#MSCOVID19: specifically for NHS England

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Barts-MS rose-tinted-odometer: ★★★★★

Early on in the pandemic, I did a blog post on why I thought oral cladribine was the ideal DMT for managing MS (26-April-2020) remotely. I summarised cladribine’s attributes in a simple 12-point list. This list can now be updated to include (1) data on good COVID-19 outcomes in pwMS who have been treated with cladribine, (2) about vaccine readiness, i.e. pwMS vaccinated with COVID-19 vaccine make a good antibody response and (3) on its cost-effectiveness and value.

The Mouse Doctor prodded me by email yesterday to ask NHS England to allow us to use cladribine more liberally because of the pandemic and the unique challenges it is placing on MS services. MD suggests using or at least offering it 1st-line to patients with just active MS and not only those with highly-active disease. I can’t really do what MD wants because NHS England has a process for changing its advice. I also need to remind MD that as the principal investigator on the phase 3 CLARITY study I am so conflicted that nobody would take anything I say seriously. Hence an updated blog post.

Cladribine’s pros:

Cladribine is a high-efficacy DMT therefore it potentially allows you to flip the pyramid and offer it first-line.

Cladribine is an oral therapy; hence no visits to COVID-19 hot hospitals or institutions.

Cladribine kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we try to avoid because they increase your chances of getting severe COVID-19. 

Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.

T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections. 

In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab. 

Cladribine-treated pwMS who get COVID-19 are not at increased risk of getting severe COVID-19.

Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 85-90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. These are the cells you need to make vaccine responses.

Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines.

In relation to vaccines both live and inactivated component vaccines can be given after cladribine. New data indicates that cladribine-treated with MS make good antibody response to COVID-19 vaccines (see vaccine post from yesterday).

The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done at month 4 and 7 in each treatment year. The rationale for this is that the 4-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.

When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells. 

Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial. 

Please note that I am not saying cladribine is entirely safe. It has a well-defined risk-benefit profile that is less risky than what has been suggested by many people. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.

Oral cladribine is cost-effective. NHS England has negotiated a value-based pricing deal with the manufacturer for a rebate if anyone treated with cladribine switches to another agent within 4-years of starting treatment. This makes cladribine a very good option; you are only paying for the drug if it is effective. Isn’t this the future of pharmaceutical drug pricing?

We think cladribine is a highly effective therapy that has many positive attributes for managing MS during the COVID-19 pandemic.  

P.S. MD adds Point 17. Risk of PML in JC+ individuals is low (Thanks Jason)

Do you agree? 

CoI: multiple

Twitter: @gavinGiovannoni                                         Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

22 comments

Leave a Reply to Ra Cancel reply

    • I don’t know, however that the NHS go aginst the label for the Pfizer vaccine, shows that it should be possible and easy, if you know the right people. But if they don’t read the blog they wont know. Australia could lead the way as their neuros do not have straight jackets

  • Isn’t also a good reason for cladribine the PML risk if JCV+ is much lower than other DMTs.
    My neuro gave me 3 options which reduced to 2 when I came out positive.
    I’m glad I chose clad.

  • Why are we not all taking cladribine….sounds great. Most patients will be referred to the table provided by the NHS which places cladribine firmly behind Ocrevus in the effectiveness stakes. However, if it does 90% of what Ocrevus does to b-cells and with all the advantages of tcell depletion, cns penetrant, infections fighting in tact, is it actually considered more effective in the long run?

    • Risks:

      1. Grade 3 & 4 lymphopaenia , about 1 in 20 treated subjects
      2. Other bone marrow suppression, e.g. neutropaenia
      3. Potentially teratogenic
      4. Potential long-term secondary cancer signal
      5. Skin hypersensitivity
      7. Rare liver toxicity, which has been linked to viral hepatitis
      8. Rare opportunistic infections
      9. Zoster
      10. As it is CNS penetrant we have seen headaches on cladribine treated subjects
      11. There have been cases with myocarditis on cladribine, likely to be rare viral myocarditis

      As it is an IRT there may be a risk of early rebound, similar to what is seen with alemtuzumab. To date, I have only seen one case and that was with our subcuatneous off-label protocol. We also must assume there may be risk of secondary autoimmunity with cladribine, but this is likely to be very low.

      The major con is that the drug is an IRT. Some pwMS simply don’t like waiting for their disease to reactivate and waiting to see if they need additional courses of treatment,

      To me, the big downside is that the brain volume loss (BVL) data in the CLARITY study is not as good as with alemtuzumab or HSCT. However, in the ORACLE or cladribine CIS study, the BVL data was very good. What we really need is head studies of cladribine against alemtuzumab to see how good they are.

      We suspect there will be a cohort of non-responders to cladribine, i.e. a small number of people who don’t deplete on the drug. The latter is likely to be due to variants in the enzymatic pathway that drug works via.

    • Cons…you can buy subcutaneous cladribine for £65 verses £2000 a tablet…seems like a con to me:-)

      Ther are cons to every thing the side effects are listed in the label search “cladribine INN” and EMA or and FDA

  • Any research as to whether or not it is worth switching from ocrelizumab to cladribine to decrease risk and increase CNS penetration? Have had 8 full doses of ocrelizumab, no relapses, no new lesions. Is cladribine less of a “hammer” and is it a logical tail end treatment as one ages?

  • Your post raises a few questions in my head. “Just” active disease. I appreciate that you can look at a mri and see if there are loads of new lesions or if someone has had a catastrophic relapse. But I’ve always been told by my care team they cannot predict the course of ms, ie someone can go active to severely active and vice versa. It seems to me that treatment for ms is reactive and not pro active, which if I’ve understood correctly from your past posts, is not what you think it should be? How do you know if treatment will do more harm than good long term. How do you know if someone will suddenly worsen. I’ve never really understood the approach. You also mentioned “counsel”. I do not know other people’s treatment experiences, but my neurologist never discussed the pro and cons of any treatment with me. I simply got a phone call from my ms nurse saying I was entitled to x,y,z. Was referred to the MS Trust decisions page. I thought of questions to ask my nurse, but in my personal opinion this is not counselling/ advising. After all to ask a meaningful question you need to be suitable informed.

  • Thanks for this post
    As far as you know, has it been established whether cladribine is a potential treatment for slowly deteriorating secondary progressive?
    Thanks

    • I think most people with MS, even early RRMS, have slowly deteriorating SPMS or smouldering MS. The CLARITY phase 3 cladribine trial included these patients, but the data has not been analysed yet to see what happens to PIRA (progression independent of relapse activity).

  • Re “In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections.”
    Is the reactivation of herpes zoster an exception in this regard? Or does the reactivation occur via other routes (suppression of other cells)?

  • I have an idea that could help you out. You mentioned you had a hard time getting funding for a Haart trial in MS. Well I was thinking maybe you could try and reach out to the Bill & Melinda Gates Foundation concerning the Haart trial for EBV in MS ?

    They also might be interested in helping to accelerate Moderna’s EBV vaccine. What do you think ?

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