how to do translational neurology and drug discovery in ... · small molecule therapeutics cns...

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Barbara Slusher, PhD, MAS

Professor, Neurology, Psychiatry, and

Neuroscience

Director, Johns Hopkins Drug Discovery

July 2015

How to do Translational Neurology and Drug Discovery

in Academia?

Topics to Cover

� What it takes to discover and develop a new drug? Quiz

� Changing Ecosystem of Drug Discoverywhat has changed?

� What’s unique about doing drug discovery in academia?

� Example of an academic drug discovery centerand an academic/Pharma collaborative project

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Drug Discovery and Development

�Average TIME from discovery to market new drug?

�Average COST to discover and market new drug?

�Average SUCCESS RATE?

QUIZ

Drug Discovery and Development

�Average TIME from discovery to market new drug?

15-20 YEARS

�Average COST to discover and market new drug?

$1-2 BILLION

�Average SUCCESS RATE?< 2%

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Costs are $264 M per drug approved

Phase of Discovery/Development Average cost

($ M)Target to Drug Screening Hit 1

Screening Hit to Lead 2.5

Lead to Clinical Candidate 10

Candidate to IND filing 5

Phase 1 15

Phase 2 40

Phase 3 150

NDA filing / Launch 40

Market 264

But not all projects succeed and there is a cost of attrition

Phase

Average cost

per project

($ M)

Average

success

rate

# projects

per launch

Cumulative cost of

phase per launch

($ M)

Target to Hit 1 80% 64 64

Hit to Lead 2.5 75% 51 129

Lead to Candidate 10 85% 39 386

Candidate to IND 5 69% 33 164

Phase 1 15 54% 23 339

Phase 2 40 18%* 12 488

Phase 3 150 50%* 2.2 330

NDA / Launch 40 91% 1.1 44

Market 264 1 $1,943

Data from Nat. Rev. Drug Discovery 9, 203 (2010)*Updated for Phase 2 and 3 from J. Arrowsmith at Nat. Rev. Drug Discovery (2011)

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Drug Discovery Drug Development

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What takes so long?

1000’s compounds

100’s 5-10

Why do we fail so often?

Lessons learned from the fate of AstraZeneca’s drug pipelineNature Reviews Drug Discovery

Vol 13 pg 419, June 2014

Pfizer: “in the majority of efficacy failures, it was not possible to conclude if the mechanism had been adequately engaged”. More PK/PD,

exposure, PET, biomarkers, functional

pharmacology needed

Drug Discovery Today Vol 17, No9/10

May 2012

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What does it mean for you?

Cost to discover and develop the drug

Cost to discover and develop the failed drugs

Cost of making the drug

Topics to Cover





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Pharma:Business Model Under Challenge

Approved drugs per $1B spent is 50-fold worse than 30 yrs ago

Scannell et al Nat Rev Drug Discovery 11, 191 (2012)

� $130B of patented sales to face generics by 2016 (57% of 2010 US sales)

� >50K jobs lost / reduced internal research efforts

CNS Programs in Pharma 2009 vs 2014: 267 to 129 programs

Abbott/AbbVie 17 10

AstraZeneca 21 7

Bristol-Myers Squibb 12 2

Glaxo SmithKline 40 14

Johnson & Johnson 18 17

Lilly 16 9

Merck/Schering-Plough 32 7

Novartis 14 15

Pfizer/Wyeth 46 15

Roche/Genentech 22 21

Sanofi/Genzyme 29 12

Includes discovery, preclinical, and clinical drug development programs

Pharma: Dramatic decline in number of CNS

programs past 5 years

Choi et al., Neuron 84:554–563

(Nov. 5, 2014)

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Pharma: Rise of Open Innovationenhancing collaborations, shared risk

Closed Innovation 20th century

Secretive, intramural

Open Innovation 21st century

Porous, world is our lab

�NIH Roadmap; Translational Research–Clinical and Translational Science Awards (CTSA)

–Molecular Libraries Program

–Rapid Access to Interventional Development (RAID)

–Cures Acceleration Network (CAN)

�National Center for Advancing Translational Sciences (NCATS)

–Catalyze public-private translational research

–Repurposing Drugs

–Rare Disease Therapeutics

–Re-engineering Translational Sciences

�Although NIH 2014 budget is flat, NCATS increased by 14%

NIH: increasing efforts in drug discovery and translation

“Initiatives designed to transform the Nation’s medical

research capabilities and improve the translation of research into practice”

E. ZERHOUNI

F. COLLINS

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*Approx. 6 centers; Based upon Academic Drug Discovery Consortium (ADDC) Membership

Academia: Drug Discovery Centers in 1990


*Approx. 17 centers; Based upon Academic Drug Discovery Consortium (ADDC) Membership

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*Approx. 100 centers; Based upon Academic Drug Discovery Consortium (ADDC) Membership, Molecular Libraries Program, and CTSA catalog


Academic-Industrial Partnerships On the Rise

diabetes painCNS

Parkinson’s T cell therapy

diabetes

antibiotics

Elan

Alzheimer’s

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Not just 1:1 Partnerships broad alliances, new programs

� embedding into academic space

– State-of-the-art laboratories and incubators in Boston, CA, NY, Texas

� - to bring academic ideas to pre-clinical proof of concept

–$90 million; led by P Schultz; close to UCSD, Scripps, Salk Institute

�Abbott, BMS, GSK, Janssen, Sanofi, Pfizer, AstraZeneca, and Lilly - made 58 of their abandoned clinical compounds available to academics through NCATS

–Discovering New Therapeutic Uses for Existing Molecules Pilot Program

Topics to Cover





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Survey Results: Academia and Pharma have distinct strengthens

52.73%

23.64%

16.36%

3.64%

3.64%

Medicinal Chemistry

40%

34.55%

18.18%

7.273%

Assay Development and Screening

25.45%

20%

20%

23.64%

10.91%

Organizational Commitment & Stability

1.82%3.64%

30.91%

40%

23.64%

Aligned with Needs and Values of Society

1.82%

5.45%

21.82%

40%

30.91%

Innovation

3.64%16.36%

41.82%

38.18%

Disease Expertise

Comparison Between Industry and Academia

much better in industry

somewhat better in industry

about the same

somewhat better in academia

much better in academia

Survey of 78 US drug discovery centers

Nature Reviews

Drug Discovery,

June 2011, 409-10.

Academic Drug Discovery

ADVANTAGES� Academia has long-term focus

Unparalleled depth of knowledge on specific

diseases/targets

� Climate of creativity / innovationCould lead to diversified drug discovery approaches

� Less time/market pressuresFreedom to tackle complex, risky problems, orphan and

3rd world diseases

� Enhanced clinical interactionsMany team members are physician-scientists who treat

patients in field of interest

� Access to new biology, tools, animal models

CHALLENGES� Funding

� reliance on grants with long cycle times, philanthropy, partnerships

� Reward System� Independent scientist, not team orientation

� Hypothesis-driven scholarly research, not product development

� Timely publications which can compromise patent strategy

� Chemical libraries� less diverse and proprietary

� Unrealistic expectations/lack of expertise

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Academic Drug Discovery

CHALLENGES�Funding

grants with long cycle times, philanthropy, partnerships

�Reward SystemIndependent scientist, not team orientation

Hypothesis-driven scholarly research, not product

development

�Publication can compromise patent strategy

�Chemical librariesless diverse and proprietary

�Unrealistic expectations/lack of expertise

ADVANTAGES� Academia has long-term focus

Unparalleled depth of knowledge on specific diseases/targets

� Climate of creativity / innovationCould lead to diversified drug discovery approaches

� Less time/market pressuresFreedom to tackle complex, risky problems, orphan and 3rd

world diseases

� Enhanced clinical interactionsMany team members are physician-scientists who treat patients in field of interest

� Access to new biology, tools, animal models

Topics to Cover




� Example of an academic drug discovery centerand collaborative project with Pharma

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Johns Hopkins’ Brain Science Institute (BSi)

Started from a philanthropic pledge $100M from an anonymous donor

Mission of BSi� Solve fundamental BASIC SCIENCEquestions about brain development/function and to use these insights to understand the mechanisms of brain disease

� Aide in the TRANSLATION of these basic science discoveries into small molecule therapeutics

CNS DrugsValley of Death

Basic Science Clinic

Drug discovery team from Pharma moved to Brain Science Institute in 2010

� MGI Pharma (Baltimore) acquired for $3.8B by Eisai

� Team of drug discovery scientists left Eisai and joined Bsi� Medicinal Chemists, Drug Metabolism, Pharmacokinetics, Assay Developers,

Screening, Animal Pharmacology, Toxicology

NEW JOB: Work collaboratively with faculty to translate Hopkins’ brain discoveries into clinical therapeutics

Drug Discovery Center Expertise

Novel

Drug Target

Identification

JHU Faculty

Expertise

Drugability

Evaluation HTSHit to

Lead

Lead

Optimization

Candidate

Selection

JHU Faculty

Expertise

Clinical

Trials

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Drug Discovery Capabilities

Assay

Development

and Screening

Molecular

Modeling

Protein

Purification

Medicinal

Chemistry

Drug metabolism

and

Pharmacokinetics

Animal

Pharmacology/Toxicology

� ~20 STAFF� Average of 15 years PHARMA experience drug discovery

� Support translational activities on campus

� Training and education

� Commercialization

� Secured external funding

� Founded Academic Drug Discovery Consortium

� Collaborative drug discovery

Johns Hopkins Drug Discovery first 5 years….

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Provided translational services to >90 faculty (2010-2014)

Neurology

Psychiatry

Neurosurgery

Neuroscience

Gastroenterology

Oncology

Ophthalmology

Immunology

Pathology

Biophysics

BCMB

Comparative Med

JHU Tech Ventures

ICTR

Contribute to educational mission

� 2 New JH Graduate Courses in Drug DiscoveryBasics of Drug Discovery Case Studies in Drug Discovery

� Post Doctoral Drug Discovery WorkshopDrug Discovery & Development / Pharma R&D

� 3 Drug Discovery ConferencesNeuroTranslational ConferenceWorld Health Summit with Carey Business SchoolDrug Discovery in Academia

� 5-yr NIH Drug Development Course

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Obtained external funding and executed Pharma collaborations

Multiple sources of funding Collaborative with faculty

� Applied for 49 drug discovery grants/contracts� 32 awarded totaling >$14M ($10 direct; $4M indirect)

Internal BSi

In Collaboration with JHU Faculty

Disease Foundations

NIH

Pharma

Founded New Baltimore Company

� Co-founded by JHU faculty Sol Snyder/Barb Slusher

� Sol Bauer (Celgene) Chairman of the Board

� Raised $65M in financing

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� Drug Discovery Education

� Foster Academia/Pharma partnerships

� Enhance collaboration between university drug discovery centers

� Advocacy to NCATs

In first 2 years , >115 academic centers and 1200 members joined the consortium

Founded an international consortium

ADDC in the News…

to aide in Academic

Irreproducibility IssuesConference; Oct 2014

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5 collaborative drug discovery programs

*SCHIZOPHRENIAD-Amino Acid Oxidase (DAAO) InhibitorsDrs. Sawa

INFLAMMATORY BOWEL DISEASEGCPII inhibitorsDrs. Weinberger, Li, Kaplin, Rahn

* PAIN / ITCHMrgX1 Agonist/ AntagonistsDrs. Xinzhong Dong and Yun Guan

CANCER / IMMUNOLOGY Glutaminase Inhibitors / Glutamine AnalogsDrs. Le, Hanes, Powell, Raabe, Zink, Griffin, Raabe

* BRAIN CANCER / EPILEPSY System xc- InhibitorsDrs. Riggins, Calabresi, Powell

* Collaborating with Pharma

Academic/Pharma Collaborative Drug Discovery

System xc- Inhibitor

Project

Drug Discovery

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System xC- cystine/glutamate antiporter

(SLC7A11)

�cellular uptake of cystine to maintain glutathione

�non-vesicular glutamate release

Constitutive expression in CNS (astrocytes, microglia, immature cortical neurons) and immune cells

(macrophages, thymus, spleen)

System xc-is Upregulated in Disease

Brain Cancer� J Neurosci 1999, 19, 10767

� Cancer Res 1999 59: 4383-4391

� J Neurosci 2005, 25 (31), 7101-7110

� Nat Med 2008, 14, 629

� J Cell Physiol 2008 215:593-602

� J Neurochem 2008 105(2):287

� J Neurochem 2009 110(1) 182-193

� Ann Anat 2010, 192, 309

� Oncotarget. 2011 2(11): 823–824

� Amino Acids 2011, 42(1) 231-246

� Nat Med 2011, 17; 1190–119

� Neurosurgery 2013 72(1) 33-41

� Cell Death and Disease 2015 6

Other cancers Triple negative breast cancer

� Cancer Cell 2013 14:24(4):450-65

Hepatocellular carcinoma

� Oncol Rep 2013 29(2) 68509

NeuroAIDs� J Neurochem 1998, 71, 2079.

� Invest Opthalmol Vis Sci 2004 45(9) 2906;

� Neurosci Lett 2010, 485, 233

Multiple Sclerosis� J. Neuroinflammation 2011, 8, 63

ALS� Brain. 2015 Jan;138(Pt 1):53-68

� Exp Neurol. 2013 Dec;250:69-73.

Alzheimer’s Disease� J. Neurosci. 2006, 26, 3345

Parkinson’s Disease� FASEB J, 2011, 25, 1359

Epilepsy� Antioxid Redox Signal 2014 20:2907-22

CNSCANCER CELLS

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GLIOMAupregulated system xc-; down regulated Glu transport

J Neurosci 1999, 19, 10767 Ann Anat 2010, 192, 309

Normal RESULT

GLU release + GLU uptake =

HIGH EXTRACELLULAR GLUTAMATE

� SEIZURES

� EXCITOTOXIC DEATH TO SURROUNDING TISSUE

System xc- inhibitors decrease tumor volume, block edema, and prolong survival

Nat Med 2008, 14, 629; Chung et al, J Neurosci 2005

survival(S-4CPG)

tumor volume (Sulfasalazine)

perifocal edema(S-4CPG)

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System xc- siRNA blocks edema, peritumoral neurodegeneration and prolongs survival

Nat Med 2008, 14, 629

PERITUMORALNEURODEGENERATIONGFP+ KNOCKDOWN TUMORS/PROPIDIUM IODIDE

Confidential

SURVIVALEDEMA

contrast agenr,T2 weighted scans

System xc- inhibitor blocks tumor associated glutamate release and seizures in mice

Nat Med 2014 17, 1269–1274

Tumor mice develop abnormal EEG events consistent with progressive epileptic activity

system Xc- inhibitor blocks glutamate release and abnormal EEG events

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High system xc- expression associated with high glutamate, seizures, and poor prognosis in patients with glioma

Sci Transl Med. 2015 May 27;7(289)

Patients with reduced xCT expression live 9 mo. longer.

Tumor xCT expression correlates with peritumoral glutamate release

Why has system xc- received little attention

as a therapeutic target?

1. Blockade of system xc- has been thought to

deplete cells of glutathione and induce oxidative stress

�Two different strains of mice lacking system xc- were reported to be

healthy and fertile, no enhanced oxidative stress

�Neither siRNAs against system xc- nor system xc

- inhibitors have shown any major side effects

2. No good inhibitors to assess therapeutic utility

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No Potent, Selective, Drug like xC- Inhibitors

Available

Sulfasalazine

(S)-4-Carboxyphenylglycine (S-4CPG)

Sulfasalazine (IC50= 30uM)

Extensively metabolized by azoreductases to sulfapyridine/salicylate(Br J Clin Pharmacol 1982, 13, 523)

S-4CPG (IC50= 15uM)

Non selective: also group I mGluR

(J Neurosci 1994, 14, 3370)

* Presence of carboxylates hinder brain penetration

Our attempts to optimize Sulfasalazine failed

Bioorg Med Chem Lett 2012, 21, 6184-7

� Increase metabolic

stability (diazo to alkyne)

� Carboxylate

necessary

� Truncated analogs

not potent

� Potency remained

poor

DISCONTINUED EFFORT

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Our attempts to optimize 4-SCPG failed

� Carboxylate and amine groups essential for activity� Analogs lost potency

DISCONTINUED EFFORT

Established High Throughput Screening

(HTS) assay for xC-

Fluorescence assay using STTG1 astrocytoma cells

c1 c2 c3 c4 c5 c6 c7 c8 c9 c10 c11 c12 c13 c14 c15 c16 c17 c18 c19 c20 c21 c22 c23 c24

384-well

plate

A 229 165 163 171 855 804 713 750 218 170 250 165 755 814 804 790 231 180 199 155 757 785 819 942 A

B 149 161 163 163 873 822 808 794 167 164 159 163 884 875 932 871 162 158 177 170 864 886 923 833 B

C 169 152 175 157 854 796 880 798 168 159 162 150 864 889 899 849 158 163 167 147 848 835 923 844 C

D 192 153 161 141 812 780 835 844 166 161 166 164 884 931 838 865 165 165 167 151 847 856 883 862 D

E 152 159 160 151 851 795 861 819 146 159 174 163 855 866 848 802 155 152 148 147 806 840 889 813 E

F 207 160 148 148 814 801 792 809 152 161 163 149 850 850 793 856 157 159 156 149 807 822 951 837 F

G 182 143 150 144 796 840 795 810 167 148 173 163 834 901 783 889 161 153 167 156 820 820 883 854 G

H 152 152 148 141 752 802 757 841 153 160 164 173 799 906 782 873 155 161 153 151 782 833 833 832 H

I 157 157 137 157 777 797 806 883 152 173 148 159 860 900 848 867 152 170 153 155 742 880 895 742 I

J 182 152 147 150 812 814 820 815 157 167 148 168 879 915 844 948 167 158 161 157 818 896 900 778 J

K 153 152 154 162 791 766 813 822 153 163 162 161 798 893 854 874 162 153 160 157 812 885 947 808 K

L 146 150 153 154 793 788 816 838 163 174 158 165 895 875 848 922 162 177 160 156 836 845 835 776 L

M 152 151 151 164 819 808 831 845 156 162 161 162 905 931 848 863 157 160 154 151 808 890 890 799 M

N 162 172 168 167 841 844 776 801 159 169 166 171 886 934 866 923 152 177 152 159 842 867 949 824 N

O 158 170 173 161 827 830 785 860 161 168 172 170 864 908 857 908 155 170 168 166 843 892 923 882 O

P 277 175 167 168 778 849 808 835 176 222 177 229 825 877 796 791 169 209 182 213 781 823 854 982 P

with outliers with outliers with outliers compositelow high low high low high low high

162 813 ave 167 863 ave 163 850 ave 164 842 ave

21 32 stdv 18 44 stdv 15 52 stdv 18 48 stdv

s/b Z' s/b Z' s/b Z' s/b Z'

5.02 0.76 5.18 0.73 5.21 0.71 5.14 0.71

CONTROLS TOTALS CONTROLS TOTALS TOTALSCONTROLS

� Assay in 384-well format� Z’ ~ 0.5 – 0.7 / good reproducibilityred: controls; green: totals

STTG1

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Executed High Throughput Screening Agreement with Pharma

� JHU shares target and validated HTS assay

� Eisai screens their drug library against JHU targets

� JHU conducts drug discovery on “hit” compounds and develops clinical candidate

� Eisai licenses the clinical candidate for commercialization

“WIN-WIN”

JHU: access to a large diverse drug library

PHARMA: access to novel targets

Roles of PharmaRoles of JHU

6mo

12mo

6mo

12-24 mo

12-24 mo

Disclosure of Target

Selection of Target

HTS assay development/optimization

HTS of Eisai-library compounds

HTS-hits confirmation/2nd screening

JHU-led Research Collabo Research

HTS hit

Lead Series

Candidate Selection

How Collaborative Drug Discovery works

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Lead series xCT inhibitors recently identified

nM potency

Epilepsy – NINDS ASP /Dr Kehne

Glioma – Dr. Riggins

NeuroAIDS – Dr. Volsky

Multiple Sclerosis – Dr. Rahn/Calabresi

Neuroinflammation – Dr. Rojas

Exploring therapeutic utility

IC50 = 60 nM

potency correlates w/ Inhibition of Glu release

0.001

0.01

0.1

10.01 0.1 1 10

Glutamate

release m

M

xCT IC50 µµµµM

0 2 4 60

1000

2000

3000Plasma

Brain

Time (hr)

Concentr

ati

on (

nM

)

Orally available / brain penetrable

Summary

� What it takes to discover and develop a new drug? costly, long timelines, risky, multi-discliplinary (team sport)

� Changing Ecosystem of Drug Discovery�Pharma under challenge; decreased internal discovery; open innovation�Academia/NIH are increasing efforts in drug translation�Academic-Industry partnerships on the rise

� What’s unique about academic drug discovery? longer term focus, less market pressures, more innovation/creativity/flexibility, clinical interaction, newer biology models

� Example of an academic drug discovery center and project Hopkins Bsi Drug Discovery / xCT collaborative relationship

with JHU/Eisai

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Johns Hopkins Drug Discovery

how to do translational neurology and drug discovery in ... · small molecule therapeutics cns...

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