Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis

Leist, Thomas; Cook, Stuart D.; Comı, Gıancarlo; Montalbán, Xavier; Giovannoni, Gavin; Nolting, Axel; Damian, Doris; Syed, Serajuddaula; Galazka, Andrew

doi:10.1016/j.msard.2020.102572

Cited by 45 publications

(58 citation statements)

References 19 publications

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“…The results are consistent with previously reported safety data for cladribine tablet treatment [ 17 , 18 ]. Three categories of adverse events—namely lymphopenia, infections, and malignancies—were pre-defined as serious adverse effects of special interest (AESIs).…”

Section: Discussionsupporting

confidence: 93%

Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study

Rejdak

Zasybska

Pietruczuk

et al. 2021

JCM

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Cladribine is currently registered as a 10-milligram tablet formulation with a fixed cumulative dosage of 3.5 mg/kg over 2 years. It is important to investigate if an increased dosage may lead to further clinical stability with preserved safety. This study used an off-label subcutaneous (s.c.) formulation of cladribine and compared outcomes (Expanded Disability Status Scale (EDSS) scores and disease progression) between 52 relapsing multiple sclerosis (RMS) patients receiving different s.c. dosing regimens with up to 20 years of follow-up. The study group received induction therapy with s.c. cladribine (1.8 mg/kg cumulative dose; consistent with 3.5 mg/kg of cladribine tablets). Patients were subsequently offered maintenance therapy (repeated courses of 0.3 mg/kg s.c. cladribine during 5–20-year follow-up). Forty-one patients received an increased cumulative dose (higher than the induction dose of 1.8 mg/kg); 11 received the standard induction dose. Risk of progression on the EDSS correlated with lower cumulative dose (p < 0.05) and more advanced disability at treatment initiation (p < 0.05) as assessed by EDSS change between year 1 and years 5 and 10 as the last follow-up. Maintenance treatment was safe and well-tolerated, based on limited source data. Subcutaneous cladribine with increased cumulative maintenance dosage was associated with disease stability and favorable safety over a prolonged period of follow-up (up to 20 years) in RMS patients.

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Section: Discussionsupporting

confidence: 93%

Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study

Rejdak

Zasybska

Pietruczuk

et al. 2021

JCM

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“…The overall safety findings for patients in all treatment groups from CLARITY and CLARITY Extension, as well as a more recent safety report on the entire clinical development programme (including the final PREMIERE data), have previously been published. [12][13][14][15] The percentage of patients who had at least one treatment-emergent adverse event during CLARITY was comparable between the cladribinetreated patients who did and did not receive steroids concomitantly (84.5% and 81.6%, respectively). Blood and lymphatic system disorders were reported in a comparable percentage of cladribine-treated patients who did and did not receive steroids (33.1% and 30.1%, respectively).…”

Section: Safetymentioning

confidence: 89%

Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies

et al. 2021

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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

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“…Cladribine tablets are contraindicated in patients with active malignancy, and careful assessment of the risk–benefit profile should be performed in patients with a prior history of malignancy. However, analysis of clinical trial and long-term safety data in a final report from the clinical development program showed there was no significant increase in the rate of malignancies with cladribine tablets compared with placebo; the incidence of malignancy was 0.26 per 100 patient-years in the treatment group compared with 0.12 per 100 patient-years in the placebo group [ 107 , 109 ]. Moreover, malignancies associated with immunosuppression were not increased in patients receiving cladribine tablets.…”

Section: Management Of Patients Receiving Cladribine Tabletsmentioning

confidence: 99%

“…Moreover, malignancies associated with immunosuppression were not increased in patients receiving cladribine tablets. When this population of patients was compared with an external reference population (GLOBOCAN matched reference population), the rates of malignancies were similar between patients receiving cladribine tablets and the matched cohort [ 107 , 109 , 110 ]. The ongoing CLARION post-approval safety study (EU PAS Register number: EUPAS24484) will further characterize the real-world safety profile of cladribine tablets, including the risk of malignancy and other AEs of special interest [ 111 ].…”

Section: Management Of Patients Receiving Cladribine Tabletsmentioning

confidence: 99%

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

Giovannoni

Mathews

2022

Neurol Ther

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Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis

Cited by 45 publications

References 19 publications

Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study

Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study

Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

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