Transcript Neurotranslation Program

Changing Landscape of Drug
Discovery
Barbara Slusher, PhD, MBA
Director, Johns Hopkins BSi
NeuroTranslational
Drug Discovery Program
Associate Professor,
Neurology and Psychiatry
February 2012
Changing Landscape of Drug Discovery
AGENDA
• What’s changed?
–
–
–
–
Pharma
Academia
NIH
Partnerships
• Academic Drug Discovery Centers
– Example
• Distinct attributes of academic drug discovery
US drug discovery ecosystem is changing
OBSERVATION 1:
The Pharmaceutical industry is Under Challenge
• The industry is investing more than three times as much as a
decade a ago to produce less than half as many new products
• Phase II timelines have nearly doubled; Phase III timelines have
increased by ~50%
• Number of NMEs per $1B spent is a factor 50 worse
than 30 years ago
• $130 billion of patented sales
to face generics by 2016
(57% of 2010 US sales)
• >100K jobs lost in the last 2 yrs
Bernstein research 2011;
figure modified by Dr. S Paul
Inverse Moore’s Law for Pharmaceuticals
US drug discovery ecosystem is changing
OBSERVATION 2:
Academia and NIH are increasing efforts in drug
translation
In Academia:
• In 1995 there were less
than 10 academic drug
discovery centers
• In 2012, there are over 100
academic drug discovery
centers
At NIH:
• National Center for
Advancing Translational
Sciences (NCATS)
established in 2011
• $639 million budget
• NIH 2013 budget is flat,
NCATS increases by 11%
Sources:
• Frye, S., Crosby, M., Edwards, T., & Juliana, R. (2011). US Academic Drug Discovery. Nature Reviews Drug Discovery, 409-410.
• Harris, G. (2011, January 22). Federal Research Center Will Help Develop Medicines. Retrieved from The New York Times:
http://www.nytimes.com/2011/01/23/health/policy/23drug.html
• Rare Diseases Clinical Research Network. (2012, January). National Center for Advancing Translational Sciences (NCATS) Established.
Retrieved from Newsletter of the NIH Rare Diseases Clinical Research Network:
http://rarediseasesnetwork.epi.usf.edu/spotlight/January2012/NCATS/
100+ Academic Drug Discovery Centers and
Programs in the US
Baylor University
Center for Drug Discovery
Johns Hopkins University
Johns Hopkins Brain Science Ins
Brigham Young University
Cancer Research Center
Louisiana State University
Neuroscience Center of
Excellence
Case Western Reserve University
Case Comprehensive Cancer
Center - Drug Discovery and
Development
Colorado State University
Colorado Center for Drug
Discovery
Cornell University
Memorial Sloane-Kettering
Cancer Center - Experimental
Therapeutics
Duke University
Drug Discovery Center
Emory University
Chemical Biology Discovery
Center
Florida Atlantic University-Boca
Raton
Harbor Branch - Marine Drug
Discovery
Georgia State University
Center for Biotechnology & Drug
Design
Georgetown University
Drug Discovery Program
Georgia Institute of Technology
Center for Drug Design,
Development and Delivery
Harvard University
Center for Applied Cancer Science
Harvard Neuro Discovery Center
Institute of Chemistry and Cell
Biology
Institute in Systems
Temple University
Moulder Center for Drug
Discovery Research
University of Alabama at
Birmingham
Alabama Drug Discovery Alliance
Massachusetts Institute of
Technology
Broad Institute of Harvard & MIT
North Carolina Central University
Biomanufacturing Research
Institute and Technology
Enterprise (BRITE)
Northeastern University
Center for Drug Discovery
Northwestern University
Center for Molecular Innovation
and Drug Discovery
Oregon State University
Oregon Translational Research
and Drug Development Institute
(OTRADI)
Pennsylvania State University
Drug Discovery, Delivery and
Development Core
Purdue University
Bindley Bioscience Center
Purdue Center for Combinatorial
Chemical Biology
University of Arizona
Southwest Comprehensive Center
For Drug Discovery And
Development
University of California - San
Diego
Division of Pediatric
Pharmacology & Drug Discovery
University of California-San
Francisco
Small Molecule Discovery Center
Department of Bioengineering &
Therapeutic Sciences
California Center for Antiviral
Drug Discovery (UCLS/UCSF
Collaboration)
University of California-Santa
Cruz
Chemical Screening Center
University of Cincinnati
Drug Discovery Center
University of Florida
Center for Drug Discovery
Rice University
Chemical Genomics (GCC CG)
University of Georgia
Center for Drug Discovery
The Rockefeller University
High Throughput Screening
Resource Center
University of Illinois at Chicago
Institute of Tuberculosis Research
University of Kansas
High Throughput Screening
Laboratory
Kansas Specialized Chemistry
Center
University of Michigan-Ann
Arbor
Center for Chemical Genomics
Vahlteich Medicinal Chemistry
Core
University of Minnesota - Twin
Cities
Center for Drug Design
Institute for Therapeutics,
Discovery & Development
Stanford University
University of Texas at Austin
MD Anderson Cancer Center for
Targeted Therapy
University of Mississippi
National Center for Natural
Products Research
University of Toledo
Center for Drug Design and
Development
University of New Mexico
New Mexico Molecular Libraries
Screening Center
University of Utah
Huntsman Cancer Institute’s
Center for Investigational
Therapeutics Program
University of North Carolina at
Chapel Hill
Center for Integrative Chemical
Biology and Drug Discovery
University of North Carolina at
Greensboro
Center for Drug Discovery
University of Washington-Seattle
Campus
Institute for Stem cell and
Regenerative Medicine - Quellos
High Throuput Screening Core
University of Oregon
Oregon Translational Research
and Drug Development Institute
University of Wisconsin-Madison
UW National Cooperative Drug
Discovery Groups
Small Molecule Screening and
Medicinal Chemistry Core Facility
University of Pennsylvania
Penn Center for Molecular
Discovery
Vanderbilt University
Vanderbilt Program in Drug
Discovery
University of Pittsburgh
Drug Discovery Institute
University of Pittsburgh Molecular
Libraries Screening Center
Virginia Commonwealth
University
VCU Institute for Structural
Biology and Drug Discovery
(ISBDD)
University of South Carolina
MUSC Hollings Cancer Center
Drug Discovery
and the list goes on…
Saint Louis University
Center for World Health and
Medicine
USC Center for Molecular
Pathways and Drug Discovery
University of Tennessee,
University of Tennessee Health
Science Center Drug Discovery
Research Area
Texas Institute for Drug and
Diagnostics Development
University of South Florida
Center for Drug Discovery and
West Virginia University
Blanchette Rockefeller Neuro
Sciences Institute
Yale University
US drug discovery ecosystem is changing
OBSERVATION 3:
Academic-Industrial Partnerships on the Rise
• Pharma sees academia’s strengths in biology /target
identification
• Academia realizes limitations in translating its technologies
• Response: form collaborations to leverage each other’s
strengths and overcome weaknesses
• SHARED RISK approach
Sources:
* Scudellari, M. (2011). Clinical Drive Prompts Pharma and
Academia to Partner Up. Retrieved from Nature Medicine:
http://www.nature.com/nm/journal/v17/n1/full/nm0111-3.html
* Ledford, H. (2011, June 22). Drug Buddies. Retrieved from
Nature News:
http://www.nature.com/news/2011/110622/full/474433a.html
In the Headlines
Jan 2010:
Johnson & Johnson, Vanderbilt University partner to
develop Schizphrenia Drugs
($10M over 3 years)
January 2011:
Sanofi-Aventis Enters into Two Research &
Development Collaborations with UCSF
(Covers multiple therapeutic areas; amount undisclosed)
March 2010:
University of Pennsylvania School of Medicine and
AstraZeneca Working Together to Find New Therapies for
Alzheimer’s Disease
(2-year agreement, amount undisclosed)
January 2011:
Bayer HealthCare, UCSF Sign Pact for Research Projects
(Covers multiple research projects; amount undisclosed)
July 2010:
J&J Teams With Koch Institute
(5-year agreement; amount undisclosed)
October 2010:
Harvard, Sanofi-Aventis in Collaboration
(Covers multiple therapeutic areas; amount undisclosed)
November 2010:
UCSF Partners With Pfizer to Improve Drug Discovery,
Development
($85M over 5 years)
January 2011:
Johns Hopkins Brain Science Instit enters into an
agreement with Ortho-McNeil-Janssen Pharmaceuticals
(5-year agreement; amount undisclosed)
February 2011:
GSK Seeks to Fund Academic "Superstars" for New
Drugs
(Long-term relationship that will endure 10+ years)
March 2011:
Yale and Gilead Sciences Announce Cancer Research
Collaboration
($100M over 3 years)
Oct 2011:
EISAI Enters into a Neurological Drug Discovery
Research Collaboration with Johns Hopkins Brain
Science
(5-year agreement; amount undisclosed)
• Lyman, S. (2011, May 10). Pharma-Academic Alliances: What the Numbers
Don’t Tell You . Retrieved from Xconomy:
http://www.xconomy.com/seattle/2011/05/10/pharma-academic-allianceswhat-the-numbers-dont-tell-you/
• Scudellari, M. (2011). Clinical Drive Prompts Pharma and Academia to
Partner Up. Nature Medicine, 3.
Drugs Coming from Academia is not new concept
252 NDA (1998-2007)
134 “Me-Too”
118 Novel
25%
44%
31%
Novel = priority review;
scientifically
innovative; respond to
unmet medical needs
47%
novel
53%
“me-too”
11%
18%
71%
Sources:
• Kneller, R. The importance of new companies for drug discovery: origins of a decade of new drugs. Nat Rev Drug
Discov 9, 867-882 (2010).
• Stevens, A.J. et al. The Role of Public-Sector Research in the Discovery of Drugs and Vaccines. New England
Journal of Medicine 364, 535-541 (2011).
• Slide courtesy of Tim Willson, GSK
1st Academic/Industry Research
Partnership in 1920s
 In 1921, Dr. Frederick Banting
and Charles Best of the
University of Toronto
discovered insulin as the
treatment of diabetes
 Unable to mass produce
insulin, the University of
Toronto entered into a
partnership with Eli Lilly to
see if a manufacturing
process could be developed.
Recent examples of Drugs
Discovered by Academia
•
•
•
•
•
•
•
•
•
•
Lyrica (NorthWestern) neuropathic pain
Vimpat (NIH, University of Houston) epilepsy
Remicade (NYU) rheumatoid arthritis
Vorinostat (Columbia, MSK) T cell lymphoma
Ziagen (University of Minnesota) AIDS
Restasis (University of Georgia) Dry eye
Gardasil (Georgetown, U Rochester) human papillomavirus
Epivir (Emory University) AIDS
Alimta (Princeton University) Lung Cancer
Renova (University of Pennsylvania) skin care/acne
…and many more
Source:
• Stevens, A. J., D., P., Jensen, J. J., Wyller, K., Kilgore, P. C., Chatterjee, S., & Rohrbaugh, M. L. (2011). The Role of Public-Sector
Research in the Discovery of Drugs and Vaccines. New England Journal of Medicine, 535-541.
Science Translational Medicine, 2009
Changing Landscape of Drug Discovery
AGENDA
• What has Changed?
–
–
–
–
Pharma
Academia
NIH
Partnerships
• Academic Drug Discovery Centers - example
• Distinct attributes of academic drug
discovery
JHU Brain Science Institute (BSi)
 Started in 2007 from a philanthropic gift of >$100M
from an anonymous donor
 Mission of BSi
 Solve fundamental questions about brain
development and 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
Hopkins’ BSi NeuroTranslational Drug Discovery
turning Hopkins’ brain discoveries into clinical therapeutics
 20 drug discovery scientists from PHARMA industry


Expertise in medicinal chemistry, animal pharmacology and toxicology, drug
metabolism, pharmacokinetics, assay development
Average of 15 years PHARMA experience in small molecule drug discovery
 Working collaboratively with >450 JHU brain scientists
JHU
Faculty
Expertise
Novel
Drug Target
Identification
BSI NT Drug Discovery Center Expertise
Drugability
Evaluation
HTS
Hit to
Lead
Lead
Optimization
Candidate
Selection
JHU
Faculty
Expertise
Clinical
Trials
First 2 Years at JHU
1. Built collaboration network
2. Initiated drug discovery projects
3. Started training and education courses
4. Established partnerships with industry to
assist in drug discovery and commercialization
Built Awareness of Druggable Targets at Hopkins
 Held individual meetings with >100 faculty interested in
brain sciences
 School of Medicine, Public Health, Homewood, KKI
Anesthesiology, Biology, Comparative Medicine, Neurology, Neurosurgery,
Neuroscience, Ophthalmology, Psychiatry, Medicine, Mind Brain Institute,
Pharmacology, Oncology, Immunology, Radiology
 Purpose
Become aware of possible drug discovery projects on campus
Assemble a database of faculty research to be used with PHARMA interested in
collaborations with JHU
Initiated Twenty Collaborations
 Synthesizing “tool compounds”

Pin-1 inhibitor (P Worley); Wyeth BACE inhibitor (J Griffin); Rapamycin derivative (G
Ming); Sutent analogs (D Zack); MrgX agonists and antagonist (X Dong); curcumin
derivatives (T Dawson); lactosylceramide synthase inhibitor (S Chatterjee); mGlr1 PAM (R
Huganir); GLS1 inhibitor (C Dang; G Riggins); Petidomimetic BACE inhibitors (P Wong);
Biotinylated glutaminase inhibitor (C Dang); DMT inhibitor (Sumner); 4-Hydroxytamoxifen
(Caterina)
 Conducting drug metabolism and pharmacokinetics
studies




Ethoxyquin (A Hoke)
RR-DPT (A Sawa)
Cyclo GRGDSP (T Nguyen)
NAC / NACA (P Campochiaro)
 Aiding in assay development






MCT1 / gliagenesis (J Rothstein)
Mechanoreceptors (X Dong)
Neurite outgrowth (A Hoke)
Retinal ganglion cell survival (D Zack)
Glutamate release (J Bressler)
MrgX agonist/antagonist (X Dong)
First 2 Years at JHU
1. Built collaboration network at JHU
2. Initiated drug discovery projects
3. Started training and education courses
4. Established partnerships with industry to
assist in drug discovery and commercialization
Established 4 Integrated Drug Discovery Projects
 D-Amino Acid Oxidase (DAAO)
Inhibitors for Schizophrenia
Collaboration with Akira Sawa (Psychiatry) and Michaela Gallagher
(Psychology)
 Glutaminase Inhibitors for Cancer and
Neurodegeneration
Collaboration with Chi Dang (Medicine), Greg Riggins (Neurosurgery),
Christine Zink (Comparative Medicine), Peter Calabresi (Neurology),
Jeff Rothstein (Neurology), Walter Kauffman (KKI)
 MrgX1 Ligands for Pain / Pruritis
Collaboration with Xinzhong Dong (Neuroscience)
 GCPII inhibitor for Peripheral
Neuropathy and MS
Collaboration with Mohamed Farah (Neurology), Adam Kaplin
(Psychiatry)
Initiated 3 Exploratory Drug Discovery Projects
 System xc- Inhibitors for Brain cancer
Collaboration with Dr. Greg Riggins (Neurosurgery)
 MCT inhibitors/activators for
Cancer/Neurodegeneration
Collaboration with Jeff Rothstein (Neurology)
 Protein Kinase inhibition for Retinal
Disorders
Collaboration with Dr. Don Zack (Opthalmology)
First 2 Years at JHU
1. Built collaboration network at JHU
2. Initiated drug discovery projects
3. Started training and education courses
4. Established partnerships with industry to
assist in drug discovery and commercialization
Contributing to JHU’s Educational Mission
by Teaching/Training Drug Discovery
 Drug Discovery Course for graduate students
 Drug Discovery & Development Workshop for post doc fellows
 NeuroTranslational conference co-organized
with Carey Business School
 Initiated Entrepreneurs'
“Boot Camp” and “Vine-andVenture” seminar series
on commercialization
 Drug Discovery Training program:
post docs, undergrad, HS students
First 2 Years at JHU
1. Built collaboration network at JHU
2. Initiated drug discovery projects
3. Sustained our funding
4. Started training and education courses
5. Established partnerships with industry
to assist in drug discovery and
commercialization
Partnered Drug Discovery Program with PHARMA;
Supported Pharma product development;
Spun-Out New Company
Press Release
Eisai Enters Licensing Agreement
on GCPII Inhibitors With Johns
Hopkins Brain Science Institute
By PR Newswire 03/12/10 - 09:30 AM EST
Helsinn
HealthCare
sponsors JHU to
evaluate MOA of
its CIPN drug
Press Release May 24, 2011 09:00 ET
Cerecor, Inc
Appoints Management Team and Board of
Directors; Plans for a $20 Million Series
Executed a Unique Pharma Collaborative High
Throughput Screening Agreement
 JHU identifies new brain targets and develops screening assays
 Eisai screens their internal drug library collection and share
“hits” with JHU
 JHU conducts medicinal chemistry/drug discovery and identify
new clinical candidate compounds
 Eisai licenses the clinical candidates and provide JHU with
milestone payments and royalties
 True “WIN-WIN”
 JHU: access to a large diverse library
 Eisai: access to novel targets
PHARMA – ACADEMIA
partnerships
Changing Landscape of Drug Discovery
AGENDA
• What has Changed?
–
–
–
–
Pharma
Academia
NIH
Partnerships
• Academic Drug Discovery Centers on the Rise
– Example
• Distinct attributes of academic drug discovery
Academia vs Pharma: Survey Results
Comparison Between Industry and Academia
Medicinal Chemistry
Assay Development and Screening
3.64%
7.273%
3.64%
16.36%
18.18%
40%
52.73%
23.64%
34.55%
Organizational Commitment & Stability
10.91%
25.45%
Aligned with Needs and Values of Society
1.82%
3.64%
23.64%
30.91%
23.64%
Survey of 78 US
academic drug
discovery
centers
Nature Reviews
Drug Discovery,
June 2011, 409-10.
20%
40%
20%
Innovation
Disease Expertise
1.82%
5.45%
30.91%
21.82%
40%
3.64%
16.36%
38.18%
41.82%
much better in industry
somewhat better in industry
about the same
somewhat better in academia
much better in academia
Academia vs Pharma: personal perspective
• Academic strengths in Drug Discovery
– Depth of knowledge on specific diseases/targets
unparalleled in Pharma
– Enhanced clinical interactions
– Access to new animal models
– Can assume more risk
less time line pressures
Academia vs Pharma: personal perspective
• Academic weaknesses in Drug Discovery
– Individual vs. team oriented
– Lack of expertise/interest
– Rewards are based on
publishing/grants, hypothesis-driven
scholarly research, not product
development
– Funding/resources limited; reliance on
grants
– Pressure to publish will compromise
patent strategy
Summary
Changing Landscape of Drug Discovery
Academia/Industry partnerships will be key to
leverage each other’s strengths and overcome
weaknesses
Partnership structures will benefit all involved
— most importantly, patients.