Expert Patient Advocates & 21st Century Therapies Forum Nov 19 - 20, 2015

1. Durhane Wong-Rieger, PhD
President,
Canadian Organization for Rare
Disorders
November 2015
Canada Managed Access Case
Studies: What Works, What Doesn’t

2. What
is
aHUS
— Atypical
Hemoly3c
Uremic
Syndrome
(aHUS)
is
a
life-­‐
threatening
and
progressive
ultra-­‐rare,
gene3c
disease
that
causes
the
forma3on
of
blood
clots
throughout
the
body,
which
can
lead
to
stroke,
heart
aBack
and
kidney
failure.
The
disease
can
affect
both
adults
and
children.

3. What
is
Soliris
(eculizumab)
— Eculizumab
is
a
monoclonal
an3body
and
has
a
Health
Canada
indica3on
for
the
treatment
of
pa3ents
with
aHUS
to
reduce
complement-­‐mediated
thrombo3c
microangiopathy
(TMA).
Eculizumab
is
approved
for
adults
and
adolescents
and
approved
with
monitoring
for
children
less
than
13
years
of
age.

4. Pa3ent
submission:
Current
therapy
— Plasma therapy “virtually ineffective” in acute
phase to stop systemic clotting or control
systemic thrombosis
— PT
only
in
major
hospitals;
pa3ents
must
travel,
increasing
3me
and
financial
burdens
on
families;
children
miss
30-­‐40%
of
school
year,
parent
has
20-­‐40%
absenteeism
from
work
— PT
and
dialysis
merely
buy
3me
before
end
stage
renal
disease;
pa3ents
not
eligible
for
kidney
transplant.
Hemodialysis
requires
at
least
4
hours,
3
days
per
week.

5. Pa3ent
submission:
Soliris
experience
— Soliris
controls
systema3c
cloWng
throughout
the
body,
increasing
the
odds
of
survival
and
allowing
a
pa3ent’s
kidneys
to
be
saved
even
in
the
acute
phase.
Soliris
clearly
controls
complement
ac3vity
beBer
than
plasma
therapy,
which
becomes
ineffec3ve
over
3me.

6. CDEC:
Eculizumab
Not
Be
Listed
for
aHUS
— No
established
clinical
benefit
from
2
uncontrolled
prospec3ve
studies;
no
clear
diagnos3c
criteria,
no
comparator
group,
short
follow-­‐up,
and
lack
clinical
outcomes
data.
— Small
sample;
subpopula3ons
likely
to
benefit
not
iden3fied
— No
evidence
of
impact
on
renal
complica3ons
and
mortality

7. PBAC
(Australia):
Eculizumab
for
aHUS
— March
2014:
Only
through
special
arrangements
¡ Pa3ents
who
achieve
remission
would
be
discon3nue
a^er
six
months
¡ Managed
Entry
Scheme:
price
to
be
jus3fied
by
evidence
÷ Newly
diagnosed
and
nondialysis
pa/ents
achieve
complete
remission.
÷ Rebates
to
PBAC
¢ Par$al
rebate
for
dialysis
pa$ents
not
achieving
normal
renal
func$on
¢ Full
rebate
for
pa$ents
who
fail
to
achieve
25%
improvement
in
renal
func$on,
die
in
6
months
or
have
ESRD

8. PBAC
(Australia):
Eculizumab
for
aHUS
— June
2014:
PBAC
proposed
review
at
12
months
(not
company’s
24
months)
based
on
available
evidence
and
significant
cost
differen$al;
welcome
(rapidly)
emerging
data
for
reconsidera$on
— July
2014:
¡ PBAC
proposed:
Con$nua$on
criteria
aQer
12
months
treatment
if
pa$ent
demonstrates
both
response
AND
evidence
of
severe
cardiac,
neurological,
or
pulmonary
impairment
OR
serious
chronic
kidney
disease
¡ Sponsor
proposal:
pa$ents
at
higher
risk
of
either
early
mortality
or
significant
morbidity,
given
(accepted)
CT
data
that
long-­‐term
eculizumab
inhibits
TMA
and
improves
renal
func$on;
no
evidence
that
short-­‐term
eculizumab
achieves
[same]
long-­‐term
benefits
of
con$nuous
therap
— August
2014:
Government
to
proceed
with
lis$ng
without
MES
or
rebated

9. NICE
(UK)
Observa3ons
re:
Soliris
for
aHUS
— In
all
of
the
studies,
treatment
led
to
a
substan3al
reduc3on
in
thrombo3c
microangiopathy
ac3vity,
and
improvement
in
kidney
func3on
and
quality
of
life
in
most
pa3ents.
— Clinical
experts
remarked:
benefits
seen
beBer
than
originally
an3cipated.
Many
pa3ents
were
able
to
stop
dialysis,
and
non-­‐renal
benefits,
e.g.,
GI
symptoms.
— CommiBee
concluded
eculizumab
a
very
effec3ve
treatment
op3on
for
pa3ents
with
aHUS.

10. NICE
Recommenda3ons
re:
Soliris
for
aHUS
— Eculizumab
recommended
for
funding
if
all
following
condi3ons
¡ Coordina3on
of
use
through
an
expert
centre
monitoring
systems
¡ Na3onal
protocol
for
star3ng
and
stopping
eculizumab
when
used
for
clinical
reasons
¡ Research
programme
with
robust
methods
to
evaluate
when
stopping
treatment
or
dose
adjustment
might
occur.

11. CDEC
2nd
Recommenda3on
Soliris
for
aHUS
— Ra3onale
¡ RCT
could
be
very
challenging,
due
to
the
rarity
of
aHUS.
¡ Clinician
and
pa3ent
comment:
Plasma
exchange
provides
modest
symptom
relief
but
limited
long-­‐term
efficacy
— Proposed:
pa3ents
who
meet
all
three
diagnos3c
criteria
¡ Confirmed
diagnosis
of
aHUS
at
ini3al
presenta3on,
defined
by
presence
of
TMA
¡ Evidence
of
ongoing
ac3ve
TMA,
defined
by
laboratory
test
abnormali3es
despite
plasmapheresis
(minimum
of
4
plasma
exchanges
required
over
4
successive
days).
¡ Evidence
of
at
least
one
of
the
following
documented
clinical
features
of
ac3ve
organ
damage
or
impairment:
÷ Kidney
impairment

12. What
is
TSC
— Tuberous
sclerosis
complex
(TSC)
is
a
gene3c
disease
wherein
non-­‐malignant
tumors
develop
on
vital
organs,
including
the
brain,
heart,
kidneys,
lungs
and
skin
— TSC
primarily
affects
central
nervous
system;
may
manifest
as
developmental
delays,
intellectual
disabili3es,
behavioral
problems,
seizures
and
au3sm
— Other
features
include
kidney
diseases
and
skin
abnormali3es

13. Health
Canada/EMA
Regulatory
Approval
— Everolimus
treat
benign
(non-­‐cancerous)
tumours
caused
by
TSC
¡ Shrank
brain
tumours
(SEGA)
by
half
in
approximately
30%
of
pa3ents
and
by
about
a
third
in
around
70%
of
pa3ents
¡ Shrank
kidney
tumours
in
angiomyolipoma,
(AML)
pa3ents
by
half
in
42%
of
pa3ents
— Everolimus
helps
block
mTOR,
which
controls
cell
division
and
the
growth
of
blood
vessels

14. CDEC:
Do
Not
List
Soliris
for
aHUS
— In
DB,
RCT,
reduced
size
of
angiomyolipomas
(AML)
in
42%
of
treated
pa$ents.
However,
not
defini$vely
established
that
reduc$on
in
AML
size
is
correlated
with
a
reduc$on
in
bleeding
complica$ons,
avoidance
of
surgery,
or
long-­‐term
preserva$on
of
renal
func$on.
—
CDEC
considered
subpopula$ons
of
pa$ents
for
whom
everolimus
could
be
recommended
(e.g.,
those
who
are
experiencing
AML
growth
and
who
are
not
candidates
for
surgery);
however,
there
was
no
evidence
for
making
such
recommenda$ons

15. CDEC:
Do
Not
List
Soliris
for
aHUS
— Lack
of
evidence
defini$vely
linking
a
reduc$on
in
tumour
size
to
clinically
relevant
outcomes
such
as
bleeding,
renal
func$on,
and
quality
of
life
precluded
an
analysis
of
cost-­‐effec$veness.
— Cost
effec$veness:
ranges
from
$40,254
to
$59,901
over
one
year
compared
with
standard
care.
but
substan$al
uncertainty
¡ Watchful
wai$ng
(ac$ve
monitoring)
might
be
an
appropriate
comparator.
In
the
absence
of
analysis,
cost-­‐effec$ve
is
unknown.

16. Ontario
Lis3ng
Soliris
for
aHUS
— For
treatment
of
AML
with
all
the
following
condi$ons:
¡ Presence
of
coalescent
or
mul$focal
AMLs
in
either
one
or
both
kidneys;
AND
¡ AML
progression
despite
previous
emboliza$on
and/or
surgery;
AND
¡ Further
emboliza$on
and/or
surgery
not
recommended
due
to
a
documented
clinical
reason
— Case-­‐by-­‐Case
considera$on
will
be
considered
in
pa$ents
who
have
never
been
treated
with
invasive
procedures
such
as
emboliza$on
and/or
surgery.
— Exclusion
criteria:
pa$ents
with
SEGA
— Renewals:
No
AML
progression
or
reduc$on
in
AML
volue
¡
(i.e.
no
significant
new
lesions
and
increase
in
kidney
volume,
as
well
as
no
significant
AML
related
bleeding);
AND
¡ There
is
a
reduc$on
in
volume
of
AMLs
iden$fied
prior
to
treatment
with
the
everolimus.

17. What
is
PKU
(Phenylketonuria)
— Phenylketonuria
(PKU)
is
a
gene$c
disorder:
deficiency
or
absence
of
phenylalanine
hydroxylase
(PAH),
required
for
the
conversion
of
the
phenylalanine
(PHE)
to
tyrosine.
— High
PHE
levels
in
the
blood
and
brain
lead
to
complica$ons
including
abnormal
brain
development,
impaired
cogni$ve
ability,
mental
illness,
tremors,
and
seizures;
also
psychiatric
symptoms,
— Treatment
is
a
PHE
restricted
diet,
which
severely
limits
natural
protein;
may
require
nutri$onal
replacement
products
— Adherence
to
the
PHE
restric$ve
diet
is
difficult.
Discon$nua$on
may
result
in
asthma,
headaches,
eczema,
neurological
symptoms,
hyperac$vity
and/or
lethargy,
phobias,
and
depression

18. What
is
Kuvan
— Sapropterin
is
a
synthe$c
form
of
tetrahydrobiopterin
(BH4),
the
cofactor
for
Phe
hydroxylase.
It
is
approved
by
Health
Canada
in
conjunc$on
with
a
Phe-­‐restricted
diet
to
reduce
blood
Phe
levels
in
pa$ents
with
hyperphenylalaninemia
due
to
BH4-­‐responsive
PKU.
— Pa$ents
with
mild
PAH
deficiency
most
likely
to
respond
(25%
to
50%
overall)
— Two
DB-­‐RCTs:
¡ Change
in
blood
Phe
level
AND
Phe
supplement
tolerance
while
maintaining
[desired]
blood
Phe
levels
¡ Other
outcomes:
quality
of
life,
nutri$onal
status,
adverse
events,
and
serious
adverse
events
— Neither
trial
included
validated
measures
of
neuropsychological
performance,
quality
of
life,
growth,
or
diet
liberaliza$on

19. Pa3ent
input:
Kuvan
for
PKU
— Phe-­‐restricted
diets
were
described
as
complicated,
unpalatable,
and
financially
burdensome
in
the
case
of
pa3ents
who
do
not
have
coverage
for
low-­‐protein
foods.
— The
outcome
of
greatest
importance
to
pa3ents
is
the
ability
to
eat
a
more
ordinary
diet
while
avoiding
the
adverse
consequences
of
increased
blood
Phe
levels.
— Liberaliza3on
of
diet
is
expected
to
decrease
the
financial
burden
on
pa3ents
and
improve
their
quality
of
life.

20. CDEC:
Do
Not
List
Kuvan
for
PKU
— The
Canadian
Expert
Drug
Advisory
Commijee
(CEDAC)
recommends
that
sapropterin
not
be
listed.
— Although
the
Commijee
found
sufficient
evidence
that
sapropterin
lowers
blood
phenylalanine
(Phe)
levels
in
certain
pa$ents
with
phenylketonuria
(PKU),
the
submission
did
not
provide
sufficient
details
of
how
to
iden$fy
the
pa$ents
who
would
benefit
in
a
cost-­‐effec$ve
manner.
The
proposed
Kuvan
Starter
Program
is
suitable
only
to
screen
pa$ents
to
iden$fy
“responders,”
but
such
a
response
in
the
clinical
trials
did
not
differen$ate
low
response
from
clinically
important
response.
Star$ng
and
stopping
rules,
beyond
the
screening
stage,
that
are
linked
to
substan$ve
benefit
are
needed

21. California
Health
Services:
Kuvan
for
PKU
— Sapropterin
may
be
considered
as
an
adjunc$ve
therapy
for
any
PAH
deficient
client.
— A
trial,
not
to
exceed
two
months,
to
determine
responsiveness,
may
be
authorized
— At
least
one
of
the
following
criteria
must
be
met
to
determine
responsiveness
and
jus$fy
con$nued
therapy
with
the
medica$on:
¡ A
clinically
significant
reduc$on
in
blood
PHE.
A
30%
reduc$on
is
frequently
regarded
as
responsive
¡ An
increase
in
PHE
tolerance,
that
is,
increase
in
tolerance
is
determined
by
maintenance
of
low
blood
PHE
levels
or
improvement
in
neuropsychiatric
symptoms
with
increased
dietary
PHE.
¡ A
documented
improvement
in
neuropsychiatric
symptoms,
improved
seizure
control
or
enhanced
mental
func$oning
leading
to
improved
func$oning
at
school,
work
or
social
obliga$ons

22. Canada:
Consensus
Guidelines
Kuvan
for
PKU
— SubmiBed
to
Ontario
(March
2014)
¡ Have
hyperphenylalaninemia
requiring
treatment,
based
on
Phe
level;
AND
¡ Respond
to
Kuvan,
defined
as
a
decrease
of
blood
phenylalanine
levels
of
at
least
30%
from
baseline
during
a
4
week
Kuvan
challenge;
AND
¡ Demonstrate
therapeu3c
blood
phenylalanine
levels
while
on
Kuvan,
defined
as
blood
phenylalanine
levels
consistently
in
the
control
range
— Phenylalanine
control
will
be
audited
at
6
months
a^er
comple3ng
the
Kuvan
responsiveness
trial
and
therea^er
every
12
months.

23. Ontario
Access
Guidelines:
Kuvan
for
PKU
— Ini$al
6
months
paid
by
Manufacturer,
with
criteria
including
baseline
Phe
>
360
μmol/L
despite
low-­‐protein
diet
— Reimbursement
criteria
including
¡ Compliance
with
low
protein
diet,
AND
¡ Normal
sustained
blood
Phe
levels
OR
Sustained
blood
Phe
reduc$on
of
at
least
30%
or
50%
(depending
on
Phe
baseline)
¡ Demonstrated
increase
of
dietary
protein
tolerance
based
on
targets
set;
AND
¡ Clinically
meaningful
age-­‐appropriate
improvement
in:
neuro-­‐
behavioural
or
neuro-­‐cogni$ve
func$on
or
impairment;
OR
Demonstrated
improvement
in
QoL
using
peer
reviewed
validated
scales

24. Thank You!
November 2015Rare Disease Drug Access
Durhane Wong-Rieger, PhD
President
Canadian Organization for Rare Disorders
www.raredisorders.ca
416-969-7435
durhane@sympatico.ca