Tuesday, 19 May 2015

ClinicSpeak: DMF is neuroprotective; the rationale for the SPMS trial

Are you eligible for the dimethyl fumarate (DMF, Tecfidera) SPMS trial? #ClinicSpeak #MSBlog #MSResearch

"The following animal study in a stroke model shows that DMF (dimethyl fumarate) is neuroprotective. Is this important? I have always made the case for disease-specific and disease non-specific mechanisms. The latter refer to mechanisms that are typically downstream of primary events and can be targeted across many diseases. For example, all diseases associated with nerve cell loss, be it acute as in stroke, or more chronic as in MS have mechanisms that can be targeted to reduce nerve cell loss. The so called programme cell survival pathway that is controlled by the master transcription factor Nrf2 is one such pathway. We have evidence that this pathway is responsible for the neuroprotection that is seen with DMF. This study therefore supports the principle of testing DMF in progressive MS."


The following are more details on the DMF SPMS trial:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of BG00012 in Delaying Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis

Purpose: The primary objective of the study is to investigate whether treatment with BG00012 (dimethyl fumarate) compared with placebo slows the accumulation of disability not related to relapses in participants with SPMS; The secondary objective of the study is to assess the effect of BG00012 compared with placebo on patient-reported outcomes, brain atrophy, and cognitive function.

Primary Outcome Measures: Time to onset of confirmed progression of disability as measured by worsening on one or more of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW) or 9-Hole Peg Test (9HPT). 

Secondary Outcome Measures: Change from Baseline to 2 years on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12). Change from Baseline to Week 108 in ABILHAND Questionnaire Score. Percentage change from Baseline to Week 108 in whole brain volume. Change from Baseline to Week 108 in cognitive function as measured by the Symbol Digit Modalities Test (SDMT)

Estimated Enrollment: 1170

Study Start Date: May 2015

Estimated Study Completion Date: June 2019

Eligibility: Ages Eligible for Study: 18 Years to 58 Years

Key Inclusion Criteria:
  1. Onset of SPMS at least 1 to 2 years prior to randomization. SPMS is defined as relapsing-remitting disease followed by progression of disability independent of or not explained by relapses.
  2. Have documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to randomization.
  3. Have EDSS score of 3.0 to 6.5, inclusive.
  4. Have an multiple sclerosis (MS) Severity Score of 4 or higher.
Key Exclusion Criteria:
  1. Have a diagnosis of relapsing remitting multiple sclerosis (RRMS) or primary progressive MS as defined by the revised McDonald criteria.
  2. Had a recent clinical relapse (within 3 months) prior to randomization.
  3. Uncontrolled intercurrent illness including, but not limited to- ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; serious or acute liver, kidney, or bone marrow dysfunction; uncontrolled diabetes; serious or acute psychiatric illness that would limit compliance with study requirements.
ClinicalTrials.gov identifier: NCT02430532

Epub: Zhao et al. Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2. Stroke. 2015 May 14. pii: STROKEAHA.115.009398.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. 

HYPOTHESIS: We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), would act as effective treatment for ICH-mediated damage.

METHODS: Male rats and mice, including Nrf2 knockouts, were subjected to intracerebral injection of blood (to mimic ICH) and then treated with DMF. Neurological deficit, brain edema, gene induction profile and hematoma resolution were evaluated. Phagocytic functions of primary microglia in culture were used to study hematoma resolution.

RESULTS: Treatment with DMF induced Nrf2-target genes, improved hematoma resolution, reduced brain edema, and ultimately enhanced neurological recovery in rats and wild-type, but not Nrf2 knockout, mice. Most importantly, the treatment of ICH with DMF showed a 24 h window of therapeutic opportunity.

CONCLUSIONS: A clinically relevant dose of DMF demonstrates potent therapeutic efficacy and impressive 24 h therapeutic window of opportunity. This study merits further evaluation of this compound as potential treatment for ICH in humans.

CoI: multiple

16 comments:

  1. Didn't you post results showing that Tec had no effect on brain atrophy in RRMS? If that is the case why is this study being pursued for SPMS?

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    1. Good question!
      Tecfidera seems to don't be so effective in reducing progression and brain atrophy in RRMS....
      So, could it be more effective in SPMS?

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    2. Good guestion and suggests a high risk strategy perhaps.

      However, in mice the active phase of disease is associated with higher levels of nerve damage compared to the lower levels during the progressive phase.

      It is claimed that tecfidera works via an affect on Nrf2, which should link to a hint at neuroprotection.

      http://multiple-sclerosis-research.blogspot.com/2014/09/how-does-tecfidera-work.html

      http://multiple-sclerosis-research.blogspot.com/2012/01/research-bg12-targeting-nrf2-to-help.html

      However, does any know where the data regarding penetration into the CNS is?

      Biogen's own poster at ECTRIMS suggests that the parent dimethyl fumarate offers very limited CNS penetration and supports the comment that "Dimethyl fumarate (BG-12) is the methyl ester of fumaric acid, an intermediate in the tricarboxylic acid cycle..... Dimethyl fumarate is probably too hydrophilic to cross the Blood CNS Barrier".

      "DMF is almost completed hydrolyzed to MMF in the small intestine (<15 min) so does MMF get into the CNS. It is claimed that bioavailability of MMF is lowest among the fumarate species because it is 50% protein-bound and negatively charged and has a limited capacity to cross lipid membranes"

      Now there may be CNS permeability in active MS but where are the studies..they may be out there.

      However how much is enough? If you give enough some will get in the brain

      The anti-LINGO is claimed by Biogen speakers to be 99.9% CNS excluded. so most of it delivered will be destined for excretion without doing anything useful.


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    3. I think Tecfedera might turn out to be a better furniture antifungal than a therapy for MS.

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    4. The poster 12:58 flipped the order of their logical operators. No study has found evidence that DMF does not slow brain atrophy. The most that you can say is that one study did not find evidence that DMF slows brain atrophy.

      The CONFIRM study did not find a significant effect of DMF on atrophy. Under any interpretation, this does not mean that CONFIRM found evidence that DMF does not slow brain atrophy. To the contrary, if one doesn't conflate arbitrary p-value thresholds with evidence, then one will conclude that the study provides (weak) evidence that it does slow atrophy. The DEFINE study did find statistically significant evidence that it slows brain atrophy. The evidence from this study is also not very strong.

      The only rational interpretation of the data is that it is more likely than not that DMF slows brain atrophy. One can only draw this conclusion by moving away from the ridiculous frequentist interpretation of probability which is dominant in medicine. This does not mean that I am certain that DMF slows atrophy; I think we should be far from certain. Nonetheless, this is actionable information when weighing between different therapies.

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    5. "To the contrary, if one doesn't conflate arbitrary p-value thresholds with evidence, then one will conclude that the study provides (weak) evidence that it does slow atrophy."

      So what's the point in even providing p values? The seemingly agreed upon level of significance is 0.05 in medical trials so if you are saying you can look beyond this to infer trends then why spend so much money doing clinical trials?

      It seems "trends" are highlighted when one has a stake in ensuring positive results are needed to pursue trials to better market a drug that seems mediocre at best.

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    6. The word "trend" should be banned from use in any research/clinical trial publication IMO.

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    7. Aa always in life, things are not black and white. p values are often misunderstood (and abused of course ;)). nice writeup on this matter is here http://www.scientificamerican.com/article/scientists-perturbed-by-loss-of-stat-tools-to-sift-research-fudge-from-fact/

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    8. The humble p value is pooh-poohed in the journal but we all need to apply the "smack you in the eye test"....it the data doesn't do that...it's probably a pile of pants:-)

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    9. Isn't dmf responsible for helping with oxidative stress? And has been used in HIV with success too which would encourage the EBV theory and the oxidative stress theory?
      Is BG12 not a similar action too? In that they help increase glutathione and helps with mitochondrial issues?
      There's something common in all this

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    10. Unless it gets in the CNS then it is all irrelevant, as we still haven't seen the data presented

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  2. There's evidence of things like N acetylsysteine getting into the cns and effecting glutathione isn't there? Now that's a cheap way to help!

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    1. Well there is some data of some value of NAC in acute EAE (http://www.ncbi.nlm.nih.gov/pubmed/8300856) but when we tried it, it was dead as a dodo as a DMT in both experiments

      I remember doing this experiment for a bloke and have just looked through my unpublished data box and the dose was massive, twice a day so a pain to do the experiment because of the weekends

      We did consider NAC as a neuroprotectant about ten or more years ago but when we looked then we saw paper saying tha NAC didn't get into the brain so its not going to be that good on the old glutathione levels

      There was a brain penetrant version (NACA) but the company would not give us any to test http://www.ncbi.nlm.nih.gov/pubmed/15147517..their loss and our loss or interest

      NAC has poor pharmacokinetics
      http://www.ncbi.nlm.nih.gov/pubmed/23472882

      Just looked we can buy it now as NACA. However I wonder if its use is now knackard because the patent life is long gone. We knew how to test this ten years ago, I didn't in the 1990's when we had a look at NAC as a DMT

      However just found this paper
      http://www.ncbi.nlm.nih.gov/pubmed/25765302 looking at CSF levels after twice a day 70mg/kg was 10micromolar in human CSF

      NAC is cheap as chips and is used to protect against paracetomol over-dose. Maybe worth a look if we can get funded to do it

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    2. I know it's been used for ocd and oxidative stress and to reduce glutamate and improve glutathione as I said
      It must work through the bbb too?
      I don't see that it can harm really as you said it's cheap

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    3. Isn't another similar ingredient alpha lipoic acid?
      I know the guys in Portland have a trial currently for 1200mg per day in spms after doing previous studies showing success? What's your thinking?

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  3. That study you listed looks really interesting!
    If indeed it does help with ocidative stress which helps with Ms and neurodegeneration somehow then it might be really interesting?
    I also saw it used in Alzheimer's

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