1
LeoLiving with hATTR Amyloidosis
Overview of Transthyretin amyloid (ATTR) amyloidosis
Ole B Suhr, Professor, M.D.Department of Publich Health andClinical MedicineUmeå University and University HospitalUmeå, Sweden.
Hereditary ATTR Amyloidosis(Familial amyloidosis with polyneuropathy, or FAP)
Mário Corino da Costa Andrade1906-2005. First large report on the disease
Brain 1952;75: 408-27First Swedish case. Andersson R, Kassman T. Acta Ophthalmol (Copenh) 1968; 46: 441-7.
Araki S et al. 1968 Arch Neurol. Chic) 18:593(picture courtesy of Ando Y)
In search of the protein (1980)
Amyloid and amyloidosis, 1980, Pavoa Vasim, Portugal
1. Tawara S. et al. Biochem Biophys Res Commun 1983; 116: 880-8. 2. Saraiva MJ et al. J Lab Clin Med 1983; 102: 590-603. 3. Connors LH et al. Amyloid 2003; 10: 160-84. 4. Westermark P et al. Proc Natl Acad Sci U S A 1990; 87: 2843-5. Hawkins et al. Ann Med 2015;47:625–38
Hereditary forms oftransthyretin amyloidosis (more than 130 mutations described)3
Senile systemic amyloidosis4
wild type TTR
Transthyretin (prealbumin)1,2
Produced by the liver (brain, eye).
» Nervous
– Autonomic-somatic neuropathy
– Central nervous symptoms
» Cardiac
– Arrhythmia
– Cardiomyopathy
» Gastrointestinal
» Kidney
» Eyes
» Misc: Charcot joint, carpal tunnel syndrome
Pictures courtesy of: Andersson R,Westermark P, and Ando Y.
Symptoms of disease
Case report» Woman of African descent
» At the age of 33 breast cancer, operated, recurrence at the age of 36, re-operated. Heart enlargement noted
» At the age of 39, onset of diarrhea, nausea, and vomiting, nutritional problems receive an endoscopic gastro-enterostomy. Develops faecal incontinence
» At the age of 41, disabling pain and progressive neuropathy
» At the age of 42, cardiac arrest, resuscitated by husband, receives a pacemaker.
» Biopsy: TTR-amyloidosis
» Gene testing: Ala45Gly
Evaluation at our centre:
» Positive bone scintigraphy for amyloidosis.
» Wheelchair bound, advanced autonomic neuropathy
» Adrenal insufficiency
» Too advanced disease for Tafamidis treatment
Bone-scintigraphy/CT
Treatment:
Does not tolerate Diflunisal
Heart/liver transplantation
discussed, but dies after a
new cardiac arrest at the age
of 42
Survival estimated to between 3 and 15 years from onset of symptoms
Swiecicki PL et al. Amyloid 2015;22: 123-31. Sattianayagam et al. Eur Heart J 2012; 33:1120-7. Benson MD et al. Am J Cardiol 2011; 108: 285-9. Connors LH et al. Am Heart J 2009; 158: 607-14. Kyle RA et al. Am J Med 1996;395–400. Ng B et al. Arch Intern Med 2005;165:1425–9.
Predominantly
heart
complications Predominantly
nerve
complications
Steady increase of new mutations in the Swedish population
(10 mutations during the last 10 years); likely related to increased disease awareness
Country ~ Number of Cases of hATTR with Polyneuropathy
USA 32002
Portugal 20003
Sweden 2503
Rest of EU-27 45004
Brazil >6005
Japan 4006
Estimated 10-15,000 afflicted patients worldwide1
Epidemiology of hATTR Amyloidosis with Polyneuropathy
Suggested pathway for amyloid formation1, and possible treatments
1. Halt production of circulating mutant TTR: Liver transplantation2
2. Decrease production of circulating TTR: Gene silencing3,4
3. Stabilise the TTR tetramer: Diflunisal, Tafamidis 5,6
4. Removal of Amyloid deposits: antibodies, Doxycycline 7,8
TTR-tetramer
Misfolded monomers
Full length TTR
B-fibrils1, 2 3
4
1. Hammarstrom P et al. Science 2003; 299: 713-6. 2. Holmgren G et al. Clin Genet 1991; 40:242-62. 3. Ackermann et al. Amyloid 2012;19(S1):43–4; 4. Coelho et al. N Engl J Med 2013;369:819–29. 5. Berk et al. JAMA 2013;310:2658–67. 6. Coelho T. et al. Neurology 2012; 79: 785-92. 7. Richards DB et al. N Engl J Med 2015; 373: 1106-14. 8. Cardoso I. et al. FASEB J2006; 20: 234-9.
None of the available treatments address CNS or eye complications
Factors related to amyloid fibril formation
» Concentration of amyloidogenic protein. The amyloid fibril formation process is concentration dependent1
» Mutant protein decreases stability2
» Age:
– Decreased efficacy of the immune system: antibody formation against misfolded protein3
– Decreased efficacy of housekeeping system for misfolded proteins4
1. Lachmann HJ et al. N Engl J Med 2007; 356: 2361-71. 2. Hammarstrom P et al. Science. 2003;299(5607):713-6.3. Obayashi K et al. Clin Chim Acta. 2013;419:127. 4. Santos SD et al. Journal of neuropathology and experimentalneurology. 2008;67(5):449-55
Importance of the concentrationof the amyloidogenic protein:
Regression of amyloidAA-amyloidosis
Henning Waldenströn, Acta Chir Scandinavia VolLXIII (1928)
From the department of surgical tuberculosis at St. Göran's Hospital, Stockholm, Sweden
Case III
Liver sizeOutline by ink
16/3 -25+++ hist.
1/4 -253% Proteinuria
1. Liver transplantation for ATTR amyloidosis
» Why perform liver transplantation and exchange a healthy liver?
– To decrease - eliminate the production of the amyloidogenicmutated transthyretin.
First liver transplanted ATTR amyloidosis patient.
Holmgren G et al. Clin Genet 1991; 40: 242-62.
Mutant TTR
0.
25.
50.
75.
100.
0. 5. 10. 15. 20.
Patient surv
ival (%
)
All TTR mutations (n=2044)
0.
25.
50.
75.
100.
0. 3.75 7.5 11.25 15.
Patient surv
ival (%
)
Years after transplantation
Val30Met - Early onset
Val30Met - Late onset
Non-Val30Met - Early onset
Non-Val30Met - Late onset
n=1342
n=170
n=109n=81
Ericzon BG et al. Transplantation 2015; 99: 1847-54.
3. TTR Stabiliser: Tafamidis/Diflunisal
Tafamidis trial: Efficacy in per
protocol analysis, but deterioration
on group level with time.
Efficacy only shown for ATTR
Val30Met amyloidosis patients in
stage I (walking without support)1,2,3.
Tafamidis is not approved in the US
Diflunisal trial: efficacy over 24
months demonstrated in a Phase
3 study, but deterioration noted in
treated patients. Long-term
outcome unknown. Not indicated
for hATTR amyloidosis
1. Coelho T et al. Neurology 2012; 79: 785-92. 2.
Coelho T et al.. J Neurol 2013; 260: 2802-14. 3.
Waddington Cruz M et al. Amyloid 2016; 23: 178-
83. 1 Berk JL et al JAMA 2013; 310: 2658-67.
Lack of efficacy of current treatments? additionalpathways for ATTR formation?
TTR-tetramer
Proteolytic clea-vage at residues46, 49 and 52
AmyloidogenicN-terminal fragment
A-fibrils
B-fibrils
Kelly JW et al. Adv Protein Chem 1997; 50: 161-81. Hammarstrom Pet al. Science2003; 299: 713-6. Thylen C et al. EMBO J 1993; 12: 743-8. Bergstrom J et al. Lab Invest 2004; 84: 981-8. Ihse E et al. Amyloid 2013; 20: 142-50. Mangione PP et al. Proc Natl Acad Sci U S A 2014; 111: 1539-44.
Misfolded monomersFull length TTR
The majority of ATTR amyloidosis patients currently without
effective treatment, a considerable unmet medical demand
Conclusions
» Currently, only a minor proportion of patients have a mutation/disease stage/phenotype that is suitable for available treatments
» Decrease production of the amyloidogenic protein (TTR), a promising therapeutic method that appears not to depend on amyloid formation pathways.
» However, no treatments are able to depress the amyloid formation caused by local TTR production in the eye or brain
Thank You!
20
Patisiran
Akshay K. Vaishnaw
Executive Vice President, R&D and Chief Medical Officer
21
Hereditary ATTR Amyloidosis (hATTR)
DESCRIPTION
Orphan disease caused by
mutant transthyretin (TTR)
amyloid deposits in nerves,
heart, gastrointestinal tract,
and other tissues
hATTR Amyloidosis with
polyneuropathy
10,000
hATTR Amyloidosis with
cardiomyopathy
40,000
Significant morbidity and fatal within
2-15 years from
symptom onset
PATIENT POPULATION*
~50,000worldwide
* Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012
22
Hereditary ATTR Amyloidosis with Polyneuropathy
Photos courtesy of Yukio Ando (Japan)
Inexorably Progressive Fatal Disease
Stage 1 Stage 2: Early Stage 2: Late Stage 34-5 yrs 2-3 yrs 1-2 yrs
23
Patisiran: Simple Approach to Treating a Complex DiseaseShutting Off Production of Disease-Causing Protein
Production of mutant and
wild type TTR
Neuropathy, cardiomyopathy
Organ deposition of monomers,
amyloid (β-pleated) fibril
Unstable circulating TTR
tetramers
Neuropathy, cardiomyopathy
stabilization or improvement
Organ deposition of monomers,
amyloid (β-pleated) fibril
prevented, clearance
promoted
Unstable circulating TTR
tetramers reduced
23
Patisiran acts to knock down both
mutant and wild type TTR production
Liver transplantation stops
mutant TTR production
Tafamidis stabilizes
TTR tetramer
24
Patisiran Phase 2 OLE Study Design
Timelines are not to scale
hATTR-PN patients previously dosed on Phase 2 trial eligible to roll over onto
Phase 2 OLE study
• Up to 2 years of dosing, 0.30 mg/kg every 3 weeks, with clinical endpoints evaluated every 6
months
• Primary objectives: Safety and tolerability of long-term dosing with patisiran
• Secondary objectives: Effects on neurologic impairment (mNIS+7 and NIS), quality of life, mBMI,
disability, mobility, grip strength, autonomic symptoms, nerve fiber density in skin biopsies, cardiac
involvement (in cardiac subgroup), serum TTR levels
W1 W2 W3
Adverse events
Serum TTR levels
mNIS+7, other
clinical measures
W1 W2 W3 W1 W2 W3
every 6 months
Cardiac biomarkers
d 0, 1, 3, 7, 17, 84, 168, 182, 231, 234…
0
0
0
0
W1 W2 W3 W1 W2 W3
Echo
d 0 (baseline)
d 0 (baseline)
d 0 (baseline)
every 3 months
every 6 months
OLE
Dose 1
OLE
Dose 2
OLE
Dose 3
OLE
Dose 4
OLE
(out to 2 years)
Patisiran dosing:
0.30 mg/kg IV q3w
25
Patisiran Phase 2 OLE Preliminary Study Results*Serum TTR Knockdown
• Mean serum pre-dose TTR knockdown of approximately 80%
• Mean serum TTR knockdown at 24 months of 84%
• Mean maximal serum post-dose TTR knockdown of 93%
• Maximal individual patient post-dose knockdown of 97%
• Similar TTR knockdown in patients on patisiran alone or on patisiran + TTR tetramer stabilizers
SEM: Standard Error of the Mean
*Suhr et al., ISA, July 2016; Data as of 12May2016
Me
an
(S
EM
) %
Se
rum
TT
R K
no
ck
do
wn
Rela
tive
to
Bas
eli
ne
100
80
60
40
20
0
Months0 2 4 6 8 10 12 14 16 18 20 22 24 26
Post-dose
Pre-dose
N=24-27 at all other time pointsN=21
N=22
N=23
26
Patisiran Phase 2 OLE Preliminary Study Results*Change in mNIS+7 Over 24 Months
*Suhr et al., ISA, July 2016; Data as of 12May2016
mN
IS+
7
0
25
50
75
100
125
150
Months
0 6 12 18 24
mNIS+7 component
Change from Baseline to Month 24 (N=24)
Mean (SEM) Median (range)
Total+ -6.7 (2.3) -6.8 (-34.6, 15.4)
NIS-weakness 1.38 (1.5) 0 (-13.5, 24.4)
NIS-reflexes -0.1 (0.5) 0 (-6.0, 7.0)
QST -7.7 (2.2) -6.0 (-40.0, 16.0)
NCS Σ5 -0.2 (0.2) -0.3 (-2.0, 2.5)
Postural BP -0.1 (0.1) 0 (-1.0, 0.5)
+Partial imputation was used to recover mNIS+7 data points where components were missing at one or more
replicate measurements (per patient/visit)
27
Patisiran Phase 2 OLE Preliminary Study Results*Change in mNIS+7 Over 24 Months
*Suhr et al., ISA, July 2016; Data as of 12May2016
mN
IS+
7
0
25
50
75
100
125
150
Months
0 6 12 18 24
mNIS+7 component
Change from Baseline to Month 24 (N=24)
Mean (SEM) Median (range)
Total+ -6.7 (2.3) -6.8 (-34.6, 15.4)
NIS-weakness 1.38 (1.5) 0 (-13.5, 24.4)
NIS-reflexes -0.1 (0.5) 0 (-6.0, 7.0)
QST -7.7 (2.2) -6.0 (-40.0, 16.0)
NCS Σ5 -0.2 (0.2) -0.3 (-2.0, 2.5)
Postural BP -0.1 (0.1) 0 (-1.0, 0.5)
+Partial imputation was used to recover mNIS+7 data points where components were missing at one or more
replicate measurements (per patient/visit)
28
Me
an
Δm
NIS
+7
fro
m b
as
eli
ne
at
24
mo
s
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
20
25
30
Patisiran Phase 2 OLE Preliminary Study Results*
SEM: Standard Error of the Mean
~ Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies1Adams D et al., Neurology. 85;675-682 (2015); #Predicted progression of median NIS value from Gompertz curve fit1
2Berk JL et al., JAMA. 310:2658-67 (2013); +Linear interpolation from 2-year NIS progression measurement in longitudinal analysis set† Patisiran results similar in patients with/without concurrent TTR stabilizer therapy; mNIS+7 using full mNIS+7 set; partial imputation was used to
recover mNIS+7 data points where components were missing at one or more replicate measurements (per patient/visit)
*Suhr et al., ISA, July 2016; Data as of 12May2016
Change in mNIS+7 at 24 Months
17 out of 24 patients (71%) with no change or an improvement in
mNIS+7 at 24 months compared to baseline
Individual ΔmNIS+7 at 24mos in Patisiran Ph 2 OLE
Me
an
(S
EM
) Δ
mN
IS+
7 f
rom
ba
se
lin
e a
t 2
4m
os
~-35
-30
-25
-20
-15
-10
-5
0
5
10
15
Natu
ral H
isto
ry
(no
nli
ne
ar;
N=
28
3)1
#
Diflunisal
Ph 3 Study2+
//
Pla
ce
bo
(N=
66
)
Dif
lun
isa
l
(N=
64
)
//
Mean ΔmNIS+7 Across
hATTR Studies at 24 mos~
25.8
(9.4)
29.6
(3.1)
9.2
(2.7)
-6.7
(2.3)
20
25
30
Patisiran
Ph 2 OLE†*
(N=24)Worse
Better
29
Patisiran Phase 2 OLE Preliminary Study Results*
Note: three patients had missing D17 TTR: one was replaced by D7 and two replaced by D84.† Percent (%) TTR knockdown from baseline at Day 17 post-first dose of patisiran
*Coelho et al., ISA, July 2016; Data as of 12May2016
Correlation of TTR Knockdown with ΔmNIS+7
Percent (%) TTR KD†
Δm
NIS
+7
50 60 70 80 90 100
-30
-20
-10
0
10
20
30
40
r= -0.49 , p= 0.0099
Percent (%) TTR KD†
Δm
NIS
+7
50 60 70 80 90 100
-30
-20
-10
0
10
20
30
40
r= -0.55 , p= 0.0029
Percent (%) TTR KD†
Δm
NIS
+7
50 60 70 80 90 100
-30
-20
-10
0
10
20
30
40
r= -0.37 , p= 0.055
Percent (%) TTR KD†
Δm
NIS
+7
50 60 70 80 90 100
-30
-20
-10
0
10
20
30
40
r= -0.31 , p= 0.15
6 months (N=27)
12 months (N=27)
18 months (N=27)
24 months (N=24)
30
Mean
(S
EM
) C
han
ge F
rom
Baselin
e
-1.0
-0.50.00.5
1.01.5
2.0
2.5
3.03.5
4.0
4.55.05.5
6.0
6.57.0
Months0 6 12 18 24
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
Patisiran Phase 2 OLE Preliminary Study Results*Sweat Gland Nerve Fiber Density (SGNFD): Lower Limb
• Blinded analysis of tandem skin punch biopsies performed at central lab
• Statistically significant increase in distal thigh SGNFD at 12, 18, and 24 months and
distal leg SGNFD at 24 months
• In a separate study in hATTR polyneuropathy patients with highly pathogenic A97S
mutation,1 SGNFD correlated to autonomic system involvement and disability burden
Distal thigh sweat gland innervation†
in Patient 010-0004
†Green: PGP 9.5 (nerve fibers)Red: CD31 (blood vessels)
Blue: DAPI (nuclei)
1Chao C et al., Ann Neurol. 78:272-83 (2015)‡2-sided p values from paired t-test comparing post-baseline vs baseline
*Suhr et al., ISA, July 2016; Data as of 12May2016
Distal Leg (meters/mm3)
Distal Thigh (meters/mm3)
N=19
P = 0.0072‡
N=20
P < 0.001‡
N=21N=18
N=19
N=24
N=24
N=22
N=18
P = 0.0041‡
N=17
P = 0.0070‡
Baseline
24months
50 microns
50 microns
31
Patisiran Phase 2 OLE Preliminary Study Results*Summary of Safety and Tolerability
• 6 patients (22.2%) with 9 reports of serious adverse
events (SAEs); not related to study drug
◦ One discontinuation for gastroesophageal cancer at ~20
months; patient subsequently died
◦ One death due to myocardial infarction after patient completed
24 months of treatment
◦ One patient with 3 reports (distal femur fracture/proximal tibia
fracture/osteonecrosis/ligament rupture, dehydration/acute
prerenal failure/urinary tract infection and thermal burn); one
patient with 2 reports (ankle fracture/foot fracture/
osteonecrosis and ankle arthrodesis); one patient with venous
thrombosis of the lower limb; one patient with foot abscess and
osteomyelitis
• Majority of AEs were mild or moderate
◦ 4 patients (14.8%) had severe AEs not related to study drug
◦ Most common related AEs reported in > 3 patients were
flushing (6 patients [22.2%]) and infusion related reaction
(5 patients [18.5%]), all of which were mild
• No clinically significant changes in liver function tests,
renal function, or hematologic parameters, including
platelets
Common Adverse Events (AEs) in
≥10% of patients
AE by Preferred Term Patisiran (N=27)
Flushing 7 (25.9%)
Diarrhea 6 (22.2%)
Nasopharyngitis 6 (22.2%)
Urinary tract infection 6 (22.2%)
Vomiting 6 (22.2%)
Wound 6 (22.2%)
Infusion related reaction 5 (18.5%)
Nausea 5 (18.5%)
Insomnia 4 (14.8%)
Neuralgia 4 (14.8%)
Pyrexia 4 (14.8%)
Anemia 3 (11.1%)
Bronchitis 3 (11.1%)
Edema peripheral 3 (11.1%)
Macular degeneration 3 (11.1%)
Musculoskeletal pain 3 (11.1%)
Osteoporosis 3 (11.1%)
*Suhr et al., ISA, July 2016; Data as of 12May2016
32
APOLLO Phase 3 Study DesignEnrollment Complete
All completers eligible for patisiran treatment on Phase 3 OLE study (APOLLO-OLE)
Enrollment completed; mid-2017 data readout, supporting 2017 NDA/MAA if positive
Clinicaltrials.gov # NCT01960348
N=225
Patient Population
• hATTR: any
TTR mutation,
Stages 1 and 2
• Neurological
impairment score
(NIS) of 5-130
• Prior tetramer
stabilizer use
permitted
2:1
RA
ND
OM
IZA
TIO
N
Patisiran IV
q3W
0.3 mg/kg
Placebo IV
q3W
Primary Endpoint at
18 months
• mNIS+7
Key Secondary
Endpoints
• Norfolk QOL-DN
• NIS-weakness
• mBMI
• 10-meter walk
OR
APOLLO DMC met October 7, 2016 at Company’s request and
recommended continuing Phase 3 study of patisiran in patients
with hATTR amyloidosis without modification
33
APOLLO Patisiran Phase 3 Study
†Represents 57 different mutations, including GLU-89-GLN (n=13); THR-60-ALA (n=13); ALA-97-SER (n=15);
SER-50-ARG (n=8); as well as numerous other mutations with <5 patients per group
*Adams et al., ISA, July 2016; Data as of 01 March 2016
Baseline Demographics
Characteristic Result
Number of patients N=225
Median age, years (range) 62 years (24-82)
Gender, n (%) males 167 (74)
Race, n (%)
Asian 51 (23)
Black/African or African American 6 (3)
White / Caucasian 162 (72)
Other/Missing 6 (3)
Previous tetramer stabilizer use, n (%) 119 (53)
mBMI, kg/m2 x albumin [g/dL] 978.7 (522.1-1530.0)
Patients with cardiac involvement, n (%) 122 (54)
Mean NT-proBNP, ng/L (range) 1461 (40-7895)
Mean troponin, ng/mL (range) 0.1 (0.1-1.0)
LV wall thickness, cm (range) 1.67 (1.3, 2.6)
Ejection fraction (range) 60.6 (31.8, 82.4)
Characteristic Result
TTR genotype, n (%)
V30M 95 (42)
nonV30M* 130 (58)
FAP Stage, n (%)
1 104 (46)
2 119 (53)
3 2 (1)
PND Score, n (%)
I 57 (25)
II 65 (29)
IIIA 63 (28)
IIIB 38 (17)
IV 2 (1)
Neuropathy Impairment Scores, mean (range)
mNIS+7 78.8 (8.0-165.0)
NIS 59.3 (6.0-141.6)
34
Patient Advocacy & Scientific Leadership
• Initiation of Expanded
Access Program (EAP)
• Numerous pre-clinical
and clinical investigator-
initiated studies to date
(IIS)
• 15 primary abstracts and
publications since 2013
• Attendance at >30
congresses and >2000
peer engagements
• Symposia and facilitation
of dialogue among
specialists to increase
awareness of disease
burden
• Implementation of
Alnylam Assist to help
improve diagnosis rateso Free third-party genetic
screening and
counseling programs
o >900 individuals tested
over past 2 years
• Invited to attend >25
patient meetings over
past 2 years
Patient Advocacy Education Collaboration
35
hATTR Amyloidosis Market Landscape
Limited available therapies; no approved drugs that halt disease
progression and improve patient quality of life
• US: No approved drugs; limited use of diflunisal
• EU: tafamidis approved for Stage 1 polyneuropathy patients only; limited
access (e.g., not reimbursed in UK)
◦ Some patients receiving tafamidis may experience worsening of symptoms, often within
first year of treatment
◦ Multiple studies that document
disease progression during
tafamidis treatment
• Orthotopic liver transplantation (OLT)
use declining worldwide
◦ Generally limited to younger patients
with V30M mutation
◦ Involves significant risks and may still
result in disease progression
• Few investigational therapies in
clinical development
Cortese et al. Study Results
N 61
Baseline NIS-LL 28 ± 5
Month 6 +4.5 (62% of patients)
Month 12 +5.9 (65% of patients)
Month 18 +8.0 (65% of patients)
Cortese A. J Neurol. 2016 Mar 16;
Randomized controlled trial in 61 patients with hATTR Amyloidosis
NIS-LL = neuropathy impairment score-lower limb
36
hATTR Amyloidosis Market Opportunity
Patisiran has potential to address unmet medical needs
• Evidence for potential halting or improvement of neuropathy in Phase 2 OLE study
• APOLLO Phase 3 study will evaluate mNIS+7 and multiple QOL secondary endpoints
• Ongoing support for programs to improve diagnosis rates and enable earlier intervention
~50,000 patients WW
• Some mutations
endemic to certain
regions
• Often misdiagnosed
due to heterogeneity of
disease
◦ Variable disease
penetrance, age of
onset, symptoms at
presentation, and
comorbidities1. Based on Rapezzi et al. Eur Heart J 2013;34:520–8; Semigran et al. J Am Coll Cardiol 2016;68:173–75
Predominantly Neurologic Predominantly Cardiac
hATTR Amyloidosis
V30MEarly onset
S77Y E89L
S50R
G47A
E89Q
V30MLate onset
I68L
L111M
T60A
H88RI107V V122IF33L
F64L W41L
A36P
37
Patisiran Program Summary & Next Steps
Current therapies for hATTR Amyloidosis insufficient to meet patient needs; unmet medical need remains
• Progressive sensorimotor and autonomic neuropathy, cardiomyopathy; often fatal within 10 years
• Primary treatment option is liver transplantation
• No approved therapies in US
• Published evidence of disease progression on TTR stabilizers
Phase 2 OLE continues to provide preliminary evidence of acceptable safety profile and clinical activity at 24 months
APOLLO Phase 3 Ongoing
• Phase 2 Open-Label Extension (OLE) study has completed; majority of patients rolled onto APOLLO-OLE study
• APOLLO top-line expected in mid-2017; results in late 2017
• Assuming positive outcome, NDA/MAA filings expected year-end 2017
Preparing for commercialization following approval in US, Canada, Western Europe
• Preparing for ROW commercialization with Sanofi Genzyme following ROW approvals