Search

Therapies for infiltrative inflammation in multiple sclerosis (MS) have advanced greatly, but neurodegeneration and compartmentalized inflammation remain virtually untargeted as in other diseases of the nervous system. Consequently, many therapies are available for the relapsing–remitting form of MS, but the progressive forms remain essentially untreated. The objective of the International Progressive MS Alliance is to expedite the development of effective therapies for progressive MS through new initiatives that foster innovative thinking and concrete advancements. Based on these principles, the Alliance is developing a new funding programme that will focus on experimental medicine trials. Here, we discuss the reasons behind the focus on experimental medicine trials, the strengths and weaknesses of these approaches and of the programme, and why we hope to advance therapies while improving the understanding of progression in MS. We are soliciting public and academic feedback, which will help shape the programme and future strategies of the Alliance.

•Long-term lymphocyte counts were evaluated (CLARITY, CLARITY Extension and PREMIERE).•Absolute lymphocyte counts were evaluated to 312 weeks, B and T cells to 240 weeks.•The results suggest that cladribine tablets may be an immune reconstitution therapy.

ABSTRACTBackground: For interferon beta-1a subcutaneously three times weekly (IFN β-1a SC tiw), administration options include manually injected prefilled syringes; a preassembled, single-use autoinjector; and a reusable autoinjector. This study evaluated patient-perceived ease of use of two injection devices.Research design and methods: REDEFINE, a Phase IV, multicenter crossover study, randomized patients with multiple sclerosis and ≥5 weeks’ IFN β-1a 44 μg SC tiw use to 4 weeks using a single-use autoinjector, then 4 weeks using a reusable autoinjector, or vice versa. The primary endpoint was the proportion rating each ‘easy’ or ‘very easy’, with/without regard to previous device experience.Results: Of 97 randomized patients, 29 had most recent experience with manual injection; 23 with single-use autoinjector; and 45 with reusable autoinjector. 68.4% found using the single-use autoinjector very easy or easy, versus 77.9% for the reusable device (difference −9.5%; p = 0.200). 40.0% versus 29.5% found the respective devices very easy (difference 10.5%; p = 0.203).Conclusions: Most patients found both autoinjectors easy or very easy to use. Having two viable options may help accommodate patient preferences. Ease of administration and patient satisfaction relates to adherence; satisfied patients may more likely be adherent.Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02019550).

Individuals with multiple sclerosis (MS) experience diminished health outcomes. However, little is known about how these outcomes differ according to disease severity. The aim of this study is to compare health-related quality of life (HRQoL), work productivity, activity impairment, and resource use between MS patients and controls, as well as across MS patients with varying self-reported disease severity.

Background: Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy.Objective: The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a).Methods: In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12.Results: At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% − 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple.Conclusion:The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.

Major recent advances in the field of chromatin remodeling have dramatically changed our understanding of the ways in which genes are regulated. Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are increasingly being implicated as direct or indirect components in the regulation of expression of neuronal, immune and other tissue specific genes. HDACs and HATs have been shown to play important roles in cell growth, cell cycle control, development, differentiation and survival. Mutations in genes that encode HDAC-binding proteins cause neurological disorders, such as MeCP2 mutations in Rett's syndrome. Mutations of CBP, a gene with HAT function, cause the mental retardation-associated Rubinstein-Taybi syndrome. Recently, HDAC inhibitors have been found to ameliorate progression of the spinal muscular atrophy (SMA) motor neuron disease and the Huntington disease mouse models. The neuroprotective role of HDAC inhibitors seems to extend to other diseases that share mechanisms of oxidative stress, inflammation and neuronal cell apoptosis. HDAC inhibitors also have widespread modulatory effects on gene expression within the immune system and have been used successfully in the lupus and rheumatoid arthritis autoimmune disease models. Recently, we demonstrated the efficacy of the HDAC inhibitor Trichostatin A in ameliorating disease in the multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In this review we describe the current literature surrounding these inhibitors and propose a rationale for harnessing both their neuroprotective and anti-inflammatory effects to treat MS, an autoimmune, demyelinating and degenerative disease of the human central nervous system (CNS).

Increased expression of the costimulatory molecule CD80 (B7–1) was noted in the subventricular zone of the brain during the course of experimental autoimmune encephalomyelitis (EAE). This area of the brain is a neural stem cell (NSC) niche in the adult. We show that isolated NSCs from adult brain express CD80 and CD86 (B7–2) and this expression is increased after exposure to IFN-γ or TNF-α, the prototypical Th1 cytokines expressed during EAE. CD80 and CD86 expressed by NSCs are functional and can costimulate allogeneic cells in a mixed lymphocyte reaction. Furthermore, cross-linking of CD80 on the surface of NSCs results in apoptosis of NSCs. In vitro, we show that T cells can interact with NSCs and form conjugates with redistribution of CD3 on the surface of T cells to the area of contact. These data raise the possibility that during CNS inflammatory diseases such as EAE, NSCs may express immune molecules and interact with the inflammatory environment potentially resulting in injury to the NSCs, which may have implications for repair mechanisms in the central nervous system.

Little is known about global gene expression patterns in the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). To address this, we used high-density oligonucleotide microarray technology to compare expression levels of ∼6,800 genes in postmortem spinal cord gray matter obtained from individuals with ALS as well as normal individuals. Using Fisher discriminant analysis (FDA) and leave-one-out cross-validation (LOOCV), we discerned an ALS-specific signature. Moreover, it was possible to distinguish familial ALS (FALS) from sporadic ALS (SALS) gene expression profiles. Characterization of the specific genes significantly altered in ALS uncovered a pro-inflammatory terminal state. Moreover, we found alterations in genes involved in mitochondrial function, oxidative stress, excitotoxicity, apoptosis, cytoskeletal architecture, RNA transcription and translation, proteasomal function, and growth and signaling. It is apparent from this study that DNA microarray analysis and appropriate bioinformatics can reveal distinct phenotypic changes that underlie the terminal stages of neurodegeneration in ALS.

This study creates a compendium of gene expression in normal human tissues suitable as a reference for defining basic organ systems biology. Using oligonucleotide microarrays, we analyze 59 samples representing 19 distinct tissue types. Of ∼7,000 genes analyzed, 451 genes are expressed in all tissue types and designated as housekeeping genes. These genes display significant variation in expression levels among tissues and are sufficient for discerning tissue-specific expression signatures, indicative of fundamental differences in biochemical processes. In addition, subsets of tissue-selective genes are identified that define key biological processes characterizing each organ. This compendium highlights similarities and differences among organ systems and different individuals and also provides a publicly available resource (Human Gene Expression Index, the HuGE Index, http://www.hugeindex.org) for future studies of pathophysiology.

•Cladribine tablets reduce the risk of conversion to multiple sclerosis•Cladribine tablets reduce multiple sclerosis lesion burden on MRI•Age, number of MRI lesions, and multifocal onset are linked to MS disease recurrence•Benefits of cladribine tablets are observed in subgroups by disease characteristics•Benefits of cladribine tablets are observed in subgroups by age and sex

Histone deacetylases (HDACs) are enzymes that play a pivotal role in transcription, differentiation, and cell cycle progression. We previously cloned human HDAC3 cDNA and showed that its transfection into THP-1 cells results in G2/M cell cycle accumulation. Using bioinformatic screening and PCR, we have now cloned the murine Hdac3cDNA, which encodes a 428-amino-acid protein with near complete identity to its human ortholog. To establish a link to a potential disease locus, we performed PCR-based chromosomal mapping for the mHdac3gene and chromosomal fluorescence in situhybridization (FISH) for the human gene. mHdac3localizes to chromosome 18 and human HDAC3 gene localizes to a syntenic region in chromosome 5 at band q31.3–q32 telomeric to the cytokine gene cluster. Transfection of mHdac3into HeLa cells led to accumulation in G2/M. Our results suggest a cell cycle function for murine Hdac3,reflecting the complex regulatory roles of this gene family.

The nucleosomal histones can be modified through reversible acetylation by histone acetyltransferases (HATs) and deacetylases (HDACs). HATs induce nucleosomal relaxation and allow DNA-binding by transcriptional activators. HDACs form corepressor complexes which negatively regulate cell growth. However, the HDAC inhibitors butyrate and Trichostatin A block T cell proliferation, suggesting that not all effects of HDACs lead to repression. Using mRNA differential display and 5′RACE we isolated human HDAC3, a novel gene that is upregulated in PHA-activated T cell clones. HDAC3 is homologous to other human HDACs and yeastRPD3.In peripheral blood mononuclear cells (PBMCs), activation by PHA, PMA and α-CD3 increased HDAC mRNA but no effect was seen with IFN-γ, LPS, or IL-4. In contrast, GMCSF downregulated PBMC levels of HDAC3 mRNA. All HDACs were found to be ubiquitously expressed in immune and non-immune tissues. In human myeloid leukemia THP-1 cells, HDAC3 transfection resulted in increased size, aberrant nuclear morphology and cell cycle G2/M cell accumulation. Functional activity of the expressed HDAC3 protein was confirmed in α-HDAC3 antibody immunoprecipitates by a histone deacetylase assay. Our study suggests the participation of HDACs in cell cycle progression and activation.

The acute pathophysiologic changes during hemiplegic spells and the long-term outcome of alternating hemiplegia remain obscure. In a 41-year-old male with familial alternating hemiplegia we found an increase in right frontal cerebral blood flow 3 h into a 5-h left hemiplegic episode. A repeat high-resolution brain SPECT study performed 26 h after the resolution of the left hemiplegia revealed normalization of the frontal blood flow accompanied by hyperperfusion in the right parietal lobe. An interictal SPECT scan several weeks later showed no asymmetries. Head CT and MRI scans were negative. Neuropsychologic assessment and neurologic examination revealed evidence of a diffuse disorder which predominantly involved the right hemisphere. To our knowledge, there are no previous correlative studies of serial highresolution brain SPECT with MRI, or of detailed neuropsychologic assessment, in adult patients with such an advanced course of alternating hemiplegia of childhood.

The reversible acetylation of histones by histone deacetylases (HDACs) and acetyltransferases (HATs) plays a fundamental role in gene transcription. We previously showed that HDAC mRNA is upregulated in immune cells upon PHA-induced activation. Little is known, however, about the differential regulation of HDAC mRNAs by the HDAC inhibitors Trichostatin A (TSA) and butyrate, agents known to block proliferation and induce apoptosis. We report that apoptosis-inducing concentrations of TSA and butyrate upregulate the expression of HDAC mRNAs in a differential manner and act synergistically with PHA to induce HDAC expression, suggesting the presence of independent HDAC regulatory mechanisms. Moreover, we show that HDAC inhibitor-induced apoptosis is associated with early abrogation of γ-IFN production by Th1 lymphocytes and with p53 mRNA downregulation. Our findings highlight the dynamic interplay of cell cycle-, activation- and apoptosis-related proteins in association with time-dependent expression of HDACs and are suggestive of different specific roles for these enzymes.

IntroductionEvobrutinib (M2951) is a highly specific oral inhibitor of Bruton’s tyrosine kinase, a key regulator of B cell and macrophage functions implicated in MS.MethodsIn this double-blind, phase 2 study (NCT02975349), adult patients (≤65 years) with relapsing MS (RMS) were randomized to evobrutinib 25 mgQD, 75 mgQD, 75 mgBID, placebo, or open-label dimethyl fumarate (240 mgBID; reference arm) for 48 weeks; placebo-treated patients switched to evobrutinib 25 mgQD after 24 weeks. The primary endpoint was the total number of T1 gadolinium-enhancing (T1Gd+) lesions at Weeks 12, 16, 20, and 24. Secondary endpoints included annualized relapse rate (ARR), MRI measures at Weeks 24 and 48, and safety.ResultsAmong 261 patients, the sum of T1Gd+ lesions over Weeks 12–24 was reduced with evobrutinib 75 mgQD (p=0.002) and 75 mgBID (p=0.03); a dose response was observed (p=0.001). There was no evidence of change in effect on T1Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mgQD (0.28±0.91 to 0.85±2.87; p=0.57) or 75 mgBID (0.24±0.88 to 0.49±1.22; p=0.23). ARR (unadjusted [95%CI]) was 0.25 (0.12–0.44) for evobrutinib 75 mgQD and 0.11 (0.04–0.25) for 75 mgBID over 48 weeks, and 0.37 (0.17–0.70) for placebo over 24 weeks. Evobrutinib appeared well-tolerated. Shifts to Grade 3–4 ALT and AST elevations from normal (grade 0) occurred in 8 (5.4%) and 6 (3.9%) evobrutinib-treated patients respectively, driven by events with onset within the first 24 weeks.ConclusionsEvobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in RMS. The observed benefit-risk profile supports further clinical development.

Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.

L’Evobrutinib, inhibiteur de la tyrosine kinase de Bruton (BTK), a démontré une efficacité clinique dans le traitement de la sclérose en plaques (SEP) au cours d’une étude de phase 2.

BackgroundCladribine tablets 3.5 mg/kg (CT3.5) demonstrated efficacy in RMS patients in CLARITY/CLARITY-Extension. Lymphopenia was common (CT3.5: mechanism of action).ObjectiveEvaluate whether lymphopenia persists following treatment/re-treatment with CT3.5 in CLARITY/CLARITY- Extension.MethodsLymphopenia by grade for patients randomised to CT3.5 throughout CLARITY/CLARITY-Extension (7 mg/kg cumulative 4 year dose; n=186) are reported. Patients with Grade 0 (G0) lymphopenia (≥1.0 × 109 cells/L) before the first course of CT and G0/1 (≥0.8 × 109 cells/L) before subsequent treatment in Years 2 (Y2), 3 and 4 were analysed.Results176 patients were G0 at the start of CLARITY (167 were G0/1; CLARITY-Extension). G3 lymphopenia was observed in 1% patients (Week-13, Y1), and in 7%, 11% and 12% patients at Week-12 in Y2, 3 and 4. In each year, G3 lymphopenia was observed in 1%, 4%, 4% and 4% patients (Week-24), in 1%, 2%, 2% and 2% patients (Week-36), and in 1% patients (Week-48) in Y2 only. G3 lymphopenia was reported in <18% patients at any time-point. No patients had G4 lymphopenia at the end of each treatment year.ConclusionsIn patients meeting treatment/re-treatment guidelines, no G4 lymphopenia occurred at the end of any treatment year; G3 lymphopenia was uncommon. Lymphocyte-based re-treatment criteria minimised the incidence of severe, sustained lymphopenia during 4 years’ treatment with CT.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_Year1-4.pdf

BackgroundPatients with high disease activity (HDA) relapsing-remitting MS are less likely to attain no evidence of disease activity (NEDA; no relapses, MRI activity or progression).ObjectivePost-hocanalysis to compare the proportion of patients with NEDA with cladribine tablets 3.5 mg/kg (CT3.5) vs placebo.MethodsPatients from CLARITY were retrospectively stratified using 2 definitions of HDA based on relapse history, prior treatment, and MRI characteristics: HRA (n=261) and HRA plus disease activity on treatment (HRA+DAT) [n=289]). Data for patients treated with CT3.5 or placebo who fulfilled these criteria and achieved NEDA status were compared over the 2 years using odds ratios (OR) and 95% CI.ResultsHRA subgroup: 76% of CT3.5-treated patients were relapse-free and 84% were T1 Gd+ lesion free vs 49% and 31%, respectively, for placebo. HRA+DAT subgroup: 77% of CT3.5-treated were relapse-free and 85% were T1 Gd+ lesion free vs 50% and 32%, respectively, for placebo. In the HRA and HRA+DAT subgroups, 43.2% and 43.7%, respectively, of CT3.5-treated patients were disease activity free compared with 8.7%, (OR: 8.02; 95% CI: 3.93 to 16.35; p<0.0001) and 9.0% (OR: 7.82; 95% CI: 4.03 to 15.19; p<0.0001) respectively, for placebo. In the overall population, composite NEDA score favored CT over placebo (OR: 4.46; 95% CI: 3.18 to 6.26; p<0.0001).ConclusionsTreatment with CT3.5 significantly increased the proportion of HDA patients with NEDA vs placebo.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_NEDA.pdf

BackgroundIn CLARITY, cladribine tablets 3.5 mg/kg (CT3.5) demonstrated efficacy in relapsing MS patients. The most common AE was lymphopenia, reflecting cladribine’s mode of action. Integrated safety analysis showed infection incidence was not higher in patients receiving CT3.5 vs placebo, bar a small increase of herpes zoster (HZV).ObjectivePost-hoc analysis examined infectious AEs occurring concurrently with Grade 3/4 lymphopenia (G3/4) in CT3.5 treated patients.MethodsThe AE profile for CT3.5 during the periods of G3/4 was analysed. Adjusted-AE incidences per 100 patient years (Adj-AE/100PY) were calculated in a cohort of patients receiving CT3.5 monotherapy in clinical trials.ResultsData are presented as Adj-AE/100PY: G3/4 vs without G3/4. Adj-AE/100PY for any infections/infestations was 57.53 vs 24.50. Infections were similar between periods. ≥50% cases with G3/4 were easily-treatable upper- respiratory-tract infections (nasopharyngitis: 13.48 vs 5.24; upper-respiratory-tract infection: 9.67 vs 3.41; pharyngitis: 4.51 vs 0.73). HZV occurred in 4 patients with G3/4 (4.50 vs 0.73); cases were dermatomal and mild-to- moderate in severity. Single occurrences were reported for most infectious AEs. Opportunistic infections were single occurrences, not severe, serious or difficult-to-treat.ConclusionsG3/4 increased frequency of infections but did not affect the type of infectious AEs in CT3.5 treated patients. HZV profile was uncomplicated, consistent with findings of previous analyses.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_Grade34.pdf

IntroductionPatients with relapsing MS (RMS) who show an increased rate of relapse or disability worsening can be described as showing high disease activity (HDA). Treatment with cladribine tablets (CT) in the CLARITY study, and with CT added to interferon-β in the ONWARD study demonstrated efficacy vs. placebo (PBO) across a range of patients with active MS. Combining double-blind data from these studies allows assessment of the efficacy of treatment with CT 3.5 mg/kg (CT3.5; cumulative dose). The objective of this post-hocanalysis is to compare the effects of CT3.5 vs. PBO on the proportion of patients achieving no evidence of disease activity (NEDA) status in HDA subgroups identified using two sets of criteria in a pooled cohort of patients from CLARITY and ONWARD.MethodsPatients from CLARITY and ONWARD were retrospectively stratified using 2 sets of HDA criteria based on relapse history, prior treatment, and MRI characteristics: high relapse activity (HRA; n=314) and HRA plus disease-activity-on-treatment (HRA +DAT; n=459). Patients treated with CT3.5 or PBO who fulfilled these criteria and achieved NEDA were compared over 2 years using odds ratios (ORs) and 95%CIs.ResultsIn the HRA subgroup, 76.5% of CT3.5-treated patients were relapse-free, 86.7% were T1 Gd +lesion free vs. 50.7% and 35.8%, respectively, for PBO. In the HRA +DAT subgroup, 77.6% were relapse-free and 88.8% were T1 Gd +lesion free with CT3.5 vs. 53.9% and 40.8%, respectively for PBO. In the HRA and HRA +DAT subgroups, 42.7% and 41.3%, respectively, of CT3.5-treated patients were disease activity free compared with 9.7%, (OR 6.94, 95% CI 3.67;13.12, p<0.0001) and 13.7% (OR 4.28, 95% CI 2.62;6.99, p<0.0001) respectively, of PBO recipients. In the overall CLARITY+ONWARD population (including non-HDA patients), the composite NEDA score also favoured CT over PBO (OR 3.95, 95% CI 2.90;5.37, p<0.0001).ConclusionCompared with placebo, treatment with CT3.5 was associated with increased odds of achieving NEDA in HDA patients.

Les patients avec un syndrome cliniquement isolé à haut risque de développer une SEP ont été randomisés pour recevoir Cladribine comprimés (CC) 3,5 ou 5,25mg/kg. Une baisse du risque de conversion en SEP cliniquement définie a été observée avec CC vs. placebo.

BackgroundIn the CLARITY study, treatment with cladribine tablets (CT) vs placebo showed strong efficacy in patients with RMS. Post-hoc analysis may provide insights into the efficacy of CT in patients with HDA.ObjectiveTo compare the effects of CT 3.5 mg/kg (CT3.5) vs placebo using two HDA definitions.MethodsPatients randomised to CT3.5 (n=433) or placebo (n=437) were analysed using two HDA definitions based on high relapse activity ([HRA]≥2 relapses in the previous year) regardless of prior treatment, or a HRA plus treatment nonresponse ([HRA +TNR]≥2 relapses in the previous year, or ≥1 relapse in previous year while on DMD therapy and ≥1 T1 Gd +or ≥9 T2 lesions).ResultsIn the overall population, CT3.5 reduced risk of 6 month EDSS progression by 47% (HR=0.53,95%CI:0.36;0.79) vs placebo. A larger risk reduction for CT3.5 vs placebo of 82% was seen in the HRA and HRA +TNR subgroups (HR=0.18 each,95%CI:0.08;0.44 and 0.07;0.43). ARR was lower with CT3.5 than placebo in the overall population (RR=0.42,95%CI:0.33;0.52), and even lower for HRA (RR=0.32,95%CI:0.22;0.47) and HRA +TNR (RR=0.33;95% CI:0.23;0.48).ConclusionsPatients identified by HDA criteria showed clinical and MRI responses to CT3.5 that were generally better than, or at least comparable with, outcomes in the overall CLARITY population.

L’évobrutinib est un inhibiteur oral hautement sélectif de la tyrosine kinase de Bruton qui réduit sur le plan fonctionnel l’activation des lymphocytes B et des macrophages in vivo.

IntroductionIn ORACLE-MS (616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis), cladribine tablets (CT) 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly delayed the time-to-conversion to clinically definite multiple sclerosis (CDMS), and reduced new/persisting T1 gadolinium-enhancing (T1 Gd+), new/enlarged or active T2 and combined unique active (CUA) lesion number. Here, the timing of CT effect is evaluated.MethodsMRI scans were performed at screening and every 12 weeks, for non-converting CDMS subjects. MRI-based endpoints were analyzed using analysis of covariance (ANCOVA) and negative binomial models. The temporal effects of the first yearly treatment course of CT and placebo on T1 Gd+, active T2, and CUA lesions were evaluated.Results96 weeks: the reduction in mean T1 Gd+, active T2, or CUA lesion number per patient per scan was nominally significantly greater for CT versus placebo (p<0.0001). Early change in Gd+ lesion volume (at Week 13) from baseline was CT, -155.73 mm3; placebo, -14.76 mm3. Comparatively larger reductions in mean active T2 and CUA lesion numbers with CT at Week 13 versus placebo were observed (active T2: CT, -1.25; placebo, -1.43; CUA: CT, -1.56; placebo, -2.41). The mean number of T1 Gd+ lesions at 13 weeks following CT was 0.37 versus 1.0 with placebo.ConclusionsMRI data from ORACLE-MS subjects suggest the first yearly treatment course of CT has a rapid onset of action, with beneficial treatment effects on active lesion number and volume evident by Week 13.

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [<30 or ≥30 years], gender, first classification demyelinating event [monofocal or multifocal], presence of T1 Gd+ lesions and number of T2 lesions [<9 or ≥9]).ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.

L’étude CLARITY a démontré l’efficacité de cladribine comprimés (CC) chez des patients atteints d’une forme récurrente de SEP. Les patients à haute activité de la maladie (HDA, pour high diesease activity) ont un risque plus élevé de poussées et de progression du handicap.

Cladribine comprimés (CC) s’est révélé efficace par rapport au placebo (PBO) chez des patients atteints d’une forme récurrente de SEP (étude CLARITY). Les patients à haute activité de la maladie sont moins susceptibles de ne présenter aucun signe d’activité de la maladie.

La lymphopénie était l’effet indésirable le plus fréquent dans les études CLARITY/CLARITY Extension. La numération absolue des lymphocytes (NAL) revenait à la normale avec le temps.

Les études CLARITY/CLARITY Extension ont démontré l’efficacité de cladribine comprimés (CC) pour les formes récurrentes de la sclérose en plaques. L’effet indésirable le plus fréquent était la lymphopénie, qui est compatible avec le mécanisme d’action de CC.

BackgroundThe CLARITY study demonstrated the benefit of cladribine tablets 3.5 mg/kg (CT3.5) for patients with relapsing MS (RMS). Patients with high disease activity (HDA) RMS are at risk of clinical activity and disability progression.ObjectivePost-hocanalysis of MRI outcomes in CLARITY for CT3.5 vs placebo.MethodsRetrospective analysis using HDA definitions based on relapse history, prior treatment, and MRI characteristics: high relapse activity (HRA) and HRA plus disease activity on treatment (HRA+DAT).ResultsFor cumulative new T1 Gd+ lesions, relative risk ratios (RRR) for both subgroups (HRA: 0.087; 95% CI: 0.052 to 0.144; p<0.0001) (HRA+DAT: 0.077; 95% CI: 0.046 to 0.128; p<0.0001) were lower for CT3.5 vs placebo. Risk reductions (RR) (91% and 92%, respectively) were similar to the 90% reduction in the overall CLARITY population (0.097; 95% CI: 0.070 to 0.134; p<0.0001). Cumulative active T2 lesions RRR favoured CT3.5 vs placebo for both subgroups (HRA: 0.263; 95% CI: 0.180 to 0.383, p<0.0001) (HRA+DAT: 0.254; 95% CI: 0.178 to 0.363; p<0.0001): RRs of 74% and 75%, reflecting the 73% overall population reduction (0.272; 95% CI: 0.221 to 0.335; p<0.0001). Cumulative combined unique lesions RRR favoured CT3.5 vs placebo for HRA (0.212; 95% CI: 0.145 to 0.311; p<0.0001) and HRA+DAT (0.203; 95% CI: 0.141 to 0.291; p<0.0001): RRs were 79% and 80%, reflecting the 77% overall population reduction (0.234; 95% CI: 0.190 to 0.290; p<0.0001). There were no significant interactions between HDA and non-HDA subgroups.ConclusionsThe treatment benefit of CT3.5 on MRI outcomes was similar in HDA RMS subgroups and the overall CLARITY study population.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_HDAMRI.pdf

BackgroundLymphopenia is expected from the mechanism of action of cladribine tablets 3.5 mg/kg (CT3.5)ObjectiveInvestigate absolute lymphocyte counts (ALC; 312 weeks) and subsets (240 weeks) in RRMS patients receiving 2 annual courses of CT3.5.MethodsPooled data from patients randomised to CT3.5 over 2 years in CLARITY/CLARITY-Extension inclusive of the PREMIERE registry (n=685).ResultsBaseline: median ALC=1.86 × 109/L. Year-1: ALC reached nadir at 9 weeks post-treatment with CT3.5 (1.00 × 109/L). Year-2: ALC reached nadir at Week-55 (0.81 × 109/L), then recovered to the normal range (≥1.00 × 109/L; Week-96). ALC was in normal range in 75% of patients by Week-144. Baseline median CD4+ were 851 cells/µL. Nadirs occurred at Week-16 (385 cells/µL) in Year-1 and at Week-60 (292 cells/µL) in Year-2; values increased after nadirs and regained threshold (350 cells/µL, ~Week-120). Baseline median CD8+ were 378 cells/µL. Nadirs occurred at Week-16 (239 cells/µL; Year 1) and Week-72 (232 cells/µL; Year 2). CD8+ recovered quickly after treatment and remained above 200 cells/µL at all times. Baseline median CD19+ were 205 cells/µL. Nadirs occurred at Week-9 (18 cells/µL; Year-1) and Week-52 (31 cells/µL; Year-2). CD19+ then reached threshold of 100 cells/µL by the end of Year-2.ConclusionLymphocyte recovery begins soon after CT3.5. ALC, CD19+ B and CD4+ T cells; reached threshold by 7.5, 12 and 18 months. CD8+ cells remained above threshold.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_LongLymph.pdf

IntroductionAn independent meta-analysis; Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158) in Phase III trials (with a 2 year duration) of disease modifying drugs (DMDs) in patients with relapsing multiple sclerosis found no increased rate of malignancy with cladribine tablets (CT) versus other DMD treatments. Data from additional trials involving CT 3.5 mg/kg (CT3.5) and a safety registry (up to 8 years’ follow-up) allow further insights into malignancy risk. Objective is to assess malignancy risk with CT3.5 monotherapy and placebo (PBO) in data from 3 Phase III trials and a registry, and compare the incidence rate with a global database.MethodsThe CT 3.5 population comprised 923 patients (3433 patient-years’ [PY] total exposure time) and the PBO group comprised 641 patients (2026 PY). Individual case reports of malignancies were reviewed by independent, blinded adjudication committee. Standardised incidence ratios (SIR) were calculated using the GLOBOCAN reference population (excluding non-melanoma skin cancers [NMSCs]) and a Danish reference population for NMSC rates.ResultsThe incidence per 100 PY of confirmed malignancy was CT3.5 0.293 (95%CI 0.158–0.544) and PBO 0.148 (95%CI 0.048–0.460); the risk difference 95% CI included 0 (−0.166–0.414). The CT 3.5 malignancy SIR was almost identical (0.97, 95% CI 0.44–1.85) to the GLOBOCAN matched reference population. The PBO group SIR was numerically lower (0.48, 95% CI 0.14–1.53). There were no cases of haematological, lymphoproliferative or virus-induced cancers. There was no clustering of specific tumour types, and the incidence of skin cancer was not increased after treatment with CT3.5 versus PBO. The incidence of malignancies with CT3.5 was constant and did not increase over time.ConclusionAnalysis of malignancy rates in a cohort that includes patients with up to 8 years’ follow-up confirms the Conclusion of the earlier meta-analysis; the incidence of malignancies with CT3.5 is similar to a matched reference population.

IntroductionThe CLARITY and CLARITY Extension studies demonstrated the efficacy of cladribine tablets in patients with relapsing multiple sclerosis. The most common adverse event was lymphopenia, consistent with the mechanism of action of cladribine tablets. Objective was to evaluate whether lymphopenia persists following annual treatment with cladribine tablets.MethodsLymphopenia by grade (NCI CTCAE v3.0) for patients randomised to cladribine tablets 3.5 mg/kg in CLARITY and re-randomised to cladribine tablets 3.5 mg/kg in CLARITY Extension (7 mg/kg cumulative dose over 4 years; n=186) are reported. Patients with Grade 0 lymphopenia (≥1.0×109 cells/L) before the first course of cladribine tablets and Grade 0/1 (≥0.8×109 cells/L) prior to administration in Years 2, 3 and 4 were included in the analysis.Results176 patients were Grade 0 at CLARITY baseline and 167 were Grade 0/1 at CLARITY Extension baseline. Grade 3 lymphopenia was observed in 1% of patients at Week 13 in Year 1, and in 7%, 11% and 12% at Week 12 in Years 2, 3 and 4, respectively. By Week 24 in Years 1, 2, 3 and 4, Grade 3 lymphopenia was observed in 1%, 4%, 4% and 4% of patients, respectively. By Week 36 in Years 1, 2, 3 and 4, Grade 3 lymphopenia was observed in 1%, 2%, 2% and 2% of patients, respectively. Grade 3 lymphopenia was only observed in Week 48 of Year 2 (1% of patients). Grade 3 lymphopenia was reported in <18% of patients at any time point. No patients had Grade 4 lymphopenia at the end of any years.ConclusionNo patients included in this analysis experienced Grade 4 lymphopenia at the end of any treatment year. Grade 3 lymphopenia was uncommon. This study demonstrates the effectiveness of lymphocyte-based treatment criteria in minimising the incidence of severe, sustained lymphopenia during treatment with cladribine tablets.

L’efficacité de Cladribine comprimé (CC) a été démontrée chez les patients atteints de SEP précoce ou récurrente (SEP-R). Le regroupement des données de tolérance pour les analyses intégrées permet une caractérisation exhaustive du profil d’effets indésirables (EI) de CC.

Cladribine comprimé a significativement amélioré les résultats cliniques (poussée et progression du handicap) et IRM (CLARITY 2 ans). Deux années supplémentaires de traitement par CC vs. placebo (Pbo) ont été évaluées dans l’extension (CLARITY-EXT).

L’étude CLARITY chez des patients atteints de SEP récurrente a montré que Cladribine Comprimés (CC) administrée annuellement pendant 2 ans apportait une amélioration clinique significative vs. placebo (PBO).

BackgroundEfficacy and safety of cladribine tablets (CT) has been investigated in patients with early MS and relapsing MS (RMS).ObjectiveReport the AE profile from integrated safety data for CT3.5 mg/kg (CT3.5) monotherapy.MethodsThe monotherapy oral CT3.5 cohort comprised 923 patients (3432.65 patient years [PY] exposure); 641 patients received placebo (2025.97 PY).ResultsMean study period for CT3.5 was 194 weeks; placebo 165 weeks. Adj-AE per 100 PY rates for CT3.5 and placebo respectively: treatment emergent AEs, 103.3 and 94.3; serious AEs, 4.0 and 3.6; serious AEs leading to death, 0.26 and 0.25. For events expected with CT treatment, adj-AE per 100 PY for lymphopenia were 7.94 (CT3.5) and 1.06 (placebo), and for system organ class (SOC) infection and infestations, 24.93 (CT3.5) and 27.05 (placebo); herpes zoster, 0.83 (CT3.5) and 0.20 (placebo). Adj-AE per 100 PY for SOC neoplasms, benign, malignant and unspecified were 1.14 and 1.01, for CT3.5 and placebo, respectively.ConclusionsThe AE profile for CT3.5 monotherapy has been well-characterised. Lymphopenia was expected from cladribine tablets’ mode of action; herpes zoster was reported more frequently in patients experiencing Grade 3/4 lymphopenia; no clustering of types of malignancy, and no malignancies commonly associated with immunosuppression were observed.

BackgroundThe CLARITY study in patients with RMS allows assessment of high disease activity (HDA) definitions for identifying patients with higher rate of relapse or disability progression.ObjectiveEvaluate clinical/MRI criteria to identify HDA among placebo recipients in CLARITY.MethodsPlacebo recipients in CLARITY (n=437) were analysed using criteria of high relapse activity ([HRA]≥2 relapses in the previous year) regardless of prior treatment, or a HRA plus treatment nonresponse ([HRA +TNR]≥2 relapses in the previous year OR ≥1 relapse in previous year on DMD therapy and ≥1 T1 Gd +or ≥9 T2 lesions). Identification of HDA was assessed by relapse and disability outcomes.ResultsARR was higher in the HRA (0.5, 95% CI 0.41–0.60) and HRA+TNR subgroups (0.47, 95% CI 0.40–0.57) than the overall placebo population (0.35, 95% CI 0.31–0.39), and non-HRA and non-HRA +TNR subgroups (0.29, 95% CI 0.24–0.34 each). Time to 6 month confirmed EDSS progression (10% of patients) was 110 days for the HRA subgroup (non-HRA=330 days), 162 days for the HRA+TNR subgroup (non-HRA +TNR =329 days) and 245 days (overall placebo).ConclusionsHDA criteria based on relapse history, treatment history and MRI characteristics can identify patients at increased risk of experiencing relapses and disability progression.

BackgroundThe most common adverse event in CLARITY was lymphopenia, consistent with cladribine tablets (CT) mechanism of action.ObjectiveInvestigate absolute lymphocyte count (ALC) in RRMS patients receiving CT 3.5 mg/kg (CT3.5).MethodsPatients randomised to CT3.5 for 2 years in CLARITY/CLARITY Extension including time in PREMIERE (n=685) were pooled to provide long-term follow-up data. Patients randomised to placebo are also reported (PBO;n=435).ResultsAt baseline (start of CLARITY/CLARITY Extension), median (Q1–Q3) ALC was 1.86×109/L (1.50–2.29) for CT3.5 and 1.91×109/L (1.54–2.32) for PBO. During Year 1, CT3.5 ALC reached a nadir 9 weeks post-treatment[1.00×109/L (0.80–1.30)]. At the end of Year 1 (48 weeks), ALC increased to 1.21×109/L (0.95–1.50). During Year 2, CT3.5 ALC reached a nadir 7 weeks after re-treatment[0.81×109/L (0.60–1.04)], increasing to 1.03×109/L (0.80–1.30) at the end of Year 2 (96 weeks). At the end of Years 3 and 4 (144 and 192 weeks), ALC in the CT3.5 group (with no further treatment) increased to 1.36×109/L (1.02–1.65) and 1.40×109/L (1.10–1.81), respectively, reaching 1.76×109/L (1.17–2.65) after 6.5 years (312 weeks). In PBO, ALC was between 1.69×109/L (1.45–2.05) and 1.95×109/L (1.59–2.38).ConclusionsRapid reductions in ALC after CT3.5 treatment in Years 1 and 2 were followed by gradual returns toward baseline. ALC was within normal range beyond Year 2 (96 weeks) in all patients with follow-up data.

BackgroundIn CLARITY, cladribine tablets (CT) significantly reduced relapse rates in patients with relapsing multiple sclerosis. CLARITY Extension (EXT) compared the effects of 2 years’ additional CT treatment vs no additional treatment.ObjectiveAssess efficacy of 2 courses of CT or placebo (PBO) in CLARITY and 2 additional courses of CT or PBO in EXT.MethodsPatients receiving PBO in CLARITY were assigned to CT3.5 mg/kg; those treated with CT (3.5 or 5.25 mg/kg) were re-randomised 2:1 to CT3.5 mg/kg or PBO. Annualised relapse rates (ARR) and proportions qualifying relapse free (RF) were compared for CLARITY vs EXT within the same treatment groups: CT3.5 mg/kg in CLARITY and PBO in EXT (n=98); CT3.5 mg/kg in CLARITY and CT3.5 mg/kg in EXT (n=186); CT5.25 mg/kg in CLARITY and CT3.5 mg/kg in EXT (n=186); PBO in CLARITY and CT3.5 mg/kg in EXT (n=244).ResultsNo significant differences in ARR for CLARITY vs EXT except for PBO in CLARITY and CT3.5 mg/kg in EXT (0.26 vs 0.10, p<0.0001). The proportion RF was similar between CLARITY vs EXT across groups and >70%, except for PBO in CLARITY and CT3.5 mg/kg in EXT (58.0% vs 79.6%, p<0.0001).ConclusionsClinical benefits were maintained in patients who received CT in CLARITY and PBO in EXT demonstrating durable efficacy.