ISIS-DMPK Rx : An Antisense Drug for The Treatment of Myotonic Dystrophy Type 1. C. Frank Bennett Ph.D. Senior Vice President of Research

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1 ISIS-DMPK Rx : An Antisense Drug for The Treatment of Myotonic Dystrophy Type 1 C. Frank Bennett Ph.D. Senior Vice President of Research

2 Agenda 2 n Stages of Drug Development n Drug Development Strategies for Myotonic Dystrophy n Introduction to Antisense Technology n ISIS-DMPK Rx : Why we are excited about the drug Where we are in the development process Isis Pharmaceuticals Confidential Advances in Technology_SCrooke_070212

3 The Stages of Drug Development 3 ISIS-DMPK Rx

4 Drug Discovery Steps 4 n Identify the therapeutic target The Gene n Determine the therapeutic strategy What to target? How to target? When to target? n Screen to identify the drug candidate Activity Safety Drug Development

5 Federal, Public & Company Roles in Research & Development 5 Government, Foundation Supported, Pharmaceutical Industry Research are Complementary Pharmaceutical Research Clinical Research Translational Research Basic Research Clinical Research Translational Research Basic Research There is an ecosystem of science and biotechnology. Public organizations, patient organizations, universities, Congress, FDA, all of this is an ecosystem that is envied in the rest of the world. Government (e.g. NIH) and Public (e.g. MDF) Supported Research E. Zerhouni, Director of NIH

6 6 1 st Clue What to Target? DM is Caused by a 3 Nucleotide Expansion in the DMPK Gene

7 2 nd Clue Nucleotide Expansion Sequesters Proteins A Gain of Function Toxic RNA 7 DMWD DMPK SIX5 DNA pre-mrna mrna RIBONUCLEAR FOCI RNA BINDING PROTEIN DYSREGULATION ABERRANT mrna SPLICING DM1 CLINICAL FEATURE MBNL CUG-BP Chloride Channel Insulin Receptor Cardiac Troponin T Tau Protein Myotubularin??? Myotonia Insulin Insensitivity?Cardiac Arrhythmia?CNS Effects?Myopathic Effects Cataracts Testicular Failure Hypogammaglobulinemia 6

8 8 How to Target? Antisense Drugs

9 How Genetic Information Flows From in DNA to Protein The Central Dogma of Molecular Biology 9 Gene mrna Disease-Causing Protein Transcription Translation DISEASE

10 Antisense Drugs Target RNA, not Proteins 10 Gene (DNA) mrna Antisense Drug Inhibition of RNA function Transcription Translation X Disease-Causing Protein X DISEASE Antisense Drugs can also inhibit the function of a disease causing RNA that doesn t make a protein (a non-coding RNA) This is nearly intractable for other platforms

11 The Antisense Drug-Receptor Interaction 11 Antisense Drug RNA Target p ~16-20 base pairs required for specificity

12 Antisense Drugs Chemical Modifications Produce Desired Effects in the Body 12 Commonly Used Chemical Modifications for Antisense Drugs

13 ISIS-DMPK Rx : Promotes Degradation of the Toxic DMPK RNA An RNase H Mechanism of Action 13 13

14 Proof of Concept Studies: Systemic Delivery of Antisense Drug Reverses Myotonia and Spliceopathy in a Mouse Model of DM1 (HSA-LR) 14 6 HSA-LR mrna Level (Normalized to 18S RNA) 4 2 PBS Quad Gastroc TA Serca-1 wild-type neg. control pos. control PBS ex22 - ex22 TA Wheeler et al., Nature 488: 111, 2012

15 15 Next Step: Demonstrate Reduction of DMPK RNA in Muscle of Different Species

16 Proof of Concept: Marked Reduction of Endogenous mdmpk RNA Levels in Mice by an RNase H Antisense Drug 16 Tibialis Anterior Diaphragm mrna Expression (% PBS) PBS (25 mpk/wk) (50 mpk/wk) (100 mpk/wk) mrna Expression (% PBS) PBS (25 mpk/wk) (50 mpk/wk) (100 mpk/wk) Heart Gastrocnemius mrna Expression (% PBS) PBS (25 mpk/wk) (50 mpk/wk) (100 mpk/wk) mrna Expression (% PBS) PBS (25 mpk/wk) (50 mpk/wk) (100 mpk/wk)

17 Proof of Concept: Reduction of DMPK RNA Levels in Non-human Primates (Cynomolgus Monkey) by an Antisense Drug 17 mrna expression from several monkey tissues mrna Expression (% PBS) PBS ISIS DMPK Drug 20 0 Liver Tibialis Anterior Quadriceps Gastrocnemius Kidney Heart Dose and duration: 40 mg/kg BW; day 1,3,5,7 and then once weekly for the next 12 weeks (total of 16 doses)

18 Proof of Concept: Prolong Duration of Effect with a DMPK Targeting Antisense Drug in Monkey Muscle 18 PBS DMPK Drug 7 weeks DMPK Drug 13 weeks DMPK Drug 19 weeks DMPK Drug 26 weeks

19 19 The Screening Process The Discovery of ISIS-DMPK Rx

20 ISIS-DMPK Rx Partnered with 20 n Generation 2.5 antisense drug Constrained ethyl nucleotide 2 -MOE (methoxyethyl) n Promotes degradation of the mutant DMPK transcript by the RNase H mechanism of action n Delivered by subcutaneous injection ~once per week

21 21 The Stages of Drug Development

22 Preclinical Phase Before Testing in Humans 22 n Characterize potential adverse drug effects Define potential organ or tissue damage induced by the drug Define reversibility of toxicity n Characterize pharmacokinetics Drug levels in blood n Characterize beneficial pharmacodynamic effects Does the drug do anything to the target in the body n Guide safe use in human clinical studies Determine safe and reasonable starting does Provide monitoring guidelines for the clinical study n Provide sufficient data to conclude that patients are not exposed to unreasonable risks

23 ISIS-DMPK Rx IND Enabling Toxicology Summary 23 n Mouse 13 Week repeat-dose study with 13-week recovery n Monkey 13-week repeat dose study and a 13-week recovery n Standard genetic toxicology and safety pharmacology studies n Results from toxicology study support continued development of ISIS-DMPK Rx

24 ISIS-DMPK Rx Phase 1 CS1 Experimental Design - Single Dose 24 Study Objective: to assess the safety and tolerability of ISIS-DMPK Rx in healthy volunteers n Blinded, randomized, placebo-controlled single ascending dose n 4 single dose cohorts (randomized 3 active: 1 placebo); n Doses: 50 mg, 100 mg, 200 mg, 400 mg n Single subcutaneous injection on Day 1, and subjects are followed for 28 days n Primary Endpoints: Safety and Tolerability Pharmacokinetic measures (plasma drug levels)

25 ISIS-DMPK Rx Phase 1 CS1 Single Ascending Dose Results 25 n Phase 1 SAD in Healthy Volunteers completed No safety or tolerability concerns identified Up to 400 mg single dose tested

26 ISIS-DMPK Rx Phase 2 Multiple Dose Study in DM1 Patients 26 n Planned to start late this year in the United States n Drug will be given as a subcutaneous injection n Primary Goals: Safety & Tolerability, and PK n In addition, markers of biological activity and clinical biomarkers will be collected

27 ISIS-DMPK Rx Summary 27 n Antisense drugs demonstrate selectivity for nuclear retained RNAs n Systemic delivery of Gen 2.5 ASOs profoundly inhibited mouse DMPK RNA levels in normal mice and monkeys: treatment was well tolerated n Generation 2.5 antisense drugs have long duration of action in skeletal muscle n ISIS-DMPK Rx Phase 1 single dose study in normal volunteers has been completed n ISIS-DMPK Rx Phase 2 multiple dose study in DM1 patients to start late this year

28 Acknowledgements 28 Dr. Charles Thornton - Univ. of Rochester Dr. Thurman Wheeler - Univ. of Rochester/ Mass General Dr. Richard Moxley - Univ. of Rochester Dr. Jack Puymirat - Laval University Isis Pharmaceuticals Sanjay Pandey Robert Macleod Kathie Bishop Laury Mignon Kristina Bowyer (Lemonidis) Husam Younis Scott Henry Dan Norris Viola Kam Gene Hung Matt Buck