Transcript 11 targeting triglycerides - pace

Targeting triglycerides:
New insights from antisense
therapy
Prof. Daniel Gaudet
Universite de Montreal
Quebec, Canada
ISIS-APOCIIIRx
Interim Analysis: A Phase 2 Study with
Monotherapy Treatment of Patients with Severe
Hypertriglyceridemia
Dr. Daniel Gaudet MD PhD
Dept of Medicine, Université de Montréal and Scientific Director
of the Genome Quebec Biobank
August 31, 2013
Apolipoprotein C-III
Key Regulator of Serum Triglyceride Levels
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 ApoC-III is a 79 amino acid
glycoprotein
 Links to apoB-containing lipoproteins
and HDL
 Potent inhibitor of LPL-catalyzed
lipolysis of TG-rich lipoproteins
 Inhibits hepatic lipase which also
plays an important role in the
conversion of VLDL to IDL
 Inhibits receptor-mediated uptake of
lipoprotein remnants by the liver
ApoC-III in a complex with an SDS micelle as derived by NMR
 Independent risk factor for
cardiovascular disease
ISIS-APOCIIIRx Inhibits ApoC-III Synthesis in the
Hepatocytes
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• Structure: 20-nucleotide (20-mer) antisense oligonucleotide (ASO)
KYNAMRO™
• Complementary, specific ASO sequence that crosses the hepatocyte cell membrane and binds in
coding region of mRNA for ApoC-III
ISIS-APOCIIIRx Pre-Clinical and Early Phases Studies
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 Pre-clinical results demonstrate that ISIS-APOCIIIRx decreases TG and
apoC-III levels in animal models and improves insulin sensitivity in
hAPOC3 mice
 Early phase clinical studies suggest that ISIS-APOCIIIRx is safe and
well-tolerated with no discontinuations and low incidence of AEs
 Results of a small randomized, double-blind placebo-controlled phase 2
study evaluating the effect of ISIS-APOCIIIRx in 11 patients with high
triglycerides and type 2 diabetes showed improved lipid profile and
glucose control
 Interim results of a Phase 2 Study in 85 patients with moderate to severe
hypertriglyceridemia are now available
Results of a Randomized, Double-Blind Placebo-Controlled
Phase 2 Study Evaluating the Effect of ISIS-APOCIIIRx in
Patients with High Triglycerides and Type 2 Diabetes
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ISIS-APOCIIIRx Phase 2 Study in Patients with
Moderate to Severe Hypertriglyceridemia
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 Multicenter randomized double-blind placebo controlled study
 Study designed to demonstrate that ISIS-APOCIIIRx can decrease TG and apoC-III
levels
 Also evaluating effects of ISIS-APOCIIIRx on overall lipid-lipoprotein profile and
post-prandial metabolism
 Two cohorts:

(1) Add-on to fibrates (TG levels ≥225 and ≤2000 mg/dL); 28 patients

(2) Monotherapy (TG levels ≥440 and ≤2000 mg/dL); 57 patients
Treatment Period
13 Weeks
≤8 weeks
Screen/
Diet Run in
Post-Treatment
f/u Period
13 weeks
R
D1 D8 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 D85
ISIS-APOCIIIRx Treatment Improved Overall Lipid
Profile When Added to Fibrates (Cohort 1)
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Cohort 2: Monotherapy Baseline Characteristics*
Mean (SD)
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Placebo
Gender (F:M)
Age (yrs)
BMI (kg/m2)
(n=9)
100 mg
ISIS-APOCIIIRx
(n=9)
200 mg
ISIS-APOCIIIRx
(n=5)
300 mg
ISIS-APOCIIIRx
(n=5)
1:8
2:7
1:4
1:4
53.7 (8.4)
29.5 (4.8)
59.2 (16.7)
28.1 (2.3)
52.8 (13.5)
29.8 (2.8)
21.6 (7.5)
613 (277)
31.1 (4.7)
206 (58.3)
114 (28.6)
90.6 (34.9)
237 (55.3)
10.0 (4.7)
116 (46.9)
20.9 (6.5)
655 (438)
30.0 (4.5)
189 (74.9)
94 (16.8)
68.4 (21.1)
219 (78.6)
8.6 (3.4)
120 (85.1)
22.9 (5.4)
505 (110)
36.0 (9.6)
202 (33.4)
98 (20.5)
82.0 (23.3)
238 (29.2)
11.9 (3.5)
120 (35.9)
50.7 (13.5)
31.1 (3.6)
Fasting Lipids & Lipoproteins, mg/dL
ApoC-III
23.3 (8.9)
Triglycerides
615 (473)
HDL-C
30.6 (8.1)
Non-HDL-C
197 (98.5)
Apo B
106 (37.8)
LDL-C
80.6 (34.5)
Total Cholesterol
227 (96.1)
ApoC-III VLDL
12.0 (4.8)
VLDL-C
128 (107)
*Interim population (n=28) treated for 13 weeks out of 57 dosed
ISIS-APOCIIIRx Treatment Significantly Reduced ApoC-III
(interim Results)
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Mean % Change in ApoC-III
ISIS-APOCIIIRx Treatment Significantly Reduced
Triglycerides (Interim Results)
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Mean % Change in Fasting Triglycerides
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ISIS-APOCIIIRx Treatment Significantly Reduced
Triglycerides (Interim Results)
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Mean Fasting Triglyceride Levels
ISIS-APOCIIIRx Treatment Improved Overall Lipid
Profile in Monotherapy Patients: 300 mg group
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Comparison of the effects on key lipids for patients
treated with 300 mg/week of ISIS-APOCIIIRx
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Lipid
Parameter
(mg/dL)
ApoC-III
Triglycerides
Baseline
Average
[Range]
25 [18-33]
537 [355-702]
End of
Treatment
Average
[Range]
4.7 [2.5-8.6]
122 [105-152]
Mean %
Change
[p value]
-79% [0.003]
-75% [0.004]
VLDL ApoC-III
14 [7-24]
1.4 [0.6-2.9]
-89% [0.004]
HDL-C
34 [26-52]
57 [46-90]
+57% [<0.001]
195 [156-258]
121 [68-189]
-39% [0.007]
78 [41-126]
-23% [0.031]
Non-HDL-C
ApoB
98 [73-126]
Comparison of the effects on ApoC-III, TG and HDL-C for
patients treated with 300 mg/week of ISIS-APOCIIIRx in
Phase 2 Studies
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Mean % Change from Baseline
Lipid Parameter
Single agent
in diabetics
Single agent in
very high TG
In addition to
fibrates in very
high TG
ApoC-III
-88%
-79%
-70%
Triglycerides
-72%
-75%
-64%
VLDL ApoC-III
-92%
-89%
-77%
HDL-C
+40%
+57%
+52%
Non-HDL
-28%
-39%
-19%
Safety Summary
ISIS-APOCIIIRx Monotherapy in Patients with Severe Hypertriglyceridemia
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 Safety
No related SAEs or significant AEs
 No treatment related liver enzyme elevations
 No abnormalities in renal function
 No clinically meaningful changes in other laboratory values

 Tolerability
No flu-like reactions
 Infrequent and predominantly mild injection site reactions

ISIS-APOCIIIRx Phase 2 Summary
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 Significantly reduced triglycerides and apoC-III
 86% of patients treated with 300 mg ISIS-APOCIIIRx in both
studies achieved TG levels <150 mg/dL
 Improved lipid profile

Decreased triglycerides, total- and VLDL-ApoCIII, and non-HDL,
and increased HDL-C
 Effective as a single agent or when used in combination with
fibrates
 Equally effective irrespective of the triglyceride levels at entry
 Generally safe and well tolerated
Acknowledgements
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 Ecogene-21 Clinical Research Center; Chicoutimi, Quebec
 Clinical Trial Management Group; Greenville/Raleigh, North Carolina
 Isis Pharmaceuticals; Carlsbad, California
 The patients