Interim Results of a Phase 2 Study of ISIS-SMN

Interim Results of a Phase 2 Study of ISIS-SMNRx
in Children with Spinal Muscular Atrophy
Darras, B1; Chiriboga, C2; Swoboda, K3; Iannaccone, S4;
Montes, J2; Castro, D4; Holuba, N2; Rausch, N3; Ramos,
C3; Visyak, N1; Dunaway, S2; Trussell D3; Pasternak, A1;
Neilson, L4; De Vivo, D2; Norris, D5; Bennett, F5; Bishop, K5
1 – Boston Children’s Hospital; 2 – Columbia University Medical
Center; 3 – University of Utah; 4 – UT Southwestern Medical Center;
5 – Isis Pharmaceuticals, Inc.
ISIS-SMNRx: Modulating Splicing of SMN2 to Increase
Normal SMN Protein
2
HO
 Uniformly 2’-O-methoxyethyl modified (MOE) antisense drug
O
 Corrects the splicing disorder in SMN2, resulting in the
production of fully functional SMN protein in model systems
O
S P
O
O
 In mild and severe mouse models of SMA provides a phenotypic
and pathological benefit when delivered centrally*
 Distributes broadly to spinal cord motor neurons after
intrathecal delivery in monkeys*
B
O
OCH3
O
O
B
O
OCH3
 Has a long half life in CNS tissue (>6 months in animal models)
SMN2 Gene
SMN2 Gene
C to T
C to T
1
2a
2b
1
2
3
2
3
4
4
5
5
6
6
7
8
8
SMN2 mRNA
Defective Protein, missing exon 7
1
2b
2a
1
22
3
4
6
5
7
8
ISIS-SMNRx
3
4
5
6
7
8
SMN2 mRNA
Functional Protein
*(Hua et al., Genes Dev., 2010; Passini et al., Sci Transl Med, 2011; Hua et al., Nature, 2011)
Clinical Program for ISIS-SMNRx
3
 Granted Orphan Drug Status in US and EU and Fast Track
Designation in US
 Phase 1 Single-dose Study in Children with SMA - completed
 Phase 1b/2a Multiple-dose Study in Children with SMA - ongoing
 Phase 2 Multiple-dose Study in Infants with SMA - ongoing
 Two pivotal, controlled studies planned to start in 2014
-
Phase 3 study in Infants with SMA
-
Phase 3 study in Children with SMA
Completed Phase 1 Open-label, Single-dose Study in SMA Patients,
Including Long-term Follow-up at 9-14 Months Post-Dose
4
 Single dose given intrathecally as an LP bolus injection in male and female Type
2 and Type 3 SMA patients 2-14 years old who were medically stable
 No safety or tolerability concerns identified with single doses up to 9 mg
 Dose and time dependent Increases in HFMSE scores observed - increase of 5.75
points at 9-14 months in 9 mg group
Mean ± SEM
5.75 (p=0.008)
2.5
0.5
-1.7
Phase 2 Multiple-Ascending Dose, Open-Label Study in
Medically Stable SMA Patients 2-15 Years of Age (Ongoing)


Objectives:

Evaluate the safety and tolerability of multiple intrathecal doses of ISIS-SMNRx

Evaluate CSF, plasma PK, and clinical outcomes related to SMA (including HMFSE)
Status:

3 mg, 6 mg, and 9 mg cohorts completed; 12 mg cohort currently ongoing
Cohort
Total
Dose
n
3 mg
9 mg
8
6 mg
18 mg
8
9 mg
18 mg
9
12 mg
36 mg
9
Post-Treatment
f/u Period
24 weeks
Open
Label
Screening
(≤28 days)
Day 1
Dose
SUBJECT DEMOGRAPHICS
SMA Type
Ambulatory/Non-ambulatory
Mean age (range)
SMN2 Copy #
Day 29
f/u &
Dose
Day 85
f/u &
Dose
N=25
Type 2 = 10; Type 3 = 15
9/16
7.5 years (2-15)
2 copies = 1; 3 copies = 20; 4 copies = 4
Dose and Time Dependent Increases in HFMSE Scores
after Multiple Doses of ISIS-SMNRx
*
*
3.7
2.3
1.5
Last Dose
Study Month
Mean + SEM,
*p<0.05 compared to BL
Increases in HFMSE Scores Observed for Prolonged
Time After Last Dose of ISIS-SMNRx in SMA Children
 Patients who participated in Phase 2 multi-dose study enrolled in open-label
extension study and completed their baseline assessment
*
3.2
2.3
1.7
Last Dose
*Graph does not include one patient from the 3 mg cohort who underwent spinal surgery between D92 and D169, which
caused an immediate 6 point decline in HFMSE.
Additional Measurements of Motor Function (6MWT and
ULM) Are Consistent With Increases Observed in HMFSE
 Six Minute Walk Test (6MWT)
Study
N
Phase 2
9
OLE - Baseline Visit
10
Follow-up from
Baseline
Baseline
(+SEM)
Increase from
BL (+SEM)
9 months
230.8 m
(31.4 m)
22.7 m
(12.3 m)
12-16 months
207.7 m
(36.3 m)
24.4 m
(9.4 m)
 Upper-limb Module (ULM)
Study
N
Phase 2
10
OLE - Baseline Visit
7
Follow-up from
Baseline
Baseline
(+SEM)
Increase from
BL (+SEM)
9 months
10.5 m
(1.0 m)
2.3 m
(0.9 m)
11-16 months
9.7 m
(1.1 m)
3.1 m
(1.4 m)
8
SMN Protein Increased >2 Fold in CSF of SMA Children
After Single Doses of 9 mg of ISIS-SMNRx
 In multi-dose study, SMN protein increase of 115% (p=0.004,
n=9) observed at 3 months
 In single-dose study, SMN protein increase of 160% (p=0.09,
n=6) observed at ~ 1 year
ISIS-SMNRx Safety and Tolerability Profile in SMA Children
Supportive of Continued Development
 Exposure to ISIS-SMNRx

56 children dosed, doses up to 12 mg

Total of 183 intrathecal (IT) injections
 Safety and tolerability

No ISIS-SMNRx-related serious adverse events (SAEs)

Most adverse events mild or moderate in severity and considered not
related to drug

No study drug related changes in CSF safety labs or neurological
exams

No change in safety profile with repeated doses (most children have
received 3-5 injections)

The LP injection procedure in children with SMA has been well
tolerated and shown to be feasible
Summary of Results to Date in Studies in Children with
SMA
11
 ISIS-SMNRx has been well tolerated when given as multiple doses up
to 12 mg - no safety or tolerability concerns have been identified
 CSF and drug concentrations are dose-dependent and consistent with
predictions; CSF half-life is about 4-6 months
- Observations support infrequent administration
 Dose and time dependent increase in HFMSE scores observed (even
8-13 months after last dose)
 Additional secondary endpoints (6 MWT, ULM) supportive, although
open-label study and small numbers limit interpretation
 Treatment with ISIS-SMNRx increased CSF SMN protein levels
- Observation supports biological mechanism and is consistent with preclinical and
clinical data
 These data inform the design of a planned Phase 3 registrationenabling study in children with SMA
ISIS-SMNRx Phase 3 Study in SMA Infants – ENDEAR
(ongoing)
 A Phase 3, randomized, double-blind, sham-procedure controlled study
in infants with SMA

Global study in ~110 SMA infants ≤ 7 months old with 2 copies of SMN2

13 month study duration

Evaluate the efficacy and safety of ISIS-SMNRx

Primary efficacy endpoint is time to death/permanent ventilation

Additional efficacy endpoints include CHOP INTEND and motor milestones
 Study initiated August 2014
Study
Complete
2:1
Cohorts
Sham control
12 mg ISIS-SMNRx
≤21 days
Screening
R
2 months
11 months
4 Induction Doses
Maintenance Dose
Every 4 Months
M13
Last
Visit
OLE
ISIS-SMNRx Phase 3 Study in SMA Children - CHERISH
 A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study
in Children with SMA

Global study in ~120 SMA children with SMA

15 month study duration

Determine the efficacy and safety of ISIS-SMNRx

Primary endpoint is change in Hammersmith motor function score
 Planned 2014 initiation
Cohorts
Sham control
12 mg ISIS-SMNRx
Study
Complete
2:1
≤28 days
Screening
R
3 Induction Doses
Maintenance Dose
6 Months Later
M15
Last
Visit
OLE
Acknowledgements
14
University of Utah
Sandra Reyna
Ai Sakonju
Abby Smart
Michael Worman
Columbia University
Jose Garcia
Jonathan Marra
Douglas Sproule
Louis Weimer
Boston Children’s Hospital
Robert Graham
Wendy Liew
Rebecca Parad
Elizabeth Shriber
Peter Kang
UT Southwestern
Stephanie Trest
Margaret Cowie
ISIS 396443-CS2 DSMB
Walter Bradley, Chairperson
Anne Connolly
Patricia Dickson
Stephen Reingold
Isis Pharmaceuticals
Katie Alexander
Matt Buck
Shannon Fine
Katherine Kwoh
Laury Mignon
Dan Schulz
Mason Yamashita
Dawn McGuire
Biogen Idec
SMA Foundation
Families of SMA
The patients and families who participated in the study