multidisciplinary international group for hemapheresis therapy … · 2017. 5. 11. · foundation...

MIGHTY MEDIC Multidisciplinary International Group for Hemapheresis TherapY and MEtabolic DIsturbances

Contrast

Disclosures

Consulting agreements and research grants from:

• Aegerion

• Fresenius Medical Care

• Kaneka NV

• Isis Pharmaceutical

• Cerenis Therapeutics

• Regeneron

• Kowa

• MSD

• Amgen

• Sanofi

• Ionis

Towards an international consensus – integrating lipoprotein apheresis and new lipid-lowering drugs

Claudia Stefanutti1*, Ulrich Julius, Gerald F Watts, Mariko Harada-Shiba, Maria Cossu, Volker J Schettler, Giustina De Silvestro, Handrean Soran, Jeanine Roeters Van Lennep, Livia Pisciotta1, Hans U Klör, Kurt Widhalm, Patrick M Moriarty and the MIGHTY MEDIC Multinational Society

Accepted April 2017,

in press

Appendix 2: Additional members of the Mighty Medic Group* D’Alessandri G, Immunohematology and Transfusion Medicine, ASL3, Pistoia, Italy; Bianciardi G, Pathological Anatomy, Medical Biotechnology Dept, University of Siena, Italy; Bosco G, Paediatric Cardiology, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; De Fusco G, Immunohematology and Transfusion Medicine, “Dell’Angelo” Hospital, Mestre, Italy; Di Giacomo S, Morozzi C, Mesce D, Vitale M, Sovrano B, Extracorporeal Therapy Unit, ‘Sapienza’ University, Umberto I’Hospital, Rome, Italy; Drogari E, 1st Department of Paediatrics Medical School, “Aghia Sophia” Children’s Hospital, Athens, Greece; Ewald N, Internal Medicine Dept, General Hospital Luebbecke-Rahden, Luebbecke, Germany; Gualdi G, Emergency Radiology, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Jaeger BR, Lipid Center Nordrhein, Mu ̈lheim an der Ruhr, Germany; Lanti A, Immunohematology and Transfusion Medicine, Tor Vergata University Hospital, Rome, Italy; Marson P, Immunohematology and Transfusion Medicine, General University Hospital, Padua, Italy; Martino F, Paediatric Cardiology, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Migliori G, Immunohematology and Transfusion Medicine, G.B. Morgagni e L. Pierantoni Hospital, Forlì, Italy; Parasassi T, Translational Pharmacology, Science Research Council, Rome, Italy;

Pavan A, Immunohematology and Transfusion Medicine, S. Andrea Hospital, Rome, Italy; Perla FM, Paediatric Hemato-Oncology, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Brunelli R, Perrone G, Ginecology and Obstetrics, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Brunelli R, Ginecology and Obstetrics, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Renga S, Nephrology-Dialysis Operative Unit, Giovanni Paolo II Hospital, Olbia, Italy; Ries W, Internal Medicine Dept, Diakonissen Hospital, Flensburg, Germany; Romano N, Immunohematology and Transfusion Medicine, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Immunohematology and Transfusion Medicine, General University Hospital, Padua, Italy. Romeo S, Sahlgrenska Academy at University of Gothenburg, Department of Molecular and Clinical Medicine, Gothenburg, Sweden; Pergolini M, Labbadia G, Dept of Internal Medicine and Medical Specialties, ‘Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Di Iorio B, Complex Operative Unite Nefrology, Hospital ‘’A. Landolfi ’’ Avellino; De Palo T, Operative Unit Pediatric Nephrology and Dialysis, Hospital Giovanni XXIII, Bari; Abbate R, Dept of Medical and Surgical Critical Area, University of Florence; Marcucci R, Dept of Experimental and Clinical Medicine, University of Florence;

Appendix 2: Additional members of the Mighty Medic Group*

Poli L, Immunohematology and Transfusion Medicine, Hospital, S. Antonio Abate, Gallarate (MI); Ardissino G, Center for the Treatment and Study of Hemolytic Uremic Syndrome, Foundation IRCCS ‘’Ca Granda Ospedale Maggiore Policlinico ’’, Milano; Ottone P, Immunohematology and Transfusion Medicine, Hospital, S.Luigi, Orbassano (TO); Tison T, Immunohematology and Transfusion Medicine, Hospital, Padova; Favari E, Dept of Pharmacy, University of Parma; Borgese L, Shafii M, Gozzer M, Immunohematology and Transfusion Medicine, Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Pacella E, Dept of Sensory Organ, Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Torromeo C, Dept of Cardiovascular Sciences, Respiratory, Nephrology, Anaesthetic and Geriatric, Sapienza’ University, ‘Umberto I’ Hospital, Rome, Italy; Parassassi T, Translational Pharmacology Institute, CNR, Rome; Berni A, Complex Operative Unit, Sapienza’ University, S.Andrea Hospital, Rome; Guardamagna O, Pediatric Science Cardiovascular Prevention and Dyslipidemia, Head University of Turin; Zenti M,G, Complex Unit Operative, Endocrinology, Diabetes and Metabolic Diseases, Verona; Guitarrini M,R, Immunohematology and Transfusion Medicine Belcolle Hospital, Viterbo; Berretti D, Operative Unite, Immunohematology of Pistoia; Hohenstein B, FA for internal medicine and nephrology, University Hospital Carl Gustav Carus, Dresda, Germany; Saheb S, Endocrinologie et metabolism, Hospital, Pitiè, Salpètrière, Parigi;

Appendix 2: Additional members of the Mighty Medic Group*

3

As of 2017 there are five therapies that have been utilised in He- Ho- FH

PCSK9, proprotein convertase subtilisin/kexin type 9; HoFH, homozygous familial hypercholesterolaemia

Options

Statins ± ezetimibe

Lipo- protein

apheresis

Lomitapide Mipo-

mersen

PCSK9 inhibitors

Limited evidence of treatment with

evolocumab of HoFH subjects is available, with

contradictory findings5

In vivo data suggest mipomersen and lomitapide can cause atherosclerotic regression;3 however no human data are currently available

Modest reductions in LDL-C for HoFH patients2

Demonstrated to regress atherosclerosis and improve CV outcomes in humans1

1. Stefanutti C, et al. Transfusion 2009;49:1461–70; 2. Cuchel M, et al. Eur Heart J 2014;35:2146–57 3. Hewing B, et al. Atherosclerosis 2013;227:125–9; 4. Mullick AE, et al. J Lipid Res 2011;52:885–96

5. France M, et al. Clin Lipidol 2014;9:101–18

Lipoprotein apheresis (LA) reduces signs of atherosclerosis in HoFH

Serial coronary and aorta cathetherisation in 11 HoFH children; LA weekly/biweekly; follow-up: 2–17 years

Data like these have led LA + statins to become the gold standard backbone for therapy in HoFH

Mea

n o

vera

ll at

her

oge

nic

ind

ex

p=0.03

p=0.018

The overall atherogeninc index score at baseline was significantly co-related to the basal values of TC (p=0.015), LDL-C (p=0.015), and TG (p=0.01). but not of HDLC (p=0.075) as demonstrated by the logit regression analysis. Cox and Snell pseudo-R2 = 0.67

Stefanutti C, et al. Transfusion 2009;49:1461–70 Agatston AS, et al. J Am Coll Cardiol 1990;15:827–32

Lipid levels undergo cyclical rebound between apheresis procedures

Powerful lipid-lowering effect

Rebound within 1–2 weeks

Lip

id le

vel,

mm

ol/

L

Time

TC, total cholesterol HDL-C, high-density lipoprotein-C TG, triglycerides Stefanutti C et al, J Clin Lipid, 2017, in press

Can we improve outcomes of apheresis?

• Can we aim for a more ‘physiological’ suppression of LDL-C?

– Smooth out the rebound curve?

Apheresis Modified apheresis?

Target range

LDL-

C

Time

Stefanutti C et al, J Clin Lipid, 2017, in press

Lipoprotein Apheresis in the Management of Familial Hypercholesterolaemia: Historical Perspective and Recent Advances. Stefanutti Claudia and Thompson Gilbert R; Curr Atheroscler Rep. 2015 Jan;17(1):465.doi: 10.1007/s11883-014-0465-6.

Therapy Mode of action Dependent on LDL-R?

Status

Lomitapide1 Inhibits MTP, an enzyme responsible for VLDL assembly and secretion in the liver and absorption from the intestine

No Approved for use in EU, Canada, Mexico, Norway, Iceland, Brazil, Taiwan and the US with or without apheresis

Mipomersen2 Antisense agent targeting ApoB mRNA No Approved in the US only, but not with apheresis

PCSK9 inhibitors3 Inhibit PCSK9, a molecule that binds to the LDL-R promoting receptor degradation and retention of LDL-C in plasma

Yes Under investigation

No efficacy in LDL-R negative homozygotes

1. Aegerion Pharmaceuticals Inc. Lojuxta summary of product characteristics 2013 ; Genzyme Corporation. Kynamro prescribing information 2013 2. Raal FJ, et al. Lancet 2014;384:ePub ahead of print

Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9. Page MM, Stefanutti C, Sniderman A, Watts GF. Clin Sci (Lond). 2015 Jul;129(1):63-79.

http://www.ncbi.nlm.nih.gov/pubmed/25881720






LDL-

C, m

mo

l/L

Potential benefit of lomitapide in the lipid-lowering therapy of HoFH patients

0

2

4

6

8

10

12

14

Baseline Statin Plus eze Plus LA Plus lomitapide

Baseline: 13mmol/L

Add statin: 10mmol/L (10–25% reduction)

Add ezetimibe: 8mmol/L (10–15% reduction)

Add apheresis: 4.2mmol/L* (50–70% reduction)

Add lomitapide: 4.4mmol/dL (50–70% reduction

*Post apheresis value HoFH, homozygous familial hypercholesterolaenia LDL-C, low-density lipoprotein-C LA, lipoprotein apheresis; EAS, European Atherosclerosis Society eze, ezetimibe; ACVD, atherosclerotic cardiovascular disease

EAS recommended LDL-C target for adult patients with HoFH

EAS recommended LDL-C target for adult patients with HoFH plus ACVD

Adapted from Cuchel M, et al. Eur Heart J 2014;35:2146-57

(Hypothetical model)

In a larger placebo-controlled trial, 33 HoFH Pts were allocated to E and 17 to placebo

(P). Pts who received E had a 30.9% lowering in LDL-C vs P

Post-hoc analysis

Pts with 2 defective mutations: LDL-C - 46.9% vs P

Pts with 1 defective and 1 negative mutation: LDL-C -24.5% vs P. (p: NS)

1 HoFH Pt for receptor-negative mutations: did not respond to treatment

Lp(a) was not significantly lowered by E (Raal et al, Lancet 2014)

A further, intriguing effect of PCSK9-I is to lower Lp(a) by about 20-30% in Pts with

HeFH, but not HoFH. The mechanism by which PCSK9-I lowers Lp(a) is unclear, given

that Lp(a) is considered not to directly interact with the LDLR (Gaudet et al, Am J Cardiol

2014)

Recent evidence of effects of evolocumab (E) on HoFH

Efficacy of lomitapide

Lomitapide added to maximal LLT resulted in mean 45.5% decreases in LDL-C levels at Week 126

HoFH patients in a single-arm, dose escalation (to MTD) study of lomitapide with and without concomitant apheresis to 78 weeks (n=29), and then long-

term follow up to 4.5 years (n=19)

Aegerion data on file

10

0

–10

–20

–30

–40

–50

–60

–70

Mean

ch

an

ge i

n

LD

L-C

, %±

SD

Week

Phase 3 Long-term extension

0 10 18 26 36 46 56 66 78 90 102 114 126

MTD, maximum tolerated dose

Data on File, Aegerion Pharmaceuticals

©2013 Aegerion Pharmaceuticals, Inc.

Individualised patient responses – the importance of dose titration

18

Patient MD: plasma TC and LDLC levels over time

2010 2011 2014 2013 2012

Δ TC: - 64.8 % Δ LDLC: - 77.1 %

Lip

id le

vel,

mg/

dL

2015

End of Phase 3 clinical trial

Year

LA treatment interval changed:

QW to Q2W

Δ TC: - 62.9 % Δ LDLC: - 50 %

TC, total cholesterol; LDLC, low-density lipoprotein cholesterol; LA, lipoprotein apheresis; QW, weekly; Q2W, bi-weekly

Lomitapide 60 mg/day + biweekly LA

20

Stefanutti C et al, J Clin Lipidol. 2016 Jul-Aug;10(4):782-9.

Summary data (time-averaged LDL-C)

0

50

100

150

200

250

300

350

400

1 2 3 4 5 6 7

Baseline*

Nadir**

Tim

e av

erag

ed L

DL-

C le

vel,

mg/

dL

Lomitapide dose, mg

60 30 20 10 20 5 20 10

% change in LDL-C

–83 –80 –40 –5 -61 –32 –76 –36

*Mean of 2–3 pre-lomitapide time averaged LDL-C values; **Lowest recorded time averaged LDL-C level

Able to reduce apheresis

But not always all that

glitters is gold…

How novel is this study?

This is the first controlled trial demonstrating that in complex

patients with FH alirocumab reduces the requirement for Aph,

a demanding and relatively expensive, but effective therapy. A

previous case series suggested that evolocumab could match

the reductions in LDLC achievable by weekly LA *

(*) Lappegard KT, Enebakk T, Thunhaug H, Hovland A. Transition from LDL apheresis to evolocumab in heterozygous FH is equally effective in lowering LDL, without lowering HDL cholesterol. Atherosclerosis 2016;251:119–123

What were the limitations?

Since HeFH was partly defined phenotypically, some pts might not

have had a monogenic defect. Although FCH and multigenic HC

with elevated Lp(a) can mimic HeFH, the results would still be

clinically relevant

It was unclear how many HeFH pts met recently defined criteria for

severe FH. Information on genetic testing would have been critical

had pts with HoFH been studied for null LDL-R mutations blunt

responsiveness of LDL-C to PCSK9 inhibition

Seidah NG, Awan Z, Chre´tien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res 2014;114:1022–1036. Raal FJ, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-

blind, placebo-controlled trial. Lancet 2015;385:331–340.

1

• The Aph techniques and Pts studied were heterogeneous, with those from the USA having higher baseline LDL-C, more prevalent statin intolerance, and less frequent Aph

• randomization was also only stratified by frequency of Aph and Lp(a) level

• A deficiency of the design was selecting an LDL-C reduction of 30% from BL as the threshold for discontinuing Aph. An arbitrary criterion, as many pts should be treated to absolute target levels of LDL-C, as would have been clinically required in the D cohort

• To be remarked that the choice of a pre-Aph LDL-C level in the comparative analysis would have favoured A, because use of the interval-mean LDL-C would have been lower with Aph

2

• An interval-mean reduction in LDL-C of at least 30% in Pts with HeFH could be argued to eventually trigger the discontinuation of Aph; the outcome might well have differed had HoFH Pts been studied

• A health economic evaluation of the impact of A on Aph

would have been pertinent, acknowledging the potential major cost savings

• A longer period of intervention with A would have also been

required to show a difference in psychological outcomes compared with Aph alone

• The sample size and duration of the trial were modest, and no ASCVD outcomes could be tested, implying its status as a proof-of-concept study

3

What are the clinical implications?

The implications of this study are strictly for patients with HeFH

with established ASCVD receiving regular Aph

Given that almost half the participants were not taking statins,

the ramifications also extend to the subset of Aph pts who are

statin intolerant or reluctant

The findings will have greatest impact for centres which

frequently employ LA*, particularly in D and other major

European countries (A, I, F, UK) that practice selective

techniques (*) Lipoprotein Apheresis

Homozygous*/Compound Heterozygous FH

Diet, Lifestyle, High Potency, Statin, Ezetimibe, Resin

Heterozygous FH with established ASCVD

Confirm adherence and tolerability

LDL-Ch at ideal target*

Treat with PCSK9 inhibitor

Continue and monitor therapy


Confirm suitability for apheresis

Refer to specialist centre for apheresis




Consider continuing PCSK9i and adding lomitapide or mipomersen, LT* (in younger HoFH), or enrolment in clinical trial of new therapies (*) Liver Transplantation

Yes

Yes

No

No

Yes

Yes No

No

*If known double null mutation in LDL-R, proceed directly to apheresis

*Ideal LDL-Ch target: <2.5 mmol/L (adults)

<3.8 mmol/L (children) <1.8 mmol/L (clinical ASCVD)

Efficacy and Safety of the PCSK9 Monoclonal

Antibody Alirocumab versus Placebo in 1257

Patients with Heterozygous Familial

Hypercholesterolaemia: Analyses up to 78 Weeks

from Four ODYSSEY Trials

John J.P. Kastelein1, Michel Farnier2, G. Kees Hovingh1,

Gisle Langslet3, Marie T. Baccara-Dinet4, Daniel A. Gipe5,

Umesh Chaudhari6, Jian Zhao7, Christelle Lorenzato8,

Henry N. Ginsberg9

1Department of Vascular Medicine, Academic Medical Center, University of Amsterdam,

Amsterdam, The Netherlands; 2Lipid Clinic, Point Médical, Dijon, France; 3Lipid Clinic, Oslo University Hospital, Oslo, Norway; 4Sanofi, Montpellier, France;

5Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 6Sanofi, Bridgewater, NJ, USA; 7Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 8Sanofi, Paris, France;

9Columbia University, New York, NY, USA

This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

HeFH is the most common autosomal dominant genetic dyslipidaemia

disorder (estimated prevalence 1:200 to 1:500)1

Despite treatment with LDL-C-lowering therapies, many patients with

HeFH do not achieve sufficient LDL-C reductions

– Only ~20% of patients with HeFH treated with LLTs reached a pre-defined

LDL-C target level of ≤2.59 mmol/L (100 mg/dL)2,3

– An LDL-C target level of <1.8 mmol/L (70 mg/dL) has been recommended

for patients with HeFH who are at very high CV risk4,5

Alirocumab is a fully human monoclonal antibody to PCSK9, which

has shown significant LDL-C reductions in Phase 2 and 3 studies6–10

Background

40

1. Nordestgaard BG et al. Eur Heart J. 2013;34:3478–90a; 2. Huijgen R et al. PLoS One. 2010;5:e9220; 3. Béliard S et al.

Atherosclerosis. 2014;234:136–41; 4. Bays HE et al. J Clin Lipidol. 2014;8:S1–S36; 5. Reiner Z et al. Eur Heart J. 2011,32:1769–1818; 6.

Koren MJ et al. Postgrad Med. 2015;127:125–32; 7. Roth EM et al. Int J Cardiol. 2014;176:55–61; 8. Cannon CP et al. Eur Heart J.

2015;36:1186–94; 9. Robinson JG et al. N Engl J Med. 6;372:1489–99; 10. Kereiakes DJ et al. Am Heart J. 2015;169:906–15.

CV, cardiovascular; HeFH, heterozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol;

LLT, lipid-lowering therapy; PCSK9, proprotein convertase subtilisin/kexin type 9.

This analysis determined LDL-C-lowering efficacy and safety of alirocumab in

1257 patients with HeFH on maximally-tolerated statin

± other LLT from four 18-month placebo-controlled ODYSSEY studies

Efficacy and Safety Data Analysed from

Four Phase 3 ODYSSEY Studies

41

Control: placebo Q2W

FH I, 78 weeks (n=486)

Alirocumab, n=323

Placebo, n=163

FH II, 78 weeks (n=249)

Alirocumab, n=167

Placebo, n=82

3183 randomised patients with HeFH or high CV risk receiving stable maximally tolerated

statin† ± other LLT

(2115 alirocumab, 1068 control)

Alirocumab 75/150 mg Q2W‡

Background statin

LONG TERM, 78 weeks (n=2341)

Alirocumab, n=1553

Placebo, n=788

HIGH FH, 78 weeks (n=107)

Alirocumab, n=72

Placebo, n=35

Primary endpoint in all studies: % change in calculated LDL-C from baseline to Week 24, analysed with an ITT approach§

Control: placebo Q2W

Alirocumab 150 mg Q2W

Patients with HeFH or high CV risk

(n=2341) (LDL-C level

≥1.81 mmol/L [70 mg/dL])

Patients with HeFH (n=107)

(LDL-C level ≥4.14 mmol/L

[160 mg/dL])


(LDL-C levels ≥1.81/2.59 mmol/L

[70/100 mg/dL], depending on CV risk)


Alirocumab, n=276

Placebo, n=139

†Rosuvastatin 20–40 mg, atorvastatin 40–80 mg, or simvastatin 80 mg daily, or lower doses with an investigator-documented reason e.g.

intolerance; ‡Dose adjustment to 150 mg Q2W at Week 12 if LDL-C was not at a pre-defined target by Week 8; §Based on ITT analysis –

ITT population, includes all lipid data throughout the duration of the study irrespective of adherence to the study treatment.

ITT, intent-to-treat; Q2W, every 2 weeks. Figure shows randomised patient population.

Mean Calculated LDL-C Levels (mITT) Pool of FH I and II Studies (Alirocumab 75/150 mg Q2W)

42

LS

mean L

DL

-C level

(SE

), m

mol/L

mg/d

L

Study Week

ΔW24‡:

-56.1 (2.1)%

†Alirocumab dose 75 mg Q2W increased to 150 mg Q2W in 41.8% of patients at Week 12 as their LDL-C levels at

Week 8 were ≥1.81 mmol/L [70 mg/dL]; ‡ΔW24/52/78 defined as LS mean (SE) % difference versus placebo in

calculated LDL-C from baseline to Week 24/52/78. Figure shows on-treatment analysis on modified ITT population,

including all lipid data throughout the duration of study collected while the patients were still receiving study treatment.

ΔW52‡:

-58.4 (2.5)%

ΔW78‡:

-56.1 (2.6)%

Per-protocol

Week 12 dose increase

(41.8%)

†

Mean Calculated LDL-C Levels (mITT) Pool of LONG TERM (HeFH Patients only) and HIGH FH (Alirocumab 150 mg Q2W)

43

ΔW24†:

-57.1 (2.4)%)

†ΔW24/52/78 defined as LS mean (SE) % difference versus placebo in calculated LDL-C from baseline to Week 24/52/78.

Figure shows on-treatment analysis on modified ITT population, including all lipid data throughout the duration of study

collected while the patients were still receiving study treatment.

LS

mean L

DL

-C level

(SE

), m

mol/L

Study Week

ΔW52†:

-60.1 (2.8)%

ΔW78†:

-63.2 (2.8)%

All % changes

P<0.0001 versus placebo

mg/d

L

Secondary Efficacy Endpoints at

Week 24 in Both Pooled Study Groups (ITT)

44

Mean

‡ (

SE

) %

change fro

m

ba

se

line

to

We

ek 2

4

ApoB Non-HDL-C Lp(a)

All P<0.0001 versus placebo

ApoB Non-HDL-C Lp(a)

†75 mg Q2W increased to 150 mg Q2W at W12 if LDL-C levels at Week 8 were ≥1.81 mmol/L [70 mg/dL]; ‡LS means for ApoB and non-

HDL-C from mixed effects model with repeated measures; combined estimate for adjusted mean for Lp(a)

analysed with multiple imputation followed by robust regression. Figures show ITT analyses performed on ITT populations.

41.8% had dose increase at Week 12

Alirocumab 75/150 mg Q2W † Alirocumab, n=488; placebo, n=244

Alirocumab 150 mg Q2W Alirocumab, n=346; placebo, n=174

Baseline

values 4.31 4.29

mmol/L 112.3 111.7

mg/dL 50.9 48.2

mg/dL 5.06 4.90

mmol/L 126.6 123.3

mg/dL 46.4 46.7

mg/dL

Alirocumab

Placebo

This analysis represents the single largest collection

of patients with HeFH (n=1257) included in a Phase 3

clinical study programme

– In on-treatment analyses (using measurements that were

collected while patients were still receiving treatment),

alirocumab reduced mean LDL-C levels to <2.2 mmol/L

(85 mg/dL) at Weeks 24–78 of treatment, levels hitherto

unobtainable with maximum doses of statin and addition of

other LLTs in patients with HeFH

– The incidence of TEAEs was generally similar between

alirocumab and control group patients

These findings hold potential for reducing LDL-C to

levels that were previously unobtainable with

existing currently standard-of-care therapy in

patients with HeFH

Conclusions

45

CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE

©2015, Regeneron Pharmaceuticals, Inc.



John J.P. Kastelein1, Gisle Langslet2, Paul N. Hopkins3,

Joep C. Defesche4, Werner Seiz5, Marie T. Baccara-Dinet6,

Sara Hamon7, Poulabi Banerjee7, Claudia Stefanutti8

1Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; 2Lipid Clinic, Oslo University Hospital, Oslo, Norway; 3School of Medicine, University of Utah,

Salt Lake City, UT, USA; 4Department of Clinical Genetics, Academic Medical Centre,

Amsterdam, the Netherlands; 5Clinical Investigations, Sanofi-Aventis, Frankfurt Am Main,

Germany; 6Sanofi, Montpellier, France; 7Early Clinical Development, Regeneron

Pharmaceuticals, Inc., New York, NY, USA; 8Department of Molecular Medicine, ‘Sapienza’

University of Rome, Umberto I Hospital, Rome, Italy

Efficacy of Alirocumab in 1191

Patients with a Wide Spectrum of

Mutations in Genes Causative for

Familial Hypercholesterolemia

Presented at the American College of Cardiology 65th Annual Scientific Session, Chicago, IL, USA, 02 –04 April 2016

(Poster number 1293M-05)

This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.





Study Design: Breakdown of Studies

Included in the Analysis

47

†Maximally tolerated statin (atorvastatin 40−80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg); ‡Control was placebo in all trials except ALTERNATIVE (patients were randomized to

either ezetimibe or atorvastatin only control arms); §Alirocumab 75 mg Q2W was increased to 150 mg Q2W at Week 12 depending on LDL-C at Week 8. HeFH, heterozygous familial

hypercholesterolemia; LDL, low-density lipoprotein; LLT, lipid-lowering therapy; Q2W, every two weeks; Q4W, every 4 weeks.

3497 patients with hypercholesterolemia (HeFH and non-FH) receiving

maximally tolerated statin† ± other LLT (2241 alirocumab, 1256 control‡)

Control: ezetimibe Control: placebo

Alirocumab

150 mg Q2W

Five phase 3 studies2–5

Alirocumab

75/150 mg Q2W§

77 patients with HeFH receiving maximally tolerated statin† ± other LLT with

serum LDL-C levels ≥ 100 mg/dL (62 alirocumab, 15 control)

Phase 2 study1

1. Stein EA et al. Lancet. 2012;380:29–36.

2. Moriarty PM et al. J Clin Lipidol. 2015;9:758–769.

3. Kastelein JJ et al. Eur Heart J. 2015;36:2996–3003.

4. Robinson JG et al. N Engl J Med. 2015;372:1489–1499.

5. Ginsberg HN et al. Circulation. 2014;130:2119.

Study pool comprised five phase 3 studies and one phase 2 study:

n=3574 patients with hypercholesterolemia (HeFH and non-FH) receiving maximally tolerated statin†

± other LLT (2303 alirocumab, 1271 control‡)

Alirocumab doses investigated:

150 mg Q2W (n=16); 150 mg Q4W (n=15); 300 mg Q4W (n=15)

Control:

Placebo (n=15)

ALTERNATIVE,2 24 weeks

Alirocumab, n=126

Ezetimibe, n=125

Atorvastatin, n=63

FH I,3 78 weeks

Alirocumab, n=323

Placebo, n=163

FH II,3 78 weeks

Alirocumab, n=167

Placebo, n=82

Control: placebo

LONG TERM,4 78 weeks

Alirocumab, n=1553

Placebo, n=788

HIGH FH,5 78 weeks

Alirocumab, n=72

Placebo, n=35

Kastelein et al. Presented at ACC 2016.

Poster number 1293M-05





Reduction in LDL-C Level from Baseline at Week 12

According to Mutation Status for Heterozygous FH Patients

48

SE, standard error

Me

an

perc

en

tag

e c

han

ge

in

LD

L-C

(S

E)

fro

m b

as

eli

ne

(m

g/d

L)

APOB defective LDLR defective LDLR negative PCSK9 GOF No known mutation

10

0

–10

–20

–30

–40

–50

–60

–70

–80

–90

–100

Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W Control

–48.9

–35.1

0.2

–47.3

–56.7

1.5

–43.2

–61.6

3.1

–53.3

–93.4

–43.2

–56.4

–5.3

n=21 n=6 n=18 n=133 n=99 n=132 n=172 n=93 n=148 n=5 n=1 n=0 n=88 n=73 n=111





Change in LDL-C at Week 12 for All Subjects Receiving

75 mg Q2W or 150 mg Q2W Alirocumab, According to

Mutation Status

49

150

125

100

75

50

25

0

–25

–50

–75

–100

Patients (n=337) 0 100 200 300

APOB defective APOB defective / LDLR defective APOB defective / LDLR negative LDLR defective / LDLR negative

LDLR defective LDLR negative LDLRAP1 null PCSK9 GOF

Pe

rce

nta

ge

ch

an

ge

vs

ba

se

lin

e

in L

DL

-C (

mg

/dL

)

150

125

100

75

50

25

0

–25

–50

–75

–100

Patients (n=201)

0 50 100 200

APOB defective LDLR defective / LDLR defective LDLR defective LDLR negative PCSK9 GOF

150



Pe

rce

nta

ge

ch

an

ge

vs

ba

se

lin

e

in L

DL

-C (

mg

/dL

)





Change from Baseline in LDL-C at Week 12 in Individual Patients who

are LDLR/LDLR Compound Heterozygotes, LDLR/LDLR Homozygotes,

and LDLR/APOB Double Heterozygotes

50

Me

an

perc

en

tag

e c

han

ge

in

LD

L-C

fro

m b

as

eli

ne (

mg

/dL

)

–63.9

–55.7 –52.7 –52.6

–1.4 –3.6 –4.9 –6.7

–16.3

–21.7 –22.9†

–35.1 –39.3

–15.0

7.1‡ 3.5 3.8 5.0

9.1 10

0

–10

–20

–30

–40

–50

–60

–70

–80

–90

–100

Alirocumab Control

APOB defective/LDLR defective

LDLRAP1 null

APOB defective/LDLR negative

LDLR defective/LDLR defective

LDLR defective/LDLR negative †Patient was LDLR/LDLR homozygote ‡Patient was LDLRAP1/LDLRAP1 heterozygote





Overall TEAE Incidence and Selected Adverse

Events of Interest (Safety Population)†

51

Sequenced cohort

% (n) Alirocumab (n=761) Control‡ (n=430)

Any TEAE 82.9 (631) 83.3 (358)

Treatment-emergent SAE 13.3 (101) 12.1 (52)

Deaths during study 0.7 (5) 0.2 (1)

TEAE leading to permanent treatment

discontinuation

4.1 (31) 5.8 (25)

TEAEs occurring in ≥5% of patients

Nasopharyngitis 13.4 (102) 13.3 (57)

Injection site reaction 11.4 (87) 8.8 (38)

Influenza 10.9 (83) 7.9 (34)

Headache 7.0 (53) 7.9 (34)

Myalgia 6.0 (46) 7.7 (33)

Upper respiratory tract infection 6.0 (46) 7.7 (33)

Diarrhea 5.9 (45) 3.0 (13)

Arthralgia 5.4 (41) 7.7 (33)

Back pain 5.4 (41) 5.1 (22)

Urinary tract infection 5.4 (41) 4.9 (21)

Bronchitis 5.3 (40) 5.1 (22)

†Pool of six studies: Phase 2: R727-CL-1003; Phase 3:FH I, FH II, HIGH FH, LONG TERM, ALTERNATIVE. ‡Control was placebo in all studies except

ALTERNATIVE (ezetimibe/statin control). SAE, serious adverse event; TEAE, treatment-emergent adverse event



An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

FOURIER Further cardiovascular OUtcomes

Research with PCSK9 Inhibition in

subjects with Elevated Risk

MS Sabatine, RP Giugliano, AC Keech, N Honarpour,

SM Wasserman, PS Sever, and TR Pedersen,

for the FOURIER Steering Committee & Investigators

American College of Cardiology – 66th Annual Scientific Session

Late-Breaking Clinical Trial

March 17, 2017

SC-IT-AMG145-00026



Objectives

In patients with established cardiovascular disease

on statin therapy:

• Test whether the addition of evolocumab reduces the

incidence of major cardiovascular events

• Examine the long-term safety & tolerability of

evolocumab

• Investigate the efficacy and safety of achieving

unprecedented low levels of LDL-C



Trial Design

Evolocumab SC 140 mg Q2W or 420 mg QM

Placebo SC Q2W or QM

LDL-C ≥70 mg/dL or

non-HDL-C ≥100 mg/dL

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe)

27,564 high-risk, stable patients with established CV disease

(prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED

DOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94-101



27,564 patients randomized at 1242 sites

in 49 countries between 2/2013 – 6/2015

Global Enrollment





Endpoints

• Efficacy

– Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc

– Key secondary: CV death, MI or stroke

• Safety

– AEs/SAEs

– Events of interest incl. muscle-related, new-onset diabetes,

neurocognitive

– Development of anti-evolocumab Ab (binding and neutralizing)

• TIMI Clinical Events Committee (CEC)

– Adjudicated all efficacy endpoints & new-onset diabetes

– Members unaware of treatment assignment & lipid levels

Sabatine MS et al. Am Heart J 2016;173:94-101



Baseline Characteristics

Characteristic Value

Age, years, mean (SD) 63 (9)

Male sex (%) 75

Type of cardiovascular disease (%)

Myocardial infarction 81

Stroke (non-hemorrhagic) 19

Symptomatic PAD 13

Cardiovascular risk factor (%)

Hypertension 80

Diabetes mellitus 37

Current cigarette use 28

Pooled data; no differences between treatment arms

Median time from most

recent event ~3 yrs



Lipid Lowering Therapy

& Lipid Levels at Baseline

Characteristic Value

Statin use (%)*

High-intensity 69

Moderate-intensity 30

Ezetimibe use (%) 5

Median lipid measures (IQR) – mg/dL

LDL-C 92 (80-109)

Total cholesterol 168 (151-189)

HDL-C 44 (37-53)

Triglycerides 133 (100-182)

Pooled data; no differences between treatment arms

*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.

1% were on low intensity or intensity data were missing.

Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.



0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

LD

L C

ho

les

tero

l (m

g/d

l)

Weeks

LDL Cholesterol

Evolocumab

(median 30 mg/dl, IQR 19-46 mg/dl)

Placebo

59% mean reduction (95%CI 58-60), P<0.00001

Absolute reduction: 56 mg/dl (95%CI 55-57)



0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120

LD

L C

ho

les

tero

l (m

g/d

l)

Weeks

LDL Cholesterol

Cohort of 11,077 patients who

• had all measurements through 120 weeks

• did not discontinue study drug

• did not D concomitant background lipid-lowering Rx

Evolocumab

Placebo

Similar data out to 4 years

in OSLER-1

(JAMA Cardiology online)



0%

2%

4%

6%

8%

10%

12%

14%

16%

Primary Endpoint

Evolocumab

Placebo

Months from Randomization

CV

De

ath

, M

I, S

tro

ke

,

Ho

sp

fo

r U

A,

or

Co

r R

evasc

0 6 12 18 24 30 36

Hazard ratio 0.85

(95% CI, 0.79-0.92)

P<0.0001 12.6%

14.6%



0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

Key Secondary Endpoint

Months from Randomization

CV

De

ath

, M

I, o

r S

tro

ke

0 6 12 18 24 30 36

Hazard ratio 0.80

(95% CI, 0.73-0.88)

P<0.00001

Evolocumab

Placebo 7.9%

9.9%



Comparison to Cholesterol

Treatment Trialists Collaboration

Major Coronary Events

Stroke

Coronary revascularization

Urgent

Elective

Major Vascular Events

0.78 (0.70-0.86)

0.80 (0.71-0.90)

0.77 (0.66-0.91)

0.77 (0.63-0.94)

0.75 (0.67-0.84)

0.73 (0.62-0.86)

0.84 (0.73-0.98)

0.77 (0.73-0.82)

0.83 (0.76-0.90)

Lipid-lowering therapy better Lipid-lowering therapy worse

Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C

2.0 1.0

CTTC Meta-analysis Year 2

FOURIER Year 2

CTTC data from Lancet 2010;376:1670-81

0.5



Safety

Evolocumab

(N=13,769)

Placebo

(N=13,756)

Adverse events (%)

Any 77.4 77.4

Serious 24.8 24.7

Allergic reaction 3.1 2.9

Injection-site reaction 2.1 1.6

Treatment-related and led to d/c of study drug 1.6 1.5

Muscle-related 5.0 4.8

Cataract 1.7 1.8

Diabetes (new-onset) 8.1 7.7

Neurocognitive 1.6 1.5

Laboratory results (%)

Binding Ab 0.3 n/a

Neutralizing Ab none n/a

New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC



Summary for Evolocumab

• LDL-C by 59%

– Consistent throughout duration of trial

– Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl)

• CV outcomes in patients already on statin therapy

– 15% broad primary endpoint; 20% CV death, MI, or stroke

– Consistent benefit, incl. in those on high-intensity statin, low LDL-C

– 25% reduction in CV death, MI, or stroke after 1st year

– Long-term benefits consistent w/ statins per mmol/L LDL-C

• Safe and well-tolerated

– Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo

– Rates of EvoMab discontinuation low and no greater than pbo

– No neutralizing antibodies developed



Conclusions

In patients with known cardiovascular disease:

1. PCSK9 inhibition with evolocumab

significantly & safely major cardiovascular

events when added to statin therapy

2. Benefit was achieved with lowering LDL

cholesterol well below current targets

Most Pts with HoFH due receptor-negative, or null mts, are likely

to remain impossible to adequately treat pharmacologically

without LA

Higher baseline levels of LDL-C mean that, safety concerns aside,

apoB antisense therapy is unlikely to achieve sufficient lowering

It had been hoped that, because PCSK9 increases LDL-C levels in

LDLR-/- mice, LDLR-independent mechanisms would allow PCSK9-

I to work in the setting of receptor-negative HoFH. However, the

present clinical trial evidence does not support this notion

Discussion

-

____________________________________________________________________________________________

LDL receptor

status

# of samples Coronary heart disease (%) Mortality (%)

____________________________________________________________________________________

Negative 31 45% 26%

De Defective 26 42% 4%

____________________________________________________________________________________

Watts GF, Hamilton SJ. LDL apheresis for familial hypercholesterolemia: value, indications and demand. Clin Lipidol. 2009;4:129–31

Mortality and coronary heart disease morbidity in receptor-negative and receptor-defective FH homozygotes * (*) based on data from Goldstein and Brown

With the advent of new drugs (ND) we may anticipate that a greater proportion of Pts with severe FH may be more satisfactorily treated in combination with LA LA may bring synergy through the removal of PCSK9. Hence, we consider it more likely that the use of the ND will principally affect the way in which Pts are treated with LA (e.g. smaller plasma volumes treated / longer intervals between sessions) In Pts with severe HeFH or hyperLp(a) and progressive ASCVD, it is likely that LA would be most usefully combined with PCSK9-I In the case of HoFH, lomitapide, which does not require any residual LDL-R function to work, would likely be the more useful adjunct to LA

Conclusion

Statins and ezetimibe Statins and ezetimibe Statins and ezetimibe

Sufficient response?

Add lipoprotein apheresis


Double receptor negative?

Add PCSK9 inhibitor


Add novel LLT

Treat and monitor Treat and monitor




Add PCSK9 inhibitor



Treat and monitor

Homozygous familial hypercholesterolemia Heterozygous familial hypercholesterolemia Lp(a) hyperlipoproteinema

Add novel LLT

No

No

No Yes

No No

No

No

Yes Yes Yes

Figure 1. FH therapy algorithms

No

No

Yes

Yes Yes

Stefanutti C et al, J Clin Lipid, 2017, in press Multidisciplinary International Group for Hemapheresis TherapY and MEtabolic DIsturbances Contrast

A Randomized, Double-blind, Placebo-controlled, Parallel-group Study

to Evaluate the Efficacy and Safety of Evinacumab in Patients with

Homozygous Familial Hypercholesterolemia

Amgen

Regeneron

A Randomized, Double-blind, Placebo-controlled, Parallel-group Study

to Evaluate the Efficacy and Safety of Alirocumab in Patients with

Homozygous Familial Hypercholesterolemia Regeneron

Ongoing Clinical Trials on PCSK9-I and Background Therapy including

Lipoprotein Apheresis – HeFH (Adults) HoFH (> 12 years)

Coordinating Centre for Italy: Extracorporeal Therapeutic Techniques Unit - Lipid Clinic and Atherosclerosis Prevention Centre - Immunohematology and

Transfusion Medicine - Department of Molecular Medicine, “Sapienza” University of Rome – “Umberto I” Hospital, 155 Viale

del Policlinico, 00161 Rome, Italy - EU

multidisciplinary international group for hemapheresis therapy … · 2017. 5. 11. · foundation...

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