Lymphocyte Pharmacodynamics and Safety of Natalizumab in Patients Previously Treated with Alemtuzumab

Background: Alemtuzumab had superior efficacy compared with subcutaneous interferon beta-1a (SC IFNB-1a), with manageable safety, during phase 2 and 3 studies of patients with relapsing-remitting multiple sclerosis (RRMS). Although patients and physicians may want to use other disease-modifying therapies (DMTs) after alemtuzumab treatment depending on individual patient profile, few data exist on the safety of this practice and effects on the immune system.

Objectives: To examine lymphocyte pharmacodynamics and safety in patients treated with natalizumab after receiving alemtuzumab in the alemtuzumab clinical development program for RRMS.

Methods: In phase 2 (CAMMS223; NCT00050778) and phase 3 (CARE-MS I [NCT00530348] and CARE-MS II [NCT00548405]) studies, patients with active RRMS who were either treatment-naive or who had an inadequate efficacy response to prior DMT (≥1 relapse after ≥6 months of treatment) received alemtuzumab 12 or 24 mg/day intravenously on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SC IFNB-1a 3 times/week. In an ongoing extension study (NCT00930553), retreatment with alemtuzumab 12 mg, or treatment with other DMTs including natalizumab, was permitted. Patients who received SC IFNB-1a in the CARE-MS studies could receive alemtuzumab 12 mg in the extension plus other DMTs. Lymphocyte counts were measured every 3 or 6 months and in the month following each alemtuzumab treatment course.

Results: 10 patients received natalizumab after alemtuzumab (CAMMS223: n=2; CARE-MS I: n=1; CARE-MS II: n=7); 9 had received 2 courses of alemtuzumab (24 mg: n=4; 12 mg: n=5), and 1 received SC IFNB-1a in the core study and 1 course of alemtuzumab 12 mg in the extension. Mean (SD) time of natalizumab initiation was 2.03 (0.77) years after the last alemtuzumab dose; mean (SD) follow-up time after natalizumab initiation was 1.38 (0.71) years. CD4⁺ and CD8⁺ T-cell counts and CD19⁺ B-cell counts rose after the last dose of alemtuzumab, and rose further after natalizumab initiation. No adverse event (AE) types predominated during natalizumab treatment. One serious AE was reported in 1 patient during natalizumab treatment (influenza).

Conclusions: Lymphocyte counts after switching from alemtuzumab to natalizumab were consistent with the known pharmacodynamic effects of each drug. No unexpected AEs were observed with natalizumab.

 Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals.