New Compounds for New Compounds for Spinal Muscular AtrophySpinal Muscular Atrophy

Jill Heemskerk, PhDJill Heemskerk, PhDOffice of Translational ResearchOffice of Translational Research

National Institute of Neurological Disorders and StrokeNational Institute of Neurological Disorders and Stroke

Jill Heemskerk, PhDJill Heemskerk, PhDOffice of Translational ResearchOffice of Translational Research

National Institute of Neurological Disorders and StrokeNational Institute of Neurological Disorders and Stroke

CONFIDENTIAL

Why NIH Chose SMA for a Drug Development Pilot

Urgent unmet medical need Urgent unmet medical need • Number one genetic killer of infantsNumber one genetic killer of infants

• Incidence: 1 in 6000 live birthsIncidence: 1 in 6000 live births

• No available treatmentsNo available treatments

Scientific opportunityScientific opportunity• Known cause = loss of SMN1 geneKnown cause = loss of SMN1 gene

• Defined treatment strategy: increase SMN2 Defined treatment strategy: increase SMN2

• Compounds identified that increase SMN2 in vitroCompounds identified that increase SMN2 in vitro

Urgent unmet medical need Urgent unmet medical need • Number one genetic killer of infantsNumber one genetic killer of infants

• Incidence: 1 in 6000 live birthsIncidence: 1 in 6000 live births

• No available treatmentsNo available treatments

Scientific opportunityScientific opportunity• Known cause = loss of SMN1 geneKnown cause = loss of SMN1 gene

• Defined treatment strategy: increase SMN2 Defined treatment strategy: increase SMN2

• Compounds identified that increase SMN2 in vitroCompounds identified that increase SMN2 in vitro

Indoprofen: Starting Point for Medicinal Chemistry

Indoprofen increases SMN protein in vitro:• SMN reporter assay

• SMN protein in patient fibroblasts

Indoprofen improves in utero survival of SMA mice

N

O

OH

Me

O

-B. Stockwell: Lunn et al, 2004

Optimizing Indoprofen for SMA

N

O

CH3

O

OH

Lactam Phenyl Acetic Chain

Substitutions: alkyl, halo, methoxy,

cyano, amino, aryl, heteroaryl

Substitutions: alkyl, halo,

methoxy, aryl, heteroaryl

Varied at methyl site,

length of chain, and

CO2H

Varied heterocycle

Chemistry Goals

Increase potency

Eliminate toxicity

• Cox Inhibition

Improve BBB penetration

Chemistry Goals

Increase potency

Eliminate toxicity

• Cox Inhibition

Improve BBB penetration

Benzo

CONFIDENTIAL

Chemistry Improves Potency and Activity

~1300 Indoprofen analogs synthesized and tested

Log concentration (µM)

lu

min

esce

nce

-6 -5 -4 -3 -2 -1 0 10.8

1.0

1.2

1.4

1.6

1.8

2.0

IndoprofenP407923

CONFIDENTIAL

ex6 ex8ex7 LuciferaseAndrophy/ZhouSMN-2 reporter assay

-AMRI

Untreated 5mM VPA 100nM SP869

SMA Project Compounds Increase SMN-containing Gems in Patient Fibroblasts

M. Lorson,University of MissouriConfidential

Pt C D Pt C D

Actin

SMN

1 2 3

0.0

0.5

1.0

1.5

2.0

2.5

CarrierDMSO

PatientDMSO 0.1 uM Drug

SM

N:A

ctin

SMA Project Compounds Increase SMN Protein in Patient Fibroblasts:Western Blots

Patient

Brenda Fung, CombinatoRxCONFIDENTIAL

SMA Project Compounds Stimulate Translational Read-through

-Courtesy Ellen Welch, PTC Therapeutics

UGA

+ Compound

- Compound

LuciferaseActivity

AUG UAA

Stop codon interrupts Luciferase:

CONFIDENTIAL

Positive Control

Indoprofen

-E. Welch, A. Bhattacharyya PTC Therapeutics

SMA Project Compounds Induce Translational Read Through

CONFIDENTIAL

Indoprofen Chemical Analogs are Drug-likePK: Good brain penetrance Orally bioavailable Rodent half lives around 2 hours Excellent human microsome stabilityTox: Well-tolerated in rodents (up to 50mg/kg, neonatal mice, 14 day dosing) Favorable CYP, genotox, hERG, broad target profiles Abolished Cox inhibitionIP: 2 NIH patentscover composition of matter

Half-life

Efficacy

Potency

Safety

ChemistryIP

Brain/Plasma

Pharmaceutics

CONFIDENTIAL

SMA ProjectFLOW PLAN

Candidate

August2010

Confidential

Timeline to Phase I Clinical Trial

3Q ‘10 1Q’114Q’10

28-Day GLP Tox

Formulation Development

2Q’11

ADME

GMP Synthesis

Safety Pharmacology

First in Human Trial

GLP Synthesis

3Q’11

Regulatory Submission

Radio Synthesis

14-Day GLP Tox

Dose Ranging Tox

200gm Synthesis

CONFIDENTIAL12

Acknowledgements Lead Development

John McCall Graham Johnson Paul Pearson Keith Houck Tony Bannon

NINDS Amelie Gubitz

SAIC Sabina Robinson Jim Romano

CombinatoRx Jane Staunton Brenda Fung Yang Wang Shakira Olanrewaju

AMRI Albany Keith Barnes John Lippert Nick Mayhew Ping Chen Steve Steffke Michelle Pilato

AMRI Bothell Svetlana Dobritsa Michelle Luche Sangeeta Chitnis

RTI Jim Matthews Ronnie Maitra Kimberly Ehman

Lorson Lab Chris Lorson Virginia Mattis Monique Lorson

PTC Therapeutics 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