Phase Ib Study of Icosabutate, A Novel Structurally Enhanced Fatty Acid, in Subjects with Hypercholesterolemia Authors: Yan Qin , Jonas Hallén , Tore Skjæret , Erling Odden , David Fraser , Hilde Nyheim , Karen Cornelissen , Joseph Chiesa , Svein Olaf Hustvedt 1 1 1 1 1 1 2 2 1 Pronova BioPharma Norge AS – part of BASF, Oslo, Norway, Covance Clinical Research Unit, Leeds, UK 1 2 • INTRODUCTION: • SAFETY: Icosabutate, an orally active structurally enhanced fatty acid (SEFA), has demonstrated reduction in triglycerides (TG) and cholesterol in several rodent models of dyslipidemia and diabetes. In clinical single and multiple dose studies icosabutate was well tolerated and significantly lowered LDL-C, non- HDL-C and TG in subjects with mixed dyslipidemia. The number of subjects reporting adverse events (AEs) were balanced between the treatment arms (Table 2). Baseline Table 1:Baseline Lipid Values, Geometric Mean This phase 1b study explored the lipid lowering effects of icosabutate in subjects with hypercholesterolemia. HDL-C TC • METHODS: TG Randomized double blind, placebo controlled study of icosabutate 600mg OD. Subjects with hypercholesterolemia treated with a statin for at least 3 months were screened (Figure 1). Statins were temporarily discontinued for at least 28 days prior to dosing, and for the duration of the study. Lipids were sampled at 3 screening visits, baseline (day -1), and at days 1, 7, 14, 21, 28, and 29. The exploratory analyses considered changes from baseline to day 28. Icosabutate (n (n=18) 18) mmol/L 4.5 4.3 mg/dL 174 165 mmol/L l/L 05 0.5 04 0.4 mg/dL 21 14 mmol/L 5.3 4.6 mg/dL 205 179 mmol/L 1.2 1.3 mg/dL g/d 48 8 49 9 mmol/L 6.4 6.0 mg/dL 242 231 mmol/L 22 2.2 15 1.5 mg/dL 190 134 250 150 100 Non-HDL-C Total-C HDL-C RANDO OMIZATION N 3:1 SCREENING visit 1 35-28 days prior to first dose > Statin withdrawal SCREENING visit 2 6 days prior to first dose SCREENING visit 3 3 days prior to first dose 25 Apo B* Icosabutate 600 mg N = 18 Placebo N=6 LDL-C, VLDL-C, Total-C, TG, HDL-C HDL-C, Non-HDL-C, apo C3, apo B, PCSK-9 -6% -3% -4% -7% 10% -10% -2% -16% -35% -29% -29% -35% 5 -41% Placebo Icosabutate Placebo Corrected 0 Baseline Day 28 Baseline Day 28 Pl Placebo b For details please refer to “Comment to values” at the bottom of poster I Icosabutate b 4 WEEKS 1. On statin medication > 3 months, stable dose at least > 4 weeks 2. LDL-C > 2.5 mmol/L (97 mg/dL) and an increase of > 20 % at visit 2 following withdrawal of statin PCSK-9 LDL-C Figure 3: Time Curve of Mean LDL-C (mg/dL) Statin washout 80 Double-blind Double blind treatment period 200 180 160 140 120 100 80 60 40 20 0 Figure 6: Change (%) in LS Means from Baseline to Day 28, 95% CI on Placebo Corrected Bar 60 Ch hange (%) mg/dL 24 white, male subjects with an average age of 55 (33-65) and BMI of 27,9 kg/m2 (24.7-32.2) were randomized to icosabutate, 600 mg OD, (n=18) or placebo (n=6). Baseline lipid values were well-balanced between the groups (Table 1). Efficacy results are shown in Figures 2-6. Icosabutate significantly reduced TG, non-HDL-C, LDL-C, Total-C, apo B compared to placebo. Apo C3 was significantly reduced from baseline and PCSK-9 was significantly increased compared to placebo. % 50 n 13 % 72 Mild 3 50 13 72 Moderate 1 17 3 17 Severe 0 0 0 0 No subjects reported serious AEs or discontinued treatment due to AE. • CONCLUSION: 10 -50 • RESULTS: Total n 3 15 * Apo B was only sampled on day 29, 24 hours after last dose KEY INCLUSION CRITERIA Icosabutate (n=18) 20 -30 -40 40 Placebo (n=6) Icosabutate Figure 5: LS Mean Apo C3 (μg/mL) Levels at Baseline and Day 28. SD included on bars 0 EXPLORATORY ENDPOINTS Table 2: Treatment Emergent Adverse Events Apo p C3 10 -20 DOUBLE-BLIND TREATMENT -20 -50 Placebo μg g/mL Figure 1 -10 -40 0 20 % Change LS Mean -10 10 There were no other findings of clinical importance in the clinical laboratory evaluations, vital signs, 12-lead ECGs, telemetry, physical examinations, or body weight observed during the study. -30 50 Figure 2: Change (%) in LS Means from Baseline to Day 28 (95 % CI) TG Figure 4b: Change (%) of Mean TG from Baseline 0 200 Changes in Lipids and Lipoproteins LDL-C Study y Design g Figure 4a: Absolute TG values ((Mean)) at Baseline and During Treatment (mg/dL) % Change Non-HDL-C Placebo (n (n=6) 6) mg/dL LDL-C VLDL-C • AIM: Triglycerides 40 In this exploratory phase Ib study in hypercholesterolemic subjects temporarily withdrawn from statin, 28 days treatment with icosabutate showed promising results ICOSABUTATE : • Reduced Total-C, LDL-C, non-HDL-C, TG, and apo B compared to placebo • Reduced plasma apo C3 substantially from baseline • Increased plasma PCSK-9 levels compared to placebo • Appeared safe and well tolerated The results extend and confirm pre-clinical data on icosabutate and suggest a unique pharmacological profile with large, robust reductions in both LDL-C and TGs.These explorative data indicate that icosabutate may be an important novel lipid-lowering agent in several patient populations. The results await confirmation in designated efficacy studies. 20 Screening 1 Baseline Day 1 Placebo Day 7 Day 14 Day 21 0 Day 28 Icosabutate Placebo Icosabutate Placebo Corrected • AUTHOR’S DISCLOSURE: This study was in whole sponsored by Pronova BioPharma Norge ASpart of BASF. Authors not employed by Pronova BioPharma/BASF have no conflict of interest. • COMMENT TO VALUES: There is a slight variance in values presented in the abstract and those presented in this poster: – The values in the abstract are reported as median percentage change from baseline (average of visit 2-4) to 24 hours after last dose (day 29) – The values in this poster are reported in line with the clinical study report as LS mean change from baseline (day-1) to day 28.