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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.

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.

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.

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.

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.

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.