Thursday, 7 September 2017

#ClinicSpeak & #ResearchSpeak: the maven has landed and is ready for use

Do you know what a maven is? Is cladribine a maven? #ClinicSpeak #ResearchSpeak

Summary: This post describes why cladribine is a semi-selective immune reconstitution therapy or SIRT and some of the attributes that make cladribine such a good drug to treat MS. 

I spoke at a meeting yesterday about my journey with oral cladribine. It began in 2002 with an advisory board to decide if Serono should in-license the oral formulation as a potential treatment for MS and we have finally got to the point of the drug becoming available in Europe a week ago. A journey that has taken 15 years. Who said drug development happens quickly? Another milestone in the history of oral cladribine was the publication of the CLARITY extension study; it came out as an e-publication yesterday. 

At yesterday's meeting, the chair introduced me as a maven; a compliment considering oral cladribine tablets have been named Mavenclad. Maven refers to an expert and is derived from the Yiddish word meyvn, meaning "one who understands". As you can see the usage of the word has soared in the last decade or so. I assume this is because Maven has been popularised by Malcolm Gladwell in his book 'The Tipping Point: How Little Things Can Make a Big Difference', which was published in 2000. Gladwell's use of the word is a little bit broader than that of an expert. 



Wikipedia Excerpt: Gladwell describes mavens as "information specialists", or "people we rely upon to connect us with new information". Mavens accumulate knowledge, especially about the marketplace, and know how to share it with others. Gladwell cites Mark Alpert as a prototypical Maven who is "almost pathologically helpful", further adding, "he can't help himself". In this vein, Alpert himself concedes, "A Maven is someone who wants to solve other people's problems, generally by solving his own". According to Gladwell, Mavens start "word-of-mouth epidemics" due to their knowledge, social skills, and ability to communicate. As Gladwell states: "Mavens are really information brokers, sharing and trading what they know".

Enough small talk. I have been heavily criticised by MD about the length of time it took us to get the CLARITY Extension study published. Three submissions later and six rounds of addressing reviewer's comments it is finally out. This study not only confirms cladribine as an IRT (immune reconstitution therapy) but a SIRT (semi-selective IRT).  Just 8-10 days of treatment in year-1 and a repeat cycle year-2 is sufficient to put the majority of subjects into long-term remission for up to 4 years and beyond. What proportion will need retreatment in the future is not known at present, but I suspect it will be in the same ballpark as alemtuzumab. 

There is little doubt that oral cladribine is going to disrupt the MS DMT space. The fact that it is an IRT will make it more cost-effective than the maintenance treatments. Other advantages are that it is oral, easy to use, it is not associated with a cell lysis syndrome or infusion reactions, it does not take out the innate immune system so Listeria is not a problem and the monitoring requirements are minimal. There is no secondary autoimmune signal. The fact that it is a small molecule means there are no anti-drug antibodies, or NABs. We are also excited about the fact that it penetrates the CNS and may have activity on the B-cell and plasma cell biology within the brain and spinal cord.  More importantly, it selectively targets the adaptive immune system in particular B-cells. 

In summary, cladribine is as close to the most ideal DMT we have. Is there a down side? Yes, in an attempt to make it safe I  think we have compromised on the dose. If only we can selectively target cladribine to B-cells and the leave the T-cell compartment intact we will have a real winner, an oral form of anti-CD19. Please note anti-CD19 and not anti-CD20. CD19 is expressed on a wider population of cells including plasmablasts and some plasma cells. The downside of anti-CD20 is that it does not touch plasma cells. I have previously hypothesized on the need to scrub the CNS free of pathogenic plasma cells to prevent ongoing gray matter damage and delayed worsening, or progression of MS.





Giovannoni et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
Mult Scler. 2017 Aug 1:1352458517727603.


BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS).

OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study.

METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained.

RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension.

CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.

CoI: multiple

43 comments:

  1. Can you explain please what you mean by saying that you "compromised on the dose"?

    Did you make the dose LOWER in order to reduce the PML and/or cancer risk?

    Also, HOW OFTEN will the blood-monitoring tests be?

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    1. The concern made by the regulators was that cladribine induced lymphopenia as a side effect.

      Lower lymphocyte numbers increase risks of infection or cancer. However, the risks of PML are reduced as it is an IRT, JC infection risks are reduced as you immune system in not permanently inhibited, the drug is gone within 24hour of the last dose and so your immune system can return if an infection occurs. Also as we showed Cladribine in CLARITY did not wipe out CD8 T cells so your viral immunity isn't eliminated. Perhaps this is why IRT therapies are not typically associated with PML. Peoples blood levels are checked before dosing.

      In the CLARITY trial there was about 25% moderate to severe lymphopenia. So to reduce this there is a broader dosing scheme based on weight and there are blood tests to monitor this. However this is not a side-effect but the mechanism of action so by reducing the side-effect you are potentially reducing efficacy.

      This side-effect bit of tar stuck and was even mentioned again by the regulars. However the landscape has changed with the advent of alemtuzumab and it has a liberal licence in Europe. However it induces severe lymphopenia in about 85% of people which is much more than 25% with the original dosing scheme. Part of this aspect was dose-related and so by reducing the dose you could reduce the lymphopenia The other aspect is to check for lymphopaenia before the next cycle of treatment rather than dosing without checking so the lymphopenia was lower in ORACLE than CLARITY.

      I think there will be blood tests at 2 months and 6 months after each dose to determine lymphopenia and screening can influence second cycle.

      You can reduce the issues further, but it was obviously too boring to have an ECTRIMS 2017 platform presentation.

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    2. see monitoring in the prescriber's guide above

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    3. Thank you Mouse for this very informative response. You even answered some concerns not mentioned by me. THANK YOU.
      I will be considering starting Mavenclad probably next year so need all the info I can get to talk with my neuro.

      Delete
  2. So after all the hype here in the Staes, is this better then Ocrevus? Sorry I need to cut to the chase.

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    1. Maybe...without head to head you cant say. Same mechanism same efficacyif they work optimally.

      Also ocrevus is not marketed as a IRT, however as I showed you based on phase II ocrevus extension it could be an IRT too.

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  3. Cladribine vs Ocrelizumab vs Alemtuzimab. Am I permitted to ask which of these three you would personally choose if they were all currently available in the UK - and why? Thank you for your help.

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    1. You can ask but please understand why such a question can't be given an answer. it's a decision to be made between the pwMS and their clinician armed with the latest information, which hopefully this blog can provide.

      Delete
    2. If I was JCV-seronegative I would opt for natalizumab as a holding procedure. This should allow me several years and the evidence-base to mature regarding IRTs.

      However, knowing what I know about MS I would want the option of HSCT on the table, but to be treated under the NHS and not abroad. I would then want as much information on the table as possible; prognostic profile, the state of my pension, whether or not my life insurance would pay out for these treatments, etc. As a responsible husband and father it is their futures as well as mine at stake. I would consult with my wife, children, my neurologist and haematologist and I would then make a decision.

      You will argue that I have deliberately ducked the question, but I haven't. There is no simple algorithm or easy answer to the decision, and that is the truth.

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    3. The problem is that you have to fit to the criteria of highly active MS to be able to have access to cladribine and Lemtrada. Ocrevus has also some criteria a patient has to fit in America, don't know how it will be used in EU. So for the majority of patients who fall between the types of less aggressive and the highly aggressive forms, there is not that much of an option, till they FINALLY decide officially that just hiding relaplses is NOT good enough.
      With Lemtrada, Cladribine and HSCT it seems that IRT is the way to go towards MS, and hopefully it won't take another decade to decide to use efficient therapy from the start. (just a patient opinion)

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    4. "Gavin GiovannoniThursday, September 07, 2017 7:47:00 pm
      If I was JCV-seronegative I would opt for natalizumab as a holding procedure. This should allow me several years and the evidence-base to mature regarding IRTs.

      However, knowing what I know about MS I would want the option of HSCT on the table, but to be treated under the NHS and not abroad. I would then want as much information on the table as possible; prognostic profile, the state of my pension, whether or not my life insurance would pay out for these treatments, etc. As a responsible husband and father it is their futures as well as mine at stake. I would consult with my wife, children, my neurologist and haematologist and I would then make a decision.

      You will argue that I have deliberately ducked the question, but I haven't. There is no simple algorithm or easy answer to the decision, and that is the truth."

      i took a year of my life as a patient's partner to do this (or rather to put it in front of the patient in an easy to understand way). i also dragged her to no less than 6 different neuros, one of whom was 600km away.

      the patient is doing well and happy with her choice. i'm still recovering lol.

      i must have done something well because the neuro now talks to the haemo and they seem to almost be trying to work as a team. but boy it took everything i had and i lost a job because of it (luckily, jobs grow on trees and when i was ready i got a better one).

      Delete
  4. Naive question... Currently prescribed natalizumab 6 weekly why couldn't this be combined with cladribine? Why don't I find any talk of multiple therapy usage?
    Thanks, Dan

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    1. 6 weekly!!!

      Are you sure about that?

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    2. Why are the rest of us having it every 4 weeks then?

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    3. The standard dose is monthly, we do not combine with cladribine as it is not licenced.

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    4. If you use cladribine the cells are killed so there could be nothing for natalizumab to act on but it would be a risk factor for PML

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  5. And that, my friends, is how you shoot the Ocrel Eagle point blank before it even takes off!

    Do we know do brain atrophy figures compare in the high efficiency group between Alem, natal, Ocrel and cladribine?

    No data may have been published on Ocrel yet so you are excused to leave it out.

    Tony

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    1. Ask Prof but you are not comparing like with like people in the ALEM trials were on drug within 2 years in the CLARITY it was 4-5 years, so you have 2-3 years of loss of brain reserve extra.

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  6. Huge credit to MD and Dr K, who by their dogged persistence kick-started the reactivation of cladribine as a treatment for MS (debunking the cancer risk etc etc).
    If that isn't impact, I don't know what is.

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    1. Hear hear, well said MD2. Impact, kudos, ref or whatever you call it ;-) heartfelt thanks :-)

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    2. Wholeheartedly agree with you MD2.

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    3. https://shar.es/1SBPtn

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  7. This is one of those post about to become mega intriguing. We see one of them every 6 months or so on the blog.

    Team G: perhaps you owe your readership a reply to as many questions raised in the comments section as possible.

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    1. Indeed, it would be good to see where this sits in the portfolio of options that are now starting to be available.

      Delete
    2. If our march 2017 paper is correct, They all work the same way...their activity depends on the level of depletion of memory B cells. More depletion more efficacy. Making choices based on efficacy becomes easy.

      You can then rank of safety and convenience

      How does cladribine work? Obviously, it was too boring to have an ECTRIMS 2017 late-breaking platform presentation....primate glymphatics are much more interesting:-(


      Delete
  8. Good work Team G, very exciting. I was wondering what is the % of cladribine decrease in disability to compare to placebo?

    It would be very nice if you were able to compare relapse rate, disability progression, NEDA 4 of all players so that a patient with RRMS could make an informed decision as to what is the most efficacious DMD and then weigh that against side effects.

    Also Dr. G states cladribine "penetrates the CNS and may have activity on the B-cell and plasma cell biology within the brain and spinal cord". How do you measure this? Also why was this not tested in a progressive MS trial as well if this is the case or is this trial planned or underway?

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    1. Best way is head to head studies which haven't been done but one could say HSCT is way out in front,

      In terms of cladribine we know at least of 25% of what is in the blood gets into the brain but could be more in an active lesion. There is a process called liquid crystall mass spectrometry. The chemical structure gives a mass spect signal. So another machine that goes ping.

      Oral cladribine was not tested in progressive MS yet because until it was licenced , Merck was not going to pile any more money into doing trials. No it is licenced it depends on patent life, if it takes 5-7 years to do a trial and get a licence will they go for it. Also as ocrelizumab is licenced for PPMS would they not have to compare to active (ocrelizumab) to make it ethical and so you have a $36,000,000 ($60,000 x 3 years x 300peopl) drug bill before you start.

      Cladribine (non oral variant) has been tested in progressive MS, reading between the lines it can do as least as good as other immunomodulators, which may mean a failure in some peoples eyes.

      If you support DrK in "Chariot MS" it could start next year

      Delete
    2. Thanks for your time and response MD (and Monty Python reference).

      I believe Dr. K has his heart in the right place with the "Chariot MS" trials. I am torn to donate as I personally am not sure I believe that any of the current DMDs, including cladribine, will be markedly effective in progressive MS.

      The focus probably should be elsewhere (mitochondrial/cellular dysfunction (neuroprotection), A1 astrocytes, hot microglia, remyelination and neurorestoration). Then again, with financial backing, I suppose that Dr. K will prove or disprove this.

      Delete
    3. Surely it is worth trying. We know that you need neuroprotection but it needs to go on a solid.I know of one person who had neurofilament levels of two thousand units per ml go down to normal level meaning their nerve loss was being halted was it because of neuroprotection maybe,but most likely because it was anti inflammatory.

      Delete
    4. Maybe MD but I suppose will only know if Dr. K studies it. I assume this was a progressive patient. How clinically did they make out and not just NFL levels and MRIs-did they stabilize or improve on EDSS? What was used as neuro-protectant and anti-inflammatory in this case? Thanks for your help.

      Delete
  9. I like the subtlety of this post, in particular the reference to The Tipping Point and How Little Things Can Make a Big Difference.

    Cladribine tablets being 'little things', but making a big difference.

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  10. Any estimate of when will Mavenclad be available in other countries?

    Will it be priced like the other DMTs?

    As patients, could we ask for generic cladribine on the basis of Mavenclad?
    Neurologists who would have shied away from off-label cladribine earlier may now be more willing to prescribe it.


    ReplyDelete
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    1. ProfG will know the answer, presumably Australia and Russia where it (a) was licenced should be next.

      (b) I have no idea of what it will cost?

      (c) You could be right

      Generic cladribine could be a problem for Mavenclad, or a saviour if your country can't afford oral cladribine. There may be no reason for anyone to slip through the cracks.

      Delete
  11. Could Mavenpack be the next dmt for somebody who has been taking rituximab for many years?

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    1. Find the reason for failure and the need to switch is rituximab an IRT

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    2. Rituximab hasn't failed ... but how long can one continue re-dosing?
      It can't be safe to keep using it for the rest of your life

      Delete
  12. Could you create a table of all the effective DMTs comparing various important parameters (whatever you think they might be)? This would help people to decide themselves which drug, if any, might be appropriate for them.

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    1. The MS trust has a drug comparison site, it doesn't have their memory B cell depleting activity though

      Delete
  13. Would you not expect the brain atrophy data to end up being better than Alemtuzumab considering the CNS penetration of the drug, therefore clearing the memory B and plasma cells in the CNS? Also, what is the experience regarding the effects on male fertility of cladribine?

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    1. ProfG reported CLAD brain atrophy data, I think alemtuzumab was better but as mentioned above alemtuzumab group had 2 years less disease duration.

      With respect to clearing B cells from the CNS, it is hypothetical we need to see the data. Any volunteers for a lumbar puncture?

      Claribine and fertility, please read the prescriber's guide, it is a drug that interferes with DNA,

      I think in our compassionate programme we have frozen sperm samples to be on the safe side. Males and Females should use birth control whilst on the drug. However perhaps it could allow a drug free pregnancy

      Delete
  14. So you only need treatment in the first 2 years, or do you have more treatment in years 5 and 6? Or does this depend on and breakthrough disease as shown on an annual MRI? Could it be used instead of a 3rd dose of alemtuzumab as you say the NHS isn't willing to pay for this?

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    1. You have hit the nail on the head. We know that 30-50percent of people need a third dose of alemtuzumab but NHS England won't pay for it. If Merck have been idiots which their info suggests, then they will get approval for two cycles. However I think people will breakthrough and require 3 or more treatments. As 10mg of mavenclad is equivalent to 4mg of generic an extra cycle for £500-800 may be an option. Once you are used to using the generic why bother with the oral.Interedting times ahead.

      Delete

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