Cladribine has no significant effects in progressive MS…The data says differently

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Based on the recent report that cladribine can eliminate the occurrence of oligoclonal bands in people with relapsing MS, there was a comment that cladribine has no effect on progressive MS.

So lets look back at the paper

If you  don’t think that Current Potent DMT can be useful for Progressive MS, Read this.

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Rice GP, Filippi M, Comi G. ladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group.

Neurology. 2000 Mar 14;54(5):1145-55.

OBJECTIVE:

To evaluate the safety and efficacy of two doses of cladribine in patients with progressive MS.

BACKGROUND:

Treatment of progressive MS patients with cladribine in a previous single-center, placebo-controlled clinical trial was associated with disease stabilization.

METHODS:

In the current study, 159 patients with a median baseline Kurtzke’s Expanded Disability Status Scale (EDSS) score of 6.0 were randomly assigned to receive placebo or cladribine 0.07 mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7 mg/kg or 2.1 mg/kg, respectively), followed by placebo, for a total of eight cycles. Thirty percent had primary progressive MS (PPMS) and 70% had secondary progressive MS (SPMS). EDSS and Scripps Neurologic Rating Scale (SNRS) scores were assessed bi-monthly and MRI was performed every 6 months. The primary outcome measure was disability (mean change in EDSS).

RESULTS:

Mean changes in disability did not differ among the groups at the end of the 12-month double-blind phase. Both cladribine treatments were superior to placebo for the proportion of patients having gadolinium-enhanced T1 lesions and for the mean volume and number of such lesions (p < or = 0.003).Differences were statistically significant at the 6-month evaluation time, with < or =90% reduction in volume and number of enhanced T1 lesions, which was maintained through final evaluation. This effect segregated largely with the SPMS group. The T2 burden of disease showed a modest improvement in cladribine-treated patients and worsened in placebo-treated patients. Most adverse events were mild or moderate in severity and not treatment limiting.

CONCLUSION:

No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS scores. Both doses of cladribine produced and sustained significant reductions in the presence, number, and volume of gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg reduced the accumulation of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally safe and well tolerated.
So there you have it “No significant treatment effects”.

We see straight away that the dose used was 07 to 2.1 mg/kg not the 3.5mg/kg as used in the licenced oral dose formulation, but we have to remember that the oral variant is about 50% as active as the subcutaneous or intravenous variant.
So the trial aimed to look at an effect on EDSS (which is essentially a measure of walking) over a twelve month period. Therefore the trial was doomed because they focused on lower limb function which has failed as an outcome for most trials in progressive MS and because it was only 12 months. It takes 2-3 months at the high dose to have optimal depleting effect and so you are asking the drug to work in progressive MS in 9 months. The ASCEND trial shows no effect on EDSS over 2 years and suggest trials need to 3 years to target this outcome.

However, cladribine was not inert as it was blocking gadolinium enhancing lesions. Based on studies in relapsing MS, it takes only about 6 months to detect a positive influence on this outcome and so the trial was a capable of seeing this. We know that lesions and relapses are damaging to the nerves and therefore benefit was being achieved as evidenced by a reduction in lesions. There were fewer T 2 lesions supporting this outcome.
However the study went on for 2 years in some people
Filippi M, Rovaris M, Rice GP, Sormani MP, Iannucci G, Giacomotti L, Comi G.
J Neurol Sci. 2000 May 1;176(1):42-4. We compared the changes of the volumes of T(1)-hypointense lesions seen on the magnetic resonance imaging scans of the brain from 159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T(1)-hypointense lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T(1)-hypointense lesion accumulation was found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS.

But it is too small to make any meaningful comment

He are some posts by DrK relevant to the post by Prof Rejdak



Leukaemia in children – what do these studies have to do with the use of Cladribine (2-chlorodeoxyadenosine) in pwMS?

Well, they revealed over 20 years ago that Cladribine penetrates into the spinal fluid, and in relevant concentrations (about 1/5 – 1/4 of plasma).

Whilst this property is not unique (among drugs used for pwMS) to Cladribine, it is the only drug where its mechanism of action strongly suggests a direct effect within the central nervous system.


Penetration into the brain may be important for the mechanism by which Cladribine could potentially work not only in those recently diagnosed with MS, but also in people with advanced MS (EDSS>6): Even though at this stage there is generally less significant blood brain barrier leakage and therefore less overt entry of inflammatory cells from the blood stream into the brain, we know that inflammation plays a role throughout the disease, including its advanced stage. A drug that can attack T and B lymphocytes, and perhaps plasma cells, in the brain of pwMS directly, even without overt blood brain barrier breakdown, may be effective in preserving important functions such as upper limb strength & coordination, cognition and speech.


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17 comments

  • you wrote:

    "We see straight away that the dose used was 07 to 2.1 mg/kg not the 3.5mg/kg as used in the licenced oral dose formulation, but we have to remember that the oral variant is about 50% as active as the subcutaneous or intravenous variant."

    Question: why did they use this dosage as opposed to the 3.5 mg/kg?

  • Thanks for responding to my question about the Rice study. So the short 12 month follow up was not sensitive to any potential improvement in EDSS? Ocrelizumab which has been approved now in the US for just about two years has been studied for more than 5 if we include the trials. It also has not shown any improvement in progressive MS EDSS. Virtually all improvements are in RRMS patients. I also fail to see how Cladribine would improve any EDSS outcomes, even long term, long after axons have been destroyed. Typically, any improvement in EDSS is due to remyelination. After that, like in long-standing progressive MS, it's game over

    • These agents are not going to improve EDSS they can only slow the rate of loss.

      It is not game over

      By the time progression is apparent, nerves have been lost and these are currently not coming back.

  • "Even though at this stage there is generally less significant blood brain barrier leakage and therefore less overt entry of inflammatory cells from the blood stream into the brain, we know that inflammation plays a role throughout the disease, including its advanced stage. "

    Are researchers convinced that peripheral lymphocytes are the major contributors to progressive MS and if so what are the major papers supporting this?

    Secondly, why are companies supporting these "poorly designed" studies that are doomed from the outset to give negative results in progressive MS? Focus on the nine hole peg test and not on ambulation. Are they so wealthy that they don't mind wasting money on flawed clinical trials?

    • "Are researchers convinced that peripheral lymphocytes are the major contributors to progressive MS… "

      It's about time they change their convictions.

      We had the "low hanging fruits" with relapse-focused drugs in RRMS and now with peripheral inflammation in neurodegeneration in PMS.

      You cannot teach an old dog new habits.

  • "We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS".

    I must be missing something MD. Cladribine treats the MRI, which correlates poorly with progression, but does nothing to improve the progressive MS patient's situation clinically.

    You say the trials are not long enough or are measuring the wrong thing like EDSS instead of upper limb function. This treatment, at best, will temporarily delay the inevitable incline slightly until their reserve runs out as they age.

    Time to stop this focus on the "neuroinflammation only approach" in progressive MS research and get on with remyelination, neuroprotection and neurorestoration therapies that provide a tiny glimmer of hope in this devastating disease.

    I have heard of these add on therapies for years now. How many more years or decades until they are available at a pharmacy?

    • Completely agree with Nissan..in the US, we have 12+ RRMS/anti inflammatory drugs. We know that inflammation plays a very small role in progressive, hence why HSCT and Lemtrada do NOT work to slow progression. Instead of focusing on the above mentioned therapies, protection/remyelination or harvesting stem cells for repair, we're doomed. And OcreliZumab..don't get me started. It has very modest effects on progression–25%. Wow. That means, I'll end up in a wheelchair in 4 years instead of 5. At a cost of $100k per infusion in the US, no wonder it's being pushed. But a game changer, it is not. It is another failure to deliver effective therapies to the progressive community

    • Lemtrada and HSCT normalise brain atrophy and stop progression for the 15 years of studies we now have, do you have a better argument than those studies? [These are for RRMS patients and not PMS]

    • As my post above states, HSCT and Lemtrada do NOT work to slow progression in progressive MS. I said nothing about RRMS.

    • "..in the US, we have 12+ RRMS/anti inflammatory drugs. We know that inflammation plays a very small role in progressive ms"

      Could be that it's not enough to stop inflammation..in pms..you
      probably have to get to the root of the disease..EBV. And if
      it's not EBV..then..good luck.

    • How do we know lemtrada did nothing the studies were not controlled, yes many people got worse.

      Next please clarify what you mean by inflammation.

      There is the lymphocytic inflammation which we associate with relapsing MS and glial cell inflammation which has been associated with advancing neurodegenerative lesions So my guess is it plays a big part in progressive MS

    • By inflammation, I mean active infiltration of b and t cells through the BBB. I understand that it's a matter of degree and other immune cells implicated but in progressive MS, we agree that neurodegeneration is the primary mechanism of progression. We don't know precisely how that happens and until we do, progressive MS will always progress

    • It is very likely that it is the inflammation associated with activated microglia that is a major contributor to neurodegeneration in the absence of active inflammation associated with B and T cell infiltration. Returning microglia to a quiescent state may well influence the rate of progression. Newer compounds such as BTK inhibitors may have an important role to play here, rather than just influencing relapses, which is how they are being studied at the moment.

    • Thank you for the reply. I was not aware that microglia were implicated in neurodegeneration. I will have to do some research

  • is there any data from Poland or elsewhere about how patients do on IV Cladribine?

    For example,
    -do they do better than untreated patients
    -do they do better than patients on CRABs
    -do RRMS patients do better than PPMS patients
    -do patients switch to other treatments
    -what percentage of patients get worse

    Dr K, what has been your experience with IV cladribine?

    • We have used s.c. cladribine, and the first paper is going to be out soon. The second has been presented at ECTRIMS and is currently in draft. Compassionate use is incompatible with controlled study, you do either/or, hence no controlled data (yet), but NEDA/NEPAD results look good.

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