Updated Safety of Cladribine Tablets in the Treatment of Patients with Multiple Sclerosis: Integrated Safety Analysis and Post-Approval Data

Objective: To provide an update to the previously reported treatment-emergent adverse event (TEAE) profile for cladribine tablets (CT) using the latest integrated safety data from clinical studies including final data from the PREMIERE registry, and report post-approval safety data from Europe. Background: Pooling of long-term safety data for integrated analysis from the clinical trial program allows comprehensive characterization of the CT 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) safety profile in patients with relapsing multiple sclerosis (RMS). Design/Methods: The monotherapy oral cohort (CT3.5, N=923, patient-years [PY]=3936.69; placebo [PBO], N=641, PY=2421.47) was derived from the CLARITY, CLARITY Extension, and ORACLE MS trials, and the PREMIERE registry. Incidences per 100PY were calculated for adverse events, cumulative to the end of PREMIERE. Adverse drug reactions (ADRs) including serious ADRs (SADRs; implied causality) from post-approval sources are summarized. Results: Demographics at first dosing date were balanced among treatment groups: mean age (CT3.5=37.8 years; PBO=37.2 years); proportion of females (CT3.5=66.3%; PBO=66.1%); and patients with prior disease modifying drug experience (CT3.5=19.9%; PBO=20.4%). Incidences per 100PY for: ≥1 serious TEAE were 3.80 (CT3.5) and 3.05 (PBO); serious lymphopenia (preferred term [PT]) were 0.10 (CT3.5) and 0 (PBO); serious infections and infestations (system organ class) were 0.60 (CT3.5) and 0.42 (PBO) (serious herpes zoster [PT]: 0.05 [CT3.5] and 0 [PBO]); malignant tumors were 0.26 (CT 3.5) and 0.12 (PBO). The Periodic Benefit-Risk Evaluation Report reported 922 post-approval ADRs, including 136 SADRs; none of which are new safety findings for CT3.5. Conclusions: This integrated analysis of trial data, exclusively focused on the frequency of serious TEAEs, further establishes the safety profile of CT3.5 in RMS patients, which is consistent with the previously published integrated safety analysis. No new major safety findings were identified in this latest dataset. The pattern of post-approval ADRs was consistent with the clinical safety profile for CT3.5. Disclosure: Dr. Cook has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck KGaA, Bayer HealthCare, Sanofi Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals, and Actinobac Biomed Inc. Dr. Cook has received research support from Bayer HealthCare. Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB. Dr. Giovannoni has receive research support from AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB.Dr. Leist has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, Teva Neuroscience. Dr. Leist has received research support from received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, Teva Neuroscience. Dr. Comi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with honoraria for consultancy and/or speaking activities from Almirall, Biogen, Bayer, Chugai, Genzyme, Merck Serono, Novartis, Roche, Receptos, Sanofi, Serono Symposia International Foundation, and Teva.. Dr. Comi has received personal compensation in an editorial capacity for Clinical Investigation; European Journal of Neurology and Multiple Sclerosis; Neurological Sciences. Dr. Syed has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. Dr. Nolting has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with employee of Merck KGaA, Darmstadt, Germany. Dr. Damian has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. Dr. Schick has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Merck KGaA, Darmstadt, Germany.