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 • Misculoskeletrical Diseases • Oncology • Ophtalmology Vaccines (NV&D)

UK

: • Respiratory • Gastrointestinal

Siena, Italy

:

NVGH

, Novartis Institute for Global Health

Siena, Italy

: • Vaccines ~ 6000 scientists ~ USD 2 bn/year

Emeryville, CA

: • Oncology

La Jolla, CA

.

GNF

, Genomic Institute of the Novartis Research Foundation

Switzerland

: • Autoimmunity, Transplantation and Inflammation • Oncology • Neuroscience • Musculoskeletal Diseases •Gastrointestinal

Shanghai, China

: • Oncology

Singapore

:

NITD

, Novartis Institute for Tropical Diseases

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)

2 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |

R&D innovation guided by science and medical need

Understanding molecular biology Illustrative: Proof of Concept (PoC) clinical trials Parallel indication expansion studies PoC indication Expansion 1 Expansion 2

Protein networks, molecular pathways, are the functional units of the cell

Expansion 3 Expansion n 1X 1.5X

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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  

Muckle –Wells syndrome (MWS)

 Autosomal dominant Rash, fever, fatigue, sensorineural deafness AA amyloidosis (in 25% of patients) leading to renal failure   

NOMID/CINCA

 Sporadic Progressive chronic meningitis, deafness Visual and intellectual damage Destructive arthritis 4 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |

Ilaris ® (ACZ885): Anti-IL 1β antibody

NIBR Strategy: Proof of Concept in Homogeneous Population followed by Mechanistic Expansion

CAPS 1 <0.020 Million Gout 20 Million Atherosclerosis 130 Million Normal vessel Monosodium urate crystals

1 -

Cryopyrin-associated periodic

syndrome Source for patient numbers: global prevalence estimate from Patient Base

5 | US-Russia Scientific Forum | J Orloff | 16 November 2011 | Inflammation Cholesterol crystals

Latz, et al., Nature, Vol 464|29 April 2010

Why understanding one disease can be important

IL-

1β Pathway - abnormal signal transduction leading to disease

One pathway One node NALP3 (Cryopyrin) Inflammasome Activation of Caspase-1 Caspase-1 Caspase-1 IL-1 β Precursor

Inflammation (IL 1β Pathway)

Multiple diseases CAPS 1 SJIA 2 Chronic Gout CV Risk Reduction Activated IL-1 β 1

Cryopyrin-associated periodic syndrome

2

Systemic juvenile idiopathic Arthritis

3

Chronic obstructive pulmonary disease

6 | US-Russia Scientific Forum | J Orloff | 16 November 2011 | Osteoarthritis COPD 3

Psoriasis CD3 + IL-17 + cells

IL-17 Pathway in the Clinic:

Psoriasis and related immune mediated diseases

Rheumatoid arthritis CD3 _ CD4 + IL-17 + plasmacytoid-like cells Multiple sclerosis CD3 IHC

Aperio color deconvolution method A Haider et al, NIBR

IL17 IHC Langerhans cell histiocytosis skin lesion

Page et al., Am J Pathol 2004;164:409

Crohn’s disease

Coury et al., Nature Med 2008;14:81

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Fujino et al., Gut 2003; 52:65 Tzartos et al., Am J Pathol 2008;172:146

AIN457: mAB against IL-17

Parallel indication expansion

Bechets Uveitis

in PhIII

Non infectious posterior segment uveitis

in PhIII

RA 1

in PhII

Psoriasis (Moderate to severe)

in PhII

AS 2

in PoC

Psoriatic Arthritis

in PoC

MS

in PoC

Crohn’s Disease

in PoC

1 Rheumatoid arthitis 2 Ankylosing spondylitis 3 Not all potential patients would be eligible for treatment with AIN457, if approved

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Top 7 Markets 3

3,000-6,000 50,000 – 75,000 5 million 1.2 million 1.2 million 800,000 600,000 570,000

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.

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Growth of Afinitor

®

(mTOR Inhibitor) driven by continued indication expansion

Approved 1

Number of patients

Approved

TSC SEGA 2

Unknown

Renal cell carcinoma

590k

Neuroendocrine tumors (NET)

60k+

Metastatic breast cancer

3 160k+

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 cancer Source: (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)

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One pathway/NME - multiple target indications

OA SJIA Gout

IL-1 β

COPD CAPS CV Risk Liver C Gastric C Kidney C

mTOR

Tub Scl NET Cr. dis RA Psor.

IL-17

Ank. Sp.

Ps. Arth.

MS 11 | US-Russia Scientific Forum | J Orloff | 16 November 2011 | Lymph.

Tx Breast C

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 12 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |

Orphan Drug Approvals 2009

BioMarket Trends: Jun 15 2010 (Vol. 30, No. 12) 13 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |

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 14 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |

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 15 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |

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 16 | US-Russia Scientific Forum | J Orloff | 16 November 2011 |