Cowen - Microsoft...©The Medicines Company 2018 1› Cowen 38th Annual Healthcare Conference Clive...

©The Medicines Company 2018 1›

Cowen38th Annual Healthcare Conference

Clive Meanwell • Chief Executive Officer

Safe HarborForward-looking statements

©The Medicines Company 2018 2

Statements in this presentation about The Medicines Company (the Company), the Company’s products and product candidates, the timing of clinical trial results, regulatory submissions, product or indication launches, the Company’s strategy, future financial results and operations, and future opportunities for the 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," “intends," “estimates," “potential," “outlook,” “may,” “will,” “would,” and similar expressions are intended to identify forward-looking statements. There are a number of important factors that could cause actual results or events to differ materially from those indicated by such forward looking statements, including:

whether the Company’s product candidate will advance in the clinical trials process on a timely basis or at all; whether clinical trial results will warrant submission of applications for regulatory approval; whether the Company’s product candidate will receive approvals from regulatory agencies; the extent of the commercial success of the Company’s product candidate, if approved; and such other factors as are set forth in the risk factors detailed from time to time in the Company’s periodic reports filed with the Securities and Exchange Commission (SEC) including, without limitation, the risk factors detailed in the Company’s Annual Report on Form 10-K filed with the SEC on March 1, 2018, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements whether as a result of new information, future events or otherwise

Why are we here?Our purpose

Solve major challenges in healthcare and create enormous value

Focus on atherosclerotic cardiovascular disease

− Leverage Nobel-prize-winning science, technology and data

− Devise trustworthy, human-centric solution

− Foremost cause of death, health burden

− Create significant value for shareholders and other stakeholders

Where are we?Our situation

Inclisiran in Phase IIIa / IIIb program moving aggressively

Validated plans and people in place

− Pivotal trials advancing rapidly to NDA/MAA

− Commercial scale manufacturing achieved

− CVOT set up to show low NNT for MACE and mortality benefit

− Unprecedented pricing flexibility and value demonstration opportunity

Product development track record and capabilities

Strong financial position

What to expect from usInclisiran moving forward rapidly in a high quality innovation program

Anticipate the leading product profile in the largest pharmaceutical market

Highly-differentiated from existing lipid-lowering products

− Unique attributes

− Unprecedented performance

− Highest value to patients, providers and payers

Significant news flow and catalysts in 2018

Firm-wide focus on maximizing shareholder value

InclisiranInvisible, silentSM

Inclisiran

Proven scientific foundationsInvisible, simple

Proven scientific foundations for inclisiranEpidemiology, science, technology and Phase I-II data

• Enormous global population in need of additional LDL-C lowering

• LDL-C the unambiguous cause of ASCVD

• PCSK9 the most direct approach to LDL-C lowering

• RNAi a rapidly emerging new drug platform

• Phase I-II, rapidly emerging phase III data show unique attributes

• Value window wide open – inclisiran pricing flexibility


Proven scientific foundations for inclisiranStanding on the shoulders of others

Large global population in need of LDL-C lowering

LDL-C an unambiguous cause of ASCVD

PCSK9 proven therapeutic target for LDL-C and outcome improvement

Inclisiran unique therapeutic attributes emerging rapidly

Since this conference began~2,000 people died of ASCVD

Another 38,000 will be dead by this time tomorrow



Proven scientific foundations for inclisiranEnormous population with recognized needs (many more unrecognized)

Patients with raised LDL-C on any treatment(Millions of patients)

US EU5 Japan Total

Primary prevention (>100 mg/dL) 16 20 8 44

Secondary prevention (>70 mg/dL) 23 23 10 56

FH 0.9 0.9 0.4 2.2

Treated with lipid-lowering Rx 40 44 18 102


Proven scientific foundations for inclisiranEven perfect data, organization and activation will leave millions at risk

Treated optimally (HI statin + EZ) but still not reaching LDL-C goal(Millions of patients)

US EU5 Japan Total

Primary prevention (goal 100 mg/dL) 1.2 1.4 0.6 3.2

Secondary prevention (goal 70 mg/dL) 3.4 3.4 1.5 8.3

FH 0.9 0.9 0.4 2.2

Optimally treated by still not at goal 5.5 5.7 2.4 13.7


Proven scientific foundations for inclisiranLDL-C the unambiguous cause of ASCVD

Ference B, et al. Eur Heart J. 2017;38:2459-2472.

Animal data

LDL-C induces atherosclerosis

Specificity

Independent risk factor

Genetics

LDL-C variants confer risk

Consistency

Invariant outcomes

Biological gradient

Proportional risk

Coherence

Clear correlation

Sequence

LDL-Cthen ASCVD

Intervention

Lowering LDL-C reduces events

Proven scientific foundations for inclisiranPCSK9 regulates LDL-R function and therefore LDL-C levels

LDL-R PCSK9 LDL-C

Statins

PCSK9inhibition

Proven scientific foundations for inclisiran


1: Ference B, et al. NEJM 2016:375:2144-2153. 2: Cohen J, et al. NEJM 2006;354:1264-1272. 3: Sabatine M, et al. NEJM 2017;376:1713-1722. 4. Steg G ACC.18

PCSK9 carries the essential modern hallmarks of a therapeutic target

Mendelian randomization1 Genetics2 Therapeutic intervention3,4

-0.40 -0.30 -0.20 -0.10 0 0.10

0.81 (0.74–0.89) for each 10 mg/dL LDL-C reduction

0

4

8

12

No Yes

Co

ron

ary

He

art

Dis

ea

se (

%)

PCSK9142X or PCSK9679X

Inclisiran’s unique therapeutic attributes are emerging rapidly


Inclisiran attributes emerging rapidlyDose-dependent LDL-C sustained over one year


Ray KK et al. NEJM 2017; 376: 1430-40.

Days from first injection

p-value for all comparisons to placebo <0.0001

Me

an

pe

rce

nt c

ha

ng

e (±

95

% C

I)

-60

-50

-40

-30

-20

-10

0

10

0 30 60 90 120 150 180 210 240 270 300 330 360

Placebo 100 mg

200 mg 300 mg

56% 53%

Inclisiran attributes emerging rapidlyConsistent responses as anticipated by mode of action


Ray KK et al. NEJM 2017; 376: 1430-40.

-140

-110

-80

-50

-20

10

40

Ch

an

ge i

n L

DL

-C (

mg

/dL

)

39 mg/dL (1mMol/L)

78 mg/dL (2mMol/L)

Background treatment + Inclisiran 300 mg

All patients responded

Mean -64.2 mg/dL

Max -122.0 mg/dL

Inclisiran attributes emerging rapidlyHow to get 20-30% fewer second ASCVD events

0

20

40

60

80

100

120

140

0 30 90 150 210 270 330 390 405 510 570 630

LD

L-C

(m

g/m

L)

Time (months)


Output of a simultaneous PD model using all Phase II data and mechanistic inputs

0 6 12 18

Average LDL-C reduction 55%

300 mg inclisiran given twice a year

Inclisiran attributes emerging rapidlyHow to get 20-30% fewer second ASCVD events

LDL-C levels (mg/dL) Anticipated CV outcomes

Baseline 55% Treated level annualized risk reduction1

150 83 68 50%Typical

baseline in clinical

trials

125 69 56 41%

100 55 45 33%

75 41 34 25%

50 28 23 17%

1: Assumes 5 years observation

Inclisiran attributes emerging rapidlyHow to get 30 more years in primary prevention

0

20

40

60

80

100

120

140

0 30 90 150 210 270 330 390 450 510 570 630

LD

L-C

(m

g/m

L)

Time (months)


Output of a simultaneous PD model using all Phase II data and mechanistic inputs

0 6 12 18

Average LDL-C reduction 43%

300 mg inclisiran given once a year

Inclisiran attributes emerging rapidlyHow to get 30 more years in primary prevention

1 20 40 60 80 100

5

10

0

+30 years

CumulativeLDL-C

(g/dL-years)

Age (years)

Threshold for ASCVDLDL -/- PCSK9 +/-

Inclisiran 300 mg annually

-40%Ø 63 mg/dL

NormalØ 105 mg/dL

Inclisiran attributes emerging rapidlyBiological leverage of RNAi translates into real-world efficiency

* 90% of Repatha patients use SureClick® auto-injector 26 times per year; 10% use Pushtronex® system 12 times per year (IMS)

Amount Devices Temperature

Inclisiran

600 mg/yr 2 Room temperature

mAb

2-5 g/yr 26* Refrigerated

Inclisiran attributes emerging rapidly


Inclisiran attributes emerging rapidlyShipped and stored at room temperature

6.0

7.0

8.0

9.0

10.0

11.0

12.0

100

120

140

160

180

200

220

0 10 20 30

Room temperature stability

Assay pH

Ass

ay

(mg

/mL

)

pH

Month

Prefilled syringe

Auto-injector

Inclisiran attributes emerging rapidlyManufacturing established at commercial scale

Synthesis established, automatable and high quality

− Capacity and scalability

Boulder, CO Frederick, CO

Phase IIIa pivotal LDL-C lowering trials with 18-months treatment have completed enrollment

Phase IIIa program for NDA-MAA in LDL-lowering18-months treatment trials have completed enrollment

Study Countries Main inclusion criteria Baseline LDL-C Patients

ORION-9 US, EU, SA Heterozygous FH 482

ORION-10 US ASCVD secondary prev. >70 mg/dL 1,561

ORION-11 EU, SA ASCVD secondary prev.High risk primary prev.

>70 mg/dL>100 mg/dL

1,617

Total 3,660

Phase IIIa program for NDA-MAA in LDL-loweringEmerging safety and tolerability profile

DSMB un-blinded review (March 2018)

− 2,332 patients

− Recommended continuation of Phase III studies with no changes

Ongoing review of blinded data (>3,400 patients incl. >2400 day 30)

− Very low incidence of reported mild, transient skin reactions

− No reports of significant LFT or other laboratory abnormalities


Phase IIIa program for NDA-MAA in LDL-lowering


Anticipated 10-fold increase in safety information during 2018

Rapid accumulation of safety data

− Now adding 10 patient years per day

Anticipate 10-fold increase during 2018

− ~1,700 with 3 doses

− ~300 with 4 or 5 doses

Accumulating patient-years of safety data

0

500

1000

1500

2000

2500

Phase I Phase II Phase III byend-2018

Phase IIIb cardiovascular outcomes trial in secondary ASCVD prevention is set to start enrolling in 2H 2018

Phase IIIb program for cardiovascular outcomesORION-4 is a streamlined secondary prevention clinical trial

Key design elements:

− Baseline LDL-C ≥100mg/dL

− Primary endpoint CHD death, MI, ischemic stroke, urgent revasc.

− Secondary endpoints include CHD and CV death

− Median follow-up 5 years

− 15,000 patients

OutcomeAssumed annual event rate

for placeboPower

(2P<0.01)Power

(2P<0.05)

MACE 2.7% >99% >99%

CHD death or MI 1.7% 99% >99%

CV death 0.9% 90% 97%

Phase IIIb program for cardiovascular outcomesORION-4 is powered for both primary and secondary endpoints

High quality inclisiran program moving quicklyNDA/MAA anticipated for submission by year end 2019


2012 2013 2014 2015 2016 2017 2018 2019 2020 2021

13 March

Demonstrate marketability

Confirm performance

Prove therapeutic concept and technical feasibility

Discover and develop technology

PCS iv

CV outcomes

PCSsc Pre-clinic

Phase I Phase II NDA/MAA review

CMC development

Launch

Commercial manufacturing

Phase III LDL-C

Inclisiran development to NDA and MAAAnticipated news flow 2018

First half Second half

Second DSMB review Further DSMB reviews

First patients dosed in ORION-5 Pre-filled syringe switch over in pivotal trials

Publications including ORION-1 subgroups

ESC, ADA, AHA

FinancialsSufficient funding to move deliver inclisiran development plans

Anticipate available cash & liquidity sufficient to complete

− Phase III clinical trials

− Manufacturing scale up

− NDA-MAA submission

− CVOT recruitment

Cowen - Microsoft...©The Medicines Company 2018 1› Cowen 38th Annual Healthcare Conference Clive...

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