National Lipid Association (NLA) Scientific Sessions …...ORION-3 Results – John JP Kastelein, MD PhD, Professor of Medicine, Department of Vascular Medicine, AMC, Amsterdam Q&A

National Lipid Association (NLA) Scientific Sessions

ORION-3Investor Conference Call

Miami, May 18, 2019

Agenda

Welcome

– Krishna Gorti, Vice President Investor Relations

Overview

– Mark Timney, CEO

ORION-3 Results

– John JP Kastelein, MD PhD, Professor of Medicine, Department of Vascular Medicine, AMC, Amsterdam

Q&A Session

Safe HarborForward-looking statements

Statements contained in this presentation about The Medicines Company that are not purely historical, and all other statements 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,” “plans,” “expects,” “should,” “conviction,” and “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 the ability of the Company to effectively develop inclisiran; whether inclisiran will advance in the clinical trials process on a timely basis or at all, or succeed in achieving its specified endpoints; whether the Company will make regulatory submissions for inclisiran on a timely basis; whether its regulatory submissions will receive approvals from regulatory agencies on a timely basis or at all; the extent of the commercial success of inclisiran, if approved; the strength, durability and life of the Company’s patent protection for inclisiran and whether the Company will be successful in extending exclusivity; 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 (SEC), including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the SEC on April 26, 2019, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.

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2019 is a defining year for MDCO We believe that inclisiran is a potential game-changer in treatment of CVD

• 17.3 million deaths globally – nearly 900,000 in U.S. alone – due to CVD each year

• Inclisiran is a potential simple and easy therapy to address world’s leading cause of

death

• Today we presented strong long-term extension data from ORION-3 which bolsters

our confidence in inclisiran’ s robust therapeutic profile

• Data strengthens our conviction that inclisiran addresses two critical unmet needs –

additional LDL-C lowering and poor adherence – to get many more patients to goal

ORION-3 for NLA Version 8.0

THE EXTENSION TRIAL FOR ORION-1

ORION-3Long-term inclisiran in subjectswith high CV risk and elevated LDL-C

John JP KasteleinUlf Landmesser David KallendLawrence A Leiter Peter Wijngaard

For the ORION-1 and 3 investigatorsR Scott Wright Kausik K Ray

6ORION-3 for NLA Version 8.0

Research grants• ORION-1, 2 and 3 were sponsored by MDCO with participation of AMC

Consultancy• Advisor to The Medicines Company, Amgen, Sanofi, Pfizer

DISCLOSURESJohn JP Kastelein


In ORION-1:• 300mg inclisiran given on day 1 & 90 demonstrated safe lowering of LDL-C by ≥50% and

up to 88% ─ with minimal variability and at least 6-months persistence1

• Subjects were followed up to 1-year

Could ORION-3 extend the treatment period for ORION-1 inclisiran subjects to enable the assessment of long-term safety and efficacy, and

Could a dose-PD response model from ORION-1 be validated using ORION-3 and offer insights for ongoing and future trials including Phase III?

BACKGROUND & RATIONALESafety & efficacy of inclisiran not known beyond 1-year

1. Ray KK et al. N EnglJ Med 2017; 376:1430-1440


Safety: Incidence of adverse events and laboratory changes

Efficacy: LDL-C, PCSK9 and other lipid parameters on day 210 of ORION-3

LDL-C, PCSK9 over the time course of ORION-1 & 3 combined

Dosage: Build a dose-PD response model and validate its performance

Simulation: Use the model to predict effects of inclisiran in Phase III

OBJECTIVESInvestigate the long-term safety and efficacy of inclisiran


ORION-1 double blind ORION-3 extension open labelTotal ~3 years treatment & observation

METHODSDesign of investigation

1 dose starting regimen∆LDL-C (mg/dL)

2 dose starting regimen∆LDL-C(mg/dL)

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

00 90 180 270 360 450 540 630 720 810 900 990 1080Baseline

Mean 132 days

Data Sources: ORION-1 Table 5.10.1.1 final and ORION-3 Table 5.1.1.ORN3.calc ORION-3 09 May 2019

200 mg N = 60

300 mg N = 61

500 mg N = 65

Placebo N = 65

100 mg N = 61

200 mg N = 62

300 mg N = 61

Placebo N = 62

Group 1: 300 mgEntered 290Treated 284

Randomized 501Treated 497

days


Representative of a typical moderate/high-risk ASCVD population

METHODSORION-3 Group-1 baseline1 characteristics (N = 290)

1. Baseline for ORION-1

Age Mean years (SD) 63.3 (11.1)Male N (%) 188 (65%)Diabetes N (%) 70 (24%)Prior PCI N (%) 125 (43%)

MI N (%) 104 (35%)CABG N (%) 47 (16%)

Hypertension N (%) 193 (67%)Current statin use N (%) 232 (80%)PCSK9 Mean ng/dL(±SD) 428.4 (128.5)LDL-C Mean mg/dL(±SD) 130.1 (57.3)


Highly consistent profile throughout ORION-1 and ORION-3 over ~3 years

• Injection site reactions infrequent, mild-moderate and transient

• No LFT elevations considered related to inclisiran

• No myalgias or CPK elevations considered related to inclisiran

• No renal adverse events or thrombocytopenia considered related to inclisiran

• One cerebrovascular accident death in ORION-3 related to underlying ASCVD

RESULTSExcellent tolerability and safety


Group-1 primary endpoint: Percent change in LDL-C on day 210 of ORION-3

RESULTSPersistent and robust efficacy

ITT Day 210 change from baseline1 p-value

LDL-CAll patients (N=290)

Mean (SD) - 51% (28) < 0.001Mean(SD) - 64 mg/dL (39) < 0.001

Patients randomized to 300 mg2 dose starting regimen (N = 61)

Mean(SD) - 56% (18) < 0.001Mean (SD) - 73 mg/dL (31) < 0.001

PCSK9 Mean(SD) - 77% (8) < 0.001

Non HDL-C Mean(SD) - 43% (24) < 0.001

HDL-C Mean(SD) + 9% (15) ns

Triglycerides Mean(SD) - 6% (42) ns

1. Average 22 months from baseline at the start of ORION-1


LDL-C lowering in ORION-3 over 22 months

RESULTSConsistent long-term effect of 300 mg inclisiran on LDL-C

ORION-3 extension open label Group 1 (N=290) mean change in LDL-C (mg/dL [SD])

-120

-90

-60

-30

00 90 180 270 360 450 540 630day

Time averaged LDL-C lowering ~60 mg/dL


ORION-1 double blind Mean 132 days

Consistent lowering of LDL-C >50% with no loss of effect over ~3 years

RESULTSLong-term effect of 300 mg inclisiran on LDL-C

300 mg x1 starting regimenMean ∆LDL-C(% [SD])



ORION-3 extension open label

-100

-75

-50

-25

00 90 180 270 360 450 540 630 720 810 900 990 1080

-100

-75

-50

-25

0

Baseline days


No material safety observations out to 3 years

• Primary endpoint at ~22 months from baseline showed 51% LDL-C (p-value <0.001)

• Time-averaged lowering of LDL-C in ORION-3 was ~60 mg/dL

• Well tolerated and no Rx-related elevation of liver enzymes or changes in renal function

CONCLUSIONSInclisiran given twice a year persistently lowers LDL-C


Describes relationship between dose, RNA interference of PCSK9, effect on LDL-C

METHODSDose response model

Dose

Ksynp

KsynL KdegL

Kdegp

Ke

InhibitoryEmax model

Emaxmodel

Distribution in tissue

PCSK9 in liver

LDL-C in plasma

Effect compartment

PCSK9

LDL-C


ORION-1 double blind Mean 132 days

Simulation closely matches observed results out to 3-years

RESULTSModel fit for percent reduction in LDL-C




ORION-3 extension open label

-100

-75

-50

-25

00 90 180 270 360 450 540 630 720 810 900 990 1080

-100

-75

-50

-25

0

Baseline days

ObservedSimulated


Inclisiran expected to lower LDL-C ≥50% and MACE by ≥ 25%

POTENTIAL IMPLICATIONSWhat could this mean for ongoing blinded Phase III trials?

1. MACE relative risk reduction estimate assumes 50% of effect year-1; 100% of effect thereafter; based on Cholesterol Treatment Trialists’ (CTT) Collaboration (Baigentat al, 2005)

ORION-9 ORION-10 ORION-11HeFH U.S.ASCVD EU ASCVD/RE

N = 482 N = 1561 N = 1617

Baseline LDL-C 161 mg/dL 110 mg/dL 112 mg/dLSimulation using dose-PD response model

1o endpoint: Day 510 % LDL reduction 54% 54% 54%Time-averaged % LDL-C reduction 51% 51% 51%LDL-C reduction calculated 82 mg/dL 56 mg/dL 57 mg/dL

Estimated 5 year MACE RRR1 44% 30% 31%

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Q&A

2019 is a defining year for MDCO We believe that inclisiran is a potential game-changer in treatment of CVD

• ORION-3 strengthens our conviction that inclisiran addresses two critical unmet needs – additional LDL-C lowering and poor adherence – to get many more patients to goal

• These data reinforce the potent, durable, and consistent LDL-C lowering effects of inclisiran dosed twice-a-year with no material safety observations

• Inclisiran is a potential simple and easy therapy to address world’s leading cause of death

Countdown to dataAnticipated news flow over next 12 months

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Event TimingSixth DSMB review of phase III data April 2019

ORION-1, -2 and -7, interim results from ongoing ORION-3 May 2019

Validation of manufacturing batches 3Q 2019

Phase 3 data from pivotal trials 3Q 2019

Potential NDA submission 4Q 2019

Potential MAA submission 1Q 2020

Documents

National Lipid Association (NLA) Scientific Sessions …...ORION-3 Results – John JP Kastelein, MD PhD, Professor of Medicine, Department of Vascular Medicine, AMC, Amsterdam Q&A