Targeting PCSK9 Expanding knowledge and targeting new frontiers - - PowerPoint PPT Presentation

Targeting PCSK9

Expanding knowledge and targeting new frontiers

John JP Kastelein, MD, PhD, FESC University of Amsterdam The Netherlands

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Professor Kastelein is a consultant for Akcea, AstraZeneca, CiVi Biopharma, Corvidia, CSL Behring, Daiichi Sankyo, Draupnir, Esperion Therapeutics, Gemphire, Madrigal Pharma, Matinas Bio, The Medicines Company, NorthSea Therapeutics, Novartis, Novo, Regeneron, REGENXBIO, Staten Bio DISCLOSURES

John JP Kastelein

Summary of Effects of PCSK9i Evolocumab

•  LDL-C by 59% down to a median of 30 mg/dl
•  CV outcomes in patients on statin
• Safe and well-tolerated

Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) Placebo 59% reduction P<0.00001 Absolute  56 mg/dl 14,6 9,9 12,6 7,9

5 10 15 KM Rate (%) at 3 Years

HR 0.85 (0.79-0.92) P<0.0001 HR 0.80 (0.73-0.88) P<0.0001

CVD death, MI, stroke, UA, cor revasc CVD death, MI, stroke

Sabatine MS et al. NEJM 2017;376:1713-22

10 20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120 132 144 LDL Cholesterol (mg/dl) Weeks

LDL Cholesterol

2034 patients w/ baseline LDL-C<70 mg/dL

Evolocumab (median 21 mg/dl, IQR 11.5-37 mg/dl) Placebo (median 66 mg/dl, IQR 56-78 mg/dl) 66% mean reduction (95%CI 62-69), P<0.00001

Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91

(median 0.5 mmol/L, IQR 0.3-1.0 mmol/L) (median 1.7 mmol/L, IQR 1.4-2.0 mmol/L)

CVD, MI, stroke, UA, or cor revasc HR (95% CI) Pinteraction All Patients 0.85 (0.79-0.92) Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07) Baseline LDL-C ≥70 mg/dL 0.86 (0.79-0.92)

Clinical Outcomes

by Baseline LDL-C

0.65

1.0

EvoMab better Pbo better

0.4 2.5

CVD, MI, or stroke All Patients 0.80 (0.73-0.88) Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01) Baseline LDL-C ≥70 mg/dL 0.81 (0.73-0.89)

1.0 0.4 2.5

0.44

Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91

Benefit of EvoMab Based on Multivessel Disease

Multivessel Disease

Months after Randomization

CV Death, MI, or Stroke

6 12 18 24 30 36

30% RRR HR 0.70 (95% CI 0.58-0.84) P<0.001 9.2% 12.6%

Pinteraction=0.03

D 3.4% NNT 29 Evolocumab Placebo 7.6% 8.9% D 1.3% NNT 78 No Multivessel Disease 11% RRR HR 0.89 (95% CI 0.79-1.00) P=0.055

6 12 18 24 30 36

Sabatine et al. Circ 2018;138:756-66

CV Death, MI or Stroke in Patients w/ & w/o Peripheral Artery Disease

Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50

Major Adverse Limb Events

Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50

Conclusions

1. Evolocumab reliably reduces LDL-C by ~60% 2. Reduces risk of major vascular events in Pts w/ ASCVD already on statin

• Confirms benefit from lowering LDL-C to <1 mM
• Benefit grows over time

3. Largest absolute risk reductions in Pts w/ highest baseline risk & largest amount of athero

• Diabetes, CKD
• Closer to MI, multiple prior MIs, multivessel CAD
• PAD

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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? BACKGROUND & RATIONALE

Safety & efficacy of inclisiran not known beyond 1-year

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

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Representative of a typical moderate/high-risk ASCVD population METHODS

ORION-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)

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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 OBJECTIVES

Investigate the long-term safety and efficacy of inclisiran

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Total ~3 years treatment & observation METHODS

Design of investigation

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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

RESULTS

Excellent tolerability and safety

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

Persistent and robust efficacy

ITT Day 210 change from baseline1 p-value LDL-C

All patients (N=290)

Mean (SD)

• 51%

(28)

< 0.001

Mean(SD)

• 64 mg/dL

(39)

< 0.001

Patients randomized to 300 mg 2 dose starting regimen (N = 61)

Mean(SD)

• 56%

(18)

< 0.001

Mean (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

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

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

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

What 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-11

HeFH U.S.ASCVD EU ASCVD/RE N = 482 N = 1561 N = 1617

Baseline LDL-C 161 mg/dL 110 mg/dL 112 mg/dL Simulation 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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• A small molecule oral PCSK9i is expected to reduce costs and confer

convenience to patients

• A cost effective pricing will significantly reduce the barriers for patient access to

PCSK9i

• Development of small molecule PCSK9i has proven very challenging from a

medicinal chemistry perspective

• Draupnir Bio is developing the first orally available PCSK9 inhibitor

ORAL PCSK9 INHIBITION Promises and challenges of oral PCSK9 inhibition

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• In the absence of PCSK9, LDLR

removes LDL particles by endocytosis

• LDL is metabolized in lysosomes

while LDLR recycles

• PCSK9 binds to HSPG on

hepatocytes and the PCSK9/HSPG complex hijacks LDLR for degradation ORAL PCSK9 INHIBITION PCSK9 activity depends on heparan sulfate proteoglycans (HSPG)

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• Enzymatic removal of heparan

sulfate 5 min before PCSK9 injection, results in complete LDLR protection in the liver of mice.

• mAb 5E11 restores PCSK9-

induced reductions in LDL uptake to a similar extent as evolocumab ORAL PCSK9 INHIBITION Removal of HSPG/blocking PCSK9/HSPG binding protects the LDL receptor

Evolocumab: mAb 5E11:

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ORAL PCSK9 INHIBITION Structure-based design of small molecule PCSK9i

Plasma membrane

• 3. LDL receptor degradation
• 1. PCSK9/HSPG
• 2. PCSK9/HSPG/LDLR complex

R93C LOF variant confers 50% reduction in risk of CAD Tang et al. Nature Commun 2017 PCSK9/HSPG binding involves several residues known from PCSK9 LOF variants

PCSK9 HSPG Heparan sulfate LDLR

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ORAL PCSK9 INHIBITION Draupnir PCSK9i increases LDL uptake and acts in synergy with statins

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ORAL PCSK9 INHIBITION Draupnir PCSK9i reduces cholesterol and plaque burden in mice

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• Draupnir is moving lead compound towards first in-human trials
• Lead compound has unique mechanism of action and may provide therapeutic

benefits by conferring additional protection of the vascular endothelium ORAL PCSK9 INHIBITION Clinical development of oral PCSK9i

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Exciting times ahead! Conclusion

Acknowledgements: Thanks to the Medicines Company and Draupnir Bio for providing the data