Download Program - Cytokinetics

MDA2016_SMA_MDA2016_SMA 3/17/16 12:02 PM Page 1
CK-2127107, A SELECTIVE ACTIVATOR OF THE FAST SKELETAL MUSCLE TROPONIN COMPLEX,
FOR THE POTENTIAL TREATMENT OF SPINAL MUSCULAR ATROPHY
Stacy A Rudnicki1, Jinsy A Andrews1, Fady I Malik1, Andrew A Wolff1, John W Day2
Cytokinetics, Inc. (in collaboration with Astellas Pharma, Inc.); 2Stanford University School of Medicine
1
BACKGROUND
CK-2127107 ACTIVATES
THE
R E S U LT S
FAST SKELETAL TROPONIN COMPLEX
CY 5021: CK-2127107 ADMINISTERED ORALLY
CK-2127107, a selective fast skeletal muscle troponin activator, slows the rate of calcium release from
troponin C, sensitizing the sarcomere to calcium and increasing fast skeletal muscle contractility.
TO
SMA
PATIENTS
Study Objectives
– To evaluate the safety and tolerability
– To determine potential pharmacodynamic effects
Regulatory
Complex
Β-myosin
heavy chain
Myosin
Tension, % of Baseline Max Force
– To evaluate the pharmacokinetics
Sequential dose escalation, randomized, double blind placebo controlled study
100
– Cohort 1: 150 mg bid compared to placebo
80
C O NConclusions
CLUSIONS
– Cohort 2: 450 mg bid (proposed) compared to placebo
• At end of cohort 1, safety, tolerability and pharmacodynamics reviewed to establish dose for
Cohort 2
60
Skinned
Fast Skeletal
Muscle Fiber
40
20 µM CK2127107
2.0 µM CK2127107
Vehicle
20
PATIENT POPULATION
0
10 - 8
10 - 7
10 - 6
10 - 5
[Ca+2]
Conclusions
DISC
LOSURES
10 - 4
– Patients 12 years of age and older
S Rudnicki J Andrews,
F Malik, A Wolff are
employees of Cytokinetics,
Inc. J Day has served as a
consultant to Cytokinetics
– Genetically confirmed spinal muscular atrophy Types II, III, or IV
– 72 patients equally divided between ambulatory and non-ambulatory status
CY 5013: METHODS
FORCE FREQUENCY ASSESSMENT
BY
AND
RATIONALE
EXTERNAL STIMULATION
OF
TIBIALIS ANTERIOR MUSCLE
– Stimulate a nerve-muscle pair (peroneal nerve, anterior
tibialis muscle) via external electrodes
CY 5021: STUDY DESIGN DIAGRAM
– Measure isometric force at multiple nerve stimulation
frequencies
– Reproducible when normalized to response to stimulation
at 50 Hz (tetany)
12 CK-2127107 150 mg BID
18 Ambulatory
– Voluntary contribution minimized
6 Placebo
Cohort 1
(n = 36 Paents)
Electrical smulus
Elicited force
12 CK-2127107 150 mg BID
18 Non-Ambulatory
EMG recording
6 Placebo
12 CK-2127107 450 mg BID*
18 Ambulatory
6 Placebo
Cohort 2
(n = 36 Paents)
Anterior bialis muscle ~ 25% fast (Type II) fibers
12 CK-2127107 450 mg BID*
18 Non-Ambulatory
6 Placebo
CY 5013: TRANSLATION OF MECHANISM INTO HUMANS
FREQUENCY AND CONCENTRATION DEPENDENT FORCE INCREASES
*or lower, pending the review of data from Cohort 1
CY 5021: STUDY DESIGN DIAGRAM
– Screening: up to 3 weeks
– Dosing: 8 weeks
– Follow-Up: 4 weeks after last dose
Randomizaon
2:1
Day
1
End of
Week 1
Screening
(up to 3 weeks)
End of Dosing
End of
Week 2
End of
Week 4
Double-Blind, Placebo-Controlled
(8 weeks)
CK-2127107: PHASE I CLINICAL TRIALS PROGRAM
STUDY #
CY 5011
CY 5012
CY 5013
CY 5014
CY 5015
N
35
24
16
Program
TRIAL OBJECTIVE
Approximately 15 Weeks
RESULTS
Assess safety and tolerability;
Evaluate pharmacokinetics
(increasing single doses)
Achieved highest planned dose;
No emerging pattern of adverse events;
Well tolerated
Assess safety, tolerability and
pharmacokinetics in healthy
young and elderly (multiple dose)
10-day courses of either 300 mg or 500 mg twice
daily were well tolerated by young and older
subjects;
Plasma concentrations achieved steady state;
No age-related differences in PK
Assess pharmacodynamic effects
Based on safety, pharmacokinetics, and pharmacodynamics findings in
Phase 1 studies, a Phase
2a clinical trial of
CK-2127107 is currently
enrolling patients in
the US
Statistically significant increases
(versus placebo) in peak force;
Well tolerated
24
Assess pharmacokinetics of two
different physical forms of API in
suspension
Well tolerated at 300 mg and 1000 mg;
Physical form selected
24
Assess pharmacokinetics of a
tablet formulation;
Fed vs. fasted
Well tolerated at 250 mg, 500 mg and 1000 mg;
Tablet appropriate for use in potential future
clinical trials
5 Phase I Clinical Trials Enrolling > 100 Healthy Subjects
Well Characterized Safety, Tolerability, PK/PD during Oral Administration
OUTCOME MEASURES
Respiratory
– Forced Vital Capacity
– Maximum Inspiratory Pressure
– Maximum Expiratory Pressure
Motor evaluations
– Hand held dynamometry
– Revised upper limb module (RULM)
– Hammersmith (HFMS-E) test
– Timed Up and Go (TUG)
– Six-minute walk test (6MWT)
Safety Monitoring
Pharmacokinetics
FU
End of
Week 8
Follow-up
(4 weeks)