Sunday, 9 October 2016

#ResearchSpeak: ECTRIMS highlight - durability of cladribine treatment

Will oral cladribine become the great disruptor? #ResearchSpeak #MSBlog #MSResearch #ECTRIMS2016

The following platform presentation is another of my ECTRIMS highlights. In short it shows that 2-years of treatment with oral cladribine has a durable effect in the majority of MSers with active disease. In other words cladribine is behaving like a true 'induction therapy'; you give short courses put the disease into long-term remission and hopefully where it will stay. 



I anticipate using cladribine in the same way we use alemtuzumab. The difference between cladribine and alemtuzumab is that there are no infusions, infusion reactions, or secondary autoimmunity. The latter is not a trivial point; it is the monitoring requirements for the secondary autoimmunity that is becoming such a burden to our MS service. Everyone who is treated with alemtuzumab needs monthly blood and urine monitoring for at least 5-years. 

Is cladribine as effective as alemtuzumab? I don't know. To answer this we will need a head-2-head study. DrK tried to secure funding to do a head-2-head between alemtuzumab and off-label subcutaneous cladribine, but it was unfortunately turned down as being too expensive. This was despite the proposed trial design saving the NHS millions by randomising half the patients to cheap generic cladribine. Based on indirect comparisons and brain volume data it does look as if alemtuzumab is the more effective option, but that is at a group level and does not necessarily apply to the individual patient.

What about pregnancy? Based on the data we have at present there is not indication that cladribine hangs around a long-time and hence woman are likely to be able to fall pregnant quite soon after completing their allotted cycles of treatment. I suspect the EMA will make this a 4-6 month gap (alemtuzumab is 4 months). 

What about immunosuppression? Cladribine does not take down your neutrophils and NK-cells so short-term immunosuppression for common infections is not a problem. It does however cause a reversible lymphopaenia and hence rare opportunistic infections may be a problem. To derisk the latter we would propose the same precautions we have in place at present for alemtuzumab, i.e. baseline TB screening, cervical smears and VZV, HIV & hepatitis screening. The main concern with cladribine is herpes zoster; about 1 in 50 people treated with cladribine will develop zoster. The majority of cases of zoster will be mild-to-moderate and treatable, but this is still a hassle and an unpleasant adverse event. Please note zoster is not a unique problem to cladribine and we see it with all the immunosuppressive drugs. I have already made the case for doing a vaccination study with the new VZV vaccine to see if boosting VZV immunity prior to treatment with one of the immunosuppressive drugs will reduce the incidence of zoster. 

What about secondary cancers? We have posted on this many times and we can confidently state that there is no short to intermediate term risk of secondary malignancies with cladribine. The original signal was a false signal driven by the low rate of malignancies in the placebo-arm of the CLARITY study. With regard to long-term risk we simply don't know, but will get this information from post-marketing surveillance studies.

Another potential advantage that cladribine has over alemtuzumab is that it penetrates the CNS and may have an impact on lymphocytes and plasma cells that are resident with the CNS. The latter is one of the hypotheses we want to test. If cladribine can be shown to clear the oligoclonal bands in the spinal fluid of treated MSers, and delay or prevent secondary progression, then it will almost certainly become the dominant DMT in MS. The question is will Merck have the gumption and confidence to do the studies to show this and will they do a progressive MS trial? For me this is a no-brainer; the sooner they start a progressive trial the better.  

My biggest concern is that the EMA are not going to give cladribine a liberal first-line license, similar to alemtuzumab's, and will restrict cladribine to second-line use similar to fingolimod. It is therefore up to us the community to make the case of it being used early in MS. Why shouldn't people with active MS be offered oral cladribine as an alternative to alemtuzumab first-line?



CoI: multiple

30 comments:

  1. Prof. G what about ocrelizumab? I thought that was going to be the next best thing in MS since sliced bread.

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    1. See below re B cell effects of Cladribine. It would be fascinating to test Cladribine against Ocrelizumab in a head-2-head study.

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    2. If cladribine is working via B-cell depletion, as we think it is, then it is unlikely to do as well as anti-CD20 therapies. B-cell depletion with cladribine is limited by its impact on T-cells. We had deliberately reduce the dose as not to cause too much lymphopaenia. If only we could target cladribine to B-cells only?

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    3. At active 3.5mg cladribine depletion of CD8 T cells is about 15-18%, depletion of CD4 T cells is only about 50% depletion and depletion of B cells over 90% and they don't rebound unlike alemtuzumab

      If cladribine and ocrelizumab are working via blocking T cell function through blockage of antigen presentation then maybe cladribine has an advantage. It depends how you think.

      Persistent depletion of B cells through 6 monthly cycles may lead to the development of B-cell dependent infections.

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    4. We need both cladribine and ocrelizumab available and time will tell about the merits of each treatment and places such as Scandinavian registries can tell us the winners and losers

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  2. Why is there a difference between cladribine and alemtuzumab in relation to secondary autoimmunity? As induction therapies wouldn't you expect them to have the same complications?

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    1. Alemtuzumab and Cladribine differ in the way they affect lymphocyte subsets. Whilst ALEM knocks T cells out of sight, this population is only depleted by about 40-50% with CLAD. Importantly, CLAD significantly reduces B cells (similar to Ocrelizumab), and they don't return to baseline levels within more than 12 months. After ALEM administration there is rapid return of some B cell subsets within months; we believe this plays an important role in secondary autoimmunity.

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  3. Do you know how much Merck are planning to charge for oral cladribine? Will it be as expensive as Lemtrada?

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    1. I suspect it won't be as expensive as Alemtuzumab, closer to Fingolimod or Natalizumab.

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    2. Even Fingo. and Natali. are too expensive. We need the generic cladribine.

      If a drug has to be injected daily or weekly then oral form makes sense.

      Why do we need an oral version of a drug that is taken a few times a year for a few years?

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    3. Unfortunately, Pharma is the only show in town. We need the commercial oral formulation to be a success so that it can fund the progressive MS phase 3 trial programme. Without an income stream from RRMS there will be no progressive MS trial.

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    4. I wouldn't go as far as saying nothing happens without pharma - simvastatin might go to phase III. A pharma-led trial would be preferable, but if it doesn't happen, and where a generic option is available at low cost, we should push for it. Merck can always give us a call.

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  4. What do you regard as long term risk? Ten years or so?

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    1. "With regard to long-term risk we simply don't know"

      No answer to what long-term is here???

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    2. Merck has follow-up data on the largest MS cohort (PREMIERE registry).

      Here's a 20 year follow-up study of young people with hairy cell leukaemia who were treated with Cladribine suggesting a small (statistically not significant) risk of secondary malignancies: http://www.bloodjournal.org/content/123/2/177.long?sso-checked=true

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  5. Cladibine is really easy to tolerate compared to probably all other DMTs.

    Could reduction of OCBs be used as a clinical trial outcome for progressive MS? Or could it be used when deciding whether to take an additional treatment course?

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    1. We need to see how good an effect it can have on OCB. Could this be used to determine whether to have more treatment...I doubt it because I am not convinced you would be willing to have serial lumbar punctures.

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  6. Is there any study designed to verify the action of Cladribine in PPMS and SPMS?

    And has anyone ever looked to see if the Cladribine has some action on oligloconais bands in the CSF?

    And if she has any impact neuroprotection?

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    1. The drug is a DMT and it will have an effect on active disease, whether this really has impact on progressive MS needs further analysis. It will impact on active progressive MS I believe, because it can impact on active MS block lesion formation and attacks.

      Next question is B cell depletion part of the problems with progression. Cladribine can get in the CNS and it can kill dividing and non dividing cells and may have an effect on plasma cells.

      There is some data that CLAD can have some impact on OCB, but this needs further data. I am aware that the Polish group have been looking and DrK is on the case also.

      As to neuroprotection via some of the other ro, I'm not convinced

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    2. Thanks MD. o//

      I think a lot in using Cladribine.

      I'm going after a neuro that agree to the idea of the treatment with Clad, even if it is off-label.

      I use Copaxone for almost 02 years and a half, MS is apparently controlled, but I think a lot in the future, and lately I've had local reactions injections of GA, as much swelling, redness, etc., and I do rotation of local application and make drainage at the injection site to reduce swelling.

      However I want a treatment that has greater margin of effectiveness, and I'm afraid if I "don't have enough fat tissue" to keep applying GA without adverse reactions.

      Analyzing all the pros and cons of all DMTs available Clad, in my humble opinion, remains the best option at the time.

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  7. So what is the guestimate time line for cladribine getting a licence for second line use? Having been taken off fingolimod due to arrythmias and currently being persuaded not to go for alemtuzumab I figure I will be eligible. (6 years since diagnosis)

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    1. Cladribine is back at the regulators (EMA) now, so it is up to them what happens next. If approved NICE will then have to look at the price

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  8. Does your brain volume comment reflect this: http://onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/146337/nicola.de.stefano.cladribine.effect.on.brain.volume.loss.and.its.correlation.html?f=m2

    The mean annualised PBVC rate (month 6 to 24) was greater in patients treated with placebo (-0.70%, SD 0.787, n=338) than those who received cladribine tablets 3.5 and 5.25mg/kg (-0.56%, SD 0.676, n=336 and -0.57%, SD 0.717, n=351, respectively). Furthermore, PBVC (month 6 to 24) was less in patients treated with cladribine tablets 3.5mg/kg (p=0.019) and 5.25mg/kg (p=0.018) than placebo. After adjusting for treatment group, PBVC (month 6 to 24) in all patients showed a significant correlation with the cumulative probability of 3m-CDP (hazard ratio [HR] 0.753, 95% confidence interval [CI] 0.670-0.846; p< 0.001). Compared with placebo, the risk of disability progression was significantly lower with cladribine tablets 3.5mg/kg (p=0.009) and 5.25mg/kg (p=0.003).

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  9. ...and what about a timeline for ocrelizumab? Any guesses?

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    1. Likewise at the regulators, then NICE if approved by the EMA. It should take time. Not sure what will happen in PPMS uuuuuuuuuuuuu

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  10. The clarity group showed a remarkable low level of mean EDSS score - 2.5 (ranging from 0.00 as well). How do you know that this wasn't a factor in the results - perhaps you had quite a few 'benign' cases?

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  11. if I can I will use the Cladribine, even more after understand once and for all that Reserve Cognitive has nothing to do with injury in spinal cord, ie for me injuries spinal cord are the most difficult to imagine be recovered...

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  12. Should people strongly considering (and eligible for) alemtuzumab hold out for cladribine, if the autoimmunity side effect profile is better?

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    1. Re: "Should people strongly considering (and eligible for) alemtuzumab hold out for cladribine,..."

      No. The EMA decision is moths away and they may say no or restrict its use. Then there is always the issue of cost and availability under the NHS.

      A bird in hand is worth two in the bush. Another option is to ask your neurologist to treat you with the off-label of generic product.

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