Upload
others
View
9
Download
0
Embed Size (px)
Citation preview
July 22, 2014
RNAi Roundtable: Advances in Delivery of RNAi Therapeutics
with Enhanced Stabilization Chemistry
(ESC)-GalNAc-siRNA Conjugates
Agenda
Welcome Josh Brodsky
Manager, Investor Relations and Corporate Communications
Introduction Laurence Reid, Ph.D.
Senior Vice President and Chief Business Officer
Advances in Delivery of RNAi Therapeutics with Enhanced Stabilization
Chemistry (ESC)-GalNAc-siRNA Conjugates Rachel Meyers, Ph.D.
Vice President of Research and RNAi Lead Development (RLD)
Q&A Session
2
Reminders
Event will run until ~12:00 p.m. ET
Q&A session at end presentation
» Submit questions by clicking “Ask a Question” button
» Questions may be submitted at any time
Replay and slides available at
www.alnylam.com/capella
3
Alnylam Forward Looking Statements
This presentation contains forward-looking statements, within the meaning of Section 27A
of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of
1934. There are a number of important factors that could cause actual results to differ
materially from the results anticipated by these forward-looking statements. These
important factors include our ability to discover and develop novel drug candidates and
delivery approaches, successfully demonstrate the efficacy and safety of our drug
candidates, obtain, maintain and protect intellectual property, enforce our patents and
defend our patent portfolio, obtain regulatory approval for products, establish and maintain
business alliances; our dependence on third parties for access to intellectual property; and
the outcome of litigation, as well as those risks more fully discussed in our most recent
quarterly report on Form 10-Q under the caption “Risk Factors.” If one or more of these
factors materialize, or if any underlying assumptions prove incorrect, our actual results,
performance or achievements may vary materially from any future results, performance or
achievements expressed or implied by these forward-looking statements. All forward-
looking statements speak only as of the date of this presentation and, except as required
by law, we undertake no obligation to update such statements.
4
Agenda
Welcome Josh Brodsky
Manager, Investor Relations and Corporate Communications
Introduction Laurence Reid, Ph.D.
Senior Vice President and Chief Business Officer
Advances in Delivery of RNAi Therapeutics with Enhanced Stabilization
Chemistry (ESC)-GalNAc-siRNA Conjugates Rachel Meyers, Ph.D.
Vice President of Research and RNAi Lead Development (RLD)
Q&A Session
5
Alnylam 5x15™ Strategy A Reproducible and Modular Path for Genetic Medicines
2. POC achieved in Phase 1 Blood-based biomarker with
strong disease correlation » e.g., Serum TTR, thrombin
generation, hemolytic activity,
LDL-C, HBsAg levels
GCCCCUGGAGGG
1. Liver-expressed target gene Involved in disease with high
unmet need
Validated in human genetics
GalNAc-siRNA enables SC dosing
with wide therapeutic index
3. Definable path to approval
and market Established endpoints
Focused trial size
Large treatment effect
Collaborative approach with
physicians, regulators,
patient groups, and payers
6
Discovery Development Phase 1 Phase 2 Phase 3
TTR-Mediated Amyloidosis
Hemophilia and
Rare Bleeding Disorders
Complement-Mediated Diseases
Hepatic Porphyrias
Hypercholesterolemia
Alpha-1 Antitrypsin Deficiency
Hepatitis B Virus Infection
Beta-Thalassemia and
Iron-Overload Disorders
Mixed Hyperlipidemia and
Hypertriglyceridemia
Hypertriglyceridemia
Additional Genetic Medicine
and Other Programs
Alnylam Development Pipeline
ALN-TTRsc
Patisiran (ALN-TTR02)
ALN-AT3
ALN-CC5
ALN-AS1
ALN-PCSsc
ALN-AAT
ALN-TMP
ALN-ANG
ALN-AC3
Standard Template Chemistry
(STC)-GalNAc Conjugate LNP Enhanced Stabilization Chemistry
(ESC)-GalNAc Conjugate Delivery Technology:
ALN-HBV
7
Alnylam IP on GalNAc-siRNA
8
Multiple Alnylam patent families cover
GalNAc-siRNA
Includes Tuschl and McSwiggen patents
Newly allowed Manoharan ’478 patent
provides additional protection
Claims cover modified RNA agent linked
to a biantennary or triantennary ligand
Includes GalNAc-conjugated, chemically
modified RNA
» Single or double stranded
» Any length
» Any sequence
» Toward any disease target
Agenda
Welcome Josh Brodsky
Manager, Investor Relations and Corporate Communications
Introduction Laurence Reid, Ph.D.
Senior Vice President and Chief Business Officer
Advances in Delivery of RNAi Therapeutics with Enhanced Stabilization
Chemistry (ESC)-GalNAc-siRNA Conjugates Rachel Meyers, Ph.D.
Vice President of Research and RNAi Lead Development (RLD)
Q&A Session
9
Reviewing ESC-GalNAc Conjugates Diseases and Targets
10
Goal: Review Advances in ESC-GalNAc conjugates as leading siRNA Delivery Modality Examples provided from 3 disease programs Transthyretin (TTR)-mediated amyloidosis
» TTR » Patisiran (Phase 3) and ALN-TTRsc (Phase 2)
Hemophilia and Rare Bleeding Disorders » Antithrombin (AT) » ALN-AT3 (Phase 1)
Hypercholesterolemia » PCSK9 » ALN-PCSsc (Pre-clinical)
Making Drugs Out of siRNAs The Challenge
Characteristics 21-23bp dsRNA
M.W 12,000-14,000
Size: 2 turns of helix
40 negative charges
Hydrophilic
Hydrated heavily
ca. 5.5 nm X 2 nm
Structure adapted from Klosterman et al.,
Biochemistry 38, 14784-14792 (1999)
11
The Delivery Challenge
12
PK/Tissue
Distribution
0
20
40
60
80
100
0 1 2 3 4
% I
nje
cte
d d
ose
Time (h)
Plasma Liver Spleen
The Delivery Challenge
13
Cellular Uptake
and Trafficking
The Delivery Challenge
14
RNA Release and
RISC Loading
RT-qPCR
RNAi Delivery to Liver Solved STC and ESC Platforms (NHP)
Enables advancement of innovative medicines to patients Advancement of proprietary conjugate platform for clinical translation and SC dosing
» Initial conjugates with Standard Template Chemistry (STC) achieve target knockdown with SC dosing
» Further improvements with conjugates employing Enhanced Stabilization Chemistry (ESC) platform
Maier, Oligo Ther Soc., Sep 2011; Akinc, ISTH, July 2013
100
80
60
40
20
0
-20
% T
TR
mR
NA
Sil
en
cin
g
(Rela
tive t
o C
ontr
ol)
ALN-TTRsc
(STC-GalNAc-conjugate)
mg/kg
5.0 1.0 0.2 Control
ALN-AT3
(ESC-GalNAc-conjugate)
mg/kg
100
80
60
40
20
0
-20
% A
T m
RN
A S
ilen
cin
g
(Rela
tive t
o P
re-d
ose)
0.5 0.25 0.125 Control
STC-Conjugate ESC-Conjugate
15
RNAi Delivery to Liver Solved STC and ESC Platforms (NHP)
Enables advancement of innovative medicines to patients Advancement of proprietary conjugate platform for clinical translation and SC dosing
» Initial conjugates with Standard Template Chemistry (STC) achieve target knockdown with SC dosing
» Further improvements with conjugates employing Enhanced Stabilization Chemistry (ESC) platform
Maier, Oligo Ther Soc., Sep 2011; Akinc, ISTH, July 2013
100
80
60
40
20
0
-20
% T
TR
mR
NA
Sil
en
cin
g
(Rela
tive t
o C
ontr
ol)
ALN-TTRsc
(STC-GalNAc-conjugate)
mg/kg
5.0 1.0 0.2 Control
ALN-AT3
(ESC-GalNAc-conjugate)
mg/kg
100
80
60
40
20
0
-20
% A
T m
RN
A S
ilen
cin
g
(Rela
tive t
o P
re-d
ose)
0.5 0.25 0.125 Control
STC-Conjugate ESC-Conjugate
16
GalNAc-siRNA Conjugates Targeted Delivery to Hepatocytes via ASGPR-Mediated Uptake
17
ASGPR
Clathrin-coated pit
Clathrin-coated vesicle
Endosome
Recycling
ASGPR
GalNAc-siRNA
conjugate
RISC loading
mRNA
cleavage
Target protein
ASGPR Clears desialylated serum
glycoproteins via clathrin-mediated endocytosis
Highly expressed in hepatocytes » 0.5-1 million copies/cell
High rate of uptake Recycling time ~15 minutes Conserved across species
GalNAc-siRNA GalNAc ligand conjugated to
chemically modified siRNA for targeted delivery to hepatocytes
GalNAc carbohydrate cluster with high affinity for ASGPR (nM)
Administered subcutaneously (SC)
Adapted from
Essentials of Glycobiology (2009)
Design of High-Affinity Ligand for ASGPR
Adapted from Lee et al., Carbohydrates in Chemistry and
Biology; 4:549 (2000)
18
0 20 40 60 80 1000
1000
2000
3000
4000
(GalNAc)3
(GalNAc)2
Kd = 2.48 nM
Kd = 28.8 nM
[(GalNAc)n] nM
MF
I
Spacer length
Spacer length
C2-substituent
Valency
Branching point
Y-shaped linker
Attachment
to siRNA
Ligand Mouse
Hepatocyte Ki
GalNAc2 ~24 nM
GalNAc3 2.7 nM
Biessen et al., J. Med. Chem., 38:1538 (1995); Rensen et al., J. Med. Chem., 47:5798 (2004);
Biessen et al., Bioconjugate Chem., 13:295 (2002)
Spacing of
sugar residues
Uptake of GalNAc-siRNA Conjugates 1o Mouse Hepatocytes
• Glucose conjugate does not mediate uptake
• GalNAc3 BB and EGTA block uptake
• Substantially decreased uptake in ASGR2
KO cells
G3BB
0
300
600
900
1200
1500
1800
+EGTA +G3BB
(38)
ASGR2 KO
Cells
siRNA Glu2-siRNA GalNAc2-
siRNA
Rela
tive
Up
tak
e (
MF
I)
GalNAc3-
siRNA
GalNAc3-siRNA +
19
TTR-GalNAc siRNA Biodistribution After Single SC Administration
GalNAc-siRNA conjugates efficiently target liver Achieve liver levels of >50% delivered dose
Oligo Ther Soc., Sept. 2012
4 hours post-dose
0
20000
40000
60000
80000
100000
120000
Liver Spleen Kidney Heart Lung
siR
NA
/ ti
ss
ue
(n
g/g
)
20
GalNAc Conjugates: Clinically Validated Delivery Platform ALN-TTRsc Phase 1
Randomized, double-blind, placebo-controlled SAD and MAD study in healthy volunteers Rapid, dose-dependent, consistent, and durable knockdown of serum TTR
» Significant knockdown of serum TTR (p<0.01) up to 94% TTR knockdown; Mean knockdown up to 92.4%
Generally well tolerated
Excellent correlation of human to non-human primate TTR knockdown on mg/kg basis
100
80
60
40
20
0
-20
Days ALN-TTRsc (mg/kg), qd x5; qw x5
% M
ean
TT
R K
no
ckd
ow
n
Rela
tive t
o B
aselin
e (
± S
EM
)
2.5 (n=3) 5.0 (n=3)
10.0 (n=3)
Placebo (n=3)
ALN-TTRsc
dose groups
Zimmermann, Heart Failure Society of America, Sep. 2013
0
25
50
75
100
25 50 75 100
% Mean TTR KD in non-human primate %
Me
an
TT
R K
D in
hu
ma
n
R 2 = 0.83 p < 0.001
2.5
5.0
10.0
ALN - TTRsc (mg/kg)
21
RNAi Delivery to Liver Solved STC and ESC Platforms (NHP)
Enables advancement of innovative medicines to patients Advancement of proprietary conjugate platform for clinical translation and SC dosing
» Initial conjugates with Standard Template Chemistry (STC) achieve target knockdown with SC dosing
» Further improvements with conjugates employing Enhanced Stabilization Chemistry (ESC) platform
Maier, Oligo Ther Soc., Sep 2011; Akinc, ISTH, July 2013
100
80
60
40
20
0
-20
% T
TR
mR
NA
Sil
en
cin
g
(Rela
tive t
o C
ontr
ol)
ALN-TTRsc
(STC-GalNAc-conjugate)
mg/kg
5.0 1.0 0.2 Control
ALN-AT3
(ESC-GalNAc-conjugate)
mg/kg
100
80
60
40
20
0
-20
% A
T m
RN
A S
ilen
cin
g
(Rela
tive t
o P
re-d
ose)
0.5 0.25 0.125 Control
STC-Conjugate ESC-Conjugate
22
Transitioning Standard Template Chemistry (STC) to
Enhanced Stabilization Chemistry (ESC)
5′-sense
5′-antisense
= 2′-F = 2′-O-methyl (GalNAc)3
Standard Template Chemistry, STC
(ALN-TTRsc)
5′-sense
5′-antisense
= 2′-F = 2′-O-methyl (GalNAc)3
Enhanced Stabilization Chemistry, ESC
( ALN-AT3, ALN-PCS, ALN-AAT, ALN-CC5, ALN-AS1, etc. )
Lead
Optimization
by
Further
Stabilization
Chemistries
23 Manoharan, TIDES, May 2014
ESC Leads to Higher Liver Exposure Liver Exposure and Metabolic Stability
Metabolic profiling in liver 8h post dose
= Enzymatic cleavage site (thickness reflects frequency
of corresponding cleavage products observed)
Liver Exposure
Target Compound Tmax
(h)
Cmax
(µg/g)
AUC0-t
(h·µg/g)
AUC0-48
(h·µg/g)
AT3 STC 2 59.5 735 735
AT3 ESC 8 285 21546 9697
10
100
1000
10000
100000
1000000
0 50 100 150 200Liv
er
Co
ncen
trati
on
(n
g/g
)
Time (h)
SC
ESC
Liver Exposure
STC
24
= 2′-F = 2′-O-methyl
(GalNAc)3
S 5′
Standard Template Chemistry (STC)
AS 5′
5′ AS
S 5′
Enhanced Stabilization Chemistry (ESC)
Manoharan, TIDES, May 2014
ESC Significantly Enhances Efficacy and Duration Reduction of AT Protein After Single SC Dose in NHP
25
Potent and durable silencing achieved after single SC dose >10-fold improvement in efficacy over standard template chemistry
Substantially extended duration of effect
% K
no
ck
do
wn
Se
rum
AT
(R
ela
tive
to
Pre
-do
se
)
Day
100
80
60
40
20
1.0
1.2
-10 0 10 20 30 40
STC-AT3 (10 mg/kg)
ESC-AT3 (10 mg/kg)
ESC-AT3 (1 mg/kg)
Manoharan, TIDES, May 2014
Target KD Correlates with RISC-loaded siRNA
Tmax of RISC-loaded siRNA shifted relative to total siRNA
Rate of depletion of RISC-loaded siRNA slower than total siRNA
Amount of RISC-loaded siRNA correlates well with silencing activity
0 100 200 300 400 500 600 700 800 900
0
8000
16000
Time (h)
100
80
60
40
20
0
-20
% K
no
ckd
ow
n A
T m
RN
A
Rela
tive t
o c
ontr
ol
To
tal s
iRN
A in
liver (n
g/g
)
Total siRNA vs. mRNA Silencing
ALN-AT3 2.5 mg/kg
4.0
100
80
60
40
20
0
-20
0.0
2.0
0 100 200 300 400 500 600 700 800 900
Time (h)
% K
no
ckd
ow
n A
T m
RN
A
Rela
tive t
o c
ontr
ol
RIS
C-lo
ad
ed
siR
NA
(ng
/g)
RISC-loaded siRNA vs. mRNA Silencing
ALN-AT3 2.5 mg/kg
26 OTS, October 2013
Target Gene Silencing Very Low RISC-loaded siRNA Concentrations
27
EC50 for liver drug is ~100 ng siRNA/g tissue (>120 h post-dose)
EC50 for RISC-loaded drug is ~1.5 ng siRNA/g tissue (~800 molecules/cell)
» ~100x lower than EC50 values obtained for total siRNA
100
80
60
40
20
0
-20
1.0 10 100 1000 10000
% A
T m
RN
A S
ilen
cin
g
Total siRNA in liver (ng/g)
R2 = 0.859
% A
T m
RN
A S
ile
nc
ing
R² = 0.7111
100
80
60
40
20
0.1 10.0
RISC-loaded siRNA in liver (ng/g)
1.0
Total liver siRNA RISC-loaded siRNA
OTS, October 2013
ALN-PCSsc Achieves Potent, Highly Durable PD Pre-Clinical Efficacy in NHP with Single Dose
LDL-C PCSK9
Days
0 20 40 60 80 100
1.0 3.0 6.0 10.0
% P
CS
K9
Kn
oc
kd
ow
n
(re
lative
to
pre
-ble
ed
)
Days
0 20 40 60 80 100 120
% L
DL
-C L
ow
eri
ng
(re
lative
to
pre
-ble
ed
)
100
80
60
40
20
0
-20
80
60
40
20
0
-20
100
ALN-PCSsc (mg/kg)
ALN-PCSsc (mg/kg)
1.0 3.0 6.0 10.0
ALN-PCSsc achieves highly durable PCSK9 knockdown and LDL-C reduction with single dose Single SC dose 1-10 mg/kg
Up to 96% PCSK9 knockdown
Up to 77% LDL-C lowering in absence of statins
Highly durable effects, supports once-monthly and possibly once-quarterly dosing » >50% LDL-C lowering maintained for over 3 months in 10 mg/kg group
28 Fitzgerald, ATVB, May 2014
GalNAc Platform Improves With Multidosing ALN-AT3 in NHP
29
Rela
tive
Se
rum
AT
Leve
ls
(Pre
-do
se
=1
)
SD ED50 ~1 mg/kg
SD ED80 ~10 mg/kg
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
-14 0 14 28 42 56
Days
30 mg/kg 10 mg/kg 3 mg/kg 1 mg/kg
Single Dose
MD ED80 ~0.5 mg/kg
Equivalent to QM ~1-2 mg/kg
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
-5 0 5 10 15 20 25 30 35 40 45 50 55
Re
lati
ve
AT
Ac
tivit
y (
pre
do
se
= 1
)
Saline 0.25 mg/kg 0.5 mg/kg
QW x 6 Days
Multiple Dose
GalNAc Conjugates: Repeat-Dose Platform Chronic Dosing in Mice with ESC-mTTRsc
Steady knockdown maintained with chronic dosing Sustained knockdown at both ED50 (1 mg/kg) and ED80 (2.5 mg/kg) dose levels
Absence of tachyphylaxis or sensitization
No changes in serum TTR levels in PBS control group
30
% K
no
ck
do
wn
Se
rum
TT
R
(Fra
ction
P
re-d
ose
)
0 30 60 90 120 150 180 210 240 270
Long-Term Dosing: QW Dosing with ESC-mTTRsc
100
80
60
40
20
0
-20
PBS 1.0 mg/kg 2.5mg/kg
Day
ALN-AT3 Pre-Clinical Efficacy Potent AT Knockdown and Normalization of Thrombin Generation
31
ALN-AT3 achieves potent AT knockdown and fully corrects thrombin generation in non-human primates (NHP)
Weekly SC doses for >5 months result in potent, dose-dependent, and durable AT knockdown
In NHP hemophilia “inhibitor” model, ALN-AT3 fully restores thrombin generation to normal levels
Akinc, ISTH, July 2013
Recovery
Recovery 0.25 mg/kg qw x 12
Recovery 1.5 mg/kg qw x 5
100
80
60
40
20
0
-20 0 20 40 60 80 100 120 140 160
% M
ea
n A
T K
no
ck
do
wn
(P
re-d
ose
= 1
)
Day
1 mg/kg q2w x 4
0.125 mg/kg qw x 12 0.5 mg/kg qw x 8
Normal Hemophilia A (Induced)
Pre-dose
ALN-AT3 (mg/kg) qw
Rela
tive
Th
rom
bin
Ge
nera
tio
n
(Pe
ak T
hro
mb
in)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Saline
1.6
0.25
~60%
AT
KD
0.5
p<0.01
~80%
AT
KD
ALN-AT3 Phase 1 Study Dose-escalation Study in Two Parts
Study Design Randomized, single-blinded,
placebo-controlled SAD study in
healthy volunteers
Max allowable knockdown of 40%
Positive Topline Results At 0.03 mg/kg, AT knockdown of up
to 32% and increases in thrombin
generation (p<0.01) » Major implications for ESC-GalNAc
conjugate platform; ~50x improved
potency vs. ALN-TTRsc
Well tolerated, no significant AEs
Study Design Open-label, MAD study in
subjects with moderate to severe
hemophilia A or B (N=up to 18)
Primary Objective Safety and tolerability of multi-
dose in hemophilia subjects
Secondary Objectives Assess clinical activity
» AT knockdown
» Increase in thrombin generation
Status Part A SAD completed; Positive top-line results
Advanced to Part B MAD in patients
Initial data from Part B in late ’14
Part
A Part
B
32
Key Translational Data for GalNAc-Conjugates Standard Template Chemistry vs. Enhanced Stabilization Chemistry
Dose (mg/kg)
Single-dose
Nadir KD (%)
Multi-dose
(q weekly)
Nadir KD (%)
0.1 19 ± 20 27 ± 12
0.3 25 ± 11 48 ± 22
1 52 ± 12 81 ± 13
1.5 NT >95
3 70 ± 13 NT
10 82 ± 7 NT
Dose (mg/kg)
Single-dose
Nadir KD (%)
Multi-dose
(qdx5, q weekly)
Nadir KD (%)
1.25 22 ± 1 NT*
2.5 38 ± 12 58 ± 11
5.0 47 ± 1 88 ± 7
10.0 53 ± 8 92 ± 2
Standard Template Chemistry: ALN-TTRsc in Human
Dose (mg/kg)
Single-dose
Nadir KD (%)
0.03 28-32%
Enhanced Stabilization Chemistry: ALN-AT3 in Human
Enhanced Stabilization Chemistry: ALN-AT3 in NHP
Akinc, WFH, May 2014 33
A
5-10x Increased potency
with ALN-AT3 vs. ALN-
TTRsc
A
B
B 10x Increased potency
with SD to MD
C
C 10x Increased potency in
human vs. NHP
D
D ~50x Increased potency
in humans with ALN-AT3
vs. ALN-TTRsc
ESC-GalNAc Conjugates Appear More Stable in Human
vs. NHP
34
% FL siRNA
Remaining
Mouse liver cytosol 5
NHP liver cytosol 6
Human liver cytosol 66
Cytosol Stability
NHP liver S9 Human liver S9
Metabolite Profile
5′-sense
= 2′-F = 2′-O-methyl (GalNAc)3
Standard Template Chemistry 5′-sense
5′-antisense
= 2′-F = 2′-O-methyl (GalNAc)3
Enhanced Stabilization Chemistry
Manoharan, TIDES, May 2014
GalNAc-siRNA Conjugates: Safety Assessment Wide Therapeutic Index
ALN-TTRsc GalNAc-Conjugate Cytokine/Complement Assessment
» No evidence of inflammation (cytokine, complement) in vitro or in vivo, including NHP
GLP Toxicology Study Results » Rat doses up to 300 mg/kg (10 doses) well tolerated
– No in-life findings or ISRs
– NOAEL = 30 mg/kg
» Minimal to moderate histopathology in liver (vacuolation and single-cell necrosis of hepatocytes) with
correlating increased LFTs (minimal, less than 2-fold)
» NHP doses up to 300 mg/kg (10 doses) no adverse findings – No in-life findings or adverse ISRs
– No clin path or histopath findings
– NOAEL >300 mg/kg: Likely predictive species
GLP Chronic Toxicology ongoing » Rat and NHP up to 300 mg/kg well tolerated at 6 mo mark
ESC-GalNAc Conjugates Cytokine/Complement Assessment
» No evidence of inflammation (cytokine, complement) in vitro or in vivo, including NHP
Preliminary Toxicology Results » QW x 5 at 30, 100, 300
» 3 species: mouse, rat, NHP
» NOAEL >300 mg/kg – No in-life findings or adverse ISRs
– No significant changes in serum chem, ALT/AST
– No adverse histopath findings
35
Summary
36
Alnylam has developed an effective, well tolerated, SC-administered
GalNAc-conjugate platform with proven human clinical translation Human POC established with ALN-TTRsc and ALN-AT3
Enhanced Stabilization Chemistry (ESC) of siRNA-GalNAc conjugates
has led to increased metabolic stability Increased liver exposure
Improved potency: Up to 10-fold SD potency improvement and less
injection volume
Increased duration of effect, which further increases from rodents to
NHP to humans
Greater apparent stability in humans due to attenuated nuclease
environment as compared with other species
No compromise in tolerability
ESC-GalNAc conjugates enable a reproducible and modular platform
for RNAi therapeutics as new class of medicines
Agenda
Welcome Josh Brodsky
Manager, Investor Relations and Corporate Communications
Introduction Laurence Reid, Ph.D.
Senior Vice President and Chief Business Officer
Advances in Delivery of RNAi Therapeutics with Enhanced Stabilization
Chemistry (ESC)-GalNAc-siRNA Conjugates Rachel Meyers, Ph.D.
Vice President of Research and RNAi Lead Development (RLD)
Q&A Session
37
Upcoming RNAi Roundtables
ALN-HBV for the treatment of Hepatitis B Virus (HBV) Infection Tuesday, July 29 @ 9:30 a.m. – 10:30 a.m. ET Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence
Moderator: Laurence Reid, Ph.D., Senior Vice President and Chief Business Officer
Guest Speaker: Graham Foster, Ph.D., FRCP, Professor of Hepatology at Queen Mary University of London
ALN-AT3 for the treatment of Hemophilia and Rare Bleeding Disorders Thursday, August 7 @ 9:30 a.m. – 10:30 a.m. ET Akin Akinc, Ph.D., Director, Research
Moderator: John Maraganore, Ph.D., Chief Executive Officer
Guest Speaker: Flora Peyvandi, M.D., Ph.D., Head of the Department of Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, IRCCS Maggiore Hospital, University of Milan
ALN-CC5 for the treatment of Complement-Mediated Diseases Wednesday, August 13 @ 9:30 a.m. – 10:30 a.m. ET Benny Sorenson, M.D., Ph.D., Medical Director, Clinical Development
Moderator: Barry Greene, President and Chief Operating Officer
Guest Speaker: Anita Hill, MBChB (Hons), MRCP, FRCPath, Ph.D., Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Honorary Senior Lecturer at the University of Leeds
More roundtables to be scheduled in the coming weeks; visit www.alnylam.com/capella for updates ALN-AS1 for the treatment of hepatic porphyrias
ALN-PCSsc for the treatment of hypercholesterolemia
ALN-AAT for the treatment of AAT deficiency-associated liver disease
38
Select Scientific and Clinical Meetings Mid to Late ’14
ALN-AT3, ALN-CC5,
ALN-TMP American Society of Hematology (ASH)*
» December 6-9, San Francisco, CA
ALN-CC5 International Complement Society Workshop (ICSW)*
» September 14-18, Rio de Janeiro, Brazil
Patisiran American Neurological Association (ANA)
» October 12-14, Baltimore, MD
* Pending acceptance of abstracts
ALN-TTRsc
ALN-PCSsc American Heart Association (AHA)*
» November 15-19, Chicago, IL
Alnylam 5x15
GalNAc Conjugates Oligonucleotide Therapeutics Society (OTS)*
» October 12-15, San Diego, CA
American Society of Nephrology (Kidney Week)* » November 11-16, Philadelphia, PA
Alnylam 5x15
Alnylam 5x15 High Blood Pressure Research (HBPR)*
» September 9-12, San Francisco, CA
ALN-HBV AASLD (The Liver Meeting)*
» November 7-11, Boston, MA
39
www.alnylam.com
Thank You