The SMA ProjectThe SMA Project

Jill Heemskerk, PhD

NINDS Office of Translational ResearchJill Heemskerk, PhDJill Heemskerk, PhD

NINDS Office of Translational ResearchNINDS Office of Translational Research

The SMA Project

What is it?• A NIH drug development program for SMA• A rare disease therapeutics experiment

Goal:• At least 1 IND for testing a new drug in SMA patients

What is it?What is it?•• A NIH drug development program for SMAA NIH drug development program for SMA•• A rare disease therapeutics experimentA rare disease therapeutics experiment

Goal:Goal:•• At least 1 IND for testing a new drug in SMA patientsAt least 1 IND for testing a new drug in SMA patients

Rationale for SMA as a Pilot

Defined cause = loss of SMN1 gene

Defined strategy for treatment = SMN2: identical protein, low expression

Compounds that increase SMN2 expression available as starting points

Defined cause = loss of SMN1 geneDefined cause = loss of SMN1 gene

Defined strategy for treatment = SMN2: identical Defined strategy for treatment = SMN2: identical protein, low expressionprotein, low expression

Compounds that increase SMN2 expression Compounds that increase SMN2 expression available as starting pointsavailable as starting points

TranslationalTranslationalBasicBasic ClinicalClinical

ClinicalTrialsTarget ID Assay Hit ID

Proofof

Concept

LeadOptimization

CandidateSelection

Pre-clinicalSafety

SMA Project Focus

SMA Project

MouseModel

Testing

Lead Development Team

Chemical Optimization

In vitro Testing

NINDS

Steering Committee

Pharm/Tox

SAIC Contract Monitors

Lead Development Team

Industry consultants:• John McCall

• Graham Johnson

• Donna Romero

• Paul Pearson

• Tony Bannon

AMRI: • Keith Barnes

NINDS:• Jill Heemskerk

• Amelie Gubitz

SAIC:• Jim Romano

• Sabina Robinson

Industry consultants:Industry consultants:•• John McCallJohn McCall

•• Graham JohnsonGraham Johnson

•• Donna RomeroDonna Romero

•• Paul PearsonPaul Pearson

•• Tony BannonTony Bannon

AMRI: AMRI: •• Keith BarnesKeith Barnes

NINDS:NINDS:•• Jill Heemskerk Jill Heemskerk

•• Amelie GubitzAmelie Gubitz

SAIC:SAIC:•• Jim RomanoJim Romano

•• Sabina RobinsonSabina Robinson

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

Customizing 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

CO2 H

Varied heterocycle

Chemistry GoalsIncrease potency

Eliminate toxicity• Cox Inhibition

Improve BBB penetration

Chemistry GoalsIncrease potency

Eliminate toxicity• Cox Inhibition

Improve BBB penetration

Benzo

October 1, 2009

Chemistry Improves Potency and Activity of Indoprofen

>1000 Indoprofen analogs synthesized and tested

Log concentration (uM)

Max

-fold

in

crea

se in

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

% N

ucle

i with

Gem

s

DMSO

untreate

d

5 mM VPA

10 uM

 vanadate

10 uM

 analog 1

10 uM

 analog 2

10 uM

 analog 3

10 uM

 analog 4

**

**

*

*

Optimized Indoprofen Analogs Increase the Number of Nuclear 

Gems in SMA Type I Patient Fibroblasts

‐V. Mattis, M. Lorson,  C. Lorson

Pt C D Pt C D

Actin

SMN

1 2 3

μ

0.0

0.5

1.0

1.5

2.0

2.5

3814 (parent) 3813 (patient)DMSO 0.1 uM Drug

SMN

:Act

in

Indoprofen Analogs Increase SMN Protein in Patient Fibroblasts:Western Blots

-Brenda Fung, CombinatoRx

DMSO3813 (patient)

Indoprofen Analogs Stimulate Translational Read-through

-Courtesy Ellen Welch, PTC Therapeutics

UGA

+ Compound

- Compound

LuciferaseActivity

AUG UAA

Interrupted Luciferase Construct:

Control

Indoprofen

-E. Welch, A. Bhattacharyya, PTC

Compounds Stabilize SMN∆7 Protein via Translational Readthrough

Indoprofen

Chemical Analogs are Drug-likeBrain:Plasma as high as 10:1Orally bioavailableWell-tolerated in rodentsRodent half lives around 2 hoursExcellent human microsome stabilityFavorable CYP, genotox, broad target profilesAbolished Cox inhibition2 NIH patents

Half-life

Efficacy

Potency

Safety

ChemistryIP

Brain/Plasma

Pharmaceutics

Timeline to Phase I Clinical Trial

1Q ‘10 3Q’102Q’10

28-Day GLP Tox

Formulation Development

4Q’10

ADMEGMP Synthesis

Safety Pharmacology

First in Human Trial

GLP Synthesis

1Q’11

Regulatory Submission

Radio Synthesis

14-Day GLP ToxDose Ranging Tox

200gm Synthesis

Industry Engagement

Industry experience on Steering Committee sets strategy (Robert Pacifici, Chair)

Industry consultants on development team guide work flow (John McCall, Chair)

Industry service providers conduct workIndustry collaboration to identify drug mechanism of action

Goal: Industry licensing of NIH IP to commercialize compounds

Industry experience on Steering Committee sets Industry experience on Steering Committee sets strategy strategy (Robert (Robert PacificiPacifici, Chair), Chair)

Industry consultants on development team guide Industry consultants on development team guide work flow work flow (John McCall, Chair)(John McCall, Chair)

Industry service providers conduct workIndustry service providers conduct workIndustry collaboration to identify drug mechanism of Industry collaboration to identify drug mechanism of actionaction

Goal:Goal: Industry licensing of NIH IP to commercialize Industry licensing of NIH IP to commercialize compoundscompounds

AcknowledgementsNINDS

Amelie Gubitz

SAICSabina Robinson Amy NoeJim Romano

Lead DevelopmentJohn McCallGraham JohnsonPaul PearsonKeith HouckTony Bannon

CombinatoRxJane StauntonBrenda FungYang WangShakira Olanrewaju

AMRI AlbanyKeith BarnesJohn LippertNick MayhewPing ChenSteve SteffkeMichelle Pilato

AMRI BothellSvetlana DobritsaMichelle LucheSangeeta Chitnis

RTIJim MatthewsEd GarnerKimberly Ehman

Lorson LabChris LorsonVirginia MattisMonique Lorson

PTC TherapeuticsEllen WelchNikolai NaryshkinSergey PaushkinAnu Bhattacharyya

Key ContributionsElliot AndrophyJianhua ZhouBrent StockwellCharlotte SumnerArthur BurghesGlenn MorrisMeg WinbergJill Jarecki