Update on inclisiran
Discussion of ORION-1 trial
Conference call: November 15th 2016
2:00 pm – 3:15 pm, CST
1
Inclisiran inhibits PCSK9 synthesis
by RNA interference
Forward-looking statements
Statements contained in this presentation that are not purely historical may be deemed to be forward-looking
statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995.
Without limiting the foregoing, the words "believes," "anticipates," "expects," “potential,” and similar expressions
are intended to identify forward-looking statements. These forward-looking statements involve known and
unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or
achievements to be materially different from those expressed or implied by these forward-looking statements.
Important factors that may cause or contribute to such differences include whether clinical trials for inclisiran will
advance in the clinical process on a timely basis, or at all, or succeed in achieving their specified endpoints;
whether physicians, patients and other key decision makers will accept clinical trial results; whether the Company
will make regulatory submissions for inclisiran on a timely basis, or at all; whether its regulatory submissions will
receive approvals from regulatory agencies on a timely basis, or at all; and such other factors as are set forth in
the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with
the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company's
quarterly report on Form 10-Q filed with the Securities and Exchange Commission on October 27, 2016, which
are incorporated herein by reference. The Company specifically disclaims any obligation to update these
forward-looking statements.
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Introduction
Panel
Dr. Clive Meanwell
Chief Executive Officer, The Medicines Company
Dr. John Maraganore
Chief Executive Officer, Alnylam Pharmaceuticals, Inc.
Dr. David Kallend
Dr. Evan Stein
Medical Director, Dyslipidemia, The Medicines Company
Professor of Medicine, Coronary Care Unit,
Mayo Clinic College of Medicine, Rochestor, Minnesota
Chairman of the Department of Vascular Medicine,
Academic Medical Center of the University of Amsterdam
Chief Scientific Officer, Medpace Reference Laboratories
Roger Longman
Chief Executive Officer, Real Endpoints
Dr. R Scott Wright
Dr. John JP Kastelein
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
ORION-1
Inclisiran inhibits PCSK9 synthesis by RNA interference
Planned interim analysis of a multi-center randomized controlled dose-finding trial
Kausik K Ray, Ulf Landmesser, Lawrence A Leiter, David Kallend, Peter Wijngaard
Robert Dufour, Timothy Hall, Mahir Karakas, Traci Turner, Frank LJ Visseren,
R Scott Wright, and John JP Kastelein
On behalf of the ORION-1 investigators
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Background and rationale
Inclisiran: Under investigation for LDL-C lowering
•
ASCVD remains a challenge to global
health1
•
mAbs that block PCSK9 require 12-24 s.c.
injections per year (totaling ~2-5 grams)5,6
•
LDL-C reduction is a proven strategy
to prevent ASCVD2
•
Administrative and financial burdens leave
room for more efficient agents
•
Statins are the cornerstone of treatment
but with limitations2
•
RNAi a highly efficient approach to inhibit
PCSK9 synthesis in the liver7,8
•
mAbs that block PCSK9 have
demonstrated significant LDL-C lowering
with or without statins3,4
•
Phase I 300 mg s.c. inclisiran lowered
LDL-C ~50% for 4-6 months (n=69)9
1: World Health Organization
2: AHA guidelines on dyslipidemia
5
3: Sabatine MS et al. N Engl J Med 2015;372:1500-9
4: Robinson JG et al. N Engl J Med 2015;372:1489-99
Inclisiran inhibits PCSK9 synthesis
by RNA interference
5: https://www.repathahcp.com/dosing
6: https://www.praluenthcp.com/dosing
7: Wittrup A & Lieberman J Nature Rev Gen
2015;16: 543-52
8: Fitzgerald K et al. Lancet 2013;9911:60-8
9: Fitzgerald K et al. N Engl J Med online
publication 2016:November 13
Objectives
Dosage selection for Phase III
•
Primary endpoint
- Percent change in LDL-C levels from baseline at day 180
• Secondary endpoint
- LDL-C levels at day 90 and other lipid parameters
- LDL-C and PCSK9 levels over time
- Safety and tolerability
• Interim analysis
- Pre-specified and pre-defined endpoints
- Interim analysis endpoints up to 90 days
- Change and % change from baseline in LDL-C, PCSK9, other lipids and lipoproteins
- Safety and tolerability
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Patient population
High cardiovascular risk and elevated LDL-C
Inclusion criteria
• Age ≥18 years
• With ASCVD - LDL-C >70 mg/dL
• High risk primary prevention LDL-C >100
• TG <400 mg/dL
• eGFR ≥30 mL/min
• Maximally tolerated statin
• Stable lipid Rx for ≥30 days
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Exclusion criteria
• Significant comorbidity
• HbA1c ≥10%
• NYHA Class II-IV HF
• MACE <6 months
• Uncontrolled BP
• Active liver disease
• Pregnancy or risk | nursing
• Cognitive impairment
Study design and statistics
Dose finding - placebo controlled
Day of study
Statistics
Dose (N)
1 14
30
60
90 104 120
150
180
210
Assessment
 








Interim
analysis
Placebo (65)
200 mg (60)
300 mg (62)
500 mg (66)
Two doses
Placebo (62)
100 mg (62)
200 mg (63)
300 mg (61)
Follow-up as of
25 Oct 2016
8
501
Inclisiran inhibits PCSK9 synthesis
by RNA interference
497
Final
analysis
One dose
189
Sample size of 480 patients allowed for
• 15% drop out rate
• ≥90% power to detect 30% LDL-C in
at least 1 treatment group
Pre-specified interim analysis plan
Follow-up cut-off 25 Oct 2016
• 497 patients followed to 90 days
• 189 patients followed to 180 days
Patient characteristics
Baseline demographics well balanced
Total=501
Inclisiran
Placebo
Pooled
100 mg
200 mg
300 mg
500 mg
N=127
N=374
N=62
N=123
N=123
N=66
Age mean (years)
62
64
65
63
64
62
BMI (kg/m2)
30
29
29
29
29
28
White
117 (93%)
357 (93%)
57 (92%)
114 (93%)
114 (93%)
63 (95%)
Male
75 (59%)
251 (67%)
39 (63%)
78 (63%)
87 (71%)
47 (71%)
Cardiovascular disease
91 (72%)
254 (68%)
43 (69%)
84 (68%)
91 (74%)
36 (55%)
Lipid lowering treatment
99 (78%)
307 (82%)
50 (81%)
103 (84%)
102 (83%)
52 (79%)
Statin treatment
94 (74%)
271 (72%)
44 (71%)
91 (74%)
91 (74%)
45 (68%)
LDL-C (beta quant) (mg/dL) 125
129
128
129
126
135
PCSK9 (ng/mL)
427
410
448
420
418
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
427
Inclisiran safety
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Safety of inclisiran to day 90
Treatment emergent adverse events (TEAE)
Total=497
Day 1-90
Inclisiran
Placebo
Pooled
100 mg
200 mg
300 mg
500 mg
N=127
N=370
N=61
N=122
N=122
N=65
69 (54%)
198 (54%)
38 (62%)
64 (52%)
68 (56%)
28 (43%)
Serious
5 (4%)
22 (6%)
8 (13%)
6 (5%)
6 (5%)
2 (3%)
Severe
5 (4%)
12 (3%)
3 (5%)
3 (2%)
4 (3%)
2 (3%)
Related
24 (19%)
67 (18%)
11 (18%)
20 (16%)
27 (22%)
9 (14%)
0 (0%)
1 (0.3%)
0 (0%)
0 (0%)
0 (0%)
1 (1.5%)
Any TEAE
Death
Most common TEAEs (>2%) were myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension,
diarrhea, dizziness (similar incidence to placebo)
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Safety of inclisiran to day 90
Liver and muscle TEAE1
Total=497
Day 1-90
Inclisiran
Placebo
Pooled
100 mg
200 mg
300 mg
500 mg
N=127
N=370
N=61
N=122
N=122
N=65
ALT >3x ULN
0
1 (0.3%)
0
0
1 (0.8%)
0
AST >3x ULN
0
1 (0.3%)
0
0
1 (0.8%)
0
ALP >2x ULN
0
3 (0.8%)
1 (1.6%)
0
2 (1.6%)2
0
Bilirubin >2x ULN3
0
0
0
0
0
0
CK >5x ULN
0
2 (0.6%)
0
1 (0.8%)4
1 (0.8%)
0
Myalgia
6 (4.7%)
5 (8.2%)
7 (5.7%)
8 (6.6%)
1 (1.5%)
21 (5.7%)
1: Crossing above threshold for significance at any time after randomization regardless of baseline
2: One patient above ULN at baseline
3: No patient met the criteria for Hy’s law
4: Patient >3x ULN at baseline
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Safety of inclisiran to day 90
First injection TEAE1,2
Total=497
Inclisiran
Placebo
Pooled
100 mg
200 mg
300 mg
500 mg
AE terms
N=127
N=370
N=61
N=122
N=122
N=65
Injection site erythema
0
4 (1.1%)
0
2 (1.6%)
1 (0.8%)
1 (1.5%)
Injection site pruritus
0
1 (0.3%)
0
0
1 (0.8%)
0
Injection site rash
0
0
0
0
0
0
Injection site reaction
0
7 (1.9%)
1 (1.6%)
1 (0.8%)
3 (2.5%)
2 (3.1%)
Total (observed any time)
0
12 (3.2%)
1 (1.6%)
3 (2.5%)
5 (4.1%)
3 (4.6%)
Total (observed >4 hours)
0
9 (2.4%)
1 (1.6%)
3 (2.5%)
4 (3.3%)
1 (1.5%)
1: Number of patients with adverse event classified by preferred term – each patient is counted only once
2: Pre-defined histaminic/allergic type adverse events
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Inclisiran efficacy
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Efficacy of one dose of inclisiran up to day 90
Significant, durable PCSK9 and LDL-C lowering
Mean percent change (±95% CI)
PCSK9
LDL-C
0
0
p-value for all comparisons to placebo <0.0001
-20
-40
-40
-60
-60
-80
-80
0
30
60
p-value for all comparisons to placebo <0.0001
-20
90
0
30
60
Days from first injection
Placebo (N=124)
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
100mg (N=59)
200mg (N=121)
300mg (N=120)
500mg (N=64)
90
One dose and two doses of inclisiran up to day 180
Percentage change (±95% CI)
Sustained dose dependent lowering of LDL-C
0
0
-20
-20
-40
-40
-60
-60
-80
-80
0
30
60
90
120
150
180
0
30
60
90
120
150
Placebo (N=22)
200mg (N=22)
Placebo (N=23)
100mg (N=26)
300mg (N=21)
500mg (N=23)
200mg (N=24)
300mg (N=28)
180
Days from first injection
Available data as of 25 Oct 2016
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
One dose and two doses of inclisiran up to day 180
Percentage change (±95% CI)
Efficacy of 300 mg versus placebo on LDL-C
0
0
-20
p-value for all comparisons to placebo <0.0001
-40
-20
p-value for all comparisons to placebo <0.0001
-40
-47.3
-60
-49.9
-55.7
-47.0
-38.0
-43.2
-44.3
-49.9
-60
-59.1
-80
-47.9
-47.2
-57.0
-56.7
120
150
-52.3
-80
0
30
60
90
120
150
180
0
30
60
90
180
Days from first injection
Placebo (N=22)
300mg (N=21)
Placebo (N=23)
300mg (N=28)
Available data as of 25 Oct 2016
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Individual patient response at day 180
Absolute change in LDL-C from baseline
32.5
25
Placebo
Change in LDL-C (mg/dL)
-25
Two doses
(N=23)
Mean -3.1 Median 2 mg/dL
-75
-91
-125
25
-25
300 mg
Two doses
(N=28)
-26.5
-75
-125
Mean -64.9 Median -64 mg/dL
-122
Available data as of 25 Oct 2016
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
Percent free PCSK9 reduction: monoclonal antibodies versus
inclisiran (siRNA)
Evolucumab: 420 mg Q4W dosing
Alirocumab 150 mg Q2W
Inclisiran 300mg (N=120)
% reduction at 28 days
% reduction at 14 days
% reduction 14 - 90 days
10
10
10
0
0
Diet
0
-10
-10
Diet + Atorvastatin
10mg
-20
-30
Diet + Atorvastatin
80mg
-40
-50
-20
Diet + Atorvastatin
80mg + Ezetimide
-70
Supplement to: Blom, Hala, Bolognese et al.
N Engl J Med 2014;370:1809-19
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Inclisiran inhibits PCSK9 synthesis
by RNA interference
-20
Day 14
-30
-40
-40
Day 60
-50
Day 90
-60
150mg Q2W +
Atorvastatin
80mg
-60
-70
-70
-80
-80
All
-80
-10
-30
-50
-60
150mg Q2W +
Atorvastatin
20mg
Roth, McKenney, Hanotin, Asset, Stein
N Engl J Med 2012;367:1891-1900
Ray et al.
Presentation at AHA 2016
Day 30
Discussion
Panel
Dr. Clive Meanwell
Chief Executive Officer, The Medicines Company
Dr. John Maraganore
Chief Executive Officer, Alnylam Pharmaceuticals, Inc.
Dr. David Kallend
Dr. Evan Stein
Medical Director, Dyslipidemia, The Medicines Company
Professor of Medicine, Coronary Care Unit,
Mayo Clinic College of Medicine, Rochestor, Minnesota
Chairman of the Department of Vascular Medicine,
Academic Medical Center of the University of Amsterdam
Chief Scientific Officer, Medpace Reference Laboratories
Roger Longman
Chief Executive Officer, Real Endpoints
Dr. R Scott Wright
Dr. John JP Kastelein
20
Inclisiran inhibits PCSK9 synthesis
by RNA interference
Conclusions
Inclisiran: Phase III-ready investigational compound
•
ORION-1 study met all interim analysis goals
•
A single injection of inclisiran (300 mg) lowered ‘bad cholesterol’ (LDL-C) by an average of 51%, and up to 76%
•
Two injections of inclisiran (300 mg) lowered LDL-C by an average of 57%, and up to 81%
•
Significant LDL-C reductions were sustained out to 180 days following a single 300 mg dose
•
ORION-1 study affirmed inclisiran’s potential for a highly-differentiated, infrequent, low volume dosing regimen of 2 or 3
injections per year affirmed—carrying the promise of delivering more cost-effective therapy than we have available today
•
To date, inclisiran has demonstrated highly-encouraging safety and tolerability
•
Inclisiran’s efficacy, safety and dosing profile is likely to ensure significant and durable reductions in LDL-C and thus
potentially improve cardiovascular outcomes
•
Based on the strength of the ORION-1 data, The Medicines Company expects to advance inclisiran aggressively in a
comprehensive, global Phase 3 development program
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Inclisiran inhibits PCSK9 synthesis
by RNA interference