John McKew, PhD
Chief, Therapeutics Development Branch Division of Preclinical Innovation
TRND Road Show
Therapeutics for Rare and Neglected
Diseases (TRND)
Overview
• What is TRND?
• How to Apply to TRND
• TRND Evaluation Criteria
• TRND Project Selection and Agreements
• Questions
Overview
• What is TRND?
• How to Apply to TRND
• TRND Evaluation Criteria
• TRND Project Selection and Agreements
• Questions
What is TRND?
• An effort to speed development of new drugs for rare and neglected diseases
• A resource to help advance rare and neglected disease drug discovery projects from academia or industry
• An integral part of the NIH Director’s mandate to increase translational research within the NIH
Benefits for the Applicant
• Significant in-kind research to move your project forward
• Collaboration with TRND’s experienced group of drug discovery professionals to achieve your project goals
• Access to the broad scientific, clinical, and translational expertise within the NIH
The Problem of Rare and Neglected Diseases
• ~7,000 diseases affect humankind – but only a small fraction support commercial development of therapeutic agents
• Two types of neglected diseases:
– Low prevalence, i.e., “rare” (<200,000 prevalence in U.S.)
• There are >6000 rare (orphan) diseases
• Cumulative prevalence in U.S. ~ 25 – 30 million
• Most are single gene diseases
• <200 have any pharmacotherapy available
– High prevalence but “neglected”
• Occur chiefly among impoverished and marginalized
populations in developing nations (treatment costs
prohibitive)
• Most are infectious
Preclinical Development/TRND
FDA Collaboration
Paradigm/Technology Development
Repurposing
Lead
Optimization Preclinical
Development Probe/Lead
Development Target
Validation Target FDA
approval Clinical Trials
I II III
Project Entry Point
Repurposing
Unvalidated target
Validated target
Lead compound
Preclinical development
candidate
Clinical development
candidate
Assay Dev
Target assay
TRND Project Entree
• Small Molecule and Biologic modalities accepted
• Projects enter TRND from lead optimization to IND filing • After HTS and other lead finding and validation work is completed
TRND Features • NIH Intramural Drug Development Experts Partnering
with External Disease and Target Collaborators
– Partners can be Government, Academics, Non-Profit Foundations, Biotechnology and Pharmaceutical companies, ex-US groups
• Distinguishing features
– Collaboration / Partnerships (not service center)
– Entrepreneurial culture, fast decision-making
– Building laboratory and expertise infrastructure at NIH
– Disease agnostic, exploiting cross-cutting mechanisms
– Science of preclinical drug development
– Technology/paradigm development
• 20% of effort toward improving success rates
TRND Features: R&D Capabilities
• Drug project-specific activities
– New indications for clinical stage drugs and repurposing approved drugs
– Medicinal chemistry
– Rare disease bioassay development
– Efficacy, pharmacology, ADME, toxicology, PK/PD
– Compound scale-up, formulation
– Clinical and regulatory development strategy,
natural history studies assessments
– First in human clinical trials as needed
TRND Program Timeline
• FY09: Infrastructure (May 2009)
• FY10: Infrastructure and Pilot Projects (June 2010)
– Budget $24M
– Governance, hiring, research community outreach, pilot projects
• FY11: Infrastructure and Project Solicitation
– Budget $24M
– Sept 2010 solicitation yielded 4 projects; work began May 2011
– April 2011 solicitation yielded 6 projects; work began Sept 2011
• FY12: Maturing program within NCATS
– Budget $24M
– Current projects reviewed regularly to assess progress
– Aug – Sept 2012 solicitation; expect to select 3-5 projects
• 14 projects through pilot phase & 2 public solicitations since 2009
• Mix of small molecules and biologics
• Two innovative platform technologies
• 2 investigational drugs taken into humans
• CLL: IND filed with US FDA July 12th, approved Aug 5th 2011
• Phase I trial commenced September 2011
• SCD: IND filed Oct 14th 2011, approved Nov 10th 2011
• Phase I trial commenced December 2011
• Initiated first natural history study
• HIBM: NIH Clinical Center, 1st patient enrolled September 2011
• Every project is a unique Public-Private partnership
• Many include foundation and patient advocacy input
TRND Highlights
Active TRND Projects Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease
TRND Pilot Project NPC-SOAR, Washington Univ., Einstein
College of Medicine, NICHD, NHGRI
Disease Foundation,
Academic, DIR
Repurposed
Approved Drug Niemann-Pick C
TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate
Replacement
Hereditary Inclusion Body
Myopathy
TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease
TRND Pilot Project Leukemia & Lymphoma Society, Kansas
Univ. Cancer Center
Disease Foundation,
Academic
Repurposed
Approved Drug
Chronic Lymphocytic
Leukemia
Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy
Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome
Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis
Liu, Paul NHGRI DIR Repurposed
Approved Drug Core Binding Factor Leukemia
Kimberlin, David University of Alabama Academic Nucleotide
Analog Pro-drug Neonatal Herpes Simplex
Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary
Alveolar Proteinosis
Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans
Progressiva
Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis
Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect
Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy
TRND Portfolio
Active TRND Projects Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease
TRND Pilot Project NPC-SOAR, Washington Univ., Einstein
College of Medicine, NICHD, NHGRI
Disease Foundation,
Academic, DIR
Repurposed
Approved Drug Niemann-Pick C
TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate
Replacement
Hereditary Inclusion Body
Myopathy
TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease
TRND Pilot Project Leukemia & Lymphoma Society, Kansas
Univ. Cancer Center
Disease Foundation,
Academic
Repurposed
Approved Drug
Chronic Lymphocytic
Leukemia
Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy
Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome
Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis
Liu, Paul NHGRI DIR Repurposed
Approved Drug Core Binding Factor Leukemia
Kimberlin, David University of Alabama Academic Nucleotide
Analog Pro-drug Neonatal Herpes Simplex
Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary
Alveolar Proteinosis
Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans
Progressiva
Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis
Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect
Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy
TRND Portfolio Active TRND Projects
Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease
TRND Pilot Project NPC-SOAR, Washington Univ., Einstein
College of Medicine, NICHD, NHGRI
Disease Foundation,
Academic, DIR
Repurposed
Approved Drug Niemann-Pick C
TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate
Replacement
Hereditary Inclusion Body
Myopathy
TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease
TRND Pilot Project Leukemia & Lymphoma Society, Kansas
Univ. Cancer Center
Disease Foundation,
Academic
Repurposed
Approved Drug
Chronic Lymphocytic
Leukemia
Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy
Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome
Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis
Liu, Paul NHGRI DIR Repurposed
Approved Drug Core Binding Factor Leukemia
Kimberlin, David University of Alabama Academic Nucleotide
Analog Pro-drug Neonatal Herpes Simplex
Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary
Alveolar Proteinosis
Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans
Progressiva
Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis
Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect
Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy
Screening Derived Repurposing: How quickly can we take an approved drug and use it in a new patient population?
The
Learning
Collaborative™
• Focus on rare and neglected
diseases
• Industrial scale HTS,
medicinal chemistry, and
bioinformatics capabilities
• Pharma experience
• Bench to bedside translation
in drug repurposing
• National leadership in
medicinal and pharmaceutical
chemistry
• Pharma experience
• ~ 400 active research projects
• World-wide network of blood cancer experts
• Track record of commercial partnerships
• Pharma experience
The Learning Collaborative Capitalizing on Strengths
Clinical trial sites: KU (Bhalla) NIH (Wiestner) OSU (Byrd)
CLL ─ Chronic Lymphocytic Leukemia
• 30% of all leukemias
• Progresses more slowly than other types of leukemia; 80% of patients are over age 60
• ~15,000 new diagnoses/year in US
• Standard of Care: chemotherapy (fludarabine et al) and/or anti-CD20 mab (Rituxan)
• New treatments needed for refractory CLL patients
Overview of CLL screen
• Normal B-cells and CLL cells obtained from patients at NIH Clinical Center
• Adrian Wiestner, NHLBI
• Patient samples sent frozen to the NCGC (fresh samples also tested with similar results)
• Cells from six CLL patients and five normal donors tested
• NCGC Pharmaceutical Collection screened at 9 concentrations, 1 nM to 57 uM (1:5
dilutions)
• Readout: cell viability (ATP measurement)
• Desired compound profile = Differential cell killing between normal and CLL cells
Chronic Lymphocytic Leukemia
Kills CLL but not normal donor cells
102 CLL Pan-Actives vs. Normal B-Cells
Bench-to-Bedside in Two Years
10/7/2009 In Vitro Activity Demonstrated in Primary CLL Cells
Auranofin Selected as First TLC™ Project
The Learning Collaborative™ Established through Memorandum of
Understanding 6/7/2010
11/5/2010
Cooperative Research and Development Agreement Signed 3/22/2011
8/5/2011 Clearance from FDA to Proceed to Clinical Proof of Concept in CLL
10/7/2011 First CLL Patient Dosed with Auranofin
Auranofin Project Timeline
Active TRND Projects Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease
TRND Pilot Project NPC-SOAR, Washington Univ., Einstein
College of Medicine, NICHD, NHGRI
Disease Foundation,
Academic, DIR
Repurposed
Approved Drug Niemann-Pick C
TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate
Replacement
Hereditary Inclusion Body
Myopathy
TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease
TRND Pilot Project Leukemia & Lymphoma Society, Kansas
Univ. Cancer Center
Disease Foundation,
Academic
Repurposed
Approved Drug
Chronic Lymphocytic
Leukemia
Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy
Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome
Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis
Liu, Paul NHGRI DIR Repurposed
Approved Drug Core Binding Factor Leukemia
Kimberlin, David University of Alabama Academic Nucleotide
Analog Pro-drug Neonatal Herpes Simplex
Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary
Alveolar Proteinosis
Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans
Progressiva
Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis
Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect
Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy
TRND Portfolio
Development of a Targeted New Molecular Entity
Sickle Cell Disease • Principal Collaborator: AesRx, Inc.
• Compound: 5-hydroxymethyl-2-furfural (Aes-103) – binds to sickle hemoglobin and increases oxygen affinity
• Stage of project: Late pre-clinical
• TRND collaborating with AesRx on – Preclinical toxicology
– CMC (Chemistry, Manufacturing, and Quality Control) studies
– Regulatory: interactions with FDA, IND filing
– Proof-of-concept clinical trials
• Other NIH resources collaborating to get drug to clinic – API (Aes-103) manufactured via NIH-RAID program
– NIH Clinical Center Pharmacy collaborating on formulation
– NIH Clinical Center Investigator will perform POC clinical trials
• Greg Kato, NHLBI
Gaps and Timelines - SCD
• Gap analysis: Aes-103 – Potent anti-sickling agent in vitro / in vivo – Orally bioavailable, rapidly permeates RBC membrane – Needs:
• Studies: Preclinical acute/chronic tox, safety, in vitro ADME • CMC: GMP manufacturing, formulation, sufficient amounts for (pre)clinical studies • Regulatory: Complete IND
• Timelines:
– Team / Funding / Gap Analysis / Agreements: 3 months (TRND-AesRx) – Preclinical Studies: 12 months (TRND-CRO) – IND Preparation & Submission: 4 months (TRND-CRO) – Healthy Volunteers Dosed: 1 month (TRND-CRO) – First Patient Dosed: 5 months (TRND-NIH CC)
Active TRND Projects Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease
TRND Pilot Project NPC-SOAR, Washington Univ., Einstein
College of Medicine, NICHD, NHGRI
Disease Foundation,
Academic, DIR
Repurposed
Approved Drug Niemann-Pick C
TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate
Replacement
Hereditary Inclusion Body
Myopathy
TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease
TRND Pilot Project Leukemia & Lymphoma Society, Kansas
Univ. Cancer Center
Disease Foundation,
Academic
Repurposed
Approved Drug
Chronic Lymphocytic
Leukemia
Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy
Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome
Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis
Liu, Paul NHGRI DIR Repurposed
Approved Drug Core Binding Factor Leukemia
Kimberlin, David University of Alabama Academic Nucleotide
Analog Pro-drug Neonatal Herpes Simplex
Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary
Alveolar Proteinosis
Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans
Progressiva
Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis
Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect
Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy
TRND Portfolio
Development of a Known Pathway Intermediate as a Therapeutic
• Principal Collaborators: NHGRI and New Zealand Pharmaceuticals (NZP)
• Compound: N-acetyl-D-mannosamine
– Binds to UDP N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK)
• Stage of project: Late preclinical (Clinical trial hold)
• TRND collaborating on:
– Preclinical toxicology
– CMC (Chemistry, Manufacturing, and Quality Control) studies
– Regulatory: interactions with FDA, IND filing
– Proof-of-concept clinical trials
• Other NIH resources:
– NIH Clinical Center Investigator will perform POC clinical trials and natural history study
• Bill Gahl, NHGRI
• Nuria Carrillo NCATS
– NIH Clinical Center Pharmacy collaborating on formulation
N-acetyl-D-mannosamine (ManNAc)
1 2 4 3 6 5 8 7 10 9 12 11
epimerase kinase
13
M712T D176V
Hereditary Inclusion Body Myopathy
(ManNAc)
Gaps and Timelines - HIBM
• Gap analysis: ManNAc – “Anecdotal” patient experience with orally bioavailable ManNAc – Expect no adverse effects at likely human doses – Project on clinical hold with FDA – Thorough understanding of disease progression – Needs:
• Studies: Preclinical acute/chronic toxicity, genotoxicity, safety, in vitro ADME • CMC: GMP manufacturing, formulation, sufficient amounts for (pre)clinical studies • Regulatory: Complete response to FDA clinical hold • Natural History Study
• Timelines:
– Team / Funding / Gap Analysis / Agreements: 5 months (TRND-NHGRI) – Preclinical Studies: 12 months (TRND-CRO) – Regulatory Support: 9 months [ongoing] (TRND-CRO) – Filed complete response to clinical hold 7/27/2012
Active TRND Projects Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease
TRND Pilot Project NPC-SOAR, Washington Univ., Einstein
College of Medicine, NICHD, NHGRI
Disease Foundation,
Academic, DIR
Repurposed
Approved Drug Niemann-Pick C
TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate
Replacement
Hereditary Inclusion Body
Myopathy
TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease
TRND Pilot Project Leukemia & Lymphoma Society, Kansas
Univ. Cancer Center
Disease Foundation,
Academic
Repurposed
Approved Drug
Chronic Lymphocytic
Leukemia
Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy
Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome
Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis
Liu, Paul NHGRI DIR Repurposed
Approved Drug Core Binding Factor Leukemia
Kimberlin, David University of Alabama Academic Nucleotide
Analog Pro-drug Neonatal Herpes Simplex
Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary
Alveolar Proteinosis
Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans
Progressiva
Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis
Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect
Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy
TRND Portfolio
Pathway Derived Repurposing: Changing the Route of Administration of an Approved Drug
Repurposing an Approved Drug by Changing the Route of Administration
Pulmonary Alveolar Proteinosis
• Principal Collaborator: Bruce Trapnell
(Cincinnati Children’s Hospital)
• Clinical Manifestation:
– Accumulation of surfactant in pulmonary alveoli
– Impaired gas exchange
– Hypoxemic respiratory failure
• Current Treatment
– Whole lung lavage under general anesthesia
– Requires 15 L saline
– Technically challenging, invasive, pediatric safety concerns
• Compound: GM-CSF
– Required for terminal differentiation and maturation of alveolar macrophages
– Approved in IV form (Sargromostim) for
• Myeloid reconstitution after bone marrow transplant
• Neutropenia induced by chemotherapy in AML
• Path Forward / Gaps:
– Significant human experience with GM-CSF via IV
• Initial studies indicate high doses of GM-CSF by IV or SC are needed to have impact in the lung
– Ex-US studies of inhaled GM-CSF indicate efficacy in autoimmune PAP
– To begin US study:
• Need inhaled NHP toxicology data
N Engl J Med 2007; 357:e21
Eur J Radiol 2011, May 26; http://dx.doi.org/10.1016/j.ejrad.2011.05.005
PAP infiltration 4 days post lavage
Whole Lung Lavage Fluid
Overview
• What is TRND?
• How to Apply to TRND
• TRND Evaluation Criteria
• TRND Project Selection and Agreements
• Questions
TRND is Different
Usual NIH Mechanism
Apply, Grants.Gov
Review, NIH CSR $
Funding Opportunity
Announcement
Funding Decision
Apply, Proposal CENTRAL
Review, TRND Panel
Collaborate with TRND
Milestone-Driven, In-Kind Research
Support
Solicitation Select Projects, Form Teams
TRND Mechanism
http://trnd.nih.gov
http://trnd.nih.gov
Preclinical Development/TRND
FDA Collaboration
Paradigm/Technology Development
Repurposing
Lead
Optimization Preclinical
Development Probe/Lead
Development Target
Validation Target FDA
approval Clinical Trials
I II III
Project Entry Point
Repurposing
Unvalidated target
Validated target
Lead compound
Preclinical development
candidate
Clinical development
candidate
Assay Dev
Target assay
TRND Project Entree
• Small Molecule and Biologic modalities accepted
• Projects enter TRND from lead optimization to IND filing • After HTS and other lead finding and validation work is completed
Application
Application
Application Documents
TRND Concept Application (5-page Template)
• Background
• Therapeutic Hypothesis
• Current State of Project
• Proposed Development Strategy
• Justification
• Timeline and Milestones
• Appendices
Application Documents (cont’d)
Appendices
• Compound Data Tables
• References
• Public Abstract
• Intellectual Property (IP) Information
• Key Investigators Biosketch
Application Documents (cont’d)
Appendices
• Compound Data Tables
• References
• Public Abstract
• Intellectual Property (IP) Information
• Key Investigators Biosketch
https://proposalcentral.altum.com/default.asp?GMID=80
ProposalCENTRAL
Overview
• What is TRND?
• How to Apply to TRND
• TRND Evaluation Criteria
• TRND Project Selection and Agreements
• Questions
TRND Program Evaluation: Key
Criteria (by weight)
• Target and therapeutic validation (30%)
• Strength of current data package (30%)
• Feasibility to reach First in Human (20%)
• Medical impact relative to current Standard of Care (10%)
• Likelihood of external adoption (10%)
Criteria: Strength of Data Package
• Medicinal Chemistry
• ADME
• PK/PD
• Toxicology
• In vivo models
• Secondary and tertiary assays
• Formulation
• Chemical Manufacturing and Controls (CMC) – Small molecules
• Expression/Purification – Biologics
Criteria: Feasibility to FIH
– Animal models to establish efficacy
– Clinical translation pathway, established clinical endpoints
– Patient population, well defined with registries
– Biobanks
– Natural history studies complete
– Once FDA approved, projected
ability to treat disease
40
Compound Efficacy Profile
(Conditions in parentheses)
In Vitro Biology Units Value & Class Goal
Activity
(Assay 1) - IC50 nM # < 1000
(Assay 1) - Ki nM # < 1000
(Assay 2) - IC50 nM # < 1000
(Assay 2) – Ki nM # < 1000
Selectivity
(Assay 1) - IC50 / Fold selectivity nM #, # > 100
In Vivo Biology Units Value & Class Goal (Species, dose, route) – MED nM #
(Species, dose, route) - MED nM # (Species, dose, route) - MED nM #
PK Properties Units Dose (mpk),
Route,
Species
Dose (mpk),
Route,
Species
Goal t1/2 hr # # > 3
AUC0-∞, total,
unbound hr*ng/mL #, # #, # > 500 (PO)
CL mL/min/kg # # < 25% HBF
Cmax, total, unbound ng/mL (nM) #, # #, #
Tmax hr # #
Vd L/kg # #
F % # # > 20%
Other Biology Units Value & Class Goal #
#
• Compound Profiling and Efficacy Tables in Appendix
• Enter the data that you have
• Full data tables not required to be successful
Overview
• What is TRND?
• How to Apply to TRND
• TRND Evaluation Criteria
• TRND Project Selection and Agreements
• Questions
New Project Selection
• Solicitation Opens: August 1st
• Solicitation Closes: September 30th, 11:59 pm
• Non-Responsive Applications Notified: Early October
• Initial Feedback: Mid December
• TRND Final Decisions: Late March
TRND Solicitation: Important Dates 2012 Cycle
How TRND Manages Collaborative Development Projects
TRND Management of: Project Plan, Milestones,
Ongoing Review
Implement Joint Project Plan
Project Team: TRND + Partner + Academics
+ Sub-Contractors
Collaboration Agreement
TRND OVERSIGHT
Trans-NIH Advisory
Group
Joint Research
Committee
Intellectual Property
• Collaborators retain background IP, generated prior to initiation of TRND collaboration
• Potential for development of multi-party IP depends on stage at which project enters into TRND program
• Inventorship of new IP created during TRND collaboration will be determined according to U.S. patent law
Introduction to NIH R&D Agreements
Goal for NIH is:
• To maximize innovation by facilitating industry and university collaborations and sharing of scientific/technical knowledge.
• Foster the successful commercialization of new therapeutics to treat rare and neglected diseases
Available NIH agreement are:
• MTA and CDAs - External assets and know-how can be “brought in” through these agreements.
• Research collaboration agreement (RCA)
• Collaborative Research & Development Agreement (CRADA)
• Clinical research agreements
• Standard Forms / Model Agreements can be found by searching “Model Agreements” on the TRND / NCATS website, or at:
•http://www.ncats.nih.gov/about/org/divs-offices/strategic-alliances/model-agreements.html
47
Probe Development Preclinical Development/TRND
NIH-RAID
Clinical
FDA Collaboration
Systems Toxicology
RNAi
Paradigm/Technology Development
Repurposing
Lead
Optimization Preclinical
Development Probe/Lead
Development Target
Validation Target FDA
approval Clinical Trials
I II III
Project Entry Point
Deliverables
DPI
Repurposing
Unvalidated target
Validated target
Lead compound
Preclinical development
candidate
Clinical development
candidate
Genome-wide RNAi systems biology data
Chemical genomics
systems biology data
Small molecule and siRNA research probes
More efficient/faster/cheaper translation and therapeutic development
Leads for therapeutic
development
Predictive in vitro toxicology profiles
Approved drugs effective for new
indications
New drugs for untreatable diseases
Novel clinical trial designs
Drugs suitable for adoption for further
development
Assay Dev
Assay Dev
NCATS Division of Preclinical Innovation: An Integrated Pipeline
Target assay
NCATS DPI Staff
Lab Operations Automation and Cmd Mgt,
ChemistryAssay Development and Biology
Informatics
Scientific and Admin
Management
Further Information
John McKew, Ph.D.
Branch Chief, TRND Head of Chemistry, DPI
Nora Yang, Ph.D., M.B.A.
Director, Strategy and Program Operations, TRND
Online: http://trnd.nih.gov Email: [email protected]
Andre Pilon, Ph.D.
Program Analyst, TRND
Overview
• What is TRND?
• How to Apply to TRND
• TRND Evaluation Criteria
• TRND Project Selection and Agreements
• Questions