Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data

Abstract

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

Trial registration: ClinicalTrials.gov NCT00050778 NCT00530348 NCT00548405 NCT00930553 NCT02255656.

Keywords: Multiple sclerosis; alemtuzumab; autoimmunity; post-marketing; product surveillance; risk assessment; treatment outcome.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.J.C. received consulting fees, lecture fees, and institutional grant support from Sanofi up to September 2017. J.L.J. received consulting fees and grant support (Sanofi). P.V. received consulting and/or speaking fees and research support (Almirall, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, Servier, and Teva). A.T. received consulting and/or speaking fees and grant/research support (Biogen, Chugai, Roche, Sanofi, and Teva). A.D.B. received consulting fees/fees for non-CME services from commercial interests or their agents/grant and research support (Biogen, EMD Serono, Mallinckrodt, Novartis, Roche-Genentech, Sanofi, and TG Therapeutics). A.B. received consulting fees and/or fees for non-CME services (Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva). A.C. received honoraria for presentations or advisory boards to support university/hospital research funds (Actelion, Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva) and research support (Biogen, Sanofi, and UCB). G.C. received consulting fees (Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva) and lecture fees (Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva). Ó.F. received speaking and/or consulting fees (Allergan, Almirall, Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi, and Teva); compensation for serving as a journal editor, associate editor, or member of an editorial advisory board (Revista Española de Esclerosis Múltiple); and research support (Hospital Foundation FIMABIS). G.G. received consulting and/or grant/research support (AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharma, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB). E.K.H. received honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi, and Teva), and support (Ministry of Education of Czech Republic (PROGRES Q27/LF1)). C.L. received compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi, Strativa, Teva, and UCB). X.M. received speaking honoraria and travel expenses for scientific meetings, steering committee member of clinical trials or participated in advisory boards of clinical trials in the past 3 years (Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, EXCEMED, Genzyme, MedDay, Merck, MSIF, NervGen, NMSS, Novartis, Roche, Sanofi Genzyme, Teva Pharmaceutical, and TG Therapeutics). C.O.-G. received speaking and/or consultancy fees (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). F.P. received research grants (Genzyme, Merck KGaA, and Novartis) and fees for clinical trials (serving as chair of data monitoring committee with Parexel). H.W. received consulting and/or speaking fees (Bayer, Behring, Biogen, EMD Serono, Fresenius Medical Care, Merck Serono, Novartis, Roche, Sanofi, and Teva), license fee payments (Huber Verlag), and grant/research support (Neotope Biosciences, Novartis, and PML Consortium). T.Z. received consulting and/or speaking fees (Alexion, Almirall, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Biogen, Novartis, Roche, Sanofi, and Teva).

Figures

Figure 1.

Effect of post-alemtuzumab thyroid AEs on subsequent development of immune thrombocytopenia, acquired hemophilia, antiglomerular basement membrane antibody positive, or nephropathy in clinical trials. AE: adverse event; MS: multiple sclerosis. Pooled CAMMS223, CARE-MS I, and CARE-MS II trials for patients treated with alemtuzumab 12 mg/day. Treatment-emergent thyroid AEs include the following: antithyroid antibody positive, autoimmune thyroiditis, Basedow’s disease, blood thyroid stimulating hormone abnormal, blood thyroid stimulating hormone decreased, blood thyroid stimulating hormone increased, endocrine ophthalmopathy, exophthalmos, goiter, hyperthyroidism, hypothyroidic goiter, hypothyroidism, myxedema, primary hypothyroidism, thyroid cyst, thyroid dermatopathy, thyroid disorder, thyroid function test abnormal, thyroid mass, thyroid pain, thyroidectomy, thyroiditis, thyroiditis subacute, thyrotoxicosis, thyroxine binding globulin increased, thyroxine decreased, thyroxine free decreased, thyroxine free increased, thyroxine increased, toxic nodular goiter, triiodothyronine decreased, triiodothyronine free decreased, triiodothyronine free increased, triiodothyronine increased, and triiodothyronine uptake decreased. Subsequent autoimmune events include any nephropathy event, any immune thrombocytopenia event, acquired hemophilia, and antiglomerular basement membrane antibody positive.