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Novartis Biomedical Research sites

Approach to Rare Diseases Research and Orphan Products Development John J. Orloff , MD Chief Medical Officer Novartis Pharma AG US-Russia Scientific Forum November 16 th , 2011. Novartis Biomedical Research sites. Cambridge, MA: Cardiovascular&Metabolism Infectious Diseases

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Novartis Biomedical Research sites

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  1. Approach to Rare Diseases Research and Orphan Products DevelopmentJohn J. Orloff, MDChief Medical OfficerNovartis Pharma AGUS-Russia Scientific ForumNovember 16th, 2011

  2. Novartis Biomedical Research sites • Cambridge, MA: • Cardiovascular&Metabolism • Infectious Diseases • Misculoskeletrical Diseases • Oncology • Ophtalmology • Vaccines (NV&D) Siena, Italy: NVGH, Novartis Institute for Global Health ~ 6000 scientists ~ USD 2 bn/year • UK: • Respiratory • Gastrointestinal • Siena, Italy: • Vaccines Singapore: NITD, Novartis Institute for Tropical Diseases • Switzerland: • Autoimmunity, Transplantation and Inflammation • Oncology • Neuroscience • Musculoskeletal Diseases • Gastrointestinal • Emeryville, CA: • Oncology • Shanghai, China: • Oncology La Jolla, CA. GNF, Genomic Institute of the Novartis Research Foundation Indonesia: NEHCRI, the NITD – Eijkman Institute– Hasanuddin University Clinical Research Initiative Basel, Switzerland: FMI, Friedrich Miescher Institute Novartis Institutes for Biomedical Research (NIBR) Novartis Institutes for Developing World Medical Research (part of NIBR) Novartis Vaccines and Diagnostics (NV&D)

  3. R&D innovation guided by science and medical need Understanding molecular biology Proof of Concept (PoC) clinical trials Parallel indication expansion studies Illustrative: PoC indication Expansion 1 Expansion 2 Protein networks, molecular pathways, are the functional units of the cell Expansion 3 1X Expansion n 1.5X

  4. CAPS: Broad spectrum of diseases resulting from over-expression of Interleukin-1Cryopyrin Associated Periodic Syndrome (CAPS) Familial cold autoinflammatory syndrome (FCAS) • Autosomal dominant • Rash, Arthralgia, Conjunctivitis Mild Muckle–Wells syndrome (MWS) • Autosomal dominant • Rash, fever, fatigue, sensorineural deafness • AA amyloidosis (in 25% of patients) leading to renal failure Moderate NOMID/CINCA • Sporadic • Progressive chronic meningitis, deafness • Visual and intellectual damage • Destructive arthritis Severe

  5. Ilaris® (ACZ885): Anti-IL-1β antibodyNIBR Strategy: Proof of Concept in Homogeneous Population followed by Mechanistic Expansion CAPS1<0.020 Million Gout 20 Million Atherosclerosis 130 Million Normal vessel Inflammation Monosodium urate crystals Cholesterol crystals 1- Cryopyrin-associated periodic syndromeSource for patient numbers: global prevalence estimate from Patient Base Latz, et al., Nature, Vol 464|29 April 2010

  6. Why understanding one disease can be importantIL-1β Pathway - abnormal signal transduction leading to disease Multiple diseases One pathway One node CAPS 1 NALP3 (Cryopyrin) Inflammasome SJIA 2 Activation of Caspase-1 Chronic Gout Inflammation(IL-1β Pathway) Caspase-1 IL-1βPrecursor CV Risk Reduction Caspase-1 Osteoarthritis Activated IL-1β COPD 3 1Cryopyrin-associated periodic syndrome 2 Systemic juvenile idiopathic Arthritis 3 Chronic obstructive pulmonary disease

  7. PsoriasisCD3+IL-17+ cells Multiple sclerosis Rheumatoid arthritisCD3_CD4+IL-17+ plasmacytoid-like cells CD3 IHC Aperio color deconvolution method A Haider et al, NIBR Page et al., Am J Pathol 2004;164:409 IL17 IHC Crohn’s disease Langerhans cell histiocytosisskin lesion CD3+ T cells CD68+ Cells Tzartos et al., Am J Pathol 2008;172:146 Fujino et al., Gut 2003; 52:65 Coury et al., Nature Med 2008;14:81 IL-17 Pathway in the Clinic:Psoriasis and related immune mediated diseases

  8. AIN457: mAB against IL-17Parallel indication expansion Top 7 Markets3 BechetsUveitis 3,000-6,000 in PhIII Non infectious posteriorsegment uveitis 50,000 – 75,000 in PhIII RA1 in PhII 5 million Psoriasis (Moderate to severe) in PhII 1.2 million AS2 in PoC 1.2 million Psoriatic Arthritis in PoC 800,000 MS in PoC 600,000 Crohn’s Disease in PoC 570,000 1 Rheumatoid arthitis 2Ankylosingspondylitis 3 Not all potential patients would be eligible for treatment with AIN457, if approved

  9. Tuberous Sclerosis : Rare Autosomal Dominant Genetic Disease • Estimated to be 1 in 6,000 live births • 1-2 million worldwide (50,000 US) • All sexes, races, and ethnicities • Benign tumors (hamartomas) interfering with organ function • Common sites are skin, kidney, brain, lung, eyes, and heart • Skin lesions including facial angiofibromas in >90% of patients • Neurologic manifestations are predominant clinical feature • Epilepsy in 70-80% due to cortical tubers • SEGAs (subependymal giant cell astrocytoma) in 5-20%; associated with hydrocephalus and increased intracranial pressure Figure from Krueger and Franz. Pediatr Drugs. 2008;10:299-313, with permission.

  10. Growth of Afinitor® (mTOR Inhibitor) driven by continued indication expansion Approved1 Approved Metastatic breast cancer3 160k+ Neuroendocrine tumors (NET) 60k+ TSC SEGA2 Unknown Renal cell carcinoma 590k Number of patients 1 By FDA; Submitted in EU 2 Tuberous Sclerosis Complex Subependymal giant cell astrocytomas 3 Phase III studies in ER+ breast cancer and HER2+ breast cancerSource: (RCC) Globocan worldwide prevalence; (NET) Yao JC et al, JCO 2008; (Breast Cancer) PLAN A, global oncology epidemiology database (figure shown represents metastatic breast cancer in US, EU5, and Japan only)

  11. One pathway/NME - multiple target indications Kidney C SJIA OA Gastric C mTOR Tub Scl IL-1β Liver C COPD Gout Breast C NET Tx CAPS Lymph. CV Risk Psor. RA Ank. Sp. IL-17 Cr. dis Ps. Arth. MS

  12. Orphan Drugs: Recent Trends in approvals • During the 2000s, orphan products comprised 22% of all NMEs and 31% of all SBs receiving US marketing approval • The number of orphan product designations increased from 208 in 2000-02 to 425 in 2006-08 • Novartis has 39 orphan designations and 18 orphan approvals to date

  13. Orphan Drug Approvals 2009 BioMarket Trends: Jun 15 2010 (Vol. 30, No. 12)

  14. Orphan Drug Legislation • The US Orphan Drug Act has been a success in encouraging many new drug approvals for rare diseases • More than 2100 orphan designations • Designations more than doubled during past decade • Over 350 approvals for orphan products • Similar orphan drug legislation (ODL) in other countries (EU, Japan, Australia) • But, only ~200 of > 6000 rare diseases have an approved Rx • Additional “Push” and “pull” incentives could foster greater investment in rare (and neglected) diseases

  15. Mechanisms to spur innovation for Orphan Diseases • “Push” mechanisms • Increase grant and research funding • Stronger partnership among key stakeholders (HA, industry, academia, advocacy groups), including “de-risking” programs • Increase and expand R&D tax credit to neglected diseases • “Pull” mechanisms • Extend market exclusivity (10 years) and include neglected diseases (clearly defined) • Favorable reimbursement approach – automatic • For NMEs, consider patent extension on the molecule (e.g. 6 mo similar to pediatrics) • Advance market commitments (AMCs) – subsidize purchase of product after development • Priority review voucher system (PRV) – expand and improve

  16. Opportunities and Incentives for Orphan Drugs and Neglected Diseases: Regulatory Flexibility • Apply existing regulations with greater flexibility to foster development (accelerated approval program) • Reduced requirements for clinical and preclinical program, including smaller trials and safety databases, historical controls, retrospective analyses , observational data, etc. – establish global standards (ICH) • Consider acceptance of biomarkers (e.g. PD endpoints) as surrogates for approval (reduced burden for qualification) • Conditional approval for rare & neglected diseases • Global harmonization of regulatory requirements • Partner with WHO and other health authorities – leverage expertise

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