Early MRI says cladribine works within a few months…Where should Prof Freedman really look

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Freedman MS, Coyle PK, Comi G, L Scarberry S, Damian D, Hyvert Y, Dangond F, Galazka A, Jack D, Lebson LA, Leist TP. Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2021 Feb 24;7(1):2055217321990852

Background: In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE).

Objective: To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI).

Methods: This post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter.

Results: Compared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96 weeks. Similar results were observed with the 5.25 mg/kg dosage.

Conclusion: In participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation).

So Prof Freedman, who sometimes reads the blog, has had a look at the MRI data from the ORACLE trial where people with the first demyelinating event were given cladribine. This has only taken them a decade to do:-(, as the ORACLE trial was finished by 2010. They have had a look at the MRI and conclude that cladribine works within 13 weeks.

Is this surprising? I don’t really think so. Look at the time taken to convert to MS and in the first three months you see MS developing, but at 3 months the transition to MS more or less flatlines.Next up we can actually fast forward a decade from the ORACLE study to the MAGNIFY study where they have been imaging people after cladribine

072 – Reduction in CUA MRI Lesions in the First 6 Months after Cladribine Tablets Treatment for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS Subgroup Analysis
Nicola De Stefano, MD

Background:With early and frequent magnetic resonance imaging (MRI), MAGNIFY-MS will provide valuable insights into the onset of action of CT3.5.

Objective:To report the onset of action of cladribine tablets, 3.5 mg/kg over 2 years (CT3.5), in patients with highly active relapsing multiple sclerosis (RMS) by observing changes in counts of combined unique active (CUA) lesions during the first 6 months of MAGNIFY-MS (NCT03364036), according to patient subgroups.

Design Methods: Subgroups included: high relapse activity (HRA)/non-HRA, treatment naïve/prior disease-modifying drug (DMD) treatment, and CUA lesion count >0 at baseline. MRI scans for all subgroups were performed during the baseline period (screening-baseline) and at Months 1, 2, 3, and 6 following CT3.5 treatment. Differences in CUA lesion count for post-baseline periods (Period 1: Months 1–6; Period 2: Months 2–6; Period 3: Months 3–6) were compared with the baseline period.

Results: Changes from baseline to Periods 3, 2, and 1, respectively, for least squares mean estimates of standardized CUA lesion counts were: HRA patients, -2.018, -1.801, -1.446; non-HRA, -1.201, -1.057, -0.827; treatment naïve, -1.460, -1.316, -1.092; prior DMD treatment, -1.876, -1.637, -1.269; CUA lesion count >0 at baseline, -3.132, -2.790, -2.253. For all subgroups, standardized CUA lesion counts reduced in all 3 periods (P<0.0001 all) compared with baseline.

Conclusions. Treatment with CT3.5 demonstrated an early onset of action, irrespective of patients’ baseline relapse activity or prior DMD history. In the first 6 months, on average, CUA lesions were reduced versus baseline between the first scan at end of month 1 and end of month 6.

When we see the presentation we can ask did cladribine work by 1 month (8week after) 2, month (12 week) after treatment (onset of teatment) or was it 3 months.

Also at AAN we have information on cell depletion.

209 – Extensive Long-term Immune Cell Profiling Reveals Further Targets of Oral Cladribine in MS
Tobias Moser. This has already been reported last year in Frontiers of Immunology.

Long-term peripheral immune cell profiling reveals further targets of oral cladribine in MS. Moser T, Schwenker K, Seiberl M, Feige J, Akgün K, Haschke-Becher E, Ziemssen T, Sellner J.Ann Clin Transl Neurol. 2020 Nov;7(11):2199-2212.

We show a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper-repopulation of maturing B cells. Regulatory lymphocytes and monocytes were spared. Antibody-producing B cells, cytotoxic T cells and natural killer cells (NK) were affected to a lesser extent. So this is good news for a vaccine response against COVID-19 and further suggests that this could a valuable first line therapy, but the anufacturers didnt request this and it was restricted to highly active MS…What a mistake.

Then we have MAGNIFY cladribine study and what do they see

004 – Characterization of Peripheral Immune Cell Dynamics and Repopulation Patterns in the First 12 Months of Cladribine Tablets Treatment: MAGNIFY-MS Study
Heinz Wiendl, MD, FAAN

Background The action of CT on immune cells may be key for both onset and durability of its effect in people with multiple sclerosis (MS).

Objective To report on peripheral immune cell subset dynamics and immunoglobulin levels in the first 12 months of cladribine tablets (CT) therapy.

Design Methods Longitudinal evaluation of peripheral blood immune cells in patients receiving CT in a sub-study of MAGNIFY-MS (NCT03364036). Absolute cell counts and %change from baseline were assessed for adaptive immune cell subtypes and immunoglobulins. Immunophenotyping was completed at baseline and months 1,2,3,6,12.

Results Full analysis set: 57 patients (median age 37 years; 61% female; ≥2 relapses in previous year, 70%). Effector and regulatory B cells were reduced from month 1 and showed a subtype-specific repopulation pattern. Change from baseline for CD19+ B cells: month 1,-77%; month 2,-90%; month 12,-35%. Memory B cells: month 1,-74%; month 3,-93%; month 12,-87%. Plasmablasts: month 1,-28% ( ); month 3,-78%; month 12,-51% (good news for covid19 vaccination). Regulatory B cells (CD19+, CD24bright, and CD38bright): month 1,-45%; month 3,+176%; month 6,+171%; month 12,+50%. Naïve/transitional B cells: month 1,-79%/-61%; month 3,-69%/+35%; month 12,+35%/+23%. Decrease in T cell subsets was moderate and slower, nadir occurring between 3 and 6 months (too slow for the MRI?). T-helper 17 CD4+ and terminally differentiated effector memory CD8+ T cell counts reached nadir at month 3 (-35% and -25%, respectively). No clinically meaningful change in serum IgG or IgM was observed over 12 months. (ocrelizumab drops these mainly IgM in year 1).

Conclusions: Assessment of lymphocyte dynamics following CT over 1 year demonstrates that effects occur from month 1, and are sustained in several immune cell subpopulations. CT exerts a pronounced effect on memory B cells, while immunoglobulin levels are unaffected over 12 months (good news for covid-19 vaccination). Results suggest early onset of CT action, underpinned by MAGNIFY-MS MRI results (So lucky Prof Freedman got his paper out as it will soon be out dated) , may be mediated through this specific pattern of sustained decrease and reconstitution of B and T cell subtypes in a highly active MS population.

Is ProfW saying memory B cells are important? Times are a changing…..but it is going to make it easy to understand how cladribine works.

After this work surfaces, we can do a compare and contrast but looks like what we predicted 2 years ago.

Want to know how and why cladribine works read this

Potential mechanisms of action related to the efficacy and safety of cladribine.Baker D, Pryce G, Herrod SS, Schmierer K.Mult Scler Relat Disord. 2019 ;30:176-186.

Can’t read or face it then watch the video

However

The thing that Prof Freedman should look back in the ORACLE trial is the brain atrophy data buried in the supplementary data, as to me after a re-baseline at 12 moths, as done with other DMT, the rate of whole brain atrophy loss goes back to normal.

Why dump this good data, when the CLARITY trial is what people think about?

It gave a rate of atrophy loss by about 0.6 about 6 times worse than in ORACLE at 0.1? Start treatment at onset or wait 9 years ….you snooze and you lose …brain .

However, is it too late?

So again we go to the up and coming AAN 2021 meeting they present the grey matter volume loss, why look at the “Chaff” (CLARITY) when you can look at the “Wheat”. (ORACLE), if you want to use cladribine first line at symptom onset…we need to do more... At least in Europe.

089 – Reduced Grey Matter Atrophy in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets
Marco Battaglini

Background
It is increasingly understood that GM atrophy is associated with disability progression and cognitive decline in patients with MS. Previously, we demonstrated that treatment with CT3.5 in the CLARITY study decreased brain atrophy compared with placebo, which was closely associated with a lower risk of disability progression [De Stefano et al. MSJ 2018].

Objective
Post hoc evaluation of grey matter (GM) and white matter (WM) volume changes in patients with relapsing multiple sclerosis (MS) randomized to cladribine tablets 3.5 mg/kg bodyweight (CT3.5; cumulative dose over 2 years) or placebo in the CLARITY study.

Design Methods
Images from pre-gadolinium T1-weighted magnetic resonance imaging scans of patients randomized to CT3.5 or placebo for 2 years in CLARITY were evaluated using SIENA-XL software. Images from 0–6 months (CT3.5, n=267; placebo, n=265) were analyzed independently of images from 6–24 months (CT3.5, n=184; placebo, n=186) to account for the potential effects of pseudoatrophy. Annualized mean changes in percentage of GM volume (PGMV) or WM volume (PWMV) between CT3.5 and placebo for 0–6 and 6–24 months were compared using a variance model.

Results
CT3.5 reduced GM and WM volume versus placebo in the first 6 months, consistent with pseudoatrophy (PGMV change: CT3.5 -0.53 vs. placebo -0.25 [p=0.045]; PWMV change: CT3.5 -0.49 vs. placebo -0.34 [p=0.137]). Brain volume loss from 6–24 months was reduced in patients randomized to CT3.5 with the difference between CT3.5 and placebo significant for GM (PGMV change: CT3.5 -0.90 vs. placebo -1.27 [p=0.026]; PWMV change: CT3.5 -0.32 vs. placebo -0.40 [p=0.52]).

Conclusions
Volume loss reduction in WM and, particularly, in GM was noted from 6-24 months in CT3.5-treated patients versus placebo, after a period of pseudoatrophy (0-6 months). Such findings suggest that CT3.5 significantly reduces brain atrophy predominantly in the GM, an effect that may contribute to lower risk of disability progression.

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  • PwMS are more fortunate than people with some other auto immune diseases, in that there is a good deal of research going on Covid notwithstanding. I’m thinking in-particular of an A-I D called CIDP. It stands for Chronic Inflammatory` Demyelinating Polyneuropathy, where the PERIPHERAL nervous system is attacked by the body’s immune system.
    I know of someone who now has this condition and is very disabled by it. I speculate that she probably has an EDSS of around 5-6 and was hospitalised in 2019 for 8 months at onset. I don’t know the mechanism of this condition but it appears to be almost a twin disease to MS. Yet there’s little known as it’s rarer than MS. My point is that.MS research projects come thick and fast by comparison.. We with MS are fortunate in this regard. In consequence I’ve lent her my Brain Health: Time Matters booklets in case she has brain volume loss..
    However, these 2 studies, albeit 10 yers apart, are to be welcomed. Nonetheless I sometimes wonder if there is some duplication. I appreciate that the 10 year gap renders it necessary to look at Cladribine again. Additional material and conflicting results, in similar or parallel studies are vital information to promote further studies. However, we seem to be hearing of a plethora of studies. IS there any duplication? Do we need to go off in novel directions? My dream is a really major study on the part depression plays in MS. I also ponder that MS and CIPD might be worth studying together for any possible similarities in causality etc., as the one may inform the other to the benefit of both. What do you think.?

    • You are correct There are a group of inflammatory demyelinating disease of the peripheral nervous system there are those that typically occur once and these are grouped under the name Guillain Barre Syndrome (GBS), here there is shut down of the peripheral nervous system and so you may need mechanical ventilation to keep your lungs going, here there is a infectious trigger and you typically produce antibodies against the myelin or the the nerves. The chronic variant of this is CIDP which can go chronic or relapse. You are very correct that you are lucky in MS to have so many treatments in CIDP and GBS the treatments are typical intravenous immunoglobulin, plasma exchange and steroids…like the bad old days of MS. There is an antibody that blocks an antibody killing mechanism and this costs about £0.5 million a year….no wonder they call it Solaris as it brings a ray of sunshine and a pot of gold to the manufacturer. There have been some studies with anti-CD20. I guess once oral cladribine price drops it may be tried in other autoimmune conditions like CIDP and other conditions. It has been shown to work in individual cases in neuromyelitis optica (it is in the patent literature) this is an antibody-mediated condition. You need brave patients and neurologists to use off label treatments.

      The ten year thing I think this is all about marketing and keeping cladribine in the eye of the neurologists. Did prof Freedman actually write this or was it produced by the company?
      Look in the paper it says “This study was sponsored by EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, who reviewed and provided feedback on the manuscript. (Company had their fingers all over this one). Writing and editorial support was provided by Ying Jean, PhD and Nick White of Ashfield (New York, NY, USA) so one suspects that the authors didnt do much except dotting a few i’s and crossing a few t’s. Funding was provided by the study sponsor (So it is a glorified advert using the neuros names to give it kudos…These authors may have helped plan the trials). The authors had full control of the manuscript, and provided their final approval of all content (the get out of jail clause…but is this really true. Recently there was a paper from other people and they gave a data access statement..saying you could get the data with a reasonable request. I asked the lead author for the data. They didnt have it, it was with the company, therefore how can they (neuros) have full control, did they produce the data). We (me and you) know this is the way of the world but many of my colleagues don’t and live in their own naive little bubble….Perhaps no wonder why their animal data does not reflect the human data 🙁

      With most drugs you have the trial and the follow up, like we had CARE-MS in 2012 then the 5 year followup in 2017, 7 year follow-up etc etc but with cladribine they dropped and cancelled the project in 2010 so they only have CLARITY and ORACLE to look at until they produce more data and only resurrected it in 2017. Who made the decision to drop it I don’t know probably “Dead in a Ditch”. The only thing that kept it going in the mean time was ProfK. He decided to use subcutaneous cladribine at £65 for 10mg and treated about 250 people. This data is being presented at the AAN 2021, you just have to find the GBS doc, I think the first person treated was in 2014. Do some people need treating…yes they do but we will do a post on our AAN cohort.

      • Studying MS and CIDP would be too messy and is too late you know have an array of MS licenced drugs to do a trial costs you the price of the drug. 500 person trial at £20,000 = £10,000,000 do it in the states that is 500 x $100,000 = $50,000,000.

        • Interesting observation about “data access statement” . How common is this and why is it acceptable to keep the data hidden away, especially when pharmaceutical cos have financial benefit at stake? ? If my memory is correct, the TRIUMPHANT study comparing 4 fatigue pharmaceuticals treatments didn’t give raw data or algorithm used for results. Has BArts had access to this data? When data is withheld, how is it peer reviewed? are we expected to take authors’ word for it? With TRIUMPHANT study, Isn’t it Kind of hard to critique this study without looking at how patient responses were analyzed? Do you think this lack of transparency of the data plus study’s specific definition of MS fatigue could make results misleading? It had a 2 million budget.

          • Quiet common is a toothless statement….and trial involving pharma I can guarentee the authors have not looked at the primary data. Pharma has signed up to data sharing and am currently looking at alemtuzumab and ocrelizumab trial data. This is made available via sites such as clinical study data request.com and vivli, but is all done under contract. You work inside a portal. There are gate keepers checking what you do, but the problem for me is I cant use the programmes, so you have say ten data points you are intestested, but you get given twenty files each has fifty to hundred columns and there are about 200,000 rows how do you find the ten cells you are interested in? Then you have to do graphs but again these are not the programmes you are used to. So there is transparency but it is on their terms. You have to say what you will do before you know what data is present. Any way I now nearly have assess to the data only 4 years since I first enquired:-)

  • Thank you MD, for that really detailed response to my post. I see what you mean about any co-study for MS with CIPD. It doesn’t always boil down to money, but often it does. Guillain Barré Syndrome was the person’s original diagnosis. I suppose variants of auto immune induced demyelination diseases do arise. It’s obviously not a goer in terms if co-research, but does any one disease shed light on any other, in any sort of useful way towards any disease and it’s amelioration?

    • GBS is a syndrome and so it has many other names Miller Fisher, Bickerstaffs , AMAN AIDP, SAN etc. CDP has other variants like Lewis Sumner multifocal moto neuropathy GALOP etc.

      Does any one disease shed light on any other?Absolutely it does there are many common mechanisms the targets are just different but treatments may be the same. I would think cladribine would be a good try for many, but one can have a look to see what has been tried

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