Tricoci_CSL2a - Clinical Trial Results

Report
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
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
High Rate of Early Recurrent Atherothrombotic
Events After ACS with Current Strategies
Thrombosis Rx
•
•
•
•
•
•
•
•
•
Lipid rich plaque Rx
• Statin
UFH/LMWH
Fondaparinux
Bivalirudin
GPI IIb/IIIa
Aspirin
Clopidogrel
Prasugrel
Ticagrelor
Rivaroxaban
 Thrombosis
 Bleeding
CV Death/MI/Stroke
Tricoci P, N Engl J Med 2012
Farb A, Circulation 2003
Background—HDL and Atherosclerosis
•
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—CSL112
•
•
•
•
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.
CSL112
1Diditchenko
S, Arterioscler Thromb Vasc Biol 2013
2Tardif JC, JAMA 2007
CSL112 Development Program Hypothesis
•
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 Phase 2a Trial
A phase 2a adaptive, multicenter, randomized, doubleblind, 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.
Trial Design
Double Blind
Stable Atherothrombotic
Disease (N≈40)
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
Dose group 1.7 g
CSL112
3:1*
Placebo
CSL112
Dose group 3.4 g
3:1*
Placebo
CSL112
Dose group 6.8 g
*Stratification:
CrCl >90 mL/min vs
CrCl >60 to <90 mL/min
3:1*
Placebo
Study Periods and Follow-Up
Overview
Study Endpoints
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.
Subject Disposition
Patients randomized: 45
Patients treated: 44
Completed study: 44
Baseline Characteristics
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)
56 (47–71)
7 (63.6)
29 (22–46)
8 (72.7)
65 (54–77)
4 (57.1)
29 (21–34)
6 (85.7)
57 (40–73)
9 (75.0)
33 (25–55)
9 (75.0)
60 (41–76)
12 (85.7)
29 (24–40)
12 (85.7)
60 (40–77)
25 (75.8)
31 (21–55)
27 (81.8)
CAD
Prior MI
Prior stenting
Prior CABG
PAD
11 (100)
6 (54.5)
6 (54.5)
3 (27.3)
1 (9.1)
5 (71.4)
4 (57.1)
3 (42.9)
3 (42.9)
2 (28.6)
10 (83.3)
4 (33.3)
3 (25.0)
3 (25.0)
1(8.3)
11 (73.3)
5 (33.3)
5 (33.3)
1 (6.7)
1 (6.7)
26 (76.5)
13 (38.2)
11 (32.4)
7 (20.6)
4 (11.8)
Hypertension
Diabetes mellitus
Hyperlipidemia
Statins
7 (63.6)
5 (45.5)
5 (45.5)
10 (90.9)
6 (85.7)
2 (28.6)
3 (42.9)
6 (85.7)
11 (91.7)
3 (25.0)
6 (50.0)
10 (83.3)
11 (73.3)
1 (6.7)
5 (33.3)
13 (92.9)
28 (82.4)
6 (17.6)
14 (41.2)
29 (87.9)
Age, yrs*
Male sex
BMI, kg/m2
White race
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 event
Primary endpoint:
Study–product-related AE*
Non-serious AE
SAE
Infusion–site-related AE†
Other
Causally related AE
Any AE
Maximum intensity‡
Mild
Moderate
3 (27.3)
3 (27.3)
1 (9.1)
1 (9.1)
5 (71.4)
5 (71.4)
0 (0)
1 (14.3)
5 (41.7)
5 (41.7)
0 (0)
2 (16.7)
6 (42.9)
6 (42.9)
0 (0)
5 (35.7)
16 (48.5)
16 (48.5)
0 (0)
8 (24.2)
1 (9.1)
3 (27.3)
1 (14.3)
5 (71.4)
1 (8.3)
6 (50.0)
5 (35.7)
8 (57.1)
7 (21.2)
19 (57.6)
2 (18.2)
1 (9.1)
5 (71.4)
0 (0)
6 (50)
0 (0)
8 (57.1)
0 (0)
19 (57.6)
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.
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)
CSL112
Overall
(N=33)
No elevation
1–2x ULN
2–3x ULN
>3x ULN
10 (90.9)
1 (9.1)
–
–
7 (100)
0 (0)
–
–
11 (91.7)
1 (8.3)
–
–
12 (85.7)
2 (14.3)
–
–
30 (90.9)
3 (9.1)
–
–
AST, n (%)
No elevation
1–2x ULN
2–3x ULN
10 (90.9)
1 (9.1)
–
6 (85.7)
1 (14.3)
–
12 (100)
0
–
14 (100)
0
–
32 (97.0)
1 (3.0)
–
–
–
–
–
–
ALT, n (%)
>3x ULN
Other Selected Clinical Laboratory
(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)
CSL112
Overall
(N=33)
0 (0)
11 (100)
0 (0)
0 (0)
0 (0)
6 (85.7)
1 (14.3)
0 (0)
1 (8.3)
11 (91.7)
0 (0)
0 (0)
0 (0)
14 (100)
0 (0)
0 (0)
1 (3.0)
31 (93.9)
1 (3.0)
0 (0)
0 (0)
3.1 (39.0)
0 (0)
-5.2 (28.3)
0 (0)
-10.3 (26.0)
0 (0)
4.4 (34.7)
0 (0)
-2.9 (30.3)
0.6 (1.1)
0.03 (0.07)
-0.8 (2.9)
0.04 (0.09)
-1.6 (3.8)
0.03 (0.05)
-0.8 (1.4)
0.01 (0.11)
-1.1 (2.7)
0.02 (0.08)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Renal function
S-creatinine increase, n (%)
No increase
>1–1.5x baseline
>1.5–3.0x baseline
>3.0x baseline
Hematology
Hb decrease >2 g/dL
Platelet count change (48 hrs)
Coagulation
Change aPTT (24 hrs)
INR (24 hrs)
Anti-CSL112/ApoA-1 Ig
seroconversion
• Continuous variables shown as mean (SD).
PK of ApoA-I Mean Plasma Concentrations
with Different Doses of CSL112
PK parameter
Cmax (mg/dL)
AUC0-last (mg/dL*h)
•
•
CSL112 1.7g
(N=7)
CSL112 3.4g
(N=12)
CSL112 6.8g
(N=14)
33.8 (9.1)
869 (741)
77.1 (13.0)
2044 (845)
184 (35.1)
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
Summary of Main Biomarker and Platelet
Aggregation Data
•
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.
Conclusion
In 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.
CSL112 Clinical Development Progression
•
Global phase 2b trial of CSL112 in patients postACS 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).
Investigators
Dominick J. Angiolillo, MD, PhD - Jacksonville, FL
Alison L. Bailey, MD - Lexington, KY
Michael A. Blazing, MD - Durham, NC
Louis A. Cannon, MD - Petoskey, MI
Marina Cuchel, MD, PhD - Philadelphia, PA
Paul A. Gurbel, MD - Baltimore, MD
Jonathan A. Mosley, DO - Madisonville, KY
Henry E. Paez, MD - Miami, FL
Robert Schott, MD - Chula Vista, CA
Robert J. Weiss, MD - Auburn, ME
Brion M. Winston, MD, MPH - Rapid City, SD

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