The Rising Interest in the Rare Disease Model Could Have a Critically Important Role into Biomarker’s Implementation for Stratified Medicine.

1. April
15,
2012
Strategic
Clinical
Innova1on
1

2. Candida
Fratazzi
MD
President
BBCR,
LLC
www.bostonclinicalresearch.com
S023
room
350
D-­‐F
10:30-­‐
11:30AM
Rising
interest
in
the
Rare
Disease
model
could
have
a
cri1cal
role
into
Biomarker’s
implementa1on
for
Stra1fied
Medicine
2

3. Learning
Objec1ves
• Understand
drug
development
challenges
• Biomarkers
per
pa1ents
selec1on
and
efficacy
evalua1on:
an
orphan
disease
case
study
• Discuss
strategic
clinical
innova1on
and
stra1fied
medicine
3

4. Innova1ve
Strategies
are
overdue
4

5. Which
are
the
causes
• Gaps,
that
cost
1me
and
money,
appear
in
the
clinical
research
process
• Protocols
wriVen
for
top
line
visualiza1on
that
may
be
lacking
scien1fic
rigor
• Clinical
strategies
and
plans
may
be
myopic
and
miss
greater
op1ons
• Increasing
regulatory
demand
for
transparent
study
results
and
cross
AEs
5

6. S t r a t e g y
a n d
I n n o v a 1 o n
6

7. Bridging
research
and
clinical
trials
Focus
on
clinical
strategy,
early
plan
and
study
design
7

8. Strategic
Clinical
Innova1on
is
a
bridge
• Links
preclinical
data
with
unmeet
medical
needs
• Matches
study
endpoints
with
study
objec1ves
• Connects
product
poten1al
to
treatment
benefits
• Creates
cohesive
phase
I/II
studies
to
support
first
in
man/POC
objec1ves
8

9.
Bridging
the
Chasm
Pre-­‐clinical
research
meets
FPI
Protocol
Synopsis
Trial
Design
Biomarkers
Protocol
Implementa:on/
Discovery
/
Pre-­‐Clinical
Objec1ves/
Endpoints
Safety
/
Tox
Data
Pa1ents
Selec1on
CRO
Strategy
Discovery
Pa1ents
Data
Safety
Disease
Regula1on
Pa1ents’
Staging/
Needs
KOL
9

10. S t r a 1 fi e d
M e d i c i n e
i s
t h e
g o a l
10

11. Choose
the
RIGHT
DRUG
at
the
RIGHT
DOSE
for
the
RIGHT
GROUP
OF
PEOPLE
Responders
Non-Responders
Adverse Drug Events
11

12.
Beneficial
to
some
12

13. Harmful
to
others
13

14. Advantages
of
Stra1fied
Medicine
• Avoid
adverse
events
Ø 2.2
million
people
are
hospitalized
and
100,000
deaths
occur
each
year
due
to
adverse
effects
of
prescrip1on
drugs
• BeFer
treat
disease
Ø Development
of
predic1ve
markers
would
allow
for
earlier
treatment
• Iden:fy
novel
drug
targets
Ø
Current
drugs
are
based
on
less
than
500
targets
14

15. B i o m a r k e r s
a r e
t h e
t o o l s
15

16. Why
Biomarkers
are
important
16

17. Biomarker
defini1on
A
molecule
that
indicates
an
altera1on
of
the
physiological
state
of
an
individual
in
rela1onship
to
health
or
disease
state,
drug
treatment,
toxins
etc.
Biomarkers
are,
by
virtue
of
their
short
term
availability,
predictors
of
long
term
events
17

18. Biomarkers
connect
Qualified
biomarkers
Biology
Clinical
endpoints
A qualified biomarker must link biology and
clinical end-points
18

19. Different
types
of
biomarkers
• Screening
markers:
markers
discrimina1ng
the
healthy
state
from
beginning
of
disease
state
preferen1ally
in
an
asymptoma1c
phase
(
cancer
makers
for
early
diagnos1c)
• Prognos:c
markers:
once
the
disease
state
is
established
predict
the
likely
course
of
the
disease
19

20. Different
types
of
biomarkers
• Stra:fica:on
markers:
predict
the
likelihood
of
a
response
to
a
drug
before
star1ng
treatment
classifying
pa1ents
in
responders
and
non-­‐
responders
• Efficacy
markers:
monitor
the
efficacy
of
a
drug
treatment
20

21. Biomarkers
in
clinical
innova1on
• Biomarkers
that
validate
the
importance
of
the
target
in
Target
Valida1on
human
disease
Target/Compound
• Biomarkers
that
define
the
direct
interac1on
of
the
Interac1on
compound
with
its
discrete
target
Pharmacodynamic
• Biomarkers
that
define
consequences
of
compound
Ac1vity
(PK/PD)
interac1on
with
the
target
rela1ve
to
PK
Disease
Biomarker
&
Disease
Modifica1on
•
Biomarkers
that
correlate
with
disease
Pa1ent
selec1on
and
•
Biomarkers
that
define
likelihood
of
pa1ents
to
respond
Stra1fica1on
21
(or
not)
to
the
compound

22. O r p h a n
D i s e a s e
i s
t h e
m o d e l :
C a s e
S t u d y
22

23. Gaucher
disease
Type
1
Challenge
Develop
the
new
ERT
in
an
orphan
popula1on
when
a
very
similar
product
had
the
market
monopoly
for
about
15
years
• Very
limited
number
of
naïve
pa1ents
• Newly
diagnosed
pa1ents
presented
with
early
symptoms
• Treated
pa1ents
had
improvement
on
many
of
the
clinical
features
23

24. Gaucher
disease
Type
1
Strategy
Create
a
clinical
innova1ve
strategy
and
trial
designs,
which
would
require
a
feasible
number
of
pa1ents,
and
1ght
pa1ents’
selec1on
with
study
endpoints.
Select
validated
biomarkers’
assay
with
known
intra-­‐assay
and
intra-­‐personal
variability.
Work
with
the
Regulatory
agency
upfront
to
validate
approach.
Understand
physicians
and
pa1ents
expecta1ons
versus
current
standards
of
care.
24

25. Gaucher
Disease
• Rare
disease
with
a
prevalence
1:50,000-­‐
100,000;
Type
1
is
the
most
common
Gaucher
variant
• Disease
expression
varies
from
asymptoma1c
to
significant
morbidity
• Disease
progression
in
Type
1
Gaucher
disease
occurs
over
decades,
possibly
shortens
life
expectancy
25

26. Gaucher
Disease
• Inherited
deficiency
of
lysosomal
enzyme
glucocerebrosidase
(GCD)
• Accumula1on
of
glucocerebroside
in
macrophage
lysosomes
(liver,
spleen,
bone
marrow,
brain)
• 3
variants:
type
1,
2,
and
3
26

27. Gaucher
Disease
type
1
-­‐
Clinical
Features
• Hepatosplenomegaly
• Hypersplenism
• Hematological
abnormali1es
(anemia,
thrombocytopenia)
• Lung
disease
• Bone
disease
(pain
crises,
fractures,
osteonecrosis)
• Non-­‐neuronopathic
(Types
2
&
3
are
neuronopathic)
27

28. Study
Endpoints
• Change
from
baseline
– Hemoglobin
– Platelet
count
– Spleen
volume
– Liver
volume
28

29. Summary
The
proposed
clinical
strategy
was
successful,
and
the
product
was
approved
29

30.
Clinical
Strategy
Success
• Overall
clinical
development
program
well
planned
• Clinically
meaningful
endpoints
– Natural
history
well
understood
• Each
trial
had
a
dis1nct
purpose
– studies
supported
an1cipated
use
in
both
treatment
naïve
and
switching
pa1ents
30

31. C o n c l u s i o n
31

32. Safer
and
more
Effec1ve
drugs
32

33. Strategic
Clinical
Innova1on
approach
• Develop
Early
Roadmap
• Create
Strategic
Clinical
Plan
• Customize
trial
design
• Op1mize
pa1ent
selec1on
• Visualize
goals,
ac1on
plan
and
op1ons
• Maximize
early
stage
product-­‐value
33

34. Strategic
Clinical
Innova1on
advantages
• Accelerate
enrolment
• Increase
inves1gators’
interest
• Facilitate
IRB
approval
• Reduce
pa1ents
withdrawn
from
the
study
• Reduce
blames
for
bad
trial
execu1on
• Increase
study
success
rate
34

35. Q u e s t i o n s
?
? !
35

36. Disclosure
I
have
no
relevant
financial
rela1onship
in
rela1on
to
this
educa1onal
ac1vity
36