Pharmaceutical R&D Challenges - InnVentis

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Dec 5, 2012 (4 years and 11 months ago)

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Improving Pharmaceutical Productivity

Bayer Schering: An outside, web
-
based work example and project proposal


Thomas Wilckens, InnVentis

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© Dr. Thomas Wilckens, InnVentis

Content


A.

Emerging challenges in R&D



B.

Bayer Schering: an outside view



C.

Concepts to increase efficacy and lower risks

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© Dr. Thomas Wilckens, InnVentis

A.

Challenges in R&D

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© Dr. Thomas Wilckens, InnVentis

Despite increasing expenses in R&D the output has declined

Source: Parexel’s Pharmaceutical R&D Statistical Sourcebook 2006/2007

Spiraling R&D expenses and decreased output

NME

LCM

Worldwide R&D spend

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© Dr. Thomas Wilckens, InnVentis

Source: USFDA / DH Analysis

Biotech companies have a larger share of innovative approved drugs

Innovativeness of FDA approved drugs (2001


2007)

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© Dr. Thomas Wilckens, InnVentis

Biotech companies appear to deliver more cost effective

Source: Ernst & Young

R&D expenditure per NME approval [US $bn]

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© Dr. Thomas Wilckens, InnVentis

Early
-
Stage preclinical programs are becomming overprized


Source:

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© Dr. Thomas Wilckens, InnVentis


Available early
-
stage compounds are plentiful


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© Dr. Thomas Wilckens, InnVentis

Late
-
stage deal value drivers do not apply to early
-
stage deals:

Inlicensing requires leadership in science to allow qualified risk assessments


Predicting success of Phase III is a
no brainer
, anticipating success of preclinical
products relies on factors like asking the right questions, i.e. qualified science

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© Dr. Thomas Wilckens, InnVentis

Innovation is hindered by a variety of factors

Innovation

Killers

Strategic dissonance

Poorly funded goals

Short horizon of expectation

Dinosaurs & Dynasties


Poorly aligned strategic and
organizational metrics


Redundancies and competition for power
and influence as well as financial support


Gap between financial restrictions
in funding “chaotic” science and
expectation of innovation


Measure of NMEs entering clinical
development as sole performance
criterion


Disregarding scientist thinking and
motivation


Dominance of old established
research dogmas including
collaboration and technologies


Consumption of disproportional
amount of resources

Lack of leadership


Creative teams generate innovative
concepts and ideas but lack leader
implementing their ideas

Entrepreneurship and motivation


Lack of entrepreneurial leaders
and related incentives


Lack of talents and related career
tracks

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© Dr. Thomas Wilckens, InnVentis

B.

Bayer Schering outside
-
in

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© Dr. Thomas Wilckens, InnVentis

The diverse therapeutic areas of both Bayer and Schering have been
consolidated to four focus areas creating R&D synergies

Source: Bayer HealthCare Investor Day June 2007

Bayer Schering Pharma therapeutic area focus

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© Dr. Thomas Wilckens, InnVentis

Overlapping research portfolios with regard to common modes of action result
in synergies; can these be sustained and optimally exploited?

Source: Bayer HealthCare Investor Day June 2007

Overlap of research ares

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© Dr. Thomas Wilckens, InnVentis

Outside analysis of Bayer Schering’s strengths/weaknesses in R&D


Focus on disease areas with some
synergistic overlap


Leading expertise in steroid hormone
chemistry & biology & pharmacology


In
-
house competency and assets in pre
-
selected chemical libraries and compound
research tools


Expertise in formulation technologies,
liposomes, PEGylation, …


Managerial leadership and creativity


Leadership in selected market segments


Promising late stage pipeline


Pipeline: relatively few innovative projects


Patents expiration of major products in 2 years


Restrictively defined segments in market may
not allow enough freedom for innovative
research and opportunistic products


Current inhouse technology focus (from outside)
may not enable to a first in class


No evident synergistic value chains in R&D


To much reliance on the FIPCO principle


External R: Scattered collaborations which may
not optimally leverage the internal focus


Lack of established in house competence
building and learning strategy


Access to cutting edge enabling technologies?

Strengths

Weaknesses

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© Dr. Thomas Wilckens, InnVentis

C.
Concepts to increase efficacy and lower risks

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© Dr. Thomas Wilckens, InnVentis

Optimizing R&D: selected hurdles and traps:

The Target & Technologies Project generation Trap:


Lack of substantial target knowledge:


Most innovative targets are poorly understood with respect to





their physiological function and potential for undesired effects






Few disease mechanisms are understood in detail






Disease remain complex and are polygenic in origin


Polypharmacology:



Large
-
scale mapping of polypharmacology interactions reveals





promiscuity of drugs and leads across the proteome.










Polypharmacology on a firm practical and theoretical footing





is a major challenge for the development of future






safe and clinically differentiated therapies






Example: Kinase inhibitors like NEXAVAR


The odds are against new targets:


3% chance to reach preclinical development for a NCE





against a new target versus 17% for a validated target



Does

a

lack

of

willingness



Failures

still

incease

contrasting

an

exponential

amount

of

data


for

the

killer

question

82
%

(
1996
-
99
)

to

91

%

(
2001
-
06
)

explain

late

stage

failure?
















Diverting and exploding technologies:


Drug development for emerging targets becomes increasingly





complex, costly and often lacks substantial validation


The innovation gap:



Pharma must aim to create space and incentives for enterpeneurship






Nature Reviews Drug Discovery 2006/2007

Drug Discovery Today 2006/2007

Windhover 2006

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© Dr. Thomas Wilckens, InnVentis

Optimized drug discovery: creation of synergistic “assembly lines”

Aligning a target family or disease mechanism with cutting edge technologies

Selected key issues for early stage project priorization:



Datapool on target family or disease mechanism for biology/physiology: validated/innovative, expression profiles, ….



Analysis for potential of undesired and/or off
-
target effects: identification of therapeutic windows,



Drug delivery/Formulation/Pharmacology: Route of Admin; comfort versus efficacy



Competing technologies/target approaches: requirement to be create a
significant

better drug to get approved



Surrogate markers & animal models


Project 1

Project n

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© Dr. Thomas Wilckens, InnVentis

Optimizing an R&D organization for Innovation:


A recently proposed industry model and its inherent problems

Architectural & cultural
problems :


Internal competion for
resources eliminates know
-
how transfer

Internal competions obviates
objective risk assessment


Internal career development
is the only motivation driver
that does not build
identification with a project

Innovation is not driven by
the best scientists in the field




Lack of in house scientific
leadership hinders project
evaluation and risk
assessment

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© Dr. Thomas Wilckens, InnVentis

Internal clinical development

Building leadership in drug
delivery, formulation
technologies and Med. Chem.

External/internal preclinical

development focussed on
disease mechanisms and/or
target families


Projects centered around
disease mechanisms and/or
target families;
team/Company



Team/
Company 1
Team/
Company 2
Team
/Comp. n+1

Interactiver knowledge transfer

Pharma‘s and Biotech „service“ platform:



in silico

services



eBiology



expression profiling/assay development



animal or other disease models

Interdependent external

and internal review and

risk assessment

Optimizing an R&D organization for Innovation:


Adopting entrepreneurial experience and spirits

Input on formulation/drug
delivery/PK etc for
project review

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© Dr. Thomas Wilckens, InnVentis

Optimization of the project/target selection & technology platforms

Marketed SMD drugs per target class in 2002:

SMDs comply with rule of five


Focus on successful, drugable targets and established disease mechanisms

BS core markets center around nuclear hormone receptors, enzymes and signalling pathways;

i.e. BS is ideally positioned to exploit the most successful target classes by „cheap“ SMDs

Drugable genome as of 2002


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© Dr. Thomas Wilckens, InnVentis

Bayer Schering: a leader in sex steroid related drug development

HSD: Hydroxysteroid Dehydrogenase

KSD: Hydroxysteroid Reductase


Pre
-
receptor

control of hormone
activation
-
inactivation


11ßHSD
-
1/2

BS existing IP targets:



Nuclear receptors:


ER
-

β
, SERMS



Transcription factors



Steroid hormone


metabolising enzymes

Indications:



Birth Control, m/f



Cancers



Cardiovascular D.



Prostate Cancer



Osteoporosis



Endometriosis



Angiogenesis



Leukemias



Alternative Options:



SLE, MS


Targets involved in sex steroids actions and signalling pathways: a synergistic R&D project pipeline

α
/
β

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© Dr. Thomas Wilckens, InnVentis

Optimized drug discovery:


Kill early
-

kill cheap
versus

Repositioning & Recycling

Schering’s SEGRAs as an example:



The concept (A) of separating side effects from


desired effects by “dissociated” glucocorticoid


receptor ligands SEGRAs is highly controversial


and not support by existing data (B)



There might be no more rational to further develop


these compounds in the clinic studies



The compounds, however, are a most valuable


research tool and could result in the discovery of


novel biological targets and therapeutic concepts



Novel applications might derive when drug


delivery complements the biological effects?

Consequences and actions to be taken:



Distribute compound to research groups



Compare compound biological profiles



Generate extended data pool



Identify desired tissue/disease related effects



Identify drug delivery options



Avoid high profile clinical failure

Schäcke, H., Berger, M., Rehwinkel, H., Asadullah, K.

SEGRAs: Novel ligands with an improved therapeutic index,

Molecular and Cellular Endocrinology
(2007), in press


Clark, A.R., Anti
-
inflammatory functions of glucocorticoid
-
induced genes,

Mol. Cell. Endocrinol. (2007), in press


Kleiman, A., Tuckermann, J.P., Glucocorticoid receptor action

in beneficial and side effects of steroid therapy: Lessons from conditional knockout

mice,
Molecular and Cellular Endocrinology
(2007), in press




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© Dr. Thomas Wilckens, InnVentis



Build multi
-
disciplinary
-
crossfunctional
teams



Establish in a
rigid review
built on
scientific
leadership



Establish early
stage biotech

collaborations



Project pool via

incubator/PPP



Use a corporate
fund to access
key
technologies



Focus on
emerging target
families


SMDs



Focus on
“opportunistic”
disease
mechanisms



Focus on
proven

drugable targets



Focus on
targets with
strong scientific
data pool



Leverage
technologies
over synergistic
projects



Establish tech
-
leadership in
distinct areas



Incorporate
external know
-
how at any level



Outsource too
dynamic
technologies



Outsource
rarely needed
technologies


Focus on disease
mechanisms



Identify synergistic
therapeutic
applications



Identify
opportunistic
therapeutic
applications



Actively
commercialize
unexploited
projects/IP
through out
-
licensing, spin
-
out,
partnering



Project Generation

Targets & Disease
Mechanisms

Technologies

Disease Areas

Pipeline generation can be tackled along several dimensions


Strengthen and
qualify inhouse
personal



Identify academic
leaders



Generate
competence
networks with
academia



Develop new
career tracks



Identify
entrepreneurs
and scientific
talents




Scientific
leadership

Overview of potential levers to improve R&D efficiency: Science & Technology

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© Dr. Thomas Wilckens, InnVentis


PM "self
-
conception" of defender
of project rather than "chief critic"
of project


Fear of too high attrition rate by
management


Political barriers between line
functions


Attitude or practice of avoiding
"blame" for failure by line
managers (negative image)


Competition for ressources


Identification & access to key
technologies




Establishing a pilot project along a defined core competence and product area

Actions to be taken

Barriers/challenges

What is the time horizon?

Key players

Function(s) engaged:

Buy
-
in needed (Decision Makers):

1

2

4

3


Members of all relevant R&D functions


Preclinical Res
earch
, Drug Dis
covery,
Toxicology, Pharma
cokinetics
, Drug
Delivery/Formulation


Clinical De
loment

, CMC,

Regulatory
Affairs, Safety, Quality


Project champion(s)




Executive board


6
-
12

months





Design detailed project



c
lear definition o
f goals


clear definition of t
echnologies


clear identification of team


identify talent tracking system


milestone tracking system




Steering committee






Engage review
b
oards



i
nternal experts



ixternal experts




Establish follow
-
up
evalua
tion

methods

a

b

c

d

Short term pilot projects allow a dynamic adaptation and implementation of experiences in order to
change the organization for long term challenges while creating an increasing level of interal acceptance

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© Dr. Thomas Wilckens, InnVentis

InnVentis offerings:

Cutting
-
edge insight in R&D co
-
operations and business innovative models


Translational Research Centers at US 60 AHC until 2012 with annually 500 M US$



Insight in recent early
-
stage deals in enabling technologies and selected product areas

3

Streamlined unbiased outside view available from different resources and experts


Long
-
standing observation of Bayer
-
Schering products and technologies


In depth knowledge on scientific and technological challenges possibly immanent in BS pipeline

1

Cutting
-
edge insight in emerging technologies:


InnVentis’ has access to technology leaders in each R&D segment


InnVentis know
-
how evolved in BS core areas of interest

2

Flexible interactions models:


Identification & implementation of specifically tailored pilot projects


Services range from external reviews to implementation/re
-
organization of R&D

4

InnVentis’ knowledge and services are modular and complement “classic” consulting services

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© Dr. Thomas Wilckens, InnVentis

Epilogue

Science Business, Gari P. Pisano,

Harvard Business School Press, 2007

Can Science be a business? It would appear that the answer,
based on the experience to date would be no.


This answer is, however, only correct, if we take existing
organizational and institutional arrangements and existing
management technologies as given

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© Dr. Thomas Wilckens, InnVentis

X.

BACKUP

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© Dr. Thomas Wilckens, InnVentis

Molecular biology & actions of GC receptors: a stochastic event

Unexpected complex pathways & interactions constitute a major challenge in drug development

New emerging targets require complementary tools and know
-
how for validation, while focussing on
biological pathways assures cutting
-
edge leadership, a sustained solid project flow and USP

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© Dr. Thomas Wilckens, InnVentis

Glucocorticoids: Key regulators of gene expression, apoptosis & anoikis

Source: Rhen, T. and J. A. Cidlowski (2005). N. Engl. J. Med. 353: 1711. / CEPTON

Product options create synergies



SEGRAs ?



11
-
beta
-
HSD
-
Inhibitors



Targeted GC
-
agonists/antagonist



NfkB
-
Inhibitors



IkB
-
Kinase
-
inhibitors



Drug Delivery options

Related Diseases & Mechanisms:



Cancer



Cardiovascular Diseases



Dermatological



Asthma



Inflammation/



Metabolic Syndrome



Angiogenesis, Apoptosis,…


GC effects:
most successfully targeted and still underexploited

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© Dr. Thomas Wilckens, InnVentis

Optimized drug discovery:

Incorporation of f
ormulation & drug delivery in early stage project design



systemic i.v. GC for 7 days reduced arthritis scores by 50% (not shown)



1x GC
-
liposomes enhanced efficacy 10 fold by reduces systemic effects



α
v
β
3 integrins
-
targeted liposomes induce long term remission



GC
-
Liposomes are in Phase II, nanoparticles and other to follow



targeted Drug Delivery new IP, access to new indications and therapeutic concepts



applicable to several BS compounds and in exploratory projects

Konig et al. (2006).
Arthritis Rheum.

54/4:
119


PBS

7 x GC

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© Dr. Thomas Wilckens, InnVentis

Nuclear receptors: a basic principle beyond steroids hormones

Novel targets will be identified along a a rigid focus on biologic principles

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© Dr. Thomas Wilckens, InnVentis

Increasing complexity of signalling pathways:

A clear focus assures building a core expertise and new early stage target access

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© Dr. Thomas Wilckens, InnVentis




Optimized drug discovery:

The technology explosion and increased resource requirements

NPG CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 81 NUMBER 1 | JANUARY 2007


In silico

technologies are on the rise:


Structure
-
based Drug Design replaces HTS


Chemoinformatics complements MedChem


eBiology identifies target/disease associations


Staying cutting
-
edge requires flexible interactions

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© Dr. Thomas Wilckens, InnVentis

Knowledge management: a “simple” a tool to lower development risk

Data integration: a key to successful project evaluation


Medline Hits, title & abstract


“steroid, glucocorticoid, estrogen”



216.488


“Vascular endothelial growth factor, VEFG”




19.235


“CTLA
-
4 antibody”







440


“CD28 superagonist” (Tegenero)




28




Target selection: a dynamic process for a specific target class; selected topics



Ontologies; is there a natural ligand/inhibitor for the target; what are its functions?



KO versus conditional knock
-
out, knock
-
in



Biomarkers, models systems


Drugability, Drug Delivery, tissue
-
, organ
-
specific versus systemic drug target



Available tools: iRNA, SMDs, expression profiling, labelled SMDs or antibodies,….



What is the killer experiment beyond ADME/Tox?




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© Dr. Thomas Wilckens, InnVentis

Phase of Clinical Development Among Companies with FDA
-
Approvable Products &
Emerging Company Activities



Figure 12
Company Stage of Development by Clinical Phase
Phase I, 22%
Phase II, 7%
Phase III, 15%
Preclinical, 41%
Phase IV, 15%
Figure 7
Company Activity
Medical device,
17%
Other, 13%
Research and
development,
70%
Contract
research and
testing, 17%
Production and
manufacturing,
20%
Successful exploitation of wealth of affordable early stage projects requires focussed approaches

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© Dr. Thomas Wilckens, InnVentis

Translational Research: Public Private Partnerships

Win
-
win scenarios that assure cutting
-
edge drug discovery and development


Access to untapped financial resources
to address societies medical needs


New therapies for unmet medical need


Commercial benefit for “non
-
profit”
organizations and academia by
participating in the value growth


Creation of increased pool of knowledge
and ideas


Potential to address orphan diseases
and commercially unattractive markets;
i.e. tropical disease, antimicrobials


Educating scientists and MDs to
address future challenges in R&D


Leveraging cost & risk


Access to early stage projects


Access to emerging technologies


Cutting
-
edge “brain drain”


Creation of a knowlegde leadership &
USP in the targeted research segments


Sand
-
box for new R&D ideas and
concepts for innovative business
models


Access to public financial resources


Access to qualified human resources


Image benefits



Public Health & Academia

Industry

Public Private Partnership values