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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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slide1

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

novartis biomedical research sites
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)

r d innovation guided by science and medical need
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

slide4
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

slide5
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

slide6
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

il 17 pathway in the clinic psoriasis and related immune mediated diseases

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
ain457 mab against il 17 parallel indication expansion
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

tuberous sclerosis rare autosomal dominant genetic disease
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.

growth of afinitor mtor inhibitor driven by continued indication expansion
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)

one pathway nme multiple target indications
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

orphan drugs recent trends in approvals
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
orphan drug approvals 2009
Orphan Drug Approvals 2009

BioMarket Trends: Jun 15 2010 (Vol. 30, No. 12)

orphan drug legislation
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
mechanisms to spur innovation for orphan diseases
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
opportunities and incentives for orphan drugs and neglected diseases regulatory flexibility
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