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How good is cladribine as an immune reconstitution therapy?
The CLASSIC-MS study was our attempt to get back all the pwMS who had participated in the original phase 3 programme, from 15 years ago. The following poster is from my late-breaking poster at ECTRIMS and describes what has happened to the subjects from the CLARITY and CLARITY extension study and does not include subjects with clinically isolated syndrome from the ORACLE study.
As you can see the subgroup of subjects from CLASSIC-MS is similar to the overall population of subjects in the original trial. Therefore we think these results are representative of the overall population.
The median time to follow-up in the CLASSIC-MS study was 10.9 years (range 9.3, 14.9).
The remarkable observation is how few study subjects progressed (to be presented later in more detail) with less than 1 in 5 needing a walking aid to manage 100m.
56% of cladribine treated subjects did not require a follow-on DMT compared to only 27% of subjects that were not treated with cladribine. These results indicate that the duration of action of cladribine may be much longer than we realise and is beginning to mirror what we see in clinical practice with this particular agent.
Given this data and the other attributes of cladribine, it is going to be a serious contender for the go-to DMT at the bottom of the therapeutic pyramid on which to build an induction-maintenance strategy and combination therapies.
Oral cladribine has several favourable attributes for managing MS, particularly during the COVID-19 pandemic:
- High-efficacy DMT allowing flipping of the pyramid
- Good COVID-19 outcomes
- Oral therapy, therefore reduced hospital contacts
- No cell lysis syndrome or infusion-type reactions
- No pre-dosing with steroids
- Innate immunity intact
- Only moderate reduction in T-cell counts
- Less impact on CD8+ compared to CD4+ T-cells
- Antiviral immunity relatively intact
- Vaccine immunity intact
- Low monitoring requirements
- Small risk of lymphocyte count being less than 500/mm3
- CNS penetration targeting CNS resident B and T cells
- Post-dosing immune reconstitution
- Good seroconversion post-COVID-19 vaccination
- Cost-effective; providing value to the NHS
Giovannoni et al. Long-term efficacy for patients receiving cladribine tablets in CLARITY/CLARITY extension: Primary results from 9–15 years of follow-up in the CLASSIC-MS study. ECTRIMS 2021, P975.
Introduction: CLASSIC-MS (NCT03961204) was an exploratory, ambispective Phase IV study designed to evaluate the long-term efficacy of cladribine tablets (CladT) in the real-world setting, for patients with relapsing multiple sclerosis (RMS) who were previously enrolled to Phase III (parent) trials.Objectives: To report primary results for CLASSIC-MS in terms of long-term mobility and disability beyond the treatment courses that patients received in the parent trials, with the aim of informing future treatment approaches.
Methods: This analysis represents patients in CLASSIC-MS who participated in the Phase III CLARITY trial whether or not they participated in CLARITY Extension, and who had received ≥1 course of CladT or placebo. The primary objective of CLASSIC-MS was the evaluation of long-term mobility (no wheelchair use/bedridden; i.e. EDSS <7 in the 3 months prior to first visit in CLASSIC-MS). The main secondary objective was long-term disability status (no requirement for an ambulatory device; i.e. EDSS <6 any time since last parent study dose [LPSD]). Analyses are descriptive and shown in relation to exposed/never exposed to CladT in CLARITY.
Results: The CLASSIC-MS population who previously participated in CLARITY/CLARITY Extension comprised 435 patients with RMS (67.8% female; mean±SD EDSS score, 3.87±2.07 at CLASSIC-MS baseline), with a median time since LPSD of 10.9 (range 9.3–14.9) years and a median disease duration of 20.7 (range 13.9–46.5) years at CLASSIC-MS baseline. A total of 90.6% (n=394) were exposed to CladT during CLARITY/CLARITY Extension, including 160 patients who received the approved cumulative dose of 3.5 mg/kg over 2 years; the remaining 9.4% (n=41) were never exposed. The proportion of patients not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS (i.e. EDSS <7) was 90.0% of the CladT exposed cohort and 77.8% of the never exposed cohort. Regarding long-term disability status, the proportion of patients with no requirement for an ambulatory device (i.e. EDSS <6) was 81.2% of the CladT exposed and 75.6% of the never exposed cohorts, respectively.
Conclusions: Baseline patient characteristics suggest that patients enrolled in CLASSIC-MS were a representative sample of all patients included in the original parent studies. Reported findings for CLASSIC-MS, with a median of 10.9 years’ follow-up after CLARITY/CLARITY Extension, suggests sustained efficacy of CladT in terms of long-term mobility and disability status.
Disclaimer: Please note that I am the PI on the oral cladribine programme including the CLASSIC-MS study and have been involved with the development of oral cladribine as a DMT for MS since 2002. I was a member of the original advisory panel that Serono put in place when they decided to in-license the oral formulation for development. Therefore you need to interpret what I say about cladribine and oral cladribine very carefully. In short, I am likely to be very biased.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.
Given atara biotherapeutics intention to start a phase 3 trial in a year or so do you still think a cure for ms is 10-20 years away ?
No, I think we have cured a minority of patients already who have been treated with IRTs. Please read some of the older posts on this.
https://multiple-sclerosis-research.org/2021/05/curing-ms-2/
What I meant is for the majority of ms individuals do you still think 10-20 years since atara biotherapeitics is moving forward ?
Not convinced ATARA is a cure based on data so far presented
Can you please elaborate why?
Thank you from a Cladribine patient.
In line with this research preventing cumulative neurological disability to eventually reach the level of Advanced Multiple Sclerosis should nowadays be a tangible reality with several high efficacy Disease Modifying Therapies like Cladribine addressing the adaptive immune system attacking myelin in the Central Nervous System ultimately leading to neurodegeneration.
New treatments for Progressive MS addressing for instance the innate immune system (BTK?) and remyelination strategies are also approaching the market in the next 5 to 10 years after decades of research. The hope is this will halt progressing neurodegeneration atrophying the Central Nervous System.
To prevent MS and halting its progressive course should be a more achievable goal in the next 5 to 10 years opposed to actually curing or at least improving cumulative neurological disability leading to advanced levels of MS. If we can prevent this devastating disease it will naturally disappear in time.
However currently the biggest unmet need lies with people who experience daily struggles with varied advanced levels of disability and even can expect progressive worsening over time.
Remyelination strategies will only be effective if it is applied early in the disease course when there is active inflammation and for instance neurological reserve via neuroplasticity to compensate lost neurological function. Remyelination will not cure advanced progressive disease. It might slow down progression.
Other novel to be developed strategies are needed to improve or even reverse lost neurological function ultimately curing Advanced (progressive) MS.
In an acute MS lesion, the window of opportunity for both neuroprotection and remyelination may be relatively short. In other words, if you don’t protect and remyelinate damaged axons quickly, they may degenerate and hence remyelination therapies may fail. Also, some degree of neuroinflammation particularly of the regulatory type is beneficial for regenerative responses.
This so-called ‘window of opportunity’ has been referred to as the inflammatory penumbra and may limit the potential of remyelination therapies to a biological window of potentially weeks or possibly months. After acute optic neuritis retinal nerve fibre thinning or optic nerve atrophy may take somewhere between four to six months, respectively. It is therefore hard to imagine a treatment working beyond this window.
Improving or even reversing longstanding accumulated neurological disability is the biggest unmet need in the underserved Advanced (progressive) MS community.
It should, therefore, be abundantly clear to the Advanced (progressive) MS community that remyelination therapies alone will have no to limited effect due to the inflammatory penumbra. Only new acute inflammatory lesions are suitable for remyelination and neuroprotection.
Again, like with current DMT’s mainly (Early) Relapsing MS and early progressive MS is addressed with remyelination and neuroprotection Research, and research to create adequate treatments for non-inflammatory and/or smouldering Progressive MS are still lacking.
I therefor do wonder why for instance the progressive MS Alliance and other national ms societies and foundations so strongly focus on remyelination therapies for Progressive MS. Cumulative neurological disability via axonal degeneration and CNS atrophy due to neurodegeneration and/or inflammation will not be adequately addressed with remyelination therapies alone. In best case scenario it will limited and prevent progression in (Advanced) Progressive MS.
At present PwMS, especially people with progressive MS, have unrealistically high expectations for potential remyelination therapies while those living with advanced levels of disability are likely to not benefit from them.
Therefore, we must manage the expectations to the underserved progressive MS patient community and explain the complexities and challenges posed by remyelination and neurorestorative therapies.
The way I see it, in 5 to 10 years’ time there will be roughly 2 types of MS patients.
1. Early MS diagnosis with a hit hard induction therapy with possible remyelination therapy resulting in low EDSS and stable MS. (cure?)
2. MS Patients with cumulative acquired disability with hopefully CNS penetrable medical interventions to address smouldering inflammation stopping progression and keeping them stable.
For those PwMS in the second group other novel medical interventions need to be developed next to remyelination alone to improve or even reverse longstanding accumulated neurological disability and improve quality of life.
Prof G, what did you think of Professor Thompson’s Charcot Lecture? He was quite adamant that the therapeutic window shuts in patients with progressive MS who are disabled. By saying this he is implying that ocrelizumab and siponimod don’t work in progressive MS and that BARTS-MS is wasting its time with the ORATORIO-HAND and CHARIOT-MS studies. Do you agree?
It is a pity he did not mention Kurtzke’s length-dependent axonopathy hypothesis and the rationale for multiple therapeutic windows in MS. This is why we are targeting upper limb function (#ThinkHand) in the CHARIOT-MS and ORATORIO-HAND trials. I think we differ in our position on this issue; we at Barts-MS think it is never too late to modify the course of MS.
When his conclusion gets out to the wider MS community is likely to dampen the spirits of many people living with progressive MS. Sadly his comments may undo a lot of work we have been doing with our #ThinkHand campaign.
I note he made no mention of the viral/EBV hypothesis and did not reference Michael Pender’s data nor the ATARA Bio data.
I am not sure he said ocrelizumab and siponimod don’t work. He referenced both of these therapies a few times in his talk.
Nor did he mention the data on masitinib
I read when Ocrelizumab came out approved, that 1) the patieintgroup used in phase trials were designed after what had worked for people in early rituximab trials that means ” kind of designed tets group”?? and 2) it seemed to work for 9% of the ppms which means it did not work for 81% – I find that a very low number of success.
I wonder if the International Progressive MS Alliance (Prof Thompson helped found) should be disbanded. In all honesty, I suspect Prof T is probably right. There are no effective treatments for Progressive MS. If there were, my local MS society wouldn’t be stuffed full of MSers in electric wheelchairs. Nursing homes wouldn’t have relatively youngish MSers as residents. It’s a big claim that we’ve come along way in 40 years which I would refute. We all know someone with advanced MS in a dreadful situation and there is no treatment for them. Rather than spend hundreds of millions on futile progressive trials, put the money to equipping the homes of progressive MSers with things they need. ECTRIMS 2021 ended on a sour note rather than being something hopeful.
With this attitude to people with progressive MS is he the right person to be leading the Progressive MS Alliance? I think having a more enlightened thinker with more compassion in this role would be a good start to lead this initiative.
I chose Cladrabine as a treatment from the information from this blog. I’m about to start my second corse on Monday.
Very little side effects, felt a slightly light headed, that seamed to come on for a few seconds then go away when taking 2 pills the first couple of days, and had a very mild headache the last week or so that randomly comes and goes for a few seconds at a time.
Other than that, so far so good, hopefully I will do the job for me
But thank you for the information provided on this blog regarding cladrabine, and all the other information surrounding MS.
Reading this has me thinking, why doesn’t everyone just get put on Cladribine as soon as they are diagnosed. It makes the most sense and ticks all the boxes – less side effects, no hospital visits, doesn’t effect vaccines, high efficacy on par with the other ones like Lemtrada, cost effective etc. All the high efficacy DMTs have downsides whether it’s PML or Thyroid problems but it seems to me, Cladribine doesn’t have this issue.
Any news on follow up of Alemtuzumab?
Year 9 ?
Yes. Year 10. I will do a post next week.
Thanks Prof G. If year 10 is good as year 9. Surely its time to declare Alemtuzumab cure for at least 60% for all, and almost for 100% for those taking it 2 years after diagnosis.
Thanks for the post!
What in your opinion would be good options for a maintenance therapy, following cladribine? Of course, I know there are a lot of assumptions and pros and cons, but if you were to list a couple?
Teriflunomide and BTK inhibitors have been mentioned before…
It says;
The proportion of patients not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS (i.e. EDSS <7) was 90.0% of the CladT exposed cohort and 77.8% of the never exposed cohort. That means the differens in the 2 groups are 12,2%?
Regarding long-term disability status, the proportion of patients with no requirement for an ambulatory device (i.e. EDSS <6) was 81.2% of the CladT exposed and 75.6% of the never exposed cohorts, respectively. That means the difference in the 2 groups are 5,6%.
Not really big diffrences? maybe i get this wong?
I have another question;
I read the results from Clarinet MS (follow up study)
Relapsfree RRMS – 57,8% after 5 years from last Clad treatment.
No evidence of change in EDSS for RRMS; after 5 years- 65,6%
BUT
Time to change of drugs? ONLY 30,1% of RRMS had after 5 years NOT changed drugs, that means during observation n this study that 70% startet with new drigs during the periode og 5 years- how come that is a considered good results for taking Cladribine? i think that is NOT good if 70% need to change drugs after 5 years (and 45%- as an avareage of study ex Onward and Oracle after 3 years)
And people who have gone through HSCT which did not stop their MS, why should I beleive that Cladribine should stop the MS?
How about third course of cladrabine like Alemtuzimab? Any trials into its safety?
Yes, I would really like to know the answer to this.
Anonymous – “How about third course of cladrabine”………look I am not a neuro, just a pwms with the same question.
I am not aware of any formal studies on the topic of a third course of Cladribine and I believe MD1 indicated the drug manufacture dropped that ball. However, there are several University based MS Centers in the U.S. that do offer a third course, under the circumstances noted below. Some U.S. health insurance companies will cover the third course, if approved and deemed appropriate by your neuro.
From a safety standpoint, I do not see any reason why a third course would be any more risky than the second, as long as your total lymphocytes are >800 and all other pre-treatment protocols are met. But based on the data presented by Prof. G today, I am not too worried about needing a third course any time soon.
Cladribine Break-through Disease Activity:
1. All patients who have a relapse either during or following treatment can be treated with systemic corticosteroids.
2. Switching to an alternative therapy may be considered in patients with breakthrough activity before the second course of cladribine or within a year of completing their second course.
3. In patients who exhibit activity a year beyond the second course, can be considered either for re-dosing with 1.75 mg/kg per year or a switch to an alternative therapy.
4. Prior to starting another disease modifying therapy, lymphocyte counts and contraindications should be reviewed.
Alemtuzumab Has a worse safety profile than cladrabine and is not as effective in the first 2 years at reducing relapse activity and the third dose of Alemtuzumab seams to lead to long term remission of MS and is touted at possibly the best treatment.
However given an even playing field in a head to head. Cladrabine would possibly be more effective given the same amount of doses and given at the same amount of time after disease onset
ProfK reported third dose in our Cohort
As you say Cladribin will be a contious treatment, sp what makes it a succcsess then?
From one of the follow up studies it says that 70% had changed drugs after last pill of Cladribin after 5 years, and aprox 45% after 3 years. What is working after Cladribin? and if it is just a success in 55% in 3 years, is it a succsess then? Imust be missing something here.
Tove – Why are you so skeptical of data in the CLASSIC study, which says 56% did not require another DMT for over 10 years.
Plus, the golden rule of the blog…..if you are going to challenge, you need to provide proof or actual evidence.
The whole point is after an IRT, you have a “new” immune system, which is not theoretically infected with what ever is causing MS.
I refer to the study called Clarinet-MS, i cannot prove other than the name of the study where i read about it,- and as it seems to me, (i might misunderstand) the results there are then different from the Classic, as you all explains and refer to here, and that i wonder how come.
Skeptical? it is in my nature to ask questions 🙂 and i read cochrane sometimes and prescrire and see a lot of different opinions about a lot. 🙂
I do hope you are right that this is a “cure” if 10 years “is a cure” as discussed.
But why I ask questions is because I am from Norway, and there we have 2 strong MS research communities, one tries to prove the benefit of HSCT and they beleive in HSCT, and the research is paid bay the government and others. The other community is against HSCT and only talks about drugs, and their research is paid by drugcompanies. They say the effect of HSCT do not last, but the effect of Cladribin last “forever”, which I also find a little odd to say (?). They used Alemtuzumab until one saw all the sideeffects, so now alemtuzumab is less used in Norway it seems.
A long time ago i read about a reaearch on Alemtuzumab done by the British MS centres forrlow up 7-9 years (using “real” patients, and not patients chosen for a study, i mean they have all kind of other diseases too 🙂 ), don’t ask me where i find it (i have it somwhere), where they as i remember gave the impression of that Alemtuzumab gave better EDSS only for the first years, but after 5 years it was back to baseline and a bit worse, which also differs from the first of clinical studies of Alemtuzumab that i read. This was meant as an other example. So therefore i ask why there is different outcomes as it seems from one study and the other.
My son had HSCT which is the best of IRT treatments i beleive and it did not work. Now they try Cladribin. Of course I hope it works. But i wonder why this should work, when HSCT did not work.
If 56% of patients after treatment with Cladribine not need any refill after 10 years and the disease is not developing it is fine, it is very fine, it is excellent.
(Still 44% has to change medication using cladribine too along the road). Can anyone explain why it is not working on everybody? As HSCT is not working on everybody. Do they have another disease mechanism?
I have read a lot of interesting articles here about CD4+ and CD8+ and HSCT and EBV. Which was new information. I enjoy getting information.
In what way did HSCT not work? Relapses or progression, Cladribine can get in the CNS, HSCT may not be active there…yes cyclophophamide metabolities can get in the brain but the cells have to be dividing for it to work there, long lived plasma cells are considered to be post mitotic so they do not need to divide for example
Thanks for answering.
Relapses- his MS has given relapses in the way that he feels more unwell and that he feels somthing is going on, but he never seeked solumedrol for it. His tremor is developing and his right arm is hard to use. He was studying in Barcelona at the time, and had a lot of stress i guess. (in the usa i have seen a kind of glove helping to slow down tremor, you have that in the UK?)
He was on Gilenya before HSCT, but without drugs for 6 months between Gilenya and HSCT.
So saying that HSCT did not work is because they saw 1 or 5 (2 different radiologists) new leasons/areas with damage. That was aprox year 2 after HSCT (2019) and there seems to have been one more since then. Cladribin treatment went well without any problems, year one (May og 2021).
So I would say progression because his relapses seems to be “handable”.
Excellent analysis and work Prof. G!
The sample size and duration of the study appear more than sufficient to make the results statistically relevant. I am not sure why so many of the comments to this post include a high level of skepticism, but I for one am very happy to see that over 50% of study subjects did not require any further DMTs or a third pulse of Cladribine over a ten year period. This is great news and hopefully will spark the overall MS medical community to reevaluate the true risks and benefits of Cladribine. I am also hopeful this will entice the drug manufacturer to fund your add-on/anti-viral study.
Alem is not Clad and Clad is not Alem:https://multiple-sclerosis-research.org/2021/02/cladribine-is-not-alemtuzumab-discuss/
Comprehensive Clinical Analysis of Cladribine, including how to transition to Clad:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229040/#CR26
Isn’t it possible to ask those people to be treated of OCB status ? This would provide interesting info