Potential Best-In-Class Potent, Selective & Orally Active S1P 1 Agonists for Multiple Sclerosis

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1 Potential Best-In-Class Potent, Selective & Orally Active S1P 1 Agonists for Multiple Sclerosis Art Taveras, PhD March 25, 2009

2 Therapeutic Hypothesis of S1P Agonism Multiple Sclerosis (MS): A chronic inflammatory disease involving the central nervous system (CNS) Autoreactive T-cells migrate and mediate immune responses against central neurons S1P receptor agonists prevent lymphocyte release into periphery S1P agonists cause decreased inflammation in MS patients Therapeutic potential also in neuropathic pain and RA 2

3 Biochemical Pathway of S1P: Receptor Subtypes Drive Efficacy and Safety Issues Sphingosine Sphingosine Kinase1,2 S1P Phosphatase1,2 S1P release S1P S1P Lyase Lipid Phosphate Phosphatase- 3 camp Ca 2+ Mobilization Sphingosine + P i S1P1 S1P2 S1P3 S1P4 lymphopenia Bradycardia Bronchoconstriction* Hexadecenal + phosphoethanolamine S1P5 Modified from Pyne and Pyne, Biochemical J., 349, (2000) S1P release Source: J. Med. Chem., 48, (2005) 3

4 Best-In-Class S1P Agonist Safety Strategy Medical Experts Highlight Safety Concern Decreases in forced expiratory flow and increases in respiratory systems 1 Squamous cell carcinoma 2 Dyspnea or asthma 3 ALT was significantly increased in MS patients receiving fingolimod, regardless of dose 2 Reversible posterior leukoencephalopathy syndrome seen with one patient retained significant visual complications 15 months posttreatment 2 Novartis: increase in blood pressure elevation of liver enzymes 8 macular edema 4 basal cell carcinoma and 3 melanoma two fatal viral infections in patients treated with FTY mg 4 Best-In-Class Safety Strategy Low-dose efficacy: Significant potency with low systemic exposures delivering maximal efficacy and low off-target liabilities S1P selectivity: S1P 1 receptor subtype drives efficacy; S1P 3 receptor subtype implicated in CV and respiratory toxicities Cardiovascular safety: Mouse model established at Biogen Idec to assess bradycardia liability; other models in place to assess additional CV safety liabilities Pulmonary safety: Biogen Idec has in-house assays and partnerships to assess bronchial constriction and other respiratory liabilities Exceptional drug properties: No CYP450 issues; no hepatic liabilities or genotoxicities 1 L Kappos, et. Al; New England Journal of Medicine; 2006 (355); ; 2 BA Brown, et. Al; The Annals of Pharmacology; 2007 (41); 4 3 O Conner, et. Al.; Neurology; 2009 (72) ; 4 Novartis; TRANSFORMS Initial Results; Dec 2008

5 Profile of Best-in-Class Oral S1P 1 Agonists: Competitive Efficacy-Safety Advantage Potency S1P 1 EC50 = 1-10 nm Selectivity EC50 > 10,000 nm vs. S1PX receptors Pre-Clinical Oral Activity Pharmacokinetic: Lymphopenia : Efficacy: Orally Bioavailable in Mouse, Rat, Dog, Cyno ED50 < 0.1 mpk in multiple species < 0.1 mpk in rat EAE model of MS Pre-Clinical Safety Bradycardia: Pulmonary: CYP450: herg: Genotoxicity: None significant multiples above efficacy Preliminary data promising IC50 > 10,000 nm IC50 > 10,000 nm (patch clamp) Clean 5

6 Biogen Idec s Oral S1P 1 Agonists Potently Promote Lymphopenia in Rats BIO-xxxxx Potent Inducer of Lymphopenia in Rat Orally bioavailable in multiple species (mouse, rat, dog, monkey) Lymphocyte Count (k/ul) Robust effect on surrogate biomarker in all species tested following oral dosing 0mg/kg 0.03mg/kg 0.1mg/kg 0.3mg/kg 1mg/kg 3mg/kg 10mg/kg 75mg/kg Biogen Idec has diverse chemotypes which potently induce lymphopenia at low, oral doses 6

7 Biogen Idec s S1P 1 Agonists Fully Effective in in vivo Model of MS Following Oral Administration Mean Clinical Score BIO-xxxxx Dose Response (Clinical Score) Potently blocks signs and symptoms of MS in clinically-relevant rat EAE model (Experimental Autoimmune Encephalomyelitis) Delays disease onset at sub-optimal doses in rat Full efficacy seen with multiple compounds at low, oral doses Lymphopenia correlates with improvements in disease progression Days Post Immunization Vehicle BIO-xxxxx 0.2mg/kg BIO-xxxxx 0.02mg/kg BIO-xxxxx 2mg/kg 7

8 Biogen Idec s Oral S1P 1 Agonists Do Not Exhibit CV Safety Concern in Bradycardia Mouse Model Heart Rate (bpm) BIO-xxxxx Does Not Induce Bradycardia 900 BIO-xxxxx FTY Time (hour) BIO-xxxxx 30mg/kg BIO-xxxxx 90mg/kg FTY720 9mg/kg Bradycardia reported as CV safety concern with other compounds Safety liabilities may significantly limit the use and efficacy potential of other S1P agonists No bradycardia seen in mice with Biogen Idec s preferred S1P 1 agonist orally-dosed at >350-times lymphopenia ED50 Biogen Idec s S1P 1 agonist products have the potential for a competitive efficacy and safety profile 8

9 S1P 1 Agonist Summary of Opportunity Biogen Idec announces discovery of potential Best-in-Class S1P 1 agonist, advancing into Development for MS; Anticipate IND filing 2010 Collection of diverse chemotypes demonstrate potent activity, excellent drug-like characteristics and with potential for competitive safety profile Additional therapeutic opportunities in neuropathic pain, RA Biogen Idec expects to leverage significant MS experiences/leadership to aggressively advance this potentially competitive product 9