Transcript Slide 1
Approach to Rare Diseases Research and
Orphan Products Development
John J. Orloff, MD
Chief Medical Officer
Novartis Pharma AG
US-Russia Scientific Forum
November 16th, 2011
Novartis Biomedical Research sites
Cambridge, MA:
• Cardiovascular&Metabolism
• Infectious Diseases
• Misculoskeletrical Diseases
• Oncology
• Ophtalmology
• Vaccines (NV&D)
Emeryville, CA:
• Oncology
La Jolla, CA.
GNF, Genomic
Institute of the
Novartis Research
Foundation
UK:
• Respiratory
• Gastrointestinal
Siena, Italy:
NVGH, Novartis
Institute for Global
Health
Siena, Italy:
• Vaccines
Switzerland:
• Autoimmunity,
Transplantation
and Inflammation
• Oncology
• Neuroscience
• Musculoskeletal
Diseases
•Gastrointestinal
Shanghai, China:
• Oncology
Basel, Switzerland:
FMI, Friedrich
Miescher Institute
~ 6000 scientists
~ USD 2 bn/year
Singapore:
NITD, Novartis
Institute for Tropical
Diseases
Indonesia:
NEHCRI, the NITD –
Eijkman Institute –
Hasanuddin University
Clinical Research
Initiative
Novartis Institutes for Biomedical Research (NIBR)
Novartis Institutes for Developing World Medical Research (part of NIBR)
Novartis Vaccines and Diagnostics (NV&D)
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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
Expansion 3
Protein networks, molecular pathways, are
the functional units of the cell
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)
Moderate
Mild
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
Severe
NOMID/CINCA
Sporadic
Progressive chronic meningitis, deafness
Visual and intellectual damage
Destructive arthritis
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Ilaris® (ACZ885): Anti-IL-1β antibody
NIBR Strategy: Proof of Concept in Homogeneous
Population followed by Mechanistic Expansion
CAPS1
<0.020 Million
Gout
20 Million
Atherosclerosis
130 Million
Normal vessel
Monosodium urate crystals
Inflammation
Cholesterol crystals
1-
Cryopyrin-associated periodic syndrome
Source for patient numbers: global prevalence estimate from Patient Base
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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
Multiple diseases
CAPS 1
NALP3
(Cryopyrin)
Inflammasome
SJIA 2
Activation of
Caspase-1
Caspase-1
Caspase-1
IL-1β
Precursor
Inflammation
(IL-1β Pathway)
Activated IL-1β
1 Cryopyrin-associated
periodic syndrome
2 Systemic juvenile idiopathic Arthritis
3 Chronic obstructive pulmonary disease
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Chronic Gout
CV Risk Reduction
Osteoarthritis
COPD 3
IL-17 Pathway in the Clinic:
Psoriasis and related immune mediated diseases
Psoriasis
CD3+IL-17+ cells
Rheumatoid
arthritis
_
+
CD3 CD4 IL-17+ plasmacytoid-like cells
Multiple sclerosis
CD3 IHC
Page et al., Am J Pathol 2004;164:409
Crohn’s disease
IL17 IHC
CD3+ T cells
Aperio color
deconvolution
method
A Haider et al,
NIBR
Langerhans cell histiocytosis
skin lesion
CD68+ Cells
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
Top 7 Markets3
Bechets Uveitis
in PhIII
Non infectious posterior
in PhIII
segment uveitis
RA1
Psoriasis
in PhII
3,000-6,000
50,000 – 75,000
5 million
in PhII
1.2 million
AS2
in PoC
1.2 million
Psoriatic Arthritis
in PoC
MS
in PoC
600,000
Crohn’s Disease
in PoC
570,000
(Moderate to
severe)
1
Rheumatoid arthitis
2 Ankylosing spondylitis
3 Not all potential patients would be eligible for treatment with AIN457, if approved
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800,000
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
Approved1
Approved
TSC SEGA2
Unknown
Renal cell carcinoma
Number of
patients
Neuroendocrine
tumors (NET)
Metastatic breast
cancer3
160k+
60k+
590k
1
By FDA; Submitted in EU
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)
2
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One pathway/NME - multiple target indications
Gout
Kidney C
SJIA
OA
IL-1β
Gastric C
Liver C
COPD
mTOR
Breast C
NET
CAPS
Lymph.
CV Risk
Psor.
RA
Ank. Sp.
IL-17
Cr. dis
Ps. Arth.
MS
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Tub Scl
Tx
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
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Orphan Drug Approvals 2009
BioMarket Trends: Jun 15 2010 (Vol. 30, No. 12)
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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
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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
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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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