Together we innovate … Strategy Analysis March 2009 Josselin Courselle Rebecca Deprez Julien Maurin Thomas Patard 1 This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques of Lille. The opinions expressed are our own and not necessarily those of Actelion. 2 From ambition … − 1990 : Roche discovered the first ENTDOANHELIN RECEPTOR TAGONIST − 1996 : Roche drops clinical trials on bosentan (liver toxicity). − 1997: Founding Actelion. (Allschwil, Switzerland) JP Clozel M Clozel A Muller W Fischli T Widmann CEO VP Drug Discovery, Chairman Board VP Drug Discovery, Former CEO Pharmacology Former CFO Biology Preclinical Dev 3 … to realization 10 years on − 20 countries worldwide − 1949 employees − 2000 : IPO Swiss New Market (256Mio CHF) − In the top-15 biopharmaceutical companies − 2008 : Entry into the SwissMarketIndex , Best performing stock ! Sales Marketing Development 4 3 Marketed products Zavesca® (miglustat) Type 1 Gaucher’s disease Ventavis® (iloprost) Inhaled prostacyclin for PAH therapy Tracleer® (bosentan) Oral dual endothelin receptor antagonist « Entan » For PAH & Digital Ulcers 5 Actelion : A strong communication on Pulmonary Arterial Hypertension, Endothelin,« Entans » PAH_info.com Endothelin.org Owns visual and verbal nomenclature of an entirely new class of compounds 6 Actelion in Mid-2003 Acquisition Partnership Veletri tezosentan In-Licencing Reward Risk Generics Specialty Orphan drugs Hospital drugs GP products Pharmaceuticals Actelion : A Clinical Developement Company 7 2003-2004: moving upward the DD pipeline Sept-2003 :Axovan acquisition • Phase II clazosentan GPCR • Numerous pre-clinical projects • Chemistry platform • GPCR platform Actelion : A Drug discovery Company 8 2003-2008 : Niche extension PAH & CardioVascular diseases Acquisition PGI2 agonist Partnership In-Licencing Pivlaz Reward Macitentan Clazosentan Risk Veletri tezosentan Generics Specialty Orphan drugs Hospital drugs GP products Pharmaceuticals 9 2003-2008 : Moving towards GP market Acquisition S1P1 Agonist Partnership Orexin Antagonist In-Licencing CRTH2 Antagonist Reward Risk Renin Inhibitor Generics Specialty Orphan drugs Hospital drugs GP products Pharmaceuticals 10 Major therapeutic areas & Marketed Products − Pulmonary Arterial Hypertension −Gaucher’s disease 11 What is PAH? -Sustained elevation of pulmonary vascular resistance : >25 mmHg (at rest) >30 mmHg (while exercising) right ventricular failure and premature death (median survival 2.8 y) -Small pulmonary arteries obstruction due to Vasoconstriction Thrombosis Smooth muscle and endothelial cell proliferation 12 WHO functionnal classes Class I PAH but without limitation of physical activity. Slight limitation of unsual physical activity : dyspnoea or Class II fatigue, chest pain or near syncope Comfortable at rest Marked limitation of ordinary physical activity. Class III Comfortable at rest. Inability to carry out any physical activity without Class IV symptoms. Signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest mean age of diagnosis: 36 years1 prevalence of 30-50 cases per million2 1: Sitbon O et al. Am J Resp Crit Care Med 2008 ; 2: Peacock AJ. BMJ 2003 13 Why does it develop? − Reduced production of vasodilators – Prostacyclin – NO − Increased production of vasoactive compounds – Endothelin (ET) 14 PAH therapy & Actelion portfolio 15 PGI2 pathway : Competitors ® ® Flolan (epoprostenol: PGI2) Remodulin (treprostinil) Natural prostacyclin Synthetic analogue Short half-life Preferentially given subcutaneously Intraveinous perfusion (small infusion pump) Low impact on quality of life and Pain and discomfort (85% of patients) mortality 75,000 $/year 45,000 $/year 16 Ventavis® (Iloprost) for PAH GPCR PGI2 receptor agonist 2007: CoTherix acquisition 17 Ventavis®, freedom from iv prostacyclins Inhaled formulation of iloprost ↑ stability and ↑ half-life vs natural PGI2 Approved for PAH Class III or IV Cost: 3100€ / year The only inhaled PAH therapy on the US market 18 Ventavis®, contributing to growth − Developed by Schering − 2004 :Approval & Licenced to CoTherix in US − 2007 :Acquisition of CoTherix Bayer Schering Pharma sales in EU & other countries; Actelion in US − 2008 : Sales reach CHF 94.6 m 34% increment 19 Ventavis® : Improve access to treatment I-neb Adaptative Aerosol Delivery System Pulmonary drug delivery device Battery powered Adaptive Aerosol Delivery (AAD®) technology: −Constant amount of drug is inhaled −No waste Ann Pharmacother. 2005 Jul-Aug;39(7-8):1265-74. Prodose AAD Inhaled iloprost in pulmonary arterial hypertension. Baker SE, Hockman RH. 20 Tracleer® (bosentan) for PAH GPCR Mixed ETA/ETB entan 1st in class 21 2000: in-licenced from Roche ET mediated effects in PAH British Journal of Pharmacology (2008) 153, 1105–1119 22 Bosentan Tracleer® - 2002 : PAH class III & IV - 2008 : PAH class II (EARLY) - 2008 : Digital Ulcers (PAH with connective tissue diseases like systemic sclerodermia) - Sales : CHF 1.2 b ; +17%; constant growth 23 Entans competition ICOS/Encysive/Pfizer Launched Myogen/Gilead/GSK Launched −Ambrisentan (Letairis® Volibris ® ) 2008 : $112.9 million (US); EU launched −Sitaxsentan (Thelin ® ) acquired by Pfizer in 2008 Gilead Phase III Updated from Nature Reviews Drug Discovery 986 | 2002 | VOLUME1 24 Other PAH competitors in NO pathway − Sildenafil (Revatio ® Pfizer) PDE5 inhibitor (03/2005). − Riociguat (Bayer Schering Pharma) soluble guanylate cyclase (sGC) stimulators. Phase III 25 Miglustat (ZavescaTM) Targeting Genetic disorders 2002: in licenced from OGS / then Celltech 26 Type 1 Gaucher : A bone disease − Inherited autosomal recessive disorder − Reduced activity of lysosomal ß-glucocerebrosidase − Accumulation of glucosylceramide − Necrosis of bone marrow infiltrated with Gaucher cells − Bone pain, osteonecrosis due to abnormal remodeling 27 Type 1 Gaucher : Treatment − Enzyme replacement − Substrate Reduction therapy (inb. Glucosylceramide synthase) − Chemical chaperone Glucosylceramide Defective Enzyme- glucosylceramide ß-glucocerebrosidase replacement synthase therapy (ERT) Substrate reduction CEREZYME® therapy Ceramide 60 IU/kg/2 weeks ~86 140 - 430 700 € /y Chemical chaperones to reactivate defective enzymes 3*100 mg/day ~91 881 € /y Future Lipidol. 2008 June ; 3(3): 273–300. NATURE REVIEWS | MOLECULAR CELL BIOLOGY V5 | JULY 2004 | 554 NATURE REVIEWS | CANCER V4 | AUGUST 2004 | 604 28 Miglustat sales +20% 29 Niemann-Pick type C disease − Very rare − Reduced activity of lysosomal sphingomyelinase − Accumulation of sphingomyelin − Severe SNC disabilities − Zavesca® Approved in 2008 as a sphingomyeline synthase inhibitor Substrate reduction therapy 30 Broad Clinical Portfolio 31 Life cycle management & current drug families Miglustat Iloprost & other PGI2r agonists Entans 32 Zavesca® in Cystic Fibrosis − Autosomal recessive genetic disorder − Progressive lung & pancreas dysfunction − Caused by defected CFTR chloride channel −Norez C., Noel S., Wilke M., Bijvelds M., Jorna H., Melin P., DeJonge H. and Becq F. Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. FEBS Lett. 508, 2081-86; 2006. 33 Zavesca® in Cystic Fibrosis Chemical chaperones to reactivate defective enzymes − Acts as a chemical chaperone of the CFTR (del508) − Phase IIa results expected Q2-2009 −Norez C., Noel S., Wilke M., Bijvelds M., Jorna H., Melin P., DeJonge H. and Becq F. Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. FEBS Lett. 508, 2081-86; 2006. −Antigny et al, Cell Calcium, 43, 175-183 2008 34 PGI2 agonists :Improve patient access to treatment Q2 2009 – PROWESS 15 New device to ↓ inhalation time and ↑ patient compliance Study design: 64 patients, crossover study 35 PGI2 agonists : New combinations ? 2006 :phase II/III STEP Efficacy and added benefit of using Ventavis® in patients with PAH already undergoing treatment with bosentan, or sildenafil Mc Laughlin et al., AJRCCM, 2006 Ghofrani et al., JACC, 2003 36 GPCR Improve patient access to treatment : PGI2 agonists in a pill ? − Discovered by Nippon Shinyaku − 2008: Actelion outside Japan & co-development & commercialization in Japan − First-in-class , Non-prostanoid PGI2 receptor agonist − Pro-drug offers protection to gastro-intestinal tract 37 ACT-293987: current status Results of phase I Good safety profile Linear PK after single oral dose Half-life supports twice-a-day oral dosing No accumulation after multiple dosing 2008 : A phase IIa study in PAH Objective: evaluate acute hemodynamic effects and tolerability of up-titration to 800μg bid Results are expected in Q3 2009 −Kuwano et al (2008). J Pharmacol Exp Ther 326: 691-699. 38 Bosentan : Extension of Indications 2002 Chronic Thrombo Embolic Pulmonary Hypertension 2007 2008 + Sildenafil 39 Bosentan in IPF (Idiopathic Pulmonary Fibrosis ) Ph.III − Orphan disease − Easily diagnosed (unlike PAH) − Death in 3-years − Bosentan normalizes cells with fibers − Results expected in Q2-2009 − If Bosentan goes in IPF, Fast track status and double revenue in 2 years King T.E. et al. High-resolution computed tomography (HRCT) features correlate with response to bosentan in idiopathic pulmonary fibrosis (IPF): the BUILD 1 study [abstract]. Am J Respir Crit Care Med. 175:A567; 2007. 40 Macitentan in PAH Ph.III − 100 times more potent than bosentan − Mixte ETA/ETB − Directed towards tissues to avoid vascular effects − SERAPHIN study − Expected results