S58 Mitoxantrone as a potential therapy for primary progressive multiple sclerosis Olaf St&uuml;ve 1 , Mariko Kita2, Daniel Pelletier 1 , Robert J Fox 3 , Jerome Stone 1 , Donald E Goodkin 4 and Scott S Zamvil *,1 1 Department of Neurology, University of California, San Francisco, CA, USA; 2 Virginia Mason Multiple Sclerosis Center, Seattle, WA, USA; 3Department of Neurology, Mellen Center for MS, Cleveland Clinic Foundation, Cleveland, OH, USA; 4 Multiple Sclerosis Therapeutics, Biogen, Cambridge, MA, USA Mitoxantrone (Novantrone&reg;) was the first drug approved in western Europe and North America for treatment of secondary progressive multiple sclerosis (SPMS) and progressive relapsing MS (PRMS). Pharmacological properties of mitoxantrone, its role in SPMS, the study rational and design of an ongoing multi-centre, double blind, randomized, placebo-controlled phase 2 trial will be outlined in this article. Multiple Sclerosis (2004) 10, S58-S61 Key words: genetics; immunology; magnetic resonance imaging; multiple sclerosis; pathology; primary progressive; therapies *Correspondence: Scott S Zamvil, Department of Neurology, University of California, San Francisco, 521 Parnassus Avenue, C-440, San Francisco, CA 94143-0114, USA. E-mail: zamvil@ucsf.neuroimmunol.org Introduction Multiple sclerosis (MS) is both clinically and pathologi- cally heterogeneous. An estimated 10%-15% of patients are categorized as primary progressive MS (ppMS).2-7 Gradual progression of symptoms continues from onset in the absence of relapses or remission, although some degree of clinical fluctuations may be seen.’ The clinical progression in PPMS is considered to be more rapid than in other MS subgroups.8 To date, no treatment is approved for the treatment of PPMS. Mitoxantrone is an immunosuppressive agent that is currently being used in secondary progressive MS (SPMS) and progressive relapsing MS (PRMS). Pharmaco- logical properties of mitoxantrone, its role in SPMS, the study rational and design of an ongoing multicentre, double blind, randomized, placebo-controlled phase II trial will be outlined in this article. Mitoxantrone Mitoxantrone (Novantrone&reg;), like adriamycin and dau- norubicin, is an anthracenedione that is used as an antineoplastic agent alone or in combination therapy for several neoplastic disorders, including prostate cancer, non-Hodgkin’s lymphoma, and acute nonlymphocytic leukaemia.9-’1 Mitoxantrone is currently approved by the Food and Drug Administration (FDA) for use in SPMS and PRMS at a dose of 12 mg/m2 once every three months. Due to its potential cardiotoxic effects, treatment duration with mitoxantrone has been limited to a cumu- lative dose of 140 Mg/M2, which is typically given over a period of 33 months. Mitoxantrone intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causing crosslinks and strand breaks.’ Mitoxantrone interferes with DNA topoi- somerase II, an enzyme that resolves topological bypro- ducts that occur when DNA is altered during replication or transcription.’2-14 Both dividing and nondividing cells are affected by mitoxantrone. The effects of mitoxantrone treatment in MS are believed to be due to the suppression of replication of autoreactive encephalitogenic T cells, B cells, and macrophages.15.16 In vitro studies further demonstrated that mitoxantrone impairs antigen presenta- tion and the secretion of several proinflammatory cyto- kines, including IFNy, TNF-a, and interleukin (IL)-2.~ ~ Thus, the effect of mitoxantrone on immune regulation may be multifold. Most pharmacokinetic data in humans has been gener- ated through its use in cancer patients receiving daily doses of this agent.18.19 It is known that mitoxantrone is 80% plasma protein bound, and that its serum half-life is approximately 1-3 h. The drug is extensively distributed in various tissues and metabolized primarily in the liver. Several potential adverse effects of mitoxantrone have been reported, moderate to severe congestive heart failure (CHF) being the most severe of them.11,1s A recent retro- spective analysis of three clinical trials observed an incidence of CHF of < 0.20% in patients with MS who received a mean cumulative dose of 60.5 Mg/M2 mitoxan- trone .2’ This study concluded that MS patients with a left ventricular ejection fraction of < 50% should not be treated with mitoxantrone.