Top MS trials in the UK!

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I have listed below in alphabetical order the most innovative and cutting edge clinical trials in the UK. They are almost exclusively Investigator/Institution led suggesting active interest from Clinicians and Scientists in developing targeted therapeutics for MS.

For further details please visit clinicaltrials.gov.

See the source image

BTK (Bruton Tyyrosine Kinase) inhibitors

Source: various pharmaceutical companies; Phase III clinical trials in Relapsing remitting and Progressive MS

BTK is expressed by most blood cells, especially B cells, myeloid cells (e.g. neutrophils) and platelets, with low or virtually no expression in T cells and plasma cells.

BTK inhibition leads to less B cell activation and maturation and likely to reduce the inflammatory component of MS. Despite the oral preparation they have good CNS penetrance.

The molecules currently in trial are listed below:

ProductType of BTKiSponsorClinicalTrials Gov IdentifierPhaseType of TrialPatientsStart DateEstimated Completion Date
FenebrutinibNon-covalent, reversibleHoffmann-La RocheNCT04544449III
RDB
Fenebrutinib (or placebo) vs. ocrelizumab (or placebo) 1:1 (FENtrepid)946 PPMS20202028
FenebrutinibNon-covalent, reversibleHoffmann-La RocheNCT04586023III
RDB
Fenebrutinib vs. teriflunomide 1;1 (FENhance)734 RMS20212024
FenebrutinibNon-covalent, reversibleHoffmann-La RocheNCT04586010III
RDB
Fenebrutinib vs. teriflunomide 1;1 (FENhance)734 RMS20212024
TolebrutinibCovalent, IrreversibleSanofi/PrincipiaNCT04458051III
RDB
SAR442168 (tolebrutinib) vs. placebo (PERSEUS)990 PPMS20202024
TolebrutinibCovalent, IrreversibleSanofi/PrincipiaNCT04410978III
RDB
SAR442168 (tolebrutinib) vs. teriflunomide GEMINI1900 RMS20202023
TolebrutinibCovalent, irreversibleSanofi/PrincipiaNCT04410991III
RDB
SAR442168 (tolebrutinib) vs. teriflunomide GEMINI2900 RMS20202023
TolebrutinibCovalent, irreversibleSanofi/PrincipiaNCT04411641III
RDB
SAR442168 (tolebrutinib) vs. placebo (HERCULES)1290 SPMS20202024
EvobrutinibCovalent, irreversibleMerck KGaANCT04338022III
RDB
Evobrutinib vs. teriflunomide
(EvolutionRMS 1)
930 RMS20202026
EvobrutinibCovalent, irreversibleMerck KGaANCT04338022III
RDB
Evobrutinib vs. teriflunomide
(EvolutionRMS 2)
930 RMS20202026
OrelabrutinibCovalent, irreversibleBeijing InnoCare Pharma Tech Co., Ltd.NCT04711148II
RDB
Orelabrutinib, three doses vs. placebo at 1:1:1:1 ratio160 RRMS20212024

ChariotMS

Source: Twenty UK neuroscience centres; Phase IIb Advanced Progressive MS

This is oral Cladribine (Mavenclad) for people with upper limb dysfunction in advanced progressive MS (EDSS 6.5-8.5). Oral Cladribine is already licensed for relapsing MS.

With progressive disease individuals can also start to deteriorate in upper limb strength in addition to progressive walking difficulties. Earlier pilot work demonstrated that some of these individuals have elevated Neurofilament light chain in their cerebrospinal fluid (CSF), hinting at ongoing inflammatory damage in Progressive MS that are normally not eligible for treatment. Sub-cut Cladribine was able to reduce CSF Neurofilament light chain levels and preliminary evidence suggests it impacts on clinical disease progression.

So this is a neuroprotection study to preserve upper limb function.

MS-STAT2

Source: National Hospital for Neurology and Neurosurgery; Phase III Secondary Progressive MS (SPMS) with complete enrolment.

MS-STAT 2 is high dose Simvastatin (the same drug used to treat high cholesterol) versus placebo.

STAT 1 demonstrated a reduction in brain volume loss versus placebo but no difference in the clinical scores. The concept is that there may be degree of neuroprotection in progressive MS as evidenced by the reduced brain volume loss.

In animal models of MS statins have been shown to shift the disease phenotype from a proinflammatory one (Th1) to less inflammatory one (Th2) and also from it’s vascular mode of action may protect the brain from ischaemic injury.

SIZOMUS

Source: The Royal London Hospital and National Hospital for Neurology and Neurosurgery (referral centre only); Phase I Relapsing Remitting and Progressive MS.

The first clinical trial to target Plasma cells in MS.

Plasma cells produce the vast quantities of antibodies seen in MS and become resident in the brain over the disease course maintaining the inflammatory disease.

The trial drug is Ixazomib and is being trialled as an add on to existing RRMS treatments and as a stand-alone drug in progressive MS. The goal is to see if treatment with Ixazomib can get rid of the antibody production in the CSF (i.e. the so-called oligoclonal bands).

STAR-MS

Source: multiple UK neuroscience centres; Phase III Relapsing-remitting MS.

This is a trial testing autologous Haematopoietic Stem Cell Transplantation (HSCT) in active MS.

It goes up against Ocrelizumab or Alemtuzumab which are both big hitters in the MS world.

HSCT as a treatment option works best when there is evidence of inflammatory disease (i.e. new lesions on MRI head) and used early in the disease course. Previous studies have largely demonstrated that inactive progressive MS is unlikely to improve with HSCT.

About the author

Neuro Doc Gnanapavan

19 comments

  • Dear NDG,

    Many thanks for putting this together. Trials, particularly of novel agents, give MSers hope. The investment by so many pharma companies in BTK inhibitors suggests that there is some hope that these agents will have a positive outcome. I think the Cambridge trial of potential remyelination agents starts in March.

    I’m most interested in the Sizomus trial as getting rid of the antibody producing cells in the CNS seems a good target.

    Good luck!

    • Thanks, and it’s good to see that Cambridge are having another look at remyelination. Maybe they have a more specific RXR agonist?

  • Thanks for that neurodoc. Re neuroprotection more generally, would you happen to have any thoughts on:
    a) anti-epileptics (newer generations, older ones have a heavy-duty side effect profile)
    b) co-morbid EDS?

    • Anti-epileptics and sodium channel blockers probably work in axonal neuroprotection – I believe a calcium channel and sodium channel blocker will be entering into the OCTOPUS study that will be testing multiple agents at the end of this year.
      The co-morbidity to have a worse outcome is vascular risk factors, which are also more prominent as you age.

      • Disappointing from the Octopus trial, last may they announced a trial was starting at the end of 2021.

        Total silence since, no announcement on why it hasn’t started. No doubt the golden ‘covid’ excuse will be rolled out, however the announcement that the trial will start at the back end of 2021 was made during the covid pandemic, so surely the organisers weren’t caught cold by covid.

        I find it pretty immoral, that may get peoples hopes up, with no announcement for 6 months and counting over the start date, considering the charity runs and trails funded on donations, surly it’s common courtesy to let the people know who donated and made a great effort to raise funds where the progress of the trial stands, is it was due to start last year.

      • Do you think that all anti-epileptics (including, e.g., pregabalin) are probably neuroprotective, or just the sodium channel blockers?

      • PS: that’s a pretty zen take on wheels. So far, I’ve been unable to make out your country of residence, birth, or cultural background. You seem to be pretty up on MS in the UK, appear to express yourself in American English, and I haven’t a clue as to the ethnic origin of your surname.
        As a dual US/UK citizen, I’m the 3rd generation and epigenetic pivot of a family cursed unto the 5th and counting with an autosomal dominant form of EDS. The 4thG consists of my 2 daughters only, both of whom have comorbid MS in the UK.
        I have lived long enough to have grown weary of simultaneously being patronised by/causing offence to both sets of compatriots. SS-CV-2 has probably increased this problem by an order of magnitude.
        I have lost bunnydoctor completely on this site- if she’s one of yours, could you pass on the following:
        I am no longer as enamoured of PubMed as I used to be. It spawned the tool meta-analysis, which conveniently dismisses me as an outlier on anyone’s graph, which I have found particularly unhelpful.
        Has anyone else noticed that the NHS effectively functions as an arm of the state heavily influenced by the Treasury?
        P

        • The NHS is dependent on the treasury for the level of funding, which is why it’s in dire straits due to underfunding, compared to historical levels, by successive Tory administrations since 2010.

          • Couldn’t agree more. Pandemic pressures on my GP practice have pretty much done for 3 partners over the age of 55, 2 partners under left standing. There has been a huge increase in the number of employees at all levels. For me, the upshot of this is that my journey to the canton of Zurich will be significantly earlier than planned.

      • Thanks. Re desert island, I can’t get it down to one only. I like a basic biology model, but also a basic chemistry model. What effect does excess of substrate have on any reaction?
        My various clinicians are generally happy to permit me to experiment on myself unless they have reservations about the polypharmacy involved.
        Thusly, I have opted for chelated magnesium and lamotrigine.

  • Thanks for this post NDG – does seem to be a lot of attention being given to BTK Inhibitors, but what f other neuroprotectives – most obviously Lipoic Acid, which provided very good early data.

      • To Neurodoc G, MD
        Thanks for making me laugh this morning guys- both of you. I’ve been fluctuating recently, between
        a) natura bloody well does facit saltus
        b) when what goes around comes around for the 2nd or even 3rd time is when it all starts getting Really Depressing…
        Checking back through my own pencil scribble, I seem to have hit peak polypharmacy myself a good 5 years ago now. Heigh-ho, how sad, never mind, etc.
        Best, P

        • Hey Paula, maybe my reply to this is that the wheel may have come full circle, but the conditions for the wheel are not the same as before. They are starting to diverge.

          Now, talking about things that are not changing is Elon Musk talking about a Noah’s Ark into space, that idea is prehistoric!

          • Tell me about it- my late father (1933-2002) was an actual US Cold War rocket scientist! He also used to tell me that a horse designed by committee on cost-plus contract was called an elephant…
            Dido Harding, anyone?

  • A Desert Island…

    Hello Doctor- Alpha Lipoic Acid (ALA) is another compound under active Phase 2 investigation as a neuroprotector for progressive MS (NCT03161028), which you haven’t mentioned here, perhaps because it is not “best of”. Simvastatin you have described here. I started taking ALA recently in the experimental dosage as it is available safely over the counter. I am on Simvastatin at half the experimental dose, already, for cholesterol purposes.

    So if you were stuck on a desert island and had a progressive form of MS, and ruling out any other motivations you might have for taking an anti-oxidant or a statin, which ONE compound would you rather have an abundant supply of until you were rescued? Can you give a simple brief explanation about why? Thank you for any reply.

    • Hi Tom, Yes there was reason why I didn’t put this in as the concept has been around for a while and I was weighing it up against other mounting evidence from other neuroprotectants. I may be wrong, but I’ve been disappointed in the past with high dose Biotin so will wait for further data before making a call on this one.

      Desert Island – I will be on the highest tolerated dose of a sodium channel blocker – the biology, basic science model, animal and Phase 2 trial data in SPMS is good.

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