Friday, 26 August 2016

NewsSpeak: positive SPMS trial

Siponimod reduces the rate of disease progression in SPMS. #NewsSpeak #MSBlog

"For those of you with SPMS who thought you had been forgotten some great news yesterday. Siponimod, a S1P receptor modulator, has hit its primary outcome in the EXPAND SPMS trial. This is great news for the field and for the first time progressive MSers have treatment options. This also means that it is going to become very difficult doing new studies without comparing them to existing DMTs, in this case Siponimod, in the progressive MS space."


Press release

Novartis announces positive phase III results showing efficacy of BAF312 in patients with secondary progressive MS. AUG 25, 2016
  • The Phase III EXPAND study of BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS) met its primary endpoint of reducing the risk of three-month confirmed disability progression versus placebo. 
  • There are currently very limited treatment options for SPMS, a form of MS associated with gradual worsening of symptoms and accumulation of disability, independent of relapses. 
  • EXPAND is the largest study ever conducted in SPMS, and is part of Novartis' ongoing leadership and commitment to people with MS.
Basel, August 25, 2016 - Novartis today announced the Phase III EXPAND study, evaluating the efficacy and safety of oral, once-daily, BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS), met its primary endpoint of a reduction in the risk of disability progression, compared with placebo. The EXPAND study represents the largest randomized, controlled study in SPMS to date.

"SPMS is a particularly disabling form of MS, and there is a need for effective treatment options to help delay disability progression in those living with the condition," said Vasant Narasimhan, Global Head of Drug Development and Chief Medical Officer for Novartis. "The positive EXPAND data are encouraging for a disease with such a high unmet need. We look forward to sharing the results at the upcoming ECTRIMS congress, and thank all of the study participants and investigators."

Topline results of the EXPAND study, including primary and key secondary endpoints, will be presented as a late breaking oral abstract at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 17th, in London, UK. Novartis will complete full analyses of the data and evaluate next steps in consultation with health authorities.

About the EXPAND study

The EXPAND study is a randomized, double-blinded, placebo-controlled Phase III study, comparing the efficacy and safety of BAF312 versus placebo in people with secondary progressive multiple sclerosis (SPMS). The EXPAND study is the largest randomized, controlled study in SPMS to date. The study included 1,651 people with SPMS from 31 countries. Patients were randomized to receive either 2mg BAF312 or placebo in a 2:1 ratio respectively.

The primary endpoint of the study was an improvement in the time to three-month confirmed disability progression, as measured by the expanded disability status scale (EDSS), versus placebo. Secondary endpoints included delay in the time to six-month confirmed disability progression versus placebo, the time to confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW), T2 lesion volume, annualized relapse rate (ARR), and the safety and tolerability of BAF312 in people with SPMS.

About BAF312 (siponimod):

BAF312 (siponimod) is a selective modulator of specific types of the sphingosine-1-phosphate (S1P) receptor. The S1P receptor is commonly found on the surface of specific cells residing in the central nervous system (CNS), that are responsible for causing CNS damage that drives loss of function in secondary progressive MS (SPMS). BAF312 enters the brain and by binding to these specific receptors, may prevent the activation of these harmful cells, helping to reduce loss of physical and cognitive function associated with SPMS.

CoI: Prof G is a member of the EXPAND steering committee, Barts-MS participated in the EXPAND trial and DrK is the local principal investigator for the EXPAND study.

21 comments:

  1. A few questions. When might it become available in the UK ie prescribable? If its similar to Fingolimod, why did the Fingolimod PPMS trial fail? Will the drug be more or less effective at slowing the rate of progression compared to Ocrelizumab? Thanks.

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    1. Re: "When might it become available in the UK ie prescribable?"

      The company now has to analyse the data in full and submit a data packaged to the EMA. This process takes 6-12 months. The EMA will then review the package and may, or may not, grant it a marketing authorisation. This process takes 12 months or quicker if they get fast-track status. Then NICE has to review it; this can take 6-9 months and if NICE greenlight it then there is another 3 month delay before it becomes available for SPMSers. I would estimate this whole process taking about 30 months.

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    2. Re: "If its similar to Fingolimod, why did the Fingolimod PPMS trial fail?"

      Yes, it is similar to fingolimod, but also different. It has different profile. It is important to realise that PPMS is in general less inflammatory than SPMS and the trial was much smaller. I think the outlier is the PPMS trial; the results are incongruent with what we expected to happen. There are still some ongoing analyses being done to try and explain the lack of effect of fingolimod in PPMS. I personally have a keen interest in these analyses as the fingo in PPMS trial is not consistent with the length-dependent axonopathy hypothesis.

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    3. Re: "Will the drug be more or less effective at slowing the rate of progression compared to Ocrelizumab?"

      I can't answer this at present as the data is not in the public domain. You will have to wait until ECTRIMS to see the results in more detail.

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  2. Replies
    1. At last somethig to sing and shout about but its still going to be a log wait. Who will be eligible for treatment?

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    2. Yes..a long wait. Too long for many to be of any use at all.
      They will have lost most function and be headed to bed rest.

      'I would estimate this whole process taking about 30 months.'

      2 and 1/2 years is too long for this poor soul who went from
      cane to chair in 2 years of SP. On the bright side maybe this
      can SLOW some pinky/thumb clasping function 2.5 years from now for $100,000
      2.5 years is way too long people who need this need it now
      as further damage is unrepairable. Totally Broken. Kaput.

      Does Secondary Progressive MS ever stabilize (i.e.-stop progressing)?
      "Mine has not. I have gone from cane to walker to wheelchair since being diagnosed two years ago. I am also trying a fourth med which does not seem to be helping."
      posted over 2 years ago

      https://www.mymsteam.com/questions/53191d4786087597be00077a/does-secondary-progressive-ms-ever-stabilize-i-dot-e-stop-progressing

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  3. How about using this within RRMS either as a actual treatment or a preventative measure for when RRMS migrates to SPMS. Would siponimod be retained within the CNS in preparation for the occurrence of these cells.

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  4. This is not likely to be given out for PPMS as well is it?

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  5. One side effect is slowing of heart rate, which I find kind of worrying - if less blood and oxygen is getting to the brain, this is likely to have an adverse effect on progression, isn't it?

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  6. This is great news. Is 3 months enough to determine disability progression in MS vs placebo, as the disease is so variable between all MSers? In this study, have they measured MRI activity & atrophy and neurofilament levels to see if they have decreased thereby indicating less axon damage?

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  7. This ACTRIMS trial (without) control gorup give us some hope! https://actrims.confex.com/actrims/2016/meetingapp.cgi/Paper/1484

    Prof G? Some experts told, MS is basically inflammatory disease, and it is progressive from the begining, and SPMS means that brain do not able to mask the inflammation and the age (after 35-40 yr) related progression anymore.
    Positive siponimod trial, and natalizumab trial with some positive results might verify it or not?
    Prof G! What is your opinion?

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    Replies
    1. Yes, I am in the camp that thinks MS is progressive from the beginning, which is why early effective treatment makes sense.

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    2. In this Case alemtuzumab may also will be effective SPMS treatment.

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  8. Great news. Does this mean that the expanded part of the trial at Royal London will start very soon? And that everyone that was on the trial will now get the drug not the placebo?

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  9. I wonder - is it like Ocrelizumab, which only has some effect, in some people with PPMS? Is it really going to be targetting the core of progression this time, if there is such a thing. Is it only going to work in people who still have RRMS-type inflammation, and not in PPMSers.

    So many questions. The field of MS research remains very muddy.

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  10. Wow that great news!!! o//

    See the first drugs against forms of MS Progressive is sensational!!!

    Now reading the announcement of Novartis and rios Prof.G publication I was thinking from what I've read about , S1P is a lipid mediator (fat) in the blood, which is important for the vascular and immune systems.
    The S1P regulates the T and B lymphocyte trafficking, the Siponomod even seems to have imunoduladores effects (correct me if I'm wrong).
    S1P is a lipid mediator in the blood, in particular in association with lipoproteins such as HDL, called "good" cholesterol".

    When S1P agonist, which is involved in lipid wasn't to have beneficial effects in MS, or not?
    Is that why Fingolimod failed to search for PPMS?

    I am asking this because I remembered the canandense study on the gene for susceptibility to PPMS it was located, and that seems to be related to the synthesis of lipids.

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    1. Ciara! Do you remember Timothy Vollmer and do you remember the 27 year old male who had SPMS and Gilenya cut his bvl. That's why siponimod has positive results I think. RRMS and SPMS are the same disease with same pathology! This is a progressive disease from the beginning!

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  11. While topline results are to be presented at ECTRIMS in a few weeks, I wonder whether one study for SPMS would be enough for FDA and EMA. In your opinion, do you assume that possibly the 2nd SPMS trial would be needed for regulatory approval?

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    1. It all depends on the benefits and risks of the trial. We have to wait for the data to be made public to answer this question.

      However, assuming the results are as good as the press release suggests, and there are no major undefined safety signals, then I think one trial would be sufficient. You mustn't forget there is good supporting phase 2 data from RRMS that Siponimod is an effective DMT, the drug is second in class i.e. in terms of its mode of action it is not a new drug, and the EXPAND trial was very large (>1,600 subjects). The one negative is the negative fingolimod PPMS trial. Will the latter make the regulators scratch their heads and interrogate subsets of patients? I sincerely hope for the sake of SPMSers that both the FDA and EMA acknowledge the unmet need and apply common sense.

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  12. I don't know why people are getting so excited. siponimod and fingolimod are essentially the same drug. One is unlikely to be better than the other. The effects of siponimod are probably driven by inflammatory activity, so this won't necessarily benefit people who are older who have no relapses and no MRI lesion accumulation. The real questions is, "are you hot or are you not." The clinical phenotypes are somewhat arbitrary. People who have relapses and make new lesions and are younger are likely to benefit. People who are older, make no lesions, and have no relapses are unlikely to benefit.

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