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Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98). Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment. Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis. CLARITY: NCT00213135; CLARITY Extension: NCT00641537 [ABSTRACT FROM AUTHOR]

Background: Patients with multiple sclerosis (MS) treated with cladribine tablets (CTs) are expected to experience lymphopenia because of its mechanism of action (MOA), and transient mild-to-moderate lymphopenia has been observed in most patients. Given that a reduction in overall lymphocyte counts is part of the MOA of cladribine, further studies on the severity of lymphopenia are warranted. Objectives: To examine the effect of CT 3.5 mg/kg (CT3.5, cumulative over 2 years) on grade 3/4 lymphopenia lasting ≥6 continuous months postbaseline in subjects with baseline absolute lymphocyte count (ALC) within normal limits from the CT3.5 monotherapy oral cohort, defined as the safety populations of the phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies of MS, and long-term follow-up in the PREMIERE registry. Methods: In this post hoc analysis, combined data from 2 years of phase 3 studies and the follow- up PREMIERE registry were analyzed on the incidence of grade 3/4 lymphopenia (ALC <500/mm3) lasting ≥6 months. Time to an episode and time to recovery were also assessed. Recovery from grade 3/4 lymphopenia is defined as a return to grade ≤2 lymphopenia. Results: Of the 923 patients randomized to CT3.5, 891 (96.5%) had baseline ALC within normal limits (grade 0), and in this subpopulation, 218 (23.6%) had at least a single reading of grade 3/4 lymphopenia, and 33 (3.6%) had grade 3/4 lymphopenia lasting ≥6 months (38 episodes). More patients with grade 3/4 lymphopenia lasting ≥6 months were female (81.8% vs 66.1%), had used ≥1 prior disease-modifying drug (33.3% vs 19.5%), and had more severe disease (≥9 T2 lesions [93.9% vs 88.1%], ≥1 relapse [75.8% vs 53.9%], higher median score on Expanded Disability Status Scale [3.0 vs 2.0]) at baseline vs the overall patients with baseline ALC within normal limits. Of the 33 CT3.5-treated patients with grade 3/4 lymphopenia lasting ≥6 months, more had the episode in year 2 than in year 1 of the core studies (64% vs 18%), with a median (Q1, Q3) time to first episode of 58.9 (51.1, 83.1) weeks. Of the 38 grade 3/4 lymphopenia (≥6 months) episodes, 27 (71.1%) lasted 24-48 weeks, and 11 (28.9%) lasted >48 weeks. Median (Q1, Q3) time to recovery from first grade 3/4 lymphopenia (≥6 months) episode was 36.3 (28.4, 66.3) weeks. Conclusions: The incidence of grade 3/4 lymphopenia lasting ≥6 months in patients treated with CT3.5 was low. Most episodes (71.1%) of grade 3/4 lymphopenia lasting ≥6 months resolved within 6 months to 1 year. [ABSTRACT FROM AUTHOR]

Background: Efficacy of cladribine tablets 3.5 mg/kg (CT3.5, cumulative dose over 2 years) has been reported in relapsing-remitting multiple sclerosis (RRMS) in the 96-week CLARITY study. Prior post hoc analyses of CLARITY found that CT3.5 treatment resulted in similar benefits across the age spectrums of the studied patients in risk reduction of relapse and odds of remaining free from disease activity. Objectives: This post hoc analysis further examined efficacy outcomes of CT3.5 in CLARITY patients aged ≤30 and >30 years at study enrollment. Methods: Analyses were performed by treatment (CT3.5 vs placebo) and age subgroup (≤30 and >30 years), a relatively young age cutoff with adequate N needed for analyses. End points were relapse (relapse-free status and annualized relapse rate [ARR]), 3- and 6-month confirmed disability progression (CDP, based on Expanded Disability Status Scale), magnetic resonance imaging (MRI) activity, and no evidence of disease activity (NEDA) status (no relapse, 3- or 6-month CDP, or MRI activity). P values are nominal. Results: This analysis was carried out in 870 patients: ≤30 years: CT3.5 N = 109, placebo N = 102; >30 years: CT3.5 N = 324, placebo N=335. In both age subgroups, CT3.5 significantly reduced adjusted ARR (95% CI) (≤30 years: 0.16 [0.11-0.23] vs 0.48 [0.38-0.60]; >30 years: 0.15 [0.12-0.18] vs 0.31 [0.27-0.37]; P < .0001), and increased the number of patients who were relapse-free through week 96 (≤30 years: 73.4% vs 44.1%; >30 years: 76.2% vs 57.3%) vs placebo. CT3.5 treatment increased the odds of being free from 3- or 6-month CDP through week 96 (3-month CDP at week 96 in both age subgroups: 0.84-0.88 vs 0.76 [both subgroups]; 6-month CDP at week 96: 0.89-0.94 vs 0.83-0.86) vs placebo. CT3.5 also significantly reduced the adjusted mean (95% CI) cumulative number of new T1 gadolinium-enhancing (≤30 years: 0.22 [0.15-0.33] vs 1.37 [0.97-1.93]; >30 years: 0.05 [0.03- 0.08] vs 0.77 [0.61-0.98]) and active T2 (≤30 years: 0.68 [0.53-0.88] vs 2.20 [1.73-2.81]; >30 years: 0.26 [0.21-0.32] vs 1.19 [1.01-1.41]) lesions, and increased the number of patients achieving NEDA status using 3-month (≤30 years: 30.3% vs 2.9%; >30 years: 44.4% vs 17.3%) or 6-month (≤30 years: 30.3% vs 2.9%; >30 years: 46.3% vs 17.9%) CDP vs placebo (all P < .0001) at 96 weeks. Conclusions: CT3.5 treatment improved clinical and MRI outcomes in both younger and older patients in CLARITY. Relapse and disability outcomes appeared mostly similar between the age subgroups; however, the >30 years subgroup appeared to have a greater reduction in MRI lesion activity and a higher rate of achieving NEDA status. [ABSTRACT FROM AUTHOR]

Background: Malignancy risk was previously characterized in a monotherapy oral cohort of patients with multiple sclerosis (MS) treated with cladribine tablets (CTs) 10 mg (3.5 mg/kg cumulative dose over 2 years; referred to as CT3.5) including cumulative data up to February 2015. In clinical studies, an imbalance in the number of malignancies with CT3.5 vs placebo was observed, suggesting malignancy risk may be increased. Objectives: To provide a more detailed assessment of malignancy using safety data integrated from clinical trials and a safety follow-up registry (up to May 2017), to further characterize the malignancy risk of CTs in patients with MS and investigate whether there is a dose-dependent risk. Methods: Cohorts were monotherapy oral: patients with MS receiving CTs at any dose as a monotherapy; all exposed: patients with MS receiving any formulation of cladribine to provide a larger cohort to identify rare events such as malignancies. Results: In the monotherapy oral cohort, patient numbers (patient-years [PYs]) were: placebo N = 641 (2275), CT3.5 N = 923 (3754), CT 5.25 mg/kg (CT5.25) N = 632 (2610). The incidence per 100 PYs for malignant tumors during the entire follow up was: placebo: 0.13, CT3.5: 0.27, and CT5.25: 0.23. The risk difference vs placebo was: CT3.5: 0.14 (95% CI -0.14 to 0.38) and CT5.25: 0.10 (-0.18 to 0.39). In CLARITY CT3.5 and CT5.25 patients randomized to CT3.5 in CLARITY Extension (N = 195 for each treatment group), incidence per 100 PYs by CLARITY CT dose was: 0.55 (CT3.5, 1301 PYs) and 0.31 (CT5.25, 1286 PYs) for the entire follow-up; 0.91 (CT3.5, 790 PYs) and 0.52 (CT5.25, 784 PYs) for the period following initiation of treatment in year 3. An analysis of the all exposed cohort (cladribine N = 1976; placebo N = 802) stratified by cumulative cladribine dose gave the number of patients with a malignant event (incidence per 100 PY) as: >0--3.5 mg/kg = 6 (0.37), >3.5--5.25 = 14 (0.40), >5.25--7.0 = 6 (0.29), >7.0--8.75 = 6 (0.46), >8.75 = 2 (0.21). No hematological malignancies were observed at any time in the pooled dataset. Conclusions: Overall, there was no clear evidence of a dose effect of cladribine on malignancy risk in patients with MS based on >9500 PYs of cladribine exposure. [ABSTRACT FROM AUTHOR]

Background: The mechanism of action of cladribine is thought to be related to a reduction in lymphocyte counts. As the immune system undergoes changes with aging, it is not currently well understood whether the impact of cladribine tablets (CTs) on lymphocyte counts differs in younger vs older patients. Objectives: To examine the effect of age (≤50 and >50 years) at baseline and after treatment with placebo or CT 3.5 mg/ kg (CT3.5, cumulative over 2 years) on lymphopenia in patients enrolled in the phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies, and long-term follow-up in the PREMIERE registry. Methods: In this post hoc analysis, combined data from 2 years of phase 3 studies on levels of absolute lymphocyte count (ALC), incidence of grade 3/4 lymphopenia, and time to recovery from severe lymphopenia were analyzed in patients by baseline age group. Results: This analysis was carried out in 1564 patients: age ≤50: placebo N = 566, CT3.5 N = 813; age >50: placebo N = 75, CT3.5 N = 110. In both age groups, CT3.5 treatment resulted in a 43.1%-47.6% reduction in mean ALC vs placebo at week 9, which was after completing the year-1 doses. Mean (SD) ALC in the CT3.5 groups at week 9 were: age ≤50: 1.12 (0.50) x 109/L; age >50: 1.00 (0.42) x 109/L. ALC levels in the CT3.5-treated groups gradually increased thereafter up to week 48 (mean [SD] ALC at week 48: age ≤50: 1.27 [0.45] x 109/L; age >50: 1.32 [0.51] x 109/L); ALC remained 34.5%-35.6% below those treated with placebo. In year 2 at week 55, CT3.5 treatment resulted in a 54.6%-60.8% reduction in mean ALC vs placebo (year 2 doses completed). Mean (SD) ALC in the CT3.5 groups at week 55 were: age ≤50: 0.89 (0.39) x 109/L; age >50: 0.80 (0.33) x 109/L. ALC levels in the CT3.5-treated groups gradually increased thereafter up to week 96 (mean [SD] ALC at week 96: age ≤50: 1.11 [0.42] x 109/L; age >50: 1.11 [0.37] x 109/L); ALC remained 42.8%-43.7% below those treated with placebo. Incidence of grade 3/4 lymphopenia was higher with CT3.5 vs placebo in year 1 (age ≤50: 8.3%; age >50: 10.0%; vs 0%-0.4% in placebo) and year 2 (age ≤50: 18.7%; age >50: 20.0%; vs 0%-0.2% in placebo). Median time to recovery from grade 3/4 to ≤2 lymphopenia was 1.18 and 1.54 months for CT3.5-treated patients in the age ≤50 and >50 groups, respectively. Conclusions: ALC changes in CT3.5-treated patients were similar in older and younger patients relative to placebo-treated patients during 2 years of active treatment as expected. Recovery time from lymphopenia was also similar between the age groups. [ABSTRACT FROM AUTHOR]

Background: Cladribine tablets 3.5 mg/kg (CT3.5, cumulative dose over 2 years; N = 433) treatment significantly improved clinical and magnetic resonance imaging (MRI) outcomes vs placebo (N = 437) in relapsing-remitting multiple sclerosis (RRMS) in the 96-week CLARITY study. Prior post hoc analyses of CLARITY found that patients with shorter disease duration (<3 years) responded more favorably to CT3.5 in risk reduction of relapse and odds of achieving disease-free activity status vs those with longer disease duration (≥3 years). Further analyses are needed to assess the extent of benefit of CT3.5 in patients with a relatively shorter disease duration. Objectives: This post hoc analysis further examined efficacy outcomes in CLARITY patients who were early in their disease course (<3 or <4 years newly diagnosed [YND]) at study enrollment. Methods: Analyses were performed by treatment (CT3.5 vs placebo) and MSduration groups (<3 YND, <4 YND at CLARITY enrollment). End points were relapse, 3- and 6-month confirmed disability progression (CDP, based on Expanded Disability Status Scale score), magnetic resonance imaging (MRI) activity, and no evidence of disease activity (NEDA) status (no relapse, CDP, or MRI activity). P values are nominal. Results: These MS-duration group analyses were carried out in 492 patients: <3 YND: CT3.5 N = 228, placebo N = 207; <4 YND: CT3.5 N = 256, placebo N = 236. In both MS-duration groups, CT3.5 significantly reduced annualized relapse rate (<3 YND: 0.14 vs 0.37 [60.7% reduction]; <4 YND: 0.14 vs 0.36 [61.6% reduction]; P < .0001), and increased the number of patients who were relapse-free through week 96 (<3 YND: 75.4% vs 55.1%; <4 YND: 75.0% vs 55.9%) vs placebo. CT3.5 treatment increased the probability of being free from 3- or 6-month CDP through week 96 (3-month CDP at week 96 in both groups: 0.84-0.85 vs 0.76 [both groups]; 6-month CDP at week 96: 0.89-0.90 vs 0.83-0.84) vs placebo. CT3.5 also significantly reduced the adjusted mean (95% CI) cumulative number of new T1 gadolinium-enhancing (<3 YND: 0.11 [0.08-0.16] vs 1.0 [0.73-1.36]; <4 YND: 0.11 [0.08-0.16] vs 0.93 [0.69-1.24]) and active T2 (<3 YND: 0.41 [0.33-0.51] vs 1.68 [1.36- 2.06]; <4 YND: 0.41 [0.33-0.50] vs 1.63 [1.34-1.97]) lesions, and increased the number of patients achieving NEDA status using 3-month (<3 YND: 40.4% vs 11.1%; <4 YND: 39.5% vs 11.4%) or 6-month (<3 YND: 41.2% vs 11.6%; <4 YND: 40.2% vs 12.3%) CDP vs placebo (all P < .0001) at 96 weeks. Conclusions: Overall, CT3.5 treatment improved clinical and MRI outcomes in CLARITY patients who were early in their disease course. [ABSTRACT FROM AUTHOR]