VALAMONT ADVISORS, LLC

Science Driven Strategy Design

USING TECHNICAL INNOVATON TO
MAXIMIZE MOLECULES AND MAGNIFY MARKETS
April 9, 2014
VALAMONT
Using Technical Innovaton to Maximize Molecules and Markets
Rationale for investing in technical innovation
Drug delivery and formulation technology landscape
Optimizing a drugs therapeutic profile and ease of use
Evaluating technical innovation opportunities
Choosing the right technology solution
Creating better NCEs through technical innovation
Implementing the new product development plan
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Technical Innovation to Drive Market Expansion
VALAMONT
Maximizing Product Value
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Technical Innovation to Drive Market Expansion
Clinical Applications
(Translational & Personal Medicine)
Clinical Indications
Patient Selection
Tissue/Cell Localization
Clinical Needs
(Clinical Development)
Maximize Efficacy
Enhance Tolerability
Improve Adherence
Technical Innovation
(Pharm Dev & Technical R&D)
New Formulations
Novel Delivery Routes
Enhanced Packaging
Commercial Needs
(Brand Management)
Competitive Positioning
Global Expansion, Local Needs
Product Line Extensions
VALAMONT
Why Invest in Technical Innovation?
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Technical Innovation to Drive Market Expansion
Early R&D
Clinical
Development
Post-Launch
Stabilize and solubilize active molecules and moieties
Optimize PK profile to enhance PD mechanisms
Localize tissue and cellular targeting
Address new clinical indications
Maximize efficacy and tolerability
Reduce inter- and intra- patient variability
Improve comfort, convenience and adherence
Expand pool of eligible patients, earlier treatment
Enhance brand loyalty and competitive differentiation
Expand into new patient populations, new geographies
Introduce product line extensions
Extend market exclusivity
VALAMONT
Typical Market Evolution:
Dollar Sales
$ Sales
Time
First-
in-Class
Therapeutic
Substitutes
Technical
Innovators
Generics
Typical Market Evolution:
Unit Volume
# Rx
Time
First-
in-Class
Therapeutic
Substitutes
Technical
Innovators
Generics
Technical Innovation Drives Long-Term Market Evolution
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Technical Innovation to Drive Market Expansion
The degree of technical innovation typical drives long-term value in mature markets
ILLUSTRATIVE
VALAMONT
Drug Delivery and Formulation Technology Landscape
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Technical Innovation to Drive Market Expansion
Systemic Delivery
Intravenous / Intra-arterial
SC/IM Injection
Long-acting SC/IM
Programmable Pump
Oral immediate release
Oral controlled release
Rectal suppositories
Transdermal Patches
Parenteral
Alimentary
Transdermal
Local Delivery
Targeted Parenteral
Arterial Infusion
Catheter
Surgical Implants
Surgical Materials
Ocular
Pulmonary
Nasal
Colloidal
Liquid
Topical
Respiratory
Implants / Inserts
VALAMONT
Technical Innovation Landscape: Systemic Delivery
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Technical Innovation to Drive Market Expansion
Parenteral
Alimentary
Transdermal
Solution, suspension, lyophilization,
liposomes/microsomes
Suspension, powder, dual-chamber
Depot, implantable rod, microchip
Infusion, continuous subcutaneous,
intrathecal
Immediate release tablets/capsules, rapid
dispersables, pellet sprinkles, sublingual
Extended/delayed release (e.g., osmotic),
gastroretentive, muco-adhesive buccal
Capsules, gelcaps, solutions, ointments
Passive transport, active transport,
microneedle
Intravenous /
Intra-arterial
SC/IM Injection
Long-acting SC/IM
Programmable Pump
Oral immediate release
Oral controlled release
Rectal suppositories
Transdermal Patches
Administration Route Sample Technologies
VALAMONT
Administration Route
Technical Innovation Landscape: Local Delivery
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Technical Innovation to Drive Market Expansion
Targeted
Parenteral
Respiratory
Topical
Hepatic infusion, renal infusion, tumor
artery infusion
Vascular, microcatheters (CNS, tumors)
Coated stents, coated orthopedics
Biodegradable mesh scaffolds, post-
resection topicals, adhesion barriers
Intravitreal injection, ocular inserts
HFA metered dose inhaler, dry powder
inhaler, nebulized solution/suspension
Aqueous nasal spray, dry powder inhaler,
nose-to-brain delivery systems
Cream, ointment, gel, micro/nano-
emulsions
Spray, drops
Arterial Infusion
Catheter
Surgical Implants
Surgical Materials
Ocular
Pulmonary
Nasal
Colloidal
Liquid
Implants /
Inserts
Sample Technologies
VALAMONT
Optimize PK/PD to Enhance the Clinical Profile
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Technical Innovation to Drive Market Expansion
Dose
R
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Toxic
Effect
Therapeutic
Effect
Therapeutic
Window
Illustrative
Pharmacokinetics:
What your body
does to the drug
Pharmacodynamics:
What the drug
does to your body
Safety
Efficacy
Managing PK Variability:
Reduce risk of low efficacy due to low dose
Reduce risk of intolerable dose
Blood Concentration
(ng/mL)
Above Optimal
(> 30 ng/mL)
Illustrative
% of
Patients
Sub-Optimal
(< 10 ng/mL)
Optimal Range
(10-30 ng/mL)
Inter-patient variability
Reduce
variability to
improve patient
outcomes?
>15% of pts? unknown % of pts
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Dose-to-dose and
Efficacy Safety
How can we widen the therapeutic
window and reduce PK variability to
improve overall efficacy and safety?
ILLUSTRATIVE
VALAMONT
Defining the Target PK/PD Profile
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Technical Innovation to Drive Market Expansion
Absolute bioavailability
after liver metabolism
Food effects and variable
absorption window
Compartmentalization of
drug throughout body
GI Stability
& Transit
First-Pass
Metabolism
Albumin
Binding
Oral Bioavailability?
Drug concentrations at
site of action
Tissue
Distribution
Local Toxicities?
ILLUSTRATIVE
Time
Illustrative
B
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PK / PD Relationship?
Cmax
Cmin AUC
Peak
Exposure
Trough
Exposure
Total
Exposure
Efficacy (& toxicity) due to
peak or total drug exposure?
Opportunities to widen
therapeutic window?
Maintain trough levels or
clear before next dose?
Optimal Delivery
Route &
Formulation?
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If all else fails, screen out patients at risk of toxicity or non-
response and/or actively manage to a safe therapeutic dose
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Technical Innovation to Drive Market Expansion
Clinical Toxicity
No/Low Yes/High
B
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L
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Above
Optimal
Use as
indicated
Adjust dose
downwards
Optimal
Sub-
Optimal
Adjust dose
upwards
Discontinue
(or switch
formulation)
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Increased
Efficacy
Therapeutic Dose Monitoring
and Management
ILLUSTRATIVE
Patient Selection for
Personalized Medicine
VALAMONT
Evaluating Technical Innovation Opportunities
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Technical Innovation to Drive Market Expansion
Clinical &
Commercial
Intellectual Property
& Technology Access
Competitive differentiation?
Brand identity and loyalty?
Broader patient population?
Increased penetration?
Higher pricing potential?
Extend patent life or other
market exclusivity?
Analogous product successes?
Pharmacokinetics &
Pharmacodynamics
Opportunity? Feasibility?
Widen therapeutic window?
- Improved safety?
- Enhanced efficacy?
Increased convenience,
comfort, compliance?
Drug compatibility, esp.
solubility, stability?
Activity at site of action?
Manufacturing and packaging
feasibility and cost?
Clinical / Regulatory
requirements and risks?
Development time and cost?
Likelihood of achieving
product performance
thresholds?
Internal technical capabilities
and freedom to operate?
Technology partnerships?
VALAMONT
Choosing the Right Technology Solution
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Technical Innovation to Drive Market Expansion
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Enable self-administration /
outpatient use
-- +/- - +/- ++ ++ + ++ -- -- -- -- -- + + ++ ++
Reduce / avoid local toxicity
- - +/- -- - + +/- - - - - - - - - +/- +/-
Increase oral bioavailability /
avoid first-pass metabolism
+ + + + -- - + + + + + + + + + + +
Local tissue / organ delivery
-- - - - +/- +/- +/- - + + + + + + + + +
Optimize drug loads
+ +/- +/- + + + +/- -- + - +/- +/- - +/- +/- + +
Reduce PK variability
++ + ++ + -- + +/- ++ ++ ++ +/- +/- + +/- +/- +/- +/-
Adjust or reverse dose
+/- +/- -- + + + + + +/- +/- - - - + + + +
Accelerate release /
rapid onset
++ + -- + + - + -- ++ + - - - + + +/- +/-
Delay or extend release /
increase half-life
-- - ++ + - + +/- ++ -- - + + + - - +/- +/-
Reduce Cmax:AUC ratio,
i.e., to enhance safety
- +/- ++ + - + +/- ++ -- - ++ ++ ++ +/- +/- +/- +/-
Increase Cmax:AUC ratio,
i.e., to increase efficacy
++ + -- + + +/- +/- -- ++ + -- -- -- +/- +/- +/- +/-
Narrow Cmax:Cmin peak-to-
trough at steady state
- - ++ + - + +/- ++ -- - ++ ++ ++ +/- +/- +/- +/-
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DELIVERY AND FORMULATION TECHNOLOGIES
Parenteral Alimentary
LOCAL DELIVERY
Parenteral Implants / Inserts Respiratory Topical
SYSTEMIC DELIVERY
Delivery Technology Ability to Address Target PK/PD Profile
INDICATIVE
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Examples of Transformative Technical Innovations
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Technical Innovation to Drive Market Expansion
Parenteral to
Non-Oral
Rapid Release
Examples
Imitrex Nasal Spray
Levadex Inhaled DHE
Cynapsus APL-130277
sublingual apomorphine
Clinical Challenge Addressed
Enable outpatient episodic use of potent
and rapidly acting rescue medications in
situations where patients cant self-
administer oral medications
Oral to
Transdermal
Cell-Based
Tumor
Targeting
AndroGel testosterone patch
OrthoEvra birth control patch
Nicodermnicotine patch
ResPro Labs melatonin patch
Assure sustained absorption of low
levels of potent agonists with highly
variable or low first pass oral
bioavailability, increasing efficacy and
reducing Cmax-related risks
TDM-1 trastuzumab emtansine
CRLX-101 cylcodextrin polymer
camptothecin
BIND-014 PSMA-targeted
docetaxel
Widen therapeutic window of cytotoxic
therapeutics by targeting delivery to
tumor cells of both solid tumors and
metastases
VALAMONT
Creating Better NCEs through Technical Innovation
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Technical Innovation to Drive Market Expansion
New salts / polymorphs (e.g., Transform Pharma)
Isomers / enantiomers (e.g., Sepracor Allegra/fexofenadine)
Pro-drugs / metabolites (e.g., Astra Prilosec/omeprazole)
Chemically
Modify
Technology Innovation Waves
1990s
Pegylation (e.g., PEG-Intron, Neulasta, Mircera)
Albumin (e.g., Abraxane/paclitaxel)
Fc-Fusion (e.g., Alprolix/Fc-Factor IX)
Conjugate to
Stabilize &
Solubilize
2000s
Drug-Antibody Conjugates (e.g., Immunogen)
Targeted Liposomes (e.g., BIND Therapeutics)
Nanopharmaceuticals (e.g., Cerulean)
Conjugate to
Target Site of
Action
2010s
Blood-Brain Barrier carriers / diffusion enhancers
Non-immunogenic biologics / tolerogenic inducers
Oral, intracellular antibody-like peptidomimetics
New
Frontiers
2020s?
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Implementing the New Product Development Plan
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Design &
Formulation
Feasible
Formulations
Design
Prototype
Formulate
Clinical
Proof-of-Concept
Full
Development
Stability
Testing
Safety POC
Efficacy POC
Formulation
Validation
Final
Formulation
Pilot
Production
PK Study
Market
Testing
VALAMONT ADVISORS, LLC
Science Driven Strategy Design
Technology
Grow
We enable your technologies to achieve their full potential,
your products to have the widest benefit and
your franchises to deliver maximum value.
We deploy scientific and market knowledge with
broad strategy expertise and tailored analytics
to translate innovative technologies into novel products
that restore and enhance health.
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