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
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
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].
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.
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.
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]).
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.