Mining for Therapeutic Gold · o Mining for Therapeutic Gold:Mining for Therapeutic Gold: AA MMAMAM...
Transcript of Mining for Therapeutic Gold · o Mining for Therapeutic Gold:Mining for Therapeutic Gold: AA MMAMAM...
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Mining for Therapeutic Gold:Mining for Therapeutic Gold: A A MMA MA M ore ore SStStttS rarattttegegiiii c anc and d CCd Cood C lllllllaal bbbb oraoratttitiiiveve
Approach to Drug Rescue and RepurposingApproach to Drug Rescue and Repurposing
Amy P . Patterson, M.D. Associate Director for Science Policy
National Institutes f Health
June 9-10 2011
National Institutes of Health
June 9 -10 2011 Advisory Committee to the Director
,
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Development of New TherapeuticsDevelopment of New Therapeutics Drug Discovery Pre-clinical Clinical Trials FDA
Review Clinic
1 Approved
10,000 Compounds
250 Compounds
5 Compounds
DrugCompounds Compounds Compounds
6.5 years 6 years 1.5 years
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ffi
66% d t l k f
High Attrition Rate of Late-stage Drug Development: Pool of Potential Candidate Compounds for RescuePool of Potential Candidate Compounds for Rescue
• Phase II failures (2008-Efficacy ( 2010): – 51% due to lack of
Nature Reviews Drug Discovery 10, 328-329 (May 2011)
efficacy
• Phase III and submission failures (2007-2010): – 66% due to lack of
efficacy Efficacy
3 Nature Reviews Drug Discovery 10, 87 (Feb. 2011)
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t t t
A t h l d d l
Drug Rescue and RepurposingDrug Rescue and Repurposing
• A strategy to help reduce development
timeframe, costs, and failure rates
• Leverages previous research and
development efforts
• Can lead to remarkable outcomes
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g
t t t t
Thalidomide Serendipity at workSerendipity at work
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• Initially marketed as a sedative/analgesic/antiemetic
• Later shown to cause severe birth defects
• Observed to relieve pain and skin inflammation in leprosy – Approved as treatment for
leprosy in 1998
• Later found to inhibit tumor necrosis factor alpha
A d l i l – Approved to treat multiple myeloma in 2006
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NIH Activity in Drug Rescue and R i S l t d E lRepurposing: Selected Examples
Drug Brand Name Initial Indication Subsequent
Indication(s)
AZT Retrovir Antineoplastic HIV/AIDS
Ceftriaxone Rocephin Bacterial Infection Amyotrophic
lateral sclerosislateral sclerosis
Hydroxyurea Hydrea Cancers Sickle‐cell Anemia
Metformin Glucophage Type 2 diabetes Breast cancer
Pioglitazone Actos Type 2 diabetes Hepatic steatosis
Raloxifine Evista Osteoporosis Breast Cancer
Tamoxifen Novaldex Breast cancer Bipolar disorder
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NIH Activity in Drug Rescue and R i S l t d E lRepurposing: Selected Examples
Drug Brand Name Initial Indication Subsequent
Indication(s)
AZT Retrovir Antineoplastic HIV/AIDS
Ceftriaxone Rocephin Bacterial Infection Amyotrophic
lateral sclerosislateral sclerosis
Hydroxyurea Hydrea Cancers Sickle‐cell Anemia
Metformin Glucophage Type 2 diabetes Breast cancer
Pioglitazone Actos Type 2 diabetes Hepatic steatosis
Raloxifine Evista Osteoporosis Breast Cancer
Tamoxifen Novaldex Breast cancer Bipolar disorder
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IntentionalIntentional approachapproach ttoo RR &&Intentional RRR
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Zidovudine/Azidothymidine (AZT)
• 1984: NCI program to develop anti-HIV ddrugs – Collaborated with Burroughs-
Wellcome scientists studying murineWellcome scientists studying murine retroviruses as a model for AIDS
– A BW compound—AZT—found to be ff i HIVeffective agaiinst HIV
• NIH and BW collaborated with Duke t l tU iUniversitity tto condduct cli ilinical triialls
– Demonstrated antiviral activity of AZT in humansin humans
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d d i k f b t
types o cancer
cancer
Metformin Epi and meta-analysis at work
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treatment of early-stage breast cancer
Epi and meta analysis at work
• Approved for use in diabetes
• Epidemiological studies and meta-analysis
revealed that metformin use is correlated with
decreased risk of breast cancer
• Metformin observed to inhibit growth of
severalseveral types off cancer cells in vivocells in vivo
• Ongoing NCI-sponsored phase III trial for
treatment of early stage breast
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t t
t
S di i d l k ( h lid id ild fil)
t di i d d l
Moving ForwardMoving Forward
• Range of successful approaches: – Serendipity and luck (e.g., thalidomide, sildenafil)
– Observations, epidemiology, and meta-analysis(e.g., metformin)
– Intentional pursuits (e.g., fexinidazole, AZT) and screening (e.g., ceftriaxone)
• Need to poise ourselves to pursue • future efforts Need to poise ourselves to pursue future more strategically and comprehensively
efforts
10• Why now?
• Need to use rescue and repurposing efforts as case
studies in drug development process
– Opportunity to study and re-engineer the process (e.g., optimized target validation)
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G t d l
•
• or
s o Enabled tratification f
e p t
Scientific Scientific and Technologic Advances: Creatingand Technologic Advances: Creating OOOO pporpportttt ununititiitiitii es es iiii n n TTThhThh erapeuerapeuttititii cs cs DDDD eveevellll opmenopmenttt t
•
Enabled stratification of
1111
Scientific advances have • Generated a large
inventory of potential targets for new diagnostics anddiagnostics and therapeutics Refined processes for identifying candidates fidentifying candidates for clinically useful compounds
• patient populations
Growing interest and ertise in therape ics expertise in therapeutics
development in academia
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–
Key Challenges
• Availability of and access to key resources: – Compounds and associated data are not readily
available Original investigator experience and expertise mayOriginal investigator experience and expertise may be needed
• Safety and liability concerns: • Safety and liability concerns: – Safety concerns may emerge during the course of
research and may have implications for approved products and liability
– Concerns about making toxic compounds available
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t t t t
Key ChallengesKey Challenges
• Need for umbrella framework and master aggreement that can be tailored for specific projects
• Need incentives for industryy and academic sector participation:
• May be especially challenging when there is a smallll markket or short patent liflife on theh th compound
• Potential solutions to expplore: changges to IP or data exclusivity, financial incentives, innovative approaches (e.g., patent pools, dual markets)
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markets)
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NIH – INDUSTRY ROUNDTABLE APRIL 21-22, 2011
Exploring New Uses for Abandoned and Approved Therapeutics
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N fit
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Roundtable ParticipantsRoundtable Participants
• Leaders and expperts from: • Industry • Academia • Non-profit • Government
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Roundtable Goals and Accomplishments
•
Roundtable Goals and Accomplishments
Developed a collective understanding of the landscape of drug rescue and repurposing— scientific, commercial, and regulatory
• Reviewed illuminating case studies and lessons learned
• ExpE lloredd cross-sector partnershihips • Identified attributes for success
• Articulated the core elements of a framework agreement for access to materials and data
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h
g p
g
Getting to “Yes” --A Draft Framework for Negg otiatingg Agg reements
• Prepared as background for meeting participants:
•• Principles Principles and basic and basic cconcepts oncepts inherent to NIinherent to NIH’scollaborations
• Draft NIH policy for collaborative rescue and repurposing research
• General terms for collaborative agreements • Rights to publication • General intellectual property framework • Statutory requirements—for collaborations and license
agreements • Best practices • Regulatory considerations • Data sharing considerations
• Scenarios applying the draft policy 17
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Next Steps: Centralize Access toCentralize Access to Resources & Expertise • Augment the NIH National Chemical Genomics Center
Pharmaceutical Collection
– Purpose: facilitate understanding of drug mechanismsPurpose: facilitate understanding of drug mechanisms
• Ongoing effort to construct a definitive informatics and screening resource for drug repurposing
– Current Scope: • Lists all small-molecule drugs approved for human or
veterinary use (U.S. and worldwide) • Offers a physical collection of small molecules
amenable to HTS • Contains ~9,000 unique MEs
18 – All data publicly available
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y y
Augmenting the NIH National Pharmaceuticals Collection: Enabling Cross-walk Between Drugg s and Diseasesg
• rom opf bi armaceuth
Data on investigational i tl ti
(clinical trial stage) tff dh drugs
f bi h tical partners, with affectedtargets/pathways, and possible indications
– Currently NPC contains any registeredinvestigational drug, but without data on theiractivities or stage of development
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indications for one or more approved drugs
• Listing of all human diseases, affected genes/pathways/organ systems, and
drugs with effifficacy ddat
ta (b(butt nott approved) d)
– Currently NPC only has diseases that are
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20Huang, R. et al. Sci. Transl. Med. 3.80ps16 (2011)
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fil )
d l
Next Steps: Resources & Expertise•
Resources & Expertise Work with industry to identify collections of abandonedcollections of abandoned compounds and their associated data that could be made broadly available
•
made broadly available
Explore with FDA: – Periodically
querying industry about potentially abandoned compounds (“dormant” files)
– Making a broader set of data available at the time of
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drug approval
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Next Steps: Facilitate Collaborations and Partnerships
• Match-makingMatch making • Master agreements
Incentives
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• Incentives
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t
–
• –
–
– –
tt
d i
• Future topics: –
Establish a Cross-Sector Roundtable on ransT t l i l S i S dt Fi T lational Science as a Standing Forum
Future opics:R & R
• Master agreement How to incentivize
Opportunities in biologics& device development
–
– C
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Need for intermediate endpoints Improving predictive tox Target validation Combination therapiesClearinghouses forprecompetitive data Innovative clinical trial design
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24 Nature Reviews Drug Discovery 10, 397 (June 2011)
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Final noteFinal note
More than 80% of the gold
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gin the Mother Lode is
still in the ground.