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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 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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