T Leist1, S Cook2, G Comi3, X Montalban4, G Giovannoni5, A Nolting6, D Damian7, S Syed7, A Galazka8. 1. Division of Clinical Neuroimmunology, Jefferson University, Comprehensive MS Center, Philadelphia, PA, USA. Electronic address: Thomas.Leist@jefferson.edu. 2. Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA. 3. Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy. 4. Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain. 5. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 6. Merck KGaA, Darmstadt, Germany. 7. EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, a business of Merck KGaA, Darmstadt, Germany. 8. Merck, Aubonne, Switzerland, a division of Merck KGaA, Darmstadt, Germany.
Abstract
BACKGROUND: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. METHODS: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. RESULTS: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). CONCLUSION: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.
BACKGROUND: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. METHODS: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. RESULTS: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). CONCLUSION: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.
Authors: Nicola De Stefano; Maria Pia Sormani; Gavin Giovannoni; Kottil Rammohan; Thomas Leist; Patricia K Coyle; Fernando Dangond; Birgit Keller; Nektaria Alexandri; Andrew Galazka Journal: Mult Scler Date: 2021-05-10 Impact factor: 5.855