Pierluigi Tricoci, Denise M. D’Andrea, Paul A. Gurbel, Marina Cuchel, Brion M. Winston, Robert Schott, Robert J. Weiss, Henry E. Paez, Michael A. Blazing, Louis A. Cannon, Alison L. Bailey, Dominick J. Angiolillo, Penelope Dalitz, Shelley Myles-Di Mauro, Charles Shear, John H. Alexander 

Safety and Tolerability of CSL112 in Patients with Stable Atherothrombotic Disease: Results from a Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study

Tricoci P, N Engl J Med 2012Farb A, Circulation 2003

CV Death/MI/Stroke

High Rate of Early Recurrent Atherothrombotic Events After ACS with Current Strategies Thrombosis Rx• UFH/LMWH• Fondaparinux• Bivalirudin• GPI IIb/IIIa• Aspirin• Clopidogrel• Prasugrel• Ticagrelor• Rivaroxaban

Thrombosis Bleeding

Lipid rich plaque Rx• Statin

• HDL cholesterol levels are inversely correlated with the risk of atherosclerotic cardiovascular events.

• Recent large-scale clinical drug trial experience has invalidated change in HDL cholesterol levels as a predictor of efficacy.

• Increasing HDL anti-atherosclerotic function is now the focus of novel therapeutics.

• HDL anti-atherosclerotic function is hypothesized to be largely driven through ApoA-I and the promotion of cholesterol efflux, the first step in reverse cholesterol transport.

• ApoA-I most effectively mediates cholesterol efflux from plaque through interaction with the macrophage ATP-binding cassette transporter ABCA1.

Background—HDL and Atherosclerosis

CSL1121Diditchenko S, Arterioscler Thromb Vasc Biol 2013

2Tardif JC, JAMA 2007

• CSL112 is an ApoA-I, the chief protein component of HDL, purified from human plasma and reconstituted with phospholipids to form HDL particles suitable for IV infusion. 1

• CSL112 is similar to native HDL3 in size, organization, and function. 1

• A prototype formulation, CSL111 was shown to modify atherosclerotic plaque composition on IVUS but caused transient increases in transaminases.2

• CSL112 represents a reformulation of the prototype formula with changes in excipients and increased uniformity of the product.

Background—CSL112

• A short course of treatment with CSL112 infusion(s) administered after an ACS will reduce early recurrent atherothrombotic cardiovascular events following ACS by: Rapidly increasing cholesterol efflux capacity

in serum. Modifying the composition and stability of

atherosclerotic plaques.

CSL112 Development Program Hypothesis

A phase 2a adaptive, multicenter, randomized, double-blind, placebo-controlled, single-ascending-dose clinical trial of CSL112 was designed to: 1. Assess safety in patients with stable atherothrombotic

disease who were taking standard-of-care medications, including aspirin and either clopidogrel or prasugrel.

2. Further characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of CSL112 in this population.

CSL112 Phase 2a Trial

CSL112

Dose group 1.7 g

Placebo

CSL112

Dose group 3.4 g

Placebo

CSL112

Placebo

Dose group 6.8 g

3:1*

3:1*

3:1*

Key inclusion criteria:• CAD or PVD • >1 month from acute

events• On aspirin and

clopidogrel/prasugrel

Key exclusion criteria:• CrCl <60 mL/min • Hepatobiliary disease• Poor clopidogrel

metabolism (if on clopidogrel)

• Change in Rx <1 month

Double Blind

*Stratification: CrCl >90 mL/min vs

CrCl >60 to <90 mL/min

Stable Atherothrombotic Disease (N≈40)

Trial Design

Study Periods and Follow-UpOverview

Primary safety assessments• Frequency of study–product-related adverse events.• Frequency of clinically significant elevation of alanine aminotransferase

(ALT) or aspartate aminotransferase (AST) (>3x ULN).

Secondary safety assessments• Changes from baseline in other clinical laboratory tests and assessments.• Platelet function test.

Main PK/PD evaluations• Key PK parameters (AUC, Cmax, Tmax) of ApoA-I, cholate, and

phosphatidylcholine.• Measures of reverse cholesterol transport and lipoprotein

Total and ABCA1-mediated cholesterol efflux potential (ex vivo). Serum concentrations of preBeta1 HDL, esterified and un-esterified

HDL, non-HDL cholesterol.

Study Endpoints

Patients randomized: 45

Patients treated: 44

Completed study: 44

Subject Disposition

  Placebo(N=11)

CSL112 1.7 g (N=7)

CSL112 3.4 g

(N=12)

CSL112 6.8 g

(N=14)

CSL112 Overall(N=33)

Age, yrs* 56 (47–71) 65 (54–77) 57 (40–73) 60 (41–76) 60 (40–77)Male sex 7 (63.6) 4 (57.1) 9 (75.0) 12 (85.7) 25 (75.8)BMI, kg/m2 29 (22–46) 29 (21–34) 33 (25–55) 29 (24–40) 31 (21–55)White race 8 (72.7) 6 (85.7) 9 (75.0) 12 (85.7) 27 (81.8)           CAD 11 (100) 5 (71.4) 10 (83.3) 11 (73.3) 26 (76.5)Prior MI 6 (54.5) 4 (57.1) 4 (33.3) 5 (33.3) 13 (38.2)Prior stenting 6 (54.5) 3 (42.9) 3 (25.0) 5 (33.3) 11 (32.4)Prior CABG 3 (27.3) 3 (42.9) 3 (25.0) 1 (6.7) 7 (20.6)PAD 1 (9.1) 2 (28.6) 1(8.3) 1 (6.7) 4 (11.8)           Hypertension 7 (63.6) 6 (85.7) 11 (91.7) 11 (73.3) 28 (82.4)Diabetes mellitus 5 (45.5) 2 (28.6) 3 (25.0) 1 (6.7) 6 (17.6)Hyperlipidemia 5 (45.5) 3 (42.9) 6 (50.0) 5 (33.3) 14 (41.2)Statins 10 (90.9) 6 (85.7) 10 (83.3) 13 (92.9) 29 (87.9)

Baseline Characteristics

Data presented as n (%) or median (IQR).

Primary- Endpoint - Adverse Events (Active Treatment Period)

 Placebo(N=11)

CSL112 1.7 g (N=7)

CSL112 3.4 g

(N=12)

CSL112 6.8 g

(N=14)

CSL112 Overall(N=33)

n (%) patients with eventPrimary endpoint: Study–product-related AE*

 3 (27.3)

 5 (71.4)

 5 (41.7)

 6 (42.9)

 16 (48.5)

Non-serious AE 3 (27.3) 5 (71.4) 5 (41.7) 6 (42.9) 16 (48.5)SAE 1 (9.1) 0 (0) 0 (0) 0 (0) 0 (0)

Infusion–site-related AE† 1 (9.1) 1 (14.3) 2 (16.7) 5 (35.7) 8 (24.2)           Other           Causally related AE 1 (9.1) 1 (14.3) 1 (8.3) 5 (35.7) 7 (21.2) Any AE 3 (27.3) 5 (71.4) 6 (50.0) 8 (57.1) 19 (57.6) Maximum intensity‡           Mild 2 (18.2) 5 (71.4) 6 (50) 8 (57.1) 19 (57.6) Moderate 1 (9.1) 0 (0) 0 (0) 0 (0) 0 (0)

*Occurring within 72 hrs of infusion or considered related by investigator (independent of time).†Includes IV infusion site ecchymosis/hematoma, erythema, coldness, phlebitis. ‡CTCAE v.4 grade at any timepoint.

  Placebo(N=11)

CSL112 1.7 g (N=7)

CSL112 3.4 g

(N=12)

CSL112 6.8 g

(N=14)

CSL112 Overall(N=33)

ALT, n (%)           No elevation 10 (90.9) 7 (100) 11 (91.7) 12 (85.7) 30 (90.9) 1–2x ULN 1 (9.1) 0 (0) 1 (8.3) 2 (14.3) 3 (9.1) 2–3x ULN – – – – –  >3x ULN – – – – –

AST, n (%)           No elevation 10 (90.9) 6 (85.7) 12 (100) 14 (100) 32 (97.0) 1–2x ULN 1 (9.1) 1 (14.3) 0 0 1 (3.0) 2–3x ULN – – – – – 

>3x ULN – – – – –

Primary Endpoint - Liver Safety (change from baseline during active treatment period)

  Placebo(N=11)

CSL112 1.7 g (N=7)

CSL112 3.4 g

(N=12)

CSL112 6.8 g

(N=14)

CSL112Overall(N=33)

Renal function           S-creatinine increase, n (%)           No increase 0 (0) 0 (0) 1 (8.3) 0 (0) 1 (3.0) >1–1.5x baseline 11 (100) 6 (85.7) 11 (91.7) 14 (100) 31 (93.9) >1.5–3.0x baseline 0 (0) 1 (14.3) 0 (0) 0 (0) 1 (3.0) >3.0x baseline 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Hematology           Hb decrease >2 g/dL 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Platelet count change (48 hrs) 3.1 (39.0) -5.2 (28.3) -10.3 (26.0) 4.4 (34.7) -2.9 (30.3)

Coagulation           Change aPTT (24 hrs) 0.6 (1.1) -0.8 (2.9) -1.6 (3.8) -0.8 (1.4) -1.1 (2.7) INR (24 hrs) 0.03 (0.07) 0.04 (0.09) 0.03 (0.05) 0.01 (0.11) 0.02 (0.08)Anti-CSL112/ApoA-1 Ig seroconversion 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Other Selected Clinical Laboratory(change from baseline during active treatment period)

• Continuous variables shown as mean (SD).

PK of ApoA-I Mean Plasma Concentrations with Different Doses of CSL112

  CSL112 1.7g(N=7)

CSL112 3.4g(N=12)

CSL112 6.8g(N=14)

PK parameter       Cmax (mg/dL) 33.8 (9.1) 77.1 (13.0) 184 (35.1) AUC0-last (mg/dL*h) 869 (741) 2044 (845) 5331 (1809)

• Dose-proportional PK observed• All parameters comparable to those seen in healthy subjects

Changes in Mean Global Cholesterol Efflux by Time and CSL112 Dose

• Reverse cholesterol efflux and lipids: Increase global and ABCA1-dependent cholesterol efflux. Increase preBeta1 HDL (HDL-VS) and cholesterol

esterification. No change observed in triglycerides, apo-B, non-HDL-C,

Lp(a). Full data to be presented by Andreas Gilles et al. Tuesday,

November 19 at 10:45 AM, Room C143.

• Platelet aggregometry: No significant antiplatelet effect. Full data to be presented by Paul A. Gurbel et al.

Wednesday, November 20 at 9:30 AM, Poster Hall, Core 2.

Summary of Main Biomarker and Platelet Aggregation Data

ConclusionIn this phase 2a trial among patients with stable atherothrombotic disease, a single infusion of CSL112 :

• Did not show evidence of liver toxicity.

• Had an overall favorable safety profile on adverse events.

• Did not cause significant changes in other clinical laboratory parameters.

• Produces a predictable, rapid, and dose-dependent increase in ApoA-I plasma concentration

• Was associated with a dose-dependent increase in key markers of reverse cholesterol transport.

These results on the safety and biological mechanisms of potential clinical efficacy support continued development of CSL112.

• Global phase 2b trial of CSL112 in patients post-ACS to start in early 2014

• Study objectives: Assess safety and tolerability of CSL112 immediately

following ACS. Examine effect of CSL112 on occurrence of major

adverse cardiac events (MACE).

CSL112 Clinical Development Progression

Dominick J. Angiolillo, MD, PhD - Jacksonville, FL Alison L. Bailey, MD - Lexington, KY Michael A. Blazing, MD - Durham, NCLouis A. Cannon, MD - Petoskey, MIMarina Cuchel, MD, PhD - Philadelphia, PAPaul A. Gurbel, MD - Baltimore, MD Jonathan A. Mosley, DO - Madisonville, KYHenry E. Paez, MD - Miami, FLRobert Schott, MD - Chula Vista, CA Robert J. Weiss, MD - Auburn, MEBrion M. Winston, MD, MPH - Rapid City, SD

Investigators