Cladribine for the World.

6 Min read

Easy reader

November 19, 2023

C

So this is abouts ProfKs “Kiss of Life”

Did you know that cladribine has become a World Health Organisation Essential Medicine for MS, but did you also know they selected cladribine tablets….Ugh.

WHO essential medicines are drugs that are deemed important to be available to all.

However cladribine tablets are patented and expensive, so unless the manufacturers strike a good deal in many countries then they will be too expensive for most people in the so called “Low income countries” to afford. Rituximab is also a WHO essential medicine and whilst there are biosimilars, monoclonal antibodies are not a low-cost alternative. Chemical agents can be made cheaply, you just have to look at the chemical company catalogues to see this (eg 100mg for £32 from Apollo but please note this is not for human use but you get the point this is a year’s supply). But the big question is whether the cladribine patents (e.g. W02004087101 filed 26 March 2024) will actually end in the next year and will cut-price generics appear, or will something happen to keep the patents going like the dosing schedule? There is a patent WO2006067141 on dosing valid until 20:12:2025), the drug patent has gone (US4760137 in 2005), A patent for progressive MS has been filed and granted in US (e.g US10849919B2…..so that would take us to 2038)

The WHO missed an opportunity and they should have said cladribine after all the intravenous subcutaneous and oral variants all have the same active ingredient.. They would have had an out of patent agent and if you are worried about the price of a needle…you can simply drink the subcutaneous and intravenous formulations as shown in the past by our Swedish Cladribine Guru.

ProfK resuscitates Clad

We know that subcutaneous cladribine is active in MS, thanks to the work of many different people including ProfK who started using it in a compassionate use programme in 2014.

There are over 250 people who have recieved cladribine and you can see it has performed very well, remember that about 50% fail alemtuzumab within 2 years requiremore treatment and about half of these need a third cycle (Touhy et al 2015: PMID 24849515)

This had to be put on hold such that people could be enrolled into CHARIOT MS, but if you want the details have a read:

Disease activity 4.5 years after starting cladribine: experience in 264 patients with multiple sclerosis.

Allen-Philbey K, De Trane S, MacDougall A, Adams A, Bianchi L, Campion T, Giovannoni G, Gnanapavan S, Holden DW, Marta M, Mathews J, Turner BP, Baker D, Schmierer K.Ther Adv Neurol Disord. 2023 Nov 10;16:17562864231200627. doi: 10.1177/17562864231200627.

Background: Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood.

Objectives: To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity.

Design: Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment.

Methods: Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable).

Results: Of n = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad.

Conclusion: Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad.

I think this shows why cladribine should be a WHO essential medicine…it is effective and simple to administer and monitor.

Sadly there is still some intellectual baggage from when cladribine tablets were not approved in the US/EU in 2010 making some neuros quake in their boots and seems to me that some people are unwilling to read and view the subsequent data with an open mind, but hey I’m biased.

What does ProfK say

I have half-inched (Rhyming slang) this from ProfKs LinkedIn

“#More than a decade ago, the #BartsMS team set out to resuscitate #cladribine as a disease modifying treatment for people with #multiplesclerosis #MS (pwMS). A great deal has happened since then, and >40,000 pwMS have now been treated with this compound. Our intention has remained the same – to treat pwMS as effectively & safely as possible in order to lessen the burden of MS, to halt the disease, or even help people getting better. However, access to effective DMT remains a challenge, particularly for pwMS who do not fulfil NHS England cost-effectiveness criteria, but with a clear biological rationale to nevertheless receive DMT. Fast forward and – against our expectation – cladribine tablets (#MAVENCLAD) were adopted as the only licensed, highly-effective DMT to the World Health Organization Model Lists of Essential Medicines. Congratulations to the MS International Federation (MSIF) for making this happen. Our local service cohort of pwMS, treated with off-label cladribine, has been an important part of this journey. It also provided the preliminary evidence required to help convincing five funding bodies* to support #ChariotMS (NCT04695080), the worldwide first DMT trial focussing on pwMS in wheelchairs and on maintaining their upper limb function (for more information visit www.chariotms.com and https://lnkd.in/e2YX9m6z) Our most recent paper (See above) provides important insights into the question, whether treatment with cladribine should be repeated by default four years after starting the first course of treatment”.