Inclisiran and the ORION programme · Total AMG 145 (evolocumab) Free PCSK9 Free PCSK9 concentration (ng/mL) Free evolocumab concentration (ng/mL x 0.01) LDL-C Stein EA & RaalFJ Annu

Inclisiran and the ORION clinical development

programmeSlide deck kindly donated as an educational resource by:Professor FJ Raal, University of the Witwatersrand, Johannesburg, South Africa

Derick RaalFCP(SA), FRCP, FRCPC, Cert Endo, MMED, PHD

Head, Division of Endocrinology & MetabolismDirector, Carbohydrate and Lipid Metabolism Research UnitFaculty of Health Sciences, University of the Witwatersrand

Inclisiran and the ORION Project

LDL

EndocytosisRecycling of

LDL-R

LDL receptormAb

LDL-R synthesis

Clathrin-coated vesicle

Endoplasmic reticulum

Nucleus �SREBP Hepatocyte Lysosome

EndosomeGolgi apparatus

PCSK9 processing/ex

port siRNA or ASO

m odified from H ovingh G K , et a l. Eur H eart J 2013;34:962-71modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71

Catabolism of LDL, the role of PCSK9 antibody to PCSK9

Study Day

Total AMG 145 (evolocumab)

Free PCSK9

LDL-C

Free

PCS

K9 c

once

ntra

tion

(ng/

mL)

Free

evo

locu

mab

con

cent

ratio

n (n

g/m

L x

0.01

)

Stein EA & Raal FJ Annu. Rev. Med. 2014. 65:417–31.

Pharmacokinetics of PCSK9 monoclonal antibody therapy

0 28 560

50

500

100

300

400

200

14 70 8442

LDL-C M

ean Change (%)150

350

450

250

140

120

100

80

60

40

20

0

160

Reduction in LDL-C values among healthy volunteers in single-dose studies

Stein E . N Engl J M ed 2012;366:1108-18

-60

-50

-40

-30

-20

-10

0

10

20

-70

Mea

n ch

ange

from

bas

elin

e in

LDL-

C (%

)

85 106Study Day

Placebo 50 mg 100 mg 150 mg 250 mg

8443292215118421

Stein E. N Engl J Med 2012;366:1108-18

Subcutaneous administration of Alirocumab

0

-20

-40

-60

-80

LDL-

C (%

cha

nge

from

bas

elin

e)

0 2 4 6 8 10 12Time (weeks)

Model predicted time course of LDL-C after multiple evolocumab doses

Gibbs et al. J Clin Pharm. 2017;57:616

280 mg QM420 mg QM140 mg Q2W

7

Unmet needLDL-C variability common, associated with worse outcomes

1. Ray KK et al. N Engl J Med 2017; 376:1430-14402. Bangalore S et al. JACC 2015; 65: 1539-1548

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

% c

hang

e in

LDL

-C fr

om B

L

Six month percent change in LDL-Camong statin users from starting level1

Increase in death, CV outcomes witheach 1 standard deviation of LDL-C variability2

23%

17% 16%

11%10%

Death Strok e Anyc oronary

ev ent

Any CVev ent

M I

Small interfering RNA (siRNA) targeted to PCSK9 Mechanism of action

RISC = RNA induced silencing complex Whitehead et al. Nat Rev Drug Discov 2009;8:129-38

Inclisiran:

siRNA conjugated to N-acetylgalactosamine

Subcutaneous administration

Targeted delivery to hepatocytes

Third generation with enhanced stablilisation chemistry

Asialoglycoprotein receptor (ASGPR):Highly expressed in hepatocytes only.

High rate of uptake

GalNAc-siRNA conjugates facilitate rapid hepatic uptakeBackground

10

ORION ProgramStudy Rationale and Designs

Clinical & regulatorystrategy

11

ORION clinical development program overview

ORION-2 & -5 (60 HoFH)Phase II & III

ORION-6 & -7renal & hepatic impaired) PK

ORION-13 (12 HoFH peds)Phase IIIORION-16 (40 HeFH peds)Phase III

ORION-12 TQT

ORION-14 & -15 PK/PD Japan & China

ORION-4(15,000 high risk ASCVD)Phase III

ORION-8Phase III extension

ORION-10(1500 ASCVD)Phase III

ORION-1(500 ASCVD)Phase II

ASCVD or ASCVD risk equivalentsTotal 18,500

ORION-9(400 HeFH)Phase III

ORION-3Phase II extension

HeFH & HoFH

Special populations

ORION-11(1500 ASCVD/RE)Phase III


ORION-19 HoFH (8-11)

ORION-20 HeFH (8-11)

12

ORION development program through ORION-12


Trials Relevant endpoints Patients selected (number)

Expected start time

Pivotaltrials

ORION-4 Cardiovascular M&M (Phase III) HRASCVD or ASCVD RE (N=15,000) Q2 2018

ORION-5 LDL-C lowering (Phase III) HoFH (N=60) Q2/3 2018

ORION-9 LDL-C lowering (Phase III) HeFH (N=400) Ongoing

ORION-10 LDL-C lowering (US) (Phase III) ASCVD (N=1,500) Ongoing

ORION-11 LDL-C lowering (EU) (Phase III) ASCVD or ASCVD RE (N=1,500) Ongoing

Extension trials

ORION-3 LDL-C lowering (extension of ORION-1)

ASCVD or ASCVD RE or HeFH (N=490)

Ongoing

ORION-8 LDL-C lowering (extension of ORION -9, -10, -11)

ASCVD, ASCVD risk equivalent, HeFH (N=3,460)

Q4 2019

Supportive trials

ORION-1 LDL-C lowering (Phase II) ASCVD or ASCVD RE or HeFH(N=501)

Completed

ORION-2 LDL-C lowering (Phase II) HoFH (N=10) Ongoing

Special populationsstudies

ORION-6 Pharmacokinetics Hepatic impairment (N=24-32) Q2 2018

ORION-7 Pharmacokinetics Renal impairment (N=31) Ongoing

ORION-12 TQT Healthy volunteers (N=200) Q1/2 2018

13

ORION-1Long-Term Efficacy & Safety

14

Completed (n=483)

Screening (Day -14 to Day -1)

Randomization (Day 1, n=501)

Treated (n=497)

Day 1 Study drug givenDay 14 1st follow-up visit

Monthly follow-up visitsDay 30

Day 90

Day 180

Day 210 End of study visit

Primary evaluation

Day 360 Extended follow-up

One dose starting regimen

200 mgN=60

PlaceboN=65

500 mgN=65

300 mgN=61

MethodsTrial design

Day 1 Study drug givenDay 14 1st follow-up visit

Monthly follow-up visitsDay 30

Day 90

Day 180

Day 210 End of study visit

Primary evaluation

Day 360 Extended follow-up

Two dose starting regimen

100 mgN=61

PlaceboN=62

300 mgN=61

200 mgN=62

Study drug given

Randomized (n=501)

15

Efficacy: One dose starting regimenClamped PCSK9 knockdown

-8 0

-6 0

-4 0

-2 0

0

20

0 30 60 90 12 0 15 0 18 0 21 0 24 0 27 0

Mea

n pe

rcen

t cha

nge

(±95

% C

I)

Days from first injection

Placebo

200 mg

300 mg

500 mg

End of study if LDL-Cback to baseline

P-value for all comparisons to placebo <0.0001

16

Efficacy: Two dose starting regimenClamped PCSK9 knockdown

-8 0

-6 0

-4 0

-2 0

0

20

0 30 60 90 12 0 15 0 18 0 21 0 24 0 27 0

Mea

n pe

rcen

t cha

nge

(±95

% C

I)


Placebo

100 mg

200 mg

300 mg

End of study if LDL-Cback to baseline


17

9 months time adjustedmean 41% reduction

300 mg50.9% reduction

Efficacy: One dose starting regimenRobust, sustained LDL-C reductions – 300 mg optimal

-6 0

-5 0

-4 0

-3 0

-2 0

-1 0

0

10

0 30 60 90 12 0 15 0 18 0 21 0 24 0 27 0

Mea

n p

erce

nt

chan

ge

(±95

% C

I)


Placebo

200 mg

300 mg

500 mg

300 mg38.4% reduction


18

9 months time adjustedmean 50% reduction

Efficacy: Two dose starting regimenRobust, sustained LDL-C reductions – optimal start regimen

-6 0

-5 0

-4 0

-3 0

-2 0

-1 0

0

10

0 30 60 90 12 0 15 0 18 0 21 0 24 0 27 0

Mea

n pe

rcen

t cha

nge

(±95

% C

I)


Placebo

100 mg

200 mg

300 mg

300 mg x255.5% 52.6%


19

Efficacy: Two dose starting regimenIndividual patient responses (%) at day 180

Mean 52.6%

Max 80.9%

-1 00

-8 0

-6 0

-4 0

-2 0

0

20

40

60

Cha

nge

in L

DL-

C (p

erce

nt)

PlaceboPercent reduction

Inclisiran 300 mgPercent reduction

All patients responded

20

Inclisiran dose 300mg sc Day 1, 90, 270 and 6-monthly Sustained >50% reduction in LDL-C for 6-months

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Q1

Q3

MeanMedian

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Q1

Q3

MeanMedian

Day 90

% C

hang

e in

LD

L-C

from

Bas

elin

e

Time adjusted LDL-C for 6 months = 41%

Day 270 Day 90 Day 270

One dose starting regimen (300 mg) Two dose starting regimen (300 mg)

Time adjusted LDL-C for 6 months = 51%

21

Summary Two 300 mg starting dose regimen for inclisiran selectedNo safety concerns

Optimal dosage 300 mg given twice as starting regimen

• All patients responded with significant LDL-C lowering

• At 6 months, mean LDL-C� of 52.6% (64 mg/dL), and up to 81% (122 mg/dL)

22

The ORION Phase III ProgramORION-2, -3, -5, -7, -9, -10, -11

©The Medicines Company 2018 23

ORION: Phase III trialsPivotal Phase III studies to support LDL-C lowering labeling

Study Sites Main inclusion criteria Patients

ORION-11 EU, SA ASCVD (LDL-C >70mg/dL)and risk equivalent patients(LDL-C >100 mg/dL)

1,500

ORION-10 US ASCVD (LDL-C >70 mg/dL) 1,500

ORION-9 US, EU, SA Heterozygous FH 400

ORION-5 US, EU, SA Homozygous FH 60

3,460


ORION: Phase III trialsDesign of the ORION-9, -10, -11 studies

Patients 18 month duration

HeFH, ASCVD and/or risk equivalent patients

Age ≥18 yearsHigh intensity statinLDL-C>70 mg/dL, or>100 mg/dL (RE, HeFH)

Inclisiran300 mg

Randomize1:1

l l l l

Placebo

l l l l

Visits 1 m 3 5 9 11 15 17 18

25

ORION-9 ORION-10 ORION-11Male or female subjects ≥ 18 years of age

Male or female subjects ≥ 18 years of age

Male or female subjects ≥ 18 years of age

History of HeFH with a diagnosis of HeFH by genetic testing; and/or a documented history of untreated LDL-C of > 4.9 mmol/L (>190 mg/dL), and a family history of FH, elevated cholesterol or early heart disease may indicate FH

History of ASCVD (CHD, CVD or PAD*)

History of ASCVD (CHD, CVD or PAD*) or ASCVD-risk equivalents (type 2 diabetes, familial hypercholesterolemia, and including subjects whose 10-year risk of a CV event assessed by Framingham Risk Score or equivalent has a target LDL C of < 2.6 mmol/L (< 100 mg/dL).

Stable on a low-fat diet (e.g., NCEP)

N/A N/A

Serum LDL-C ≥ 2.6 mmol/L (≥ 100 mg/dL) at screening

Serum LDL-C ≥ 1.8 mmol/L (≥ 70 mg/dL) at screening

Serum LDL-C ≥ 1.8 mmol/L (≥70 mg/dL) for ASCVD subjects or ≥ 2.6 mmol/L (≥ 100 mg/dL) for ASCVD-risk equivalent subjects at screening

* Coronary heart disease (CHD), Cerebrovascular disease (CVD); Peripheral arterial disease (PAD) [Protocol Appendix A]

ORION-9, ORION-10 and ORION-11Common inclusion criteria


26

Elevated triglyceride at screening

Mild and Moderate renal impairment

Maximum tolerated statin and other LLTs

Stable lipid-lower therapies for ≥ 30 days before screening with no planned medication or dose change during study participation

Subjects must be willing and able to give informed consent

ORION-9, ORION-10 and ORION-11Inclusion criteria identical for all studies


27

Exclusion criteria are similar to those used in many lipid lowering trials for the last 20 years and reflect the lack of restrictions required for subjects on inclisiran

• Significant medical conditions that will affect the subject participation of the interpretation of the results

• Major adverse cardiovascular event within 3 months prior to randomization• Uncontrolled blood pressure• Active liver disease• Pregnant or women of child bearing potential not using contraception• Male not using acceptable contraception• Alcohol or drug abuse• Patients unsuitable for a clinical trial

ORION-9, ORION-10 and ORION-11Exclusion criteria identical for all studies


28

Primary endpoint: • Percentage change in LDL-C from baseline to Day 510

• Time adjusted percentage change in LDL-C from baseline between Day 90 and

Day 540. This is the average percentage change in LDL-C from baseline over

the period between Day 90 and Day 540

Key secondary endpoints: • Absolute change in LDL-C from baseline to Day 510

• Time adjusted absolute change in LDL-C from baseline between Day 90 and

Day 540

• Percentage change from baseline to Day 510 in PCSK9, total cholesterol, ApoB,

and non-HDL-C

ORION-9, ORION-10 and ORION-11 Common study endpoints


29

Project ORION-9 ORION-10 ORION-11Protocol # MDCO-PCS-17-03 MDCO-PCS-17-04 MDCO-PCS-17-08

Indication HeFH (Heterozygous Familial Hypercholesterolemia)

ASCVD ASCVD or ASCVD Risk Equivalents (RE)

Phase Phase III Phase III Phase III

Total # of subjects Randomized

482 1561 1617

Total # of sites 54 149 73

Recruitment period 3 months 3 months 3 months

First subject in (consented) 28 NOV 2017 15 DEC 2017 27 OCT 2017

First subject randomized 12 DEC 2017 21 DEC 2017 01 NOV 2017

Last subject In (randomized)

22 FEB 2018 07 MAR 2018 29 JAN 2018

Country/site mix CanadaCzech RepublicDenmarkNetherlands

South Africa SpainSwedenUS

United States Czech RepGermanyHungaryNetherlands

PolandSouth AfricaUKUkraine

Phase III lipid lowering trials overview



ORION: Phase III trialsReassuring safety and tolerability profile emerging

DSMB review (March 2018)− >2000 patients− Recommended continuation of Phase III studies with no changes

Ongoing review of blinded data (3,660 patients)− Very low incidence of reported mild, transient skin reactions− No reports of LFT or other significant lab abnormalities


ORION-2: Phase II HoFHRobust, durable effects in homozygous familial hypercholesterolemia

Asp227Glu/Asp227Glu variantAbsolute LDL-C reduction− 184 mg/dL at day 60− 276 mg/dL at day 120− 242 mg/dL at day 180

Standard dose -80

-60

-40

-20

0

0 30 60 90 120 150 180

Per

cent

cha

nge

Days

LDL-C

PC SK9


ORION-5: Phase III HoFHDesign of a 6-month duration efficacy study

Starts 2H 2018 – not on critical path to NDA, separate pediatric programPatients ORION-5 anticipated design

1 – 6 months EOS

6 – 24 months open label extension

Homozygous FHGenetic confirmation

RxHigh dose statinEzetimibe(Plasmapheresis)

Inclisiran300 mg

Inclisiran300 mg

l ll l

l

ConsentRandomize 2:1

Placebo Inclisiran300 mg

l ll l ll

Visits 1 m 3 m 6 m 9 m 12 m 15 m 18 m 21 m


ORION-3: Head-to-head versus Repatha®

Assess switching, comparative efficacy, safety and patient preferenceEnd of ORION-1

ORION-3

Year 1 2 3 4

Inclisiran (3) Inclisiran300 mg q180d

l l l l l l l l

Secondconsent

Placebo (1) Evolocumab140 mg q14d

Inclisiran300 mg q180d

llllllllllllllllllllllll l l l l l l

Visits 1 m 3 6 7 9 12 13 15 18 19 21 24 27 30 33 36 39 42 45


ORION-3: Head-to-head versus Repatha®

Safety profile similar to evolocumab

Interim safety data (18 April 2018 – 290 inclisiran and 92 evolocumab)− No difference in safety profile between groups− No other safety signals

Patient reported outcomes and efficacy data in 2019


ORION-7: Renal functionRenal function does not effect safety or efficacy – no dose adjustmentRenal function group

ORION-3

Calc. creat. clearance 0-48 hours Day 2-60 Day 60-180

Mild (N=8)60-89 mL/min

PK-PDSafety

PDSafety

LDL-CSafety

Moderate (N=8)30-59 mL/min

Severe (N=7)15-29 mL/min

Normal (N=8)≥90 mL/min


ORION-7: Renal function

-100

-80

-60

-40

-20

0

0 10 20 30 40 50 60

Per

cen

t ch

ang

e in

PC

SK

9

Days

Norm al

M i ld

M oder ate

Sev ere

Plasma PK over the first 48 hoursExposure with renal dysfunction – as anticipatedInclisiran not detectable in any group after 48 hours

PD effects on PCSK9 not significantly different

Renal function does not effect safety or efficacy – no dose adjustment

Group Cmax ng/mL

AUCh*ng/mL

Normal 421 7,600

Mild 987 11,800

Moderate 897 13,433

Severe 1,756 19,214

Inclisiran clinical trials programDuring 2018, safety data expected to increase 10-fold

Rapid accumulation of safety data

10-fold increase during 2018− 1,700 with 3 doses− 290 with 4 – 5 doses


Patient-years exposure to inclisiran

Phase I Phase II End 2018

2,360

23026

38

ORION-4Long term cardiovascular outcomes study

Clinical & regulatorystrategy Study Aims

• To assess the effect of inclisiran on major cardiovascular events

• The study will randomize ≥15,000 participants aged ≥55 years with pre-existing cardiovascular disease between inclisiran sodium 300 mg and matching placebo for a median of about 5 years.

Randomization Visit

Placebo injection (dose givenat screening)

Inclisiran sodium 300 mg

Matching placebo

ScreeningVisit

Run-in period:about 8 weeks

Follow-up visits at about 3 months andthen 6-monthly for a median of 5 years

39

ORION-4Long term cardiovascular outcomes study


Primary endpoint:

Composite of major adverse cardiovascular events (MACE), defined as:Coronary (CHD) death;Myocardial infarction;Fatal or non-fatal ischaemic stroke; orUrgent coronary revascularization procedure

Secondary endpoints:

Composite outcome of CHD death or myocardial infarctionCardiovascular death

Inhibition of PCSK9 with Inclisiran is a very promising, and potentially the simplest and most effective, approach to further reducing LDL-C, the cause of atherosclerosis• LDL-C variability within individuals is practically eliminated• Injection burden reduced substantially• Sustained effect between infrequent injections• Opportunity to improve patient adherence

Phase II and the ongoing phase III studies have shown robust long term efficacy with no safety issues

Conclusions

PCSK9 Inhibitor therapy with Inclisiran

Documents

Inclisiran and the ORION programme · Total AMG 145 (evolocumab) Free PCSK9 Free PCSK9 concentration (ng/mL) Free evolocumab concentration (ng/mL x 0.01) LDL-C Stein EA & RaalFJ Annu