inhibition of apolipoprotein c-iii with galnac-conjugated...
TRANSCRIPT
AbstractBackground: Apolipoprotein C-III (apoC-III) is synthesized principally by the liver, plays a pivotal role in regulating plasma triglyceride (TG) levels, and is causally associated with cardiovascular disease (CVD). ApoC-III inhibits the hydrolysis of TG-rich lipoproteins and delays clearance of lipoprotein remnants by the liver by inhibiting receptor-mediated uptake. AKCEA-APOCIII-LRx is a second-generation antisense oligonucleotide that selectively inhibits apoC-III protein synthesis. It contains an N-acetylgalactosamine (GalNAc) moiety targeted to hepatocytes to enhance potency.Methods: The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (age 18–65) with TGs ≥200 mg/dL. In ascending single-dose cohorts, 10, 30, 60, 90, and 120 mg given subcutaneously (sc) were evaluated sequentially. In ascending multiple-dose cohorts, 2 groups were given 15 and 30 mg weekly sc for 6 weeks and 1 group was given 60 mg every 4 weeks sc for 3 months. Results: There were significant dose-dependent mean reductions in fasting serum apoC-III and TG levels. In the ascending single-dose cohorts, apoC-III reductions of –4%, –32%, –65%, –78%, and –91%, and TG reductions of –12%, –11%, –43%, –68%, and –77% were observed with single doses of 10, 30, 60, 90 and 120 mg of AKCEA-APOCIII-LRx, respectively, 14 days after dosing. In the ascending multiple-dose cohorts, mean apoC-III reductions of –65%, –84%, and –83% and mean TG reductions of –61%, –71%, and –65% were observed in the 15 and 30 mg (weekly) and 60 mg (every 4 weeks) dosing cohorts, respectively, 1 week after the last dose. Significant reductions of up to ~–30% in apolipoprotein B (apoB) and increases of up to ~100% in high-density lipoprotein cholesterol (HDL-C) were also observed. ApoC-III protein levels remained reduced by up to 50% for ~90 days after the last dose. AKCEA-APOCIII-LRx was well tolerated with no injection-site or flu-like reactions, as well as no renal adverse events (AEs) or platelet reductions.Conclusions: Treatment with AKCEA-APOCIII-LRx results in an improved atherogenic lipid profile and durable pharmacology indicating a potential for monthly or less frequent dosing. Based on the encouraging tolerability and potential efficacy demonstrated in this study, a Phase 2 trial in subjects with high TGs and CVD has been initiated (January 2018).
IntroductionApoC-III ● ApoC-III is a 79-amino–acid glycoprotein, synthesized principally in the liver – Multiple apoC-III proteins on TG-rich lipoproteins and HDL particles● Plays a key role in determining serum TG levels – Potent inhibitor of lipoprotein lipase – Inhibits hepatic uptake of TG-rich lipoproteins
ApoC-III as a Target for CVD Risk Reduction1,2
● High plasma TG levels are known to be associated with an increased risk of CVD● Loss-of-function mutations in APOC3 have been shown to be associated with: – Marked reductions in plasma levels of TGs (mean reduction of 44%) and apoC-III – A favorable lipid profile, reduced CVD and increased longevity ● Old World Amish3; Ashkenazi Jews4; Exome Sequencing Project1; Copenhagen City cohorts2
● APOC3 is a promising therapeutic target for reducing residual cardiovascular risk
Figure 1. Antisense Technology Reduces Disease Causing Protein Levels by Targeting mRNA
AKCEA-APOCIII-LRx● Triantennary GalNac (GalNAc3) represents a new class of LIgand-Conjugated Antisense (LICA)
modifications for selectively targeting hepatocytes
Figure 2. Selective Delivery to Hepatocytes5
AKCEA-APOCIII-LRx has Improved Potency vs. non-LICA in Humans● A comparison of dose–response data of AKCEA-APOCIII-LRx and non-LICA following 6 SC doses
once-weekly for 6 weeks, or 4 weeks with 3 doses in the first week, in human subjects showed that AKCEA-APOCIII-LRx has at least 15x improved potency vs. non-LICA in reducing fasting serum apoC-III and TGs
MethodsAKCEA-APOCIII-LRx Phase 1/2a Study Design ● Ascending single- and multiple-dose dose study in subjects with TGs ≥200 mg/dL● Double-blind, placebo-controlled, dose-escalation study
Single-Dose Cohorts
Cohorts Placebo(n)
AKCEA-APOCIII-LRx
(n)
10 mga 2 6
30 mga 2 6
60 mga 2 6
90 mgb 2 6
120 mgb 2 6
aTG inclusion ≥90 mg/dL; bTG inclusion ≥200 mg/dL D, day; f/u, follow up; R, randomization
Multiple-Dose Cohorts
Cohorts Placebo(n)
AKCEA-APOCIII-LRx
(n)
15 mg/weeka 2 6
30 mg/weeka 2 6
60 mg/montha 4 6
aTG inclusion ≥200 mg/dL D, day; f/u, follow up; R, randomization
ResultsPhase I: AKCEA-APOCIII-LRx in Healthy VolunteersBaseline Characteristics of Ascending Multiple-Dose Groups
Placebo/week(n=4)
15 mg/week(n=6)
30 mg/week(n=7)
Placebo/month(n=4)
60 mg/month(n=6)
Gender (M:F) 2:2 4:2 7:0 2:2 3:3
Age (years) 53 53 42 57 50
BMI (kg/m2) 27.5 28.7 30.6 28.2 27.7
Lipids and Lipoproteins, mg/dL
ApoC-III 13 14 10 13 15
Triglycerides 225 223 189 191 301
Total Cholesterol 230 225 229 257 271
HDL-C 38 53 40 46 40
Non–HDL-C 192 173 189 211 231
LDL-C 146 128 150 173 177
BMI, body mass index; LDL-C, low-density lipoprotein cholesterol
AKCEA-APOCIII-LRx: Ascending Single-Dose Cohorts – EfficacyFigure 3. Significant, Dose-Dependent, Prolonged Mean % Reductions in Serum ApoC-III in Ascending Single-Dose Cohorts (N=40)
● Mean % reduction in apoC-III on Day 30: 10 mg, –18%; 30 mg, –31%; 60 mg, –58%; 90 mg, –72%; 120 mg, –87% (Figure 3)
Figure 4. Significant, Dose-Dependent, Prolonged Mean % Reductions in Serum TGs in Ascending Single-Dose Cohorts (N=40)
● Mean % reduction in TGs on Day 30: 10 mg, –12%; 30 mg, –4%; 60 mg, –38%; 90 mg, –60%; 120 mg, –72% (Figure 4)
Figure 5. Significant, Dose-Dependent, Sustained Mean % Reductions in Serum ApoC-III Following 6 Weekly Doses of AKCEA-APOCIII-LRx (N=17)
● Mean % reduction in apoC-III on Day 43: 15 mg, –65%; 30 mg, –84% (Figure 5)
Figure 6. Significant, Dose-Dependent, Sustained Mean % Reductions in Serum TG Following 6 Weekly Doses of AKCEA-APOCIII-LRx (N=17)
● Mean % reduction in TGs on Day 43: 15 mg, –61%; 30 mg, –71% (Figure 6)
Figure 7. Significant, Dose-Dependent, Sustained Mean % Reductions in Serum ApoB Following 6 Weekly Doses of AKCEA-APOCIII-LRx (N=17)
● Mean % reduction in apoB on Day 43: 15 mg, –15%; 30 mg, –26% (Figure 7)
Figure 8. Significant, Dose-Dependent, Sustained Mean % Increases in Serum HDL-C Following 6 Weekly Doses of AKCEA-APOCIII-LRx (N=17)
● Mean % increase in HDL-C on Day 43: 15 mg, 50%; 30 mg, 56% (Figure 8)
Figure 9. Significant, Dose-Dependent, Sustained Mean % Reductions in Serum ApoC-III Following 4 Monthly Doses of AKCEA-APOCIII-LRx (N=10)
● Mean % reduction in apoC-III: Day 43, –80%; Day 92, –83% (Figure 9)
Figure 10. Significant, Dose-Dependent, Sustained Mean % Reductions in Serum TG Following 4 Monthly Doses of AKCEA-APOCIII-LRx (N=10)
● Mean % reduction in TGs: Day 43, –61%; Day 92, –65% (Figure 10)
Figure 11. Significant, Dose-Dependent, Sustained Mean % Reductions in Serum ApoB Following 4 Monthly Doses of AKCEA-APOCIII-LRx (N=10)
● Mean % reduction in apoB: Day 43, –22%; Day 92, –30% (Figure 11)
Figure 12. Significant, Dose-Dependent, Sustained Mean % Increases in Serum HDL-C Following 4 Monthly Doses of AKCEA-APOCIII-LRx (N=10)
● Mean % reduction in HDL-C: Day 43, 64%; Day 92, 76% (Figure 12)
Improved Atherogenic Lipid Profile: Mean % Change From Baseline in Key Lipids 1 Week After Last Dose
15 mg/week Day 43
30 mg/week Day 43
60 mg/monthDay 43a
60 mg/month Day 92
ApoC-III –65%** –84%** –80%* –83%*
TGs –61%** –71%** –61%* –65%*
LDL-C –3% –17% –10% –22%
ApoB –15%* –26%** –22% –30%*
Non–HDL-C –22%* –30%** –27%* –31%*
HDL-C +50%** +56%* +64% +76%*
Lp(a) –0.1% –11% –7% –27%
aMonthly dosing Day 43, 2 weeks after second dose, shown for comparison to weekly dosing cohorts
*p≤0.05; **p≤0.01
Clinical Safety and Tolerability for AKCEA-APOCIII-LRx● No serious AEs● No AEs leading to treatment discontinuation● No hepatic or renal signals● No injection site or flu-like reactions ● No clinically significant findings in routine hematology or biochemistry● No platelet reductions
Summary● Significant, dose-dependent lowering of apoC-III total protein – Approximately 80% reduced from baseline with 6 weekly or 2 monthly doses of AKCEA-APOCIII-LRx ● Durable response – ApoC-III protein levels remained reduced by up to 50% for ~90 days after the last dose● Associated significant dose-dependent reductions in TGs – Up to 71% reduced from baseline● Associated significant dose-dependent reductions in apoB and increases in HDL-C – Up to 30% reductions in apoB and increases of up to 100% in HDL-C ● No safety signals identified
Conclusions● Treatment with AKCEA-APOCIII-LRx results in an improved atherogenic lipid
profile and durable pharmacology indicating a potential for monthly or less frequent dosing
● These data reinforce the consistency and predictability of target reduction with lower doses using Ionis’ LICA technology
● Based on the encouraging tolerability and potential efficacy demonstrated in this study, a Phase 2 trial in subjects with high TGs and CVD has been initiated (January 2018)
References1. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22–31; 2. Jorgensen AB et al. N Engl J Med 2014;371:32–41; 3. Pollin TI et al. Science 2008;322:1702–1705; 4. Atzmon G et al. PLoS Biol 2006;4:e113; 5. Prakash TP et al. Nucleic Acids Res 2014;42:8796–8807.
Conflicts of Interest: DisclosuresVeronica J. Alexander, Shuting Xia, Steve Hughes, Richard S. Geary are all employed by Ionis Pharmaceuticals. Eunju Hurh is employed by Akcea Therapeutics. Andres Digenio is a former employee of Akcea Therapeutics. Joseph L. Witztum is employed by the University of California San Diego and is a consultant for Ionis Pharmaceuticals. Sotirios Tsimikas has a joint appointment with Ionis Pharmaceuticals and the University of California San Diego.
AcknowledgmentsThe authors thank Swati Thorat at Akcea Therapeutics and ApotheCom for poster production support. This study was funded by Ionis Pharmaceuticals and Akcea Therapeutics, Inc.
Inhibition of Apolipoprotein C-III with GalNAc-Conjugated Antisense Drug Potently Lowers Fasting Serum Apolipoprotein C-III and Triglyceride Levels in Healthy Volunteers with Elevated TriglyceridesVeronica J. Alexander1, Andres Digenio2, Shuting Xia1, Eunju Hurh2, Steve Hughes1, Richard S. Geary1, Joseph L. Witztum1,3, Sotirios Tsimikas1,3 1Ionis Pharmaceuticals, Inc., Carlsbad, CA; 2Akcea Therapeutics, Cambridge, MA; 3Department of Medicine, University of California San Diego, La Jolla, CA
Post-Treatmentf/u Period
Screeningup to 28 days
1 SC Dose
3:1
D190 days
R
Post-Treatmentf/u Period
Post-Treatmentf/u Period
Screeningup to 28 days 6 SC Doses over 6 Weeks
3:1
D113 weeks
R
D8 D15 D22 D29 D36
Screeningup to 28 days 4 SC Doses over 3 Months
3:2
D113 weeks
R
D29 D57 D85
ApoC
-III (
mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Single-Dose Cohorts (N=40)
BL 32 15 30 60 90120
1508
-50
-75
***
***
***
***
**
****
*
*
**
**
******
***
**
** **
**
**
*****
**
-100
50
25
0
-25
Placebo 10 mg 30 mg 120 mg60 mg 90 mg
*
ApoC
-III (
mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Weekly Multiple-Dose Cohorts (N=17)
BL 2 15 22 29 36 43 50 64 90127
1558
-25
-50
-75
-100
50
25
0
Placebo 15 mg 30 mg
****
**
**
**
****
*
*******
****
******** **** ApoC
-III (
mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Monthly Multiple-Dose Cohorts (N=10)
BL 2 15 29 43 57 71 85 92 99113
141176
204
-50
-25
-75
-100
50
25
0
Placebo
** *
*
*** ** * * *
*
*
**
60 mg
TGs
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Weekly Multiple-Dose Cohorts (N=17)
BL 2 15 22 29 36 43 50 64 90127
1558
0
-50
-100
150
100
50
Placebo 15 mg 30 mg
***
**
*****
**
*
* ** ****
****
TGs
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Monthly Multiple-Dose Cohorts (N=10)
BL 2 15 29 43 57 71 85 92 99113
141176
204
-50
-25
-75
-100
50
25
0
Placebo
***
* *** * *
*
*
**
60 mg
ApoB
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Weekly Multiple-Dose Cohorts (N=17)
BL 2 15 22 29 36 43 50 64 90127
1558
-20
-30
-40
20
10
0
-10
Placebo 15 mg 30 mg
*
*
**
*
**** **
**** * *
**
ApoB
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Monthly Multiple-Dose Cohorts (N=10)
BL 2 15 29 43 57 71 85 92 99113
141176
204
-20
-10
-30
-40
20
10
0
Placebo
**
**
** *
60 mg
**
HDL
-C, P
reci
pita
tion
Met
hod
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Weekly Multiple-Dose Cohorts (N=17)
BL 2 15 22 29 36 43 50 64 90127
1558
20
0
-20
80
60
40
Placebo 15 mg 30 mg
*
*** *
**
****
HDL
-C, P
reci
pita
tion
Met
hod
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
Monthly Multiple-Dose Cohorts (N=10)
BL 2 15 29 43 57 71 85 92 99113
141176
204
50
0
-50
150
100
Placebo 60 mg
*p≤0.05**p≤0.001
***p≤0.0001
*** * *
**
*
****
**
Trig
lyce
rides
(mg/
dL)
Mea
n (+
/- S
EM) %
Cha
nge
from
Bas
elin
e
Visit (day)Dose
*p≤0.05**p≤0.001
***p≤0.0001
Single-Dose Cohorts (N=40)
BL 32 15 30 60 90120
1508
-25
-50
-75***
***
**
*
**
**
******
*
*
*
*
**
*
*
-100
75
50
25
0
Placebo 10 mg 30 mg 120 mg60 mg 90 mg
***
This poster was presented at ACC18 – American College of Cardiology’s 67th Annual Scientific Session & Expo, Orlando, Florida, USA, March 10–12, 2018
AKCEA-APOCIII-LRx: Ascending Multiple-Dose (Weekly and Monthly) Cohorts – Efficacy