Thursday, 28 January 2016

ResearchSpeak: what are the implications of the negative fingolimod PPMS trial

What can we learn from the negative fingolimod in PPMS trial? #MSBlog #MSResearch #ResearchSpeak

"The INFORMS, or fingolimod in PPMS, study results have just been published online. We have discussed this study before in great detail. The fact this study was negative and fingolimod did not have an impact on any of the composite endpoints including upper limb function, nor an impact on brain atrophy, raises real questions about the pathogenesis of PPMS and progressive MS in general. In short this trial suggests we don't have clue about what is driving non-relapsing progressive MS. Or do we? The positive ocrelizumab PPMS trials suggests that may be the problem in non-relapsing progressive MS has something to do with B cells and plasma cells that are responsible for producing antibodies within the intrathecal compartment (within the meninges) of the brain and spinal cord."

"Did we get the therapeutic target wrong with fingolimod? In hindsight yes. Let's hope we learn and move on. I personally think if the DMT hasn't been shown to have an impact on intrathecal B cells and plasma cells it won't work in non-relapsing progressive MS. I hope I am wrong, the siponimod SPMS trial will be the next to report. Siponimod is a follow-on S1P modulator and has the same mode of action to fingolimod. If there are enough active or relapsing SPMS subjects in this trial it should be positive."


"Please note the results of this trial challenge my length-dependent axonopathy hypothesis. I would have expected fingolimod to have an impact on upper limb function."

Lublin et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016; DOI: http://dx.doi.org/10.1016/S0140-6736(15)01314-8

Background: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis.

Methods: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25–65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2–10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed.

Findings: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87–82·51) of patients in the fingolimod group versus 80·3% (73·31–87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80–1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%).

Interpretation: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis.

CoI: multiple

11 comments:

  1. Do you think this is the end for DMF trials in PPMS as well Profs.?
    It could be a shame, DMF worked in PPMS in a little pilot study some times ago.
    May I ask your opinion?

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    1. Re: "Do you think this is the end for DMF trials in PPMS as well Profs.?"

      There is no DMF in PPMS trial that I am aware of. Biogen did stop the DMF in SPMS trial after the ASCEND trial was negative. The latter was for business reasons and necessarily scientific reasons.

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  2. INFORMS was negative as well as the ASCEND trial using natalizumab. Restricting T-cells have an impact on inflammation but not on progression. Hopefully pharma will not keep trying to pursue T-cell therapies for progression and Drs. will realize this also. This is throwing good money after bad.

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    1. Re: "INFORMS was negative as well as the ASCEND trial using natalizumab."

      Although the ASCEND was negative on the primary outcome it did slow loss of upper limb function. This data is due to presented at the AAN in April so I will be able to provide you with more information about it then.

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  3. Prof. G. in what sense the study fails to Fingolimode for PPMS affects your asynchronous event for MS Progressive, or rather the axonopathy involved in it?

    It would be because of the involvement of B cells?

    http://multiple-sclerosis-research.blogspot.com/2015/03/length-dependent-hypothesis-sensory-vs.html?m=1

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    1. Re: "Prof. G. in what sense the study fails to Fingolimod for PPMS affects your asynchronous event for MS Progressive, or rather the axonopathy involved in it?"

      I would have expected it to have an impact on upper limb function; i.e. to slow or halt worsening on the 9-hole peg test compared to placebo. This is what happened in the natalizumab SPMS or ASCEND trial.

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  4. This is certainly a disappointing result, but I fail to see why there is much optimism for Ocrelizumab and other B cell therapies, in regards to treating progressive Multiple Sclerosis. Certainly, the Ocrelizumab progressive MS trial results headlines were overblown, and very likely the drug showed efficacy only in those progressive patients displaying active inflammatory disease, by way of enhancing lesions on their MRIs. This matches what was shown in the Rituxan PPMS trials circa 2009, which were deemed a failure even though a small cohort of patients (under 50, with enhancing lesions) did display some benefit. Since only about 15% of progressive patients have enhancing lesions, these B cell approaches leave the vast majority, 85%, without any viable treatment options, even at this late date. B cells and lymphatic tissues within the CNS may be a viable target for some, particularly SPMS patients, but these tissues have rarely been demonstrated in PPMS. Enough with trying to repurpose immunosuppressant drugs to treat progressive MS, an entirely new approach is obviously needed. The B cell therapies may prove to be quite beneficial for the 15%, but the rest of us are still left high and dry, with nothing to do but slowly (or, in many cases, not so slowly) watch ourselves disappear. Distressing, to say the least.

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    1. So you mean that the PPMS is a different disease, RRMS and SPMS part of? To me it is all the same disease ...

      And MD in their publications have demonstrated that Fingolimode would have no effect on the PPMS...

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    2. The same mantra...target lymphocyte trafficking into the CNS. Another strategy needs to be implemented. It's as if pharma is trying to fit a square peg into a round hole.

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  5. MD/MD2 how can you resist not commenting on these findings? Maybe you'd care to explain your animal data: "Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis" Multiple Sclerosis 2011 Aug 17(8): 939.

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    1. Yeah looks like humans show what happened in EAE. Fingo did not stop proogression in our hands and our prediction held up. It does not bode well for siponimod in SPMS

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