Slide 1: Developing RNA Drugs and Technologies to Improve the Lives and Health of Patients
alSITS PHARMACEUTICALS Developing RNA Drugs and Technologies to Improve the Lives and Health of Patients April 2006
Slide 2: ISIS 301012: The Reduction of Atherogenic Lipids in Subjects with Hypercholesterolemia
ISIS 301012: The Reduction of Atherogenic Lipids in Subjects with Hypercholesterolemia Mark Wedel, MD, JD Senior Vice President and CMO Isis Pharmaceuticals Carlsbad, CA April 2006
Slide 3: A Second Generation Antisense Drug Inhibiting apoB-100
ISIS 301012 A Second Generation Antisense Drug Inhibiting apoB-100 ‘ Expressed in the liver vi Essential for the synthesis and transport of VLDL and LDL ol Ce | Crucial role in lipid ca management Ey (V Unapproachable with ~~ small molecules ast om
Slide 4: Phase 1 Results
ISIS 301012: Phase 1 Results
Slide 5: Dose-dependent Prolonged Reduction in Serum apoB & LDL
ISIS 301012 - Phase 1 Dose-dependent Prolonged Reduction in Serum apoB & LDL apoB LOL [=e Picoto some 100mg —--200m9 = s00mo | Se Pleccto sme ——100mG 70mg —S- a80m j j i i ic [. ie i ia io i. dn. oo. 2 Se ee 6 « @De es ese wut Doy Met Dey apoB (% reduction) Day 39 LDL (% reduction) Day 39 jo 280 50m
Slide 6: Trough Plasma Concentrations Predict Long Drug Effects & Support Infrequent Dosing
ISIS 301012 - Phase 1 Trough Plasma Concentrations Predict Long Drug Effects & Support Infrequent Dosing apoB-100 in Human Subjects (200 mg, n= 8) 4 ISIS 301012, ngimL. z —— apoB-100 (% Baseline) 2 o F a 8 & 8 = 80 8 & a a o 7m 8 ¢ = 8 oy a & 6 wo 8 E P 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105
Slide 7: ISIS 301012 (350 mg/wk for month) Lowers All Atherogenic Lipids Including Triglycerides
ISIS 301012 - Phase 1 ISIS 301012 (350 mg/wk for 1 month) Lowers All Atherogenic Lipids Including Triglycerides apoB-100 *K Placebo Z 350 mgweek LOL Ne 12 placebo! 6 treated Triglycerides
Slide 8: Study Objectives
ISIS 301012 - Phase 2a Study Objectives » Safety & tolerability > Efficacy " Statistical significance = Dose dependence * apoB « LDL + Other atherogenic lipids » PK/PD correlation
Slide 9: Study Design
ISIS 301012 - Phase 2a Study Design > n= 10 subjects per cohort (total 50 subjects) >» Concomitant placebo subjects (1:4) > Dosing duration: 3 months » Target population: hypercholesterolemic subjects failing to reach target on diet alone > Dosing cohorts: + 50 mgvk * 100 mg/vk + 200 mg/wk + midpoin
Slide 10: Phase 2a Dosing Cohorts Completed
ISIS 301012 — Phase 2a Dosing Cohorts Completed Weekly Dose Equivalent Loading Dose* 50 100 every other week 100 200 every other week 200 200 every week * 200 mg subcutaneous on days 1, 4, 8 & 11 10
Slide 11: Demographics
ISIS 301012 - Phase 2a Demographics PBO 50mgiwk 100 mg/wk 200 mg/wk Total Cholesterol 246 274 253 252 HDL 52 55 57 54 TG 177 161 125 129 (88-298) (79-330) (64-295) (62-200) VLDL 23 7 20 17 (12-45) (10-57) (7-34) (8-34)
Slide 12: apoB
apoB (Median % Change) ISIS 301012 - Phase 2a % Reduction ApoB | -® Placebo 100g Wk: > 200 mg/wk| peoie eich: = & | ‘Study Day 2
Slide 13: Statistical Evaluation for ApoB
ISIS 301012 - Phase 2a Statistical Evaluation for ApoB* PBO 50 mg/wk 100 mg/wk 200 mg/wk day 99 -3% -22% p=0.14 -23% p=0.005 -AT% p<0.001 day 115 1% -20% p=0.03 -22% p=0.008 -34% p<0.001 day 145 13% -11% p=0.03 -11% p=0.003 -27% p<0.001 day 175 2% -15% p=0.04 13% p=0.05 -26% p=0.003 “median; p value
Slide 14: LDL-Cholesterol
LDL-Cholesterol (Median % Change) ISIS 301012 - Phase 2a LDL % Reduction ~@ Placebo = 50 mg/wk ~& 100 mg/wk 200 mg/wk| ae 3828 8 8 2 Study Day 7
Slide 15: Statistical Evaluation for LDL
ISIS 301012 - Phase 2a Statistical Evaluation for LDL* PBO 100 mg/wk 200 mg/wk 50 mg/wk 9007 day 99 -2% -12% p=0.57 -22% p=0.05 ~42% p<0.001 day 115 3% -14% p=0.02 17% p=0.05 -37% p<0.001 day 145 15% -3% p=0.008 6% p=0.03 -31% p<0.001 day 175 2% 1% p=0.49 1% p=0.57 -22% p<0.001 “median ; p value ver
Slide 16: Total Cholesterol % Reduction
ISIS 301012 - Phase 2a Total Cholestero/ % Reduction | © Placebo “50 mgiwk —__-& 100 mg/wk Total Cholesterol (Median % Change) > 200 mgiwk| &se3e82 88 828 8B Study Day 16
Slide 17: Non-HDL % Reduction
ISIS 301012 - Phase 2a Non-HDL % Reduction | Placebo A 50 mgfwk == 100 give: “> 200 mg/wk) os Non-HDL Cholesterol (Median % Change) sees ‘TREATMENT RRS Sees RS 2E SR Study Day
Slide 18: Triglycerides
Triglycerides (Median % Change) B’R8ESoB ISIS 301012 - Phase 2a Triglycerides % Reduction | -@ Placebo 2 #50 mgiwk S100 malak ~ 200 mgiwk | ags8¢ses3e828 888 8
Slide 19: Duration of Effect on LDL
ISIS 301012 - Phase 2a Duration of Effect on LDL* Post Dosing 50 mg/week 0.4 months 100 mg/week 2.0 months 200 mg/week 5.2 months (projected) *Retum to 90% of baseline
Slide 20: PK/PD Model Predicts Trough Concentrations and Pharmacologic Response (50 mg weekly)
ISIS 301012 — Phase 2a PK/PD Model Predicts Trough Concentrations and Pharmacologic Response (50 mg weekly) — Predicted Plasma Trough ISIS 301012 Conc. © Observed ISIS 301012 Cone. (ngimL) —— Predicted Apo B (%Change) 4 Observed Apo B (%Change) (eBueyo %) aode wines Trough Plasma ISIS 301012 Conc. (
Slide 21: PK/PD Model Predicts Trough Concentrations and Pharmacologic Response (100 mg weekly)
ISIS 301012 — Phase 2a PK/PD Model Predicts Trough Concentrations and Pharmacologic Response (100 mg weekly) — Predicted Plasma Trough ISIS 301012 Conc. Observed Plasma Trough ISIS 301012 Conc. — Predicted Apo B (%Change) ‘4 Observed Apo B ("%Change) (eBueyD %) gode wines Trough Plasma ISIS 301012 C
Slide 22: PK/PD Model Predicts Trough Concentrations and Pharmacologic Response (200 mg weekly)
PK/PD Model Predicts Trough Concentrations and Trough Plasma ISIS 301012 Conc. (ng/mL) ISIS 301012 — Phase 2a Pharmacologic Response (200 mg weekly) — Predicted Plasma Trough ISIS 301012 Conc. Observed Plasma Trough ISIS 301012 Conc. — Predicted Apo B (%Change) ‘4 Observed Apo B ("Change) Study Day
Slide 23: Safety
ISIS 301012 - Phase 2a Safety Serious Adverse Events: = One unrelated SAE (encephalitis) Adverse Events: = Injection site reactions: Mild transient painless erythema + No impact on compliance = One subject with transient ALT rise (3.4x ULN) 60 days post last dose * No dose response relationship for
Slide 24: Conclusions
ISIS 301012 - Phase 2a Conclusions >» Low weekly subcutaneous doses of ISIS 301012 lower all atherogenic lipids & triglycerides and are well tolerated > The effects of ISIS 30102 are predictable = Dose and schedule dependent = Pharmacokinetics consistent & predictable = Pharmacodynamics highly corre
Slide 25: Next Steps
ISIS 301012 Next Steps Evaluate effects of 300 and 400mg per week for three months in patients with high cholesterol Evaluate effects of ISIS 301012 in combination with statins = Initially for 5 weeks = Then 6 months Evaluate the effects of ISIS 301012 in patients with Familial Hypercholesterolemia
Slide 26: Treatment with ISIS 301012 Significantly Reduces Aortic Sinus Plaque Burden in Transgenic Mice
ISIS 301012 Treatment with ISIS 301012 for 14 Weeks Significantly Reduces Aortic Sinus Plaque Burden in Transgenic Mice Saline 02 ISIS 301012 *50 mghkg/wk | z Volume Saline 301012 ‘301012 ae 20mgikg 50 mgikg P=0.033 (one tailed test)
Slide 27: Clinical Development Strategy
ISIS 301012 Clinical Development Strategy >» We intend for ISIS 301012 to be: " The drug of choice for patients at risk who are unable to achieve target levels on statins & ezetimibe + Initially in patients with FH + Ultimately in polygenic hypercholesterolemia » An alternative to statins for those
Slide 28: Anticipated Initial Product Profile
ISIS 301012 Anticipated Initial Product Profile » Achieves significant reductions in cholesterol via a non-statin mechanism > Combines safely with statins and ezetimibe > Enables more patients to reach target lipid levels when combined with statins and ezetimibe >» Doses at convenient intervals of w
Slide 29: Anticipated Initial Safety Profile
ISIS 301012 Anticipated Initial Safety Profile » No fat accumulation in the liver (steatosis) > No muscle toxicity (antisense drugs do not get into muscle) > No CNS toxicity (antisense drugs do not get into the CNS) > No drug-drug interactions (antisense drugs do not interact with the pathway that m
Slide 30: Searchable text section of graphics shown above
Searchable text section of graphics shown above [LOGO] Developing RNA Drugs and Technologies to Improve the Lives and Health of Patients April 2006 ISIS 301012: The Reduction of Atherogenic Lipids in Subjects with Hypercholesterolemia Mark Wedel, MD, JD Senior Vice President and CMO Isis Pharmaceuti