Contributions
Abstract: P880
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Introduction: In the phase 3 CARE-MS I and II trials (NCT00530348; NCT00548405), alemtuzumab 12 mg showed significantly improved efficacy vs SC IFN beta-1a over 2 years in patients with active relapsing-remitting MS (RRMS). The most frequent AEs with alemtuzumab were infusion-associated reactions; other AEs of interest included thyroid disorders, immune thrombocytopenia (ITP), and nephropathies. Alemtuzumab remained efficacious in a 4-year extension (NCT00930553) in the absence of continuous treatment after the initial 2 courses. The effects of alemtuzumab may be due to its selective depletion of CD52-expressing T and B lymphocytes; a distinct pattern of lymphocyte repopulation then follows.
Aims: To compare lymphocyte pharmacodynamic profiles over 2 years in alemtuzumab-treated patients who did or did not experience an autoimmune AE through 6 years.
Methods: Autoimmune AE monitoring occurred at baseline and monthly (ITP; nephropathies) or quarterly (thyroid) in the core and extension studies and continued for 48 months after the last alemtuzumab infusion (the 48-month period restarted after any retreatment). Blood cell counts in the CARE-MS studies occurred monthly; lymphocytes were phenotyped by flow cytometry quarterly and at Months 1 and 13 (ie, 1 month after receiving alemtuzumab Course 1 and 2, respectively). Pharmacodynamic assessments (in data from the pooled CARE-MS I/II studies) included total counts for lymphocytes, CD3+/CD4+/CD8+ T cells, and CD19+ B cells, as well as subset analyses for CD4+/CD8+ T cells (naïve/memory/regulatory [Treg]) and CD19+ B cells (immature/mature/memory). Further analyses examined ratios of CD19+ (total/immature/memory) to Treg (CD4+/CD8+) cell counts. The relationship between lymphocyte pharmacodynamics over 2 years and autoimmune AE incidence over 6 years (core/extension studies combined) was assessed.
Results: No difference in total lymphocyte or subset depletion or repopulation patterns was observed over 2 years in patients who did or did not experience autoimmune AEs through 6 years following alemtuzumab treatment. No correlation was observed between autoimmune AEs and any CD19+/Treg cell count ratio.
Conclusion: The current analyses do not suggest that differences in lymphocyte depletion or repopulation kinetics predict the occurrence of autoimmune AEs in alemtuzumab-treated patients with RRMS, although repopulation of specific B-cell clones potentially expressing autoimmune antibodies remains to be determined.
Disclosure: HW: Consulting and/or speaking fees, and grant/research support (Bayer, Bayer Schering Pharma, Biogen, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Novo Nordisk, Sanofi, and Teva Neuroscience). DB: Speaker panels (Biogen, Genentech, Mallinckrodt, Novartis, Sanofi, Teva) and research support (Mallinckrodt and Novartis). MC: Speaking and consulting fees, and advisory honoraria (Biogen, Genzyme, and Mallinckrodt). GC: Consulting fees (Actelion, Bayer, Merck Serono, Novartis, Sanofi, and Teva) and lecture fees (Bayer, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva). YM-D: Consulting fees and/or grant support (Acorda, Bayer, Biogen, Celgene, Chugai, EMD Serono, Genzyme, Novartis, Questor, and Teva Neuroscience) and grant support (NIH NIAID Autoimmune Center of Excellence: UM1-AIII0557; NIH NINDO R01-NS080821). GI: Speaking and advisory fees (Almirall, Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). HJK: Consulting and/or speaking fees (Bayer, Biogen, Celltrion, Eisai, Genzyme, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Teva-Handok, and UCB); research support (Genzyme, Merck Serono, Ministry of Science & ICT, Teva-Handok, and UCB); steering committee member (MedImmune); co-editor (Multiple Sclerosis Journal - Experimental, Translational, and Clinical); and associate editor (Journal of Clinical Neurology). SGM: Honoraria for lecturing, travel expenses for attending meetings and financial research support (Almirall, Amicus Therapeutics Germany, Bayer, Biogen, Celgene, Chugai Pharma, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, QuintilesIMS, Roche, Sanofi-Aventis, and Teva). GP: Speaking and advisory fees (Bayer, Biogen, EMD Serono, Genentech, Novartis, Sanofi, and Teva). BS: Research and travel grants, honoraria for expert advice on MS, and speaking fees (Biogen, Merck, Novartis, Roche, Sanofi, and Teva). CT: Honoraria for attending advisory boards and research funding (Bayer, Biogen, Novartis, and Sanofi). TZ: Consulting or speaking fees (Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Biogen, Novartis, Sanofi, and Teva). AJ, LC, and ND: Employees of Sanofi. BVW: Research and travel grants, honoraria for MS-expert advice, and speaking fees (Bayer-Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.
Abstract: P880
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Introduction: In the phase 3 CARE-MS I and II trials (NCT00530348; NCT00548405), alemtuzumab 12 mg showed significantly improved efficacy vs SC IFN beta-1a over 2 years in patients with active relapsing-remitting MS (RRMS). The most frequent AEs with alemtuzumab were infusion-associated reactions; other AEs of interest included thyroid disorders, immune thrombocytopenia (ITP), and nephropathies. Alemtuzumab remained efficacious in a 4-year extension (NCT00930553) in the absence of continuous treatment after the initial 2 courses. The effects of alemtuzumab may be due to its selective depletion of CD52-expressing T and B lymphocytes; a distinct pattern of lymphocyte repopulation then follows.
Aims: To compare lymphocyte pharmacodynamic profiles over 2 years in alemtuzumab-treated patients who did or did not experience an autoimmune AE through 6 years.
Methods: Autoimmune AE monitoring occurred at baseline and monthly (ITP; nephropathies) or quarterly (thyroid) in the core and extension studies and continued for 48 months after the last alemtuzumab infusion (the 48-month period restarted after any retreatment). Blood cell counts in the CARE-MS studies occurred monthly; lymphocytes were phenotyped by flow cytometry quarterly and at Months 1 and 13 (ie, 1 month after receiving alemtuzumab Course 1 and 2, respectively). Pharmacodynamic assessments (in data from the pooled CARE-MS I/II studies) included total counts for lymphocytes, CD3+/CD4+/CD8+ T cells, and CD19+ B cells, as well as subset analyses for CD4+/CD8+ T cells (naïve/memory/regulatory [Treg]) and CD19+ B cells (immature/mature/memory). Further analyses examined ratios of CD19+ (total/immature/memory) to Treg (CD4+/CD8+) cell counts. The relationship between lymphocyte pharmacodynamics over 2 years and autoimmune AE incidence over 6 years (core/extension studies combined) was assessed.
Results: No difference in total lymphocyte or subset depletion or repopulation patterns was observed over 2 years in patients who did or did not experience autoimmune AEs through 6 years following alemtuzumab treatment. No correlation was observed between autoimmune AEs and any CD19+/Treg cell count ratio.
Conclusion: The current analyses do not suggest that differences in lymphocyte depletion or repopulation kinetics predict the occurrence of autoimmune AEs in alemtuzumab-treated patients with RRMS, although repopulation of specific B-cell clones potentially expressing autoimmune antibodies remains to be determined.
Disclosure: HW: Consulting and/or speaking fees, and grant/research support (Bayer, Bayer Schering Pharma, Biogen, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Novo Nordisk, Sanofi, and Teva Neuroscience). DB: Speaker panels (Biogen, Genentech, Mallinckrodt, Novartis, Sanofi, Teva) and research support (Mallinckrodt and Novartis). MC: Speaking and consulting fees, and advisory honoraria (Biogen, Genzyme, and Mallinckrodt). GC: Consulting fees (Actelion, Bayer, Merck Serono, Novartis, Sanofi, and Teva) and lecture fees (Bayer, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva). YM-D: Consulting fees and/or grant support (Acorda, Bayer, Biogen, Celgene, Chugai, EMD Serono, Genzyme, Novartis, Questor, and Teva Neuroscience) and grant support (NIH NIAID Autoimmune Center of Excellence: UM1-AIII0557; NIH NINDO R01-NS080821). GI: Speaking and advisory fees (Almirall, Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). HJK: Consulting and/or speaking fees (Bayer, Biogen, Celltrion, Eisai, Genzyme, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Teva-Handok, and UCB); research support (Genzyme, Merck Serono, Ministry of Science & ICT, Teva-Handok, and UCB); steering committee member (MedImmune); co-editor (Multiple Sclerosis Journal - Experimental, Translational, and Clinical); and associate editor (Journal of Clinical Neurology). SGM: Honoraria for lecturing, travel expenses for attending meetings and financial research support (Almirall, Amicus Therapeutics Germany, Bayer, Biogen, Celgene, Chugai Pharma, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, QuintilesIMS, Roche, Sanofi-Aventis, and Teva). GP: Speaking and advisory fees (Bayer, Biogen, EMD Serono, Genentech, Novartis, Sanofi, and Teva). BS: Research and travel grants, honoraria for expert advice on MS, and speaking fees (Biogen, Merck, Novartis, Roche, Sanofi, and Teva). CT: Honoraria for attending advisory boards and research funding (Bayer, Biogen, Novartis, and Sanofi). TZ: Consulting or speaking fees (Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Biogen, Novartis, Sanofi, and Teva). AJ, LC, and ND: Employees of Sanofi. BVW: Research and travel grants, honoraria for MS-expert advice, and speaking fees (Bayer-Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.