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?