ISIS-DMPK Rx: An Antisense Drug for The Treatment of Myotonic Dystrophy Type 1 - C. Frank Bennett Ph.D. Senior Vice President of Research
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
ISIS-DMPKRx: An Antisense Drug for The Treatment of Myotonic Dystrophy Type 1 C. Frank Bennett Ph.D. Senior Vice President of Research
Agenda
2
n Stages of Drug Development
n Drug Development Strategies for Myotonic
Dystrophy
n Introduction to Antisense Technology
n ISIS-DMPKRx:
¤ Why we are excited about the drug
¤ Where we are in the development process
Isis Pharmaceuticals │ Confidential Advances in Technology_SCrooke_070212
The Stages of Drug Development
3
ISIS-DMPKRx
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
Federal, Public & Company Roles in Research & Development
5
Government, Foundation Supported, Pharmaceutical Industry
Research are Complementary
Pharmaceutical Research
“
There is an ecosystem
Clinical Clinical Research of science and
Research biotechnology. Public
organizations, patient
Translational organizations,
Research Translational universities, Congress,
Research FDA, all of this is an“
ecosystem that is
envied in the rest of the
Basic
Basic Research Research
world.
– E. Zerhouni,
Director of NIH
Government (e.g. NIH)
and Public (e.g. MDF)
Supported Research
1st Clue → What to Target?
DM is Caused by a 3 Nucleotide Expansion in the DMPK Gene
6
2nd Clue → Nucleotide Expansion Sequesters Proteins
A Gain of Function Toxic RNA
7
DMWD DMPK SIX5
DNA
pre-mRNA
mRNA
RIBONUCLEAR FOCI RNA BINDING PROTEIN ABERRANT mRNA DM1 CLINICAL
DYSREGULATION SPLICING FEATURE
Chloride Channel Myotonia
MBNL Insulin Receptor Insulin Insensitivity
Cardiac Troponin T ?Cardiac Arrhythmia
Tau Protein ?CNS Effects
CUG-BP
Myotubularin ?Myopathic Effects
? Cataracts
? Testicular Failure
? Hypogammaglobulinemia
6
How to Target?
Antisense Drugs
8
How Genetic Information Flows From in DNA to Protein
The “Central Dogma” of Molecular Biology
9
Gene mRNA
Disease-Causing
Protein
Transcription Translation
DISEASE
Antisense Drugs Target RNA, not Proteins
10
Gene (DNA) mRNA
Antisense Drug
Inhibition of RNA function
Disease-Causing
Protein
Transcription Translation
X 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 platformsThe Antisense Drug-Receptor Interaction
11
Antisense
Drug RNA Target
p ~16-20 base pairs required for specificityAntisense Drugs
Chemical Modifications Produce Desired Effects in the Body
12
12
Commonly Used Chemical Modifications for Antisense DrugsISIS-DMPKRx: Promotes Degradation of the Toxic DMPK RNA
An RNase H Mechanism of Action
13
13
13Proof of Concept Studies:
Systemic Delivery of Antisense Drug Reverses Myotonia and
Spliceopathy in a Mouse Model of DM1 (HSA-LR)
14
6
(Normalized to 18S RNA)
PBS
HSA-LR mRNA Level
4 190403
445236
445238
2
0
d
TA
c
ro
ua
t
Q
as
G
Serca-1
neg. control
pos. control
wild-type
PBS 190403 445238 445236
+ ex22
- ex22 TA
Wheeler et al., Nature 488: 111, 2012Next Step:
Demonstrate Reduction of DMPK RNA in Muscle of Different Species
15Proof of Concept:
Marked Reduction of Endogenous mDMPK RNA Levels in Mice by
an RNase H Antisense Drug
16
Tibialis Anterior Diaphragm
120 120
mRNA Expression (% PBS)
mRNA Expression (% PBS)
100 100
80 80
60 60
40 40
20 20
0 0
PBS 486178 (25 486178 (50 486178 (100 PBS 486178 (25 486178 (50 486178 (100
mpk/wk) mpk/wk) mpk/wk) mpk/wk) mpk/wk) mpk/wk)
Heart Gastrocnemius
120 140
mRNA Expression (% PBS)
mRNA Expression (% PBS)
100 120
100
80
80
60
60
40
40
20 20
0 0
PBS 486178 (25 486178 (50 486178 (100 PBS 486178 (25 486178 (50 486178 (100
mpk/wk) mpk/wk) mpk/wk) mpk/wk) mpk/wk) mpk/wk)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
140
120
100
mRNA Expression (% PBS)
80
PBS
60 DMPK
ISIS Drug
486178
40
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)Proof of Concept:
Prolong Duration of Effect with a DMPK Targeting Antisense Drug
in Monkey Muscle
18
PBS DMPK Drug DMPK Drug DMPK Drug DMPK Drug
7 weeks 13 weeks 19 weeks 26 weeksThe Screening Process
The Discovery of ISIS-DMPKRx
19Partnered with
ISIS-DMPKRx
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 weekThe Stages of Drug Development 21
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 risksISIS-DMPKRx
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-DMPKRxISIS-DMPKRx Phase 1
CS1 Experimental Design - Single Dose
24
Study Objective: to assess the safety and tolerability of
ISIS-DMPKRx 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)ISIS-DMPKRx 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 testedISIS-DMPKRx 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 collectedISIS-DMPKRx
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-DMPKRx Phase 1 single dose study in normal volunteers
has been completed
n ISIS-DMPKRx Phase 2 multiple dose study in DM1 patients to
start late this yearAcknowledgements
28
Dr. Charles Thornton - Univ. of Rochester Isis Pharmaceuticals
Dr. Thurman Wheeler - Univ. of Rochester/ Mass General Sanjay Pandey
Dr. Richard Moxley - Univ. of Rochester Robert Macleod
Dr. Jack Puymirat - Laval University
Kathie Bishop
Laury Mignon
Kristina Bowyer
(Lemonidis)
Husam Younis
Scott Henry
Dan Norris
Viola Kam
Gene Hung
Matt BuckYou can also read
