New Compounds for
Spinal Muscular Atrophy
CONFIDENTIAL
Jill Heemskerk, PhD
Office of Translational Research
National Institute of Neurological Disorders and Stroke
Why NIH Chose SMA for a Drug Development Pilot

Urgent unmet medical need
• Number one genetic killer of infants
• Incidence: 1 in 6000 live births
• No available treatments

Scientific opportunity
• Known cause = loss of SMN1 gene
• Defined treatment strategy: increase SMN2
• Compounds identified that increase SMN2 in vitro
Indoprofen:
Starting Point for Medicinal Chemistry
O
Me
N
OH
O


Indoprofen increases SMN protein in vitro:
•
•
SMN reporter assay
SMN protein in patient fibroblasts
Indoprofen improves in utero survival of
SMA mice
-B. Stockwell: Lunn et al, 2004
Optimizing Indoprofen for SMA
Chemistry Goals

O
Increase potency
CH3

Eliminate toxicity
•

N
Cox Inhibition
OH
Improve BBB penetration
O
Lactam
Phenyl
Varied Substitutions:
heterocycle alkyl, halo,
Benzo
methoxy, aryl,
Substitutions:
heteroaryl
alkyl, halo,
methoxy,
cyano, amino,
CONFIDENTIAL
aryl, heteroaryl
Acetic Chain
Varied at
methyl site,
length of
chain, and
CO2H
Chemistry Improves Potency and Activity
Androphy/Zhou
SMN-2 reporter assay
ex6
ex7
ex8
Luciferase
luminescence
2.0
Indoprofen
P407923
1.8
1.6
~1300 Indoprofen analogs
synthesized and tested
1.4
1.2
1.0
0.8
-6
-5
-4
-3
-2
-1
0
1
Log concentration (µM)
-AMRI
CONFIDENTIAL
SMA Project Compounds Increase SMN-containing Gems in Patient Fibroblasts
Untreated
5mM VPA
Confidential
100nM SP869
M. Lorson,
University of Missouri
SMA Project Compounds Increase SMN Protein in Patient Fibroblasts:
Western Blots
2.5
SMN:Actin
2.0
1.5
1.0
0.5
1
2
3
Carrier
Patient
Patient
DMSO
DMSO
0.0
0.1 uM Drug
m
Pt
C
D
Pt
C
D
SMN
Actin
CONFIDENTIAL
Brenda Fung,
CombinatoRx
SMA Project Compounds Stimulate Translational Read-through
Stop codon interrupts Luciferase:
AUG
UAA
UGA
Luciferase
Activity
- Compound
+ Compound
-Courtesy Ellen Welch, PTC Therapeutics
CONFIDENTIAL
SMA Project Compounds Induce Translational Read Through
Positive Control
Indoprofen
-E. Welch, A. Bhattacharyya
PTC Therapeutics
CONFIDENTIAL
Indoprofen Chemical Analogs are Drug-like
PK:
 Good brain penetrance
 Orally bioavailable
 Rodent half lives around 2 hours
 Excellent human microsome stability
Tox:
 Well-tolerated in rodents (up to 50mg/kg, neonatal mice, 14 day dosing)
 Favorable CYP, genotox, hERG, broad target profiles
 Abolished Cox inhibition
IP:
Half-life
Safety
Pharmaceutics
 2 NIH patents
cover composition of matter
Potency
IP
CONFIDENTIAL
Brain/Plasma
Efficacy
Chemistry
SMA Project
FLOW PLAN
August
2010
Candidate
Confidential
Timeline to Phase I Clinical Trial
3Q ‘10
4Q’10
1Q’11
2Q’11
3Q’11
200gm Synthesis
GLP Synthesis
Radio Synthesis
Dose Ranging Tox
14-Day GLP Tox
28-Day GLP Tox
Safety Pharmacology
ADME
GMP Synthesis
Formulation Development
Regulatory Submission
First in Human Trial
12
CONFIDENTIAL
Acknowledgements

Lead Development













Sabina Robinson
Jim Romano




Jane Staunton
Brenda Fung
Yang Wang
Shakira Olanrewaju
AMRI Bothell


CombinatoRx


Keith Barnes
John Lippert
Nick Mayhew
Ping Chen
Steve Steffke
Michelle Pilato
Svetlana Dobritsa
Michelle Luche
Sangeeta Chitnis
RTI



Jim Matthews
Ronnie Maitra
Kimberly Ehman
Lorson Lab

AMRI Albany

Amelie Gubitz
SAIC


John McCall
Graham Johnson
Paul Pearson
Keith Houck
Tony Bannon
NINDS







PTC Therapeutics





Chris Lorson
Virginia Mattis
Monique Lorson
Ellen Welch
Nikolai Naryshkin
Sergey Paushkin
Anu Bhattacharyya
Key Contributions








Elliot Androphy
Jianhua Zhou
Brent Stockwell
Charlotte Sumner
Arthur Burghes
Glenn Morris
Meg Winberg
Jill Jarecki