. Please note these are common infections and not opportunistic infections. If you choose to go onto daclizumab you will need to take infections seriously and get them treated promptly."

"Where will daclizumab will be placed in the current treatment paradigm? As always I say it has a role in DMT-naive MSers, typically those with more active disease, as an alternative to natalizumab or alemtuzumab. It is also a good escalation option instead of DMF, fingolimod, natalizumab or alemtuzumab. The fact that it is not overtly immunosuppressive may make it appealing to some people. The latter is particularly important that we are now seeing an opportunistic infection signal emerging with drugs that are immunosuppressive, i.e. DMF (lymphopaenics) and fingolimod. Finally, it will likely be the switch drug of choice when transitioning MSers onto who are JCV+ on natalizumab and at risk if PML onto another DMT. The fact that daclizumab is not immunosuppressive and the NK-cells may have antiviral effects make it appealing with regard to the potential carry-over risk of PML. I am aware that a safety switch study is being proposed to support this strategy."

"The downside of daclizumab is the possibility of secondary immune mediated adverse events in particular skin hypersensitivity, hepatitis and inflammatory bowel disease, hence the requirement for daclizumab treated patients to have regular monthly blood monitoring. The secondary immune-mediated events on daclizumab may be related to its impact on T-reg cell function; depriving these cells of IL2 reduced their numbers. Despite the latter hypothesis there is no definitive link between T-reg numbers, and function, and the occurrence of adverse events."

"Please note that daclizumab is another repurposed drug. At one stage in its life-cycle it was used as an add-on drug to manage solid organ transplant rejection. Hats off the the groups at the NIH, Biogen and Abbvie for developing this drug. Based on its mode of action I think daclizumab should be tested in progressive MS; let's hope Biogen and Abbvie do a progressive trial. I have always used the mode of action of daclizumab to support my viral hypothesis. If we ever get to use the drug in the UK I have several add-on studies I would like to do to test the antiviral hypothesis; i.e. another Charcot Project study."

"For the immunologists reading this post; daclizumab also reduces the numbers of lymphoid tissue inducer cells (LTIs). LTIs play a role in the development of organized lymphoid structures and hence may affect antibody responses within the central nervous system (CNS). It will be interesting to see if the treatment effect of daclizumab may relate to its effects on this population of cells and its effect of lymphoid-like structures in the central nervous system of MSers. We need more data on the latter; at this point this is only an hypothesis."

Excerpts from the FDA press release:

“Zinbryta provides an additional choice to patients who may require a new option for treatment,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The effectiveness of Zinbryta was shown in two clinical trials. One trial compared Zinbryta and Avonex in 1,841 participants who were studied for 144 weeks. Patients on Zinbryta had fewer clinical relapses than patients taking Avonex. The second trial compared Zinbryta with placebo and included 412 participants who were treated for 52 weeks. In that study, those receiving Zinbryta had fewer relapses compared to those receiving placebo.

Zinbryta should generally be used only in patients who have had an inadequate response to two or more MS drugs because Zinbryta has serious safety risks, including liver injury and immune conditions. Because of the risks, Zinbryta has a boxed warning and is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

The boxed warning tells prescribers that the drug can cause severe liver injury, including life-threatening and fatal events. Health care professionals should perform blood tests to monitor the patient’s liver function prior to starting Zinbryta, monthly before each dose, and for up to six months after the last dose.

The boxed warning also highlights other important risks of Zinbryta treatment including immune conditions, such as inflammation of the colon (non-infectious colitis), skin reactions, and enlargement of lymph nodes (lymphadenopathy).

Additional highlighted warnings include hypersensitivity reactions (anaphylaxis or angioedema), increased risk of infections, and symptoms of depression and/or suicidal ideation.

The most common adverse reactions reported by patients receiving Zinbryta in the clinical trial that compared it to Avonex include cold symptoms (nasopharyngitis), upper respiratory tract infection, rash, influenza, dermatitis, throat (oropharyngeal) pain, eczema, and enlargement of lymph nodes. The most common adverse reactions reported by patients receiving Zinbryta when compared to placebo are depression, rash, and increased alanine aminotransferase.

The CHMP (EMA) Summary of Opinion:

CoI: multiple

Drugs Studies from the AAN

ProfG on CLAD and why he thinks it will come back

Clinical efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis (RRMS): final results from the 120-week phase IIIb extension trial to the CLARITY study (Poster 3.028). Authors: Gavin Giovannoni, Giancarlo Comi, Stuart Cook, Peter Rieckmann, Kottil Rammohan, Per Soelberg-Sorensen, Patrick Vermersch, E. Martin and Fernando Dangond

Some of you could not see the poster of the Alemtuzumab 10 year data so listen to Mario Habek give an info burst. 

Finally we have Prof Mark Freedman talking Aubagio.

Final Outcomes of the Teriflunomide Phase 2 Extension Study: 13 Years of Efficacy and Safety Results (Poster 3.027). Authors: Marcelo Kremenchutzky, Mark S Freedman, Amit Bar-Or, Annie Purvis, Myriam Benamor, Philippe Truffinet, and Paul W O’Connor

Prof Freedman will be back soon and has done a Guest Post on his soon to be published research. I can't wait.

CoI: None

Saturday, 28 May 2016

CongressSpeak & BrainHealh: European Neurological Association Meeting 2016 - Copenhagen

I am trying not to neglect my own brain health, but it is difficult. #CongressSpeak #ENA2016 #BrainHealth #MSBlog

"I am not a happy bunny; I am about to spend another weekend working, including bank holiday Monday. Monday is a holiday in the UK; it is called a bank holiday because the banks are closed. I had to get-up at 6am this morning to pack and travel to Copenhagen (still in transit) to attend the 2nd congress of the European Neurological Association (ENA). I am a bit frustrated that I didn't have to time for a run. On balance my brain health is suffering (sleep deprivation and too little exercise) and my personal wellness (not enough downtime). Saying that the ENA is an important meeting that can't be missed. Although it is not one of the 'big MS meetings', it is a meeting that a large number of general neurologists attend and is therefore an excellent forum to get across our 'Brain Heath: Time Matters' message. I will get at least three opportunities to discuss the policy document."

"I have uploaded the ENA programme for you to browse; if you search the document you will find the term 'multiple sclerosis is used 166 times, in other words there is a lot of activity in relation to MS at this meeting."

"I am involved with 8 abstracts; I will personally be presenting two. I will also be talking on one of the satellite symposia  on 'The time to act: optimising patient care'.  My talk is essentially a call to action and is underpinned by all the important issues presented in our 'Brain Health: time matters' policy document. I will upload my slides after the symposium."

"When I get back to London next week I will summarise the meeting for you and give you my highlights (post and pod-cast)."

"If you haven't done so already I would recommend reading our policy document and if you agree with it please pledge your support and sign-up for updates; we have a large programme of activities planned for this year all aimed at getting the policies front of mind and acted upon. The latter however needs support from the MS community, which includes readers of this blog. Thank you."

CoI: multiple