Olympics Over…Paralympics Begins ProfK gets Gold for Marathon, after crossing the line…the starting line……..First person in!

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Every week we get a news letter of Queen Mary in the News….they forget to mention the times when we are on the naughty-list but this week we should celebrate the marthon win for ProfK.

He has been running this marathon since about 2012 and has managed to get cladribine trial (ChariotMS) over the line in 2021 and the first person has been recruited to the trial………..only another few hundred to go.

The first suggestion of ChariotMS on the Blog was on 2 November 2015 As the tutonic knight (ProfK) lay dying after being almost mortally wounded after a 3 year battle to get subcutaneous cladribine available, we admitted defeat. I had been charting progress since 2011 with the “White Knight” posts to show you how long these things take. We had woken the sleeping giant and Merck was bringing oral cladribine back….yep I know they like to call them cladribine tablets but oral clad it is.

However, in those dying moments we had some visions the “Persian Knight” to think a trial could be done in Iran..they have been on the naughty list and had already made cladribine and then we had the Mexican adventure but the other picture you can see was “ChariotMS”

Yes the new Logo is abit more slick as modelled by Prof Ford from Gods Own Country

Image
Prof Ford in a ChariotMS T shirt…..This isn’t Leeds maybe she walks to work:-)

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

17 comments

  • The armies of the cladribiners are unlike others. I have faced them many times and they exact a fear-grip on pharma’s hearts in a way that no other enemy can. Pharma execs are more prone to fear when facing a host of cladribiners, and fear is a pharma exec’s worst enemy.

  • I’m grateful to Prof K and his team for all their efforts on the Chariot MS trial.

    My questions:

    (a) If oral cladribine offers the possibility (the purpose of the trial) of slowing / halting further disability worsening in MSers with advanced MS, why isn’t there a trial for less disabled MSers eg those “transitioning” to SPMS ie less disabled MSers? I’m sure I read somewhere that cladribine administered IV cleared OCBs in some SPMSers.

    (b) What evidence is there from RRMSers on oral cladribine that the drug is having an impact on the mechanisms driving progression in addition to reducing relapses?

    • Thanks Sid.
      The answer to your question (a) is partially answered by licensing. In the US, oral cladribine is licensed for active SPMS similar to the way Ocrelizumab is licensed over here for people with active PPMS. Since the evidence is overwhelming that SP and PPMS are mechanistically the same disease, the fact that both CLAD and OCR aren’t licensed for both indications on both sides of the Atlantic is purely a result of the regulatory process. You are correct, a paper by Konrad Rejdak and his colleagues described that in a small cohort 55% of people undergoing cladribine treatment lost their oligo-clonal bands when tested 10 years later. This result relates to your question (b): Firstly, we expect that any inflammatory activity driven from the periphery will be reduced equally effectively in people with advanced MS as in people with early MS (or indeed CIS). Secondly, the capacity of cladribine to penetrate into the CNS we hope will be beneficial (certainly not detrimental) in depleting inflammatory activity directly in white and grey matter lesions, follicle-like structures, and meninges. If the drug does that (the Rejdak data provide preliminary evidence for that), and if stopping such activity affects myelin and axonal function to a degree that we can pick it up with our primary outcome, the trial will be positive. Fingers crossed…

      • How long would you suspect it to take Cladrabine to take to clear OCBs in the CNS, are there any studies on this?

        If you where one of the lucky ones where they where cleared that is.

        • Based on the longevity of plasma cells, it could take years. I’m not aware of studies that have systematically looked at this, so thank you for the suggestion. We could explore this in our cohort where people started treatment as early as Nov 2014.

          • Seams like a worthy treatment target. With not much to lose.

            It would be interesting to see how different treatments clear OCBs differently and the time taken to clear them.

          • “Based on the longevity of plasma cells, it could take years.” Why so long to get rid of the plasma cells? I assumed clabrine gets in and kills off B cells immediately. Will the drug on the Sizomus trial kill off plasma cells quicker?

          • ANONANONANON
            It may take that long since cladribine does not deplete plasma cells to the same degree as it does other immune cell populations, so the downstream effect of the drug on B cell subsets, including depletion/modulation of plasma cells, takes time to unfold. Whether suppression of plasma cells is both effective and safe is being tested by Drs Gnanapavan and Wafa in Sizomus, as you say.

  • I feel like many praises are sung for Cladribine on the blog. Makes me wonder. As far as i know the IRT’s are most effective if applied early in the disease course of MS patients. However, have there been any studies on the efficacy of IRT’s (like clad or alemtuzumab) if they’re applied after another highly effective DMT? Or to put it another way: do you believe the IRT’s need to be applied immediately to ”out-perform” other highly efficacious DMTs?

    • Regarding switching, there is literature on Alemtuzumab, HSCT, and soon on cladribine underpinning the effect you can achieve by moving from platform drugs, but also between highly effective drugs. Anti-drug antibodies play an important role in the latter.

      Your DMT goals change with the timing and severity of the individual you’re treating. If you apply highly-effective compounds from the first manifestation, you could end up with long-term remission or cure. If you’re starting treatment at a later stage, the achievable effect depends on the degree to which inflammatory activity remains the driver of disease progression and your reserve capacity. For example, over a life with MS you lose, on average, about 60% of your spinal cord axons. What goal you can achieve depends, among other elements, on where you are on the ‘sliding scale’ of neuro-axonal damage & loss. Goal setting can mean maintaining the ability to run a marathon or the ability to move the joystick of your electric wheel chair. Both are worthy goals; what you can achieve depends on where you start.

      • 60%? Wow. Does this figure depend on whether spinal lesions are present? Also, how can you determine where you are on the sliding scale? For example, a patient could run a marathon today but the damage already accrued, even if further damage is avoided through effective treatment, could catch up with them eventually?

        • Cord lesions play an important role, though are probably not the single cause of nerve fibre loss. My PhD student described her findings in this study: https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.12516 You will see that lesions are the key driver of axonal loss.

          Evidence suggests that MS can be altered by treatment at virtually any stage, the question is by how much, and whether you can ‘only’ slow down, stop, or even revert any problems accrued. If you are starting highly effective DMT very early, your chances of being able to run a marathon are good; if you are starting later, you’ll depend on what has been lost alongside a range of additional detrimental factors.

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