Form 2 NCTT Project Information Template

Form Approved
OMB NO. 0925-XXXX
Exp. Date XX/XX/2015

Name:
Institution:
Address:
E-mail:
Title:
This 5-page document should outline the scientific nature and rationale of the proposed project.
For additional information, please refer to the TRND Solicitation Instructions. Additional material
can be uploaded as appendices described in the instructions.
Background
Replace text with the requested information. Provide a brief summary of the disease to be treated and
the rationale for the type of small molecule compound or biologic therapeutic in order to provide the
reviewers an understanding of the opportunity. Include data on rare or neglected disease status, the
current standard of care for the disease, and why new therapies are needed. Very briefly describe the
competitive landscape and efficacy data on comparator compounds, if any.

Therapeutic Hypothesis
Replace text with the requested information. Include a clear statement on the therapeutic hypothesis
and the clinical indication to be targeted for FDA approval. This can include the projected reduction of
symptoms, slowing of disease progression, or the feasibility of treating the disease. Review the level of
consensus in the field supporting the proposed mechanism of disease and hypothesis that modulation
of the proposed target will substantially improve morbidity and/or mortality in the disease. Summarize
the evidence that validates the drug target from cellular or animal models and clinical studies. Assess
feasibility to reach first in human studies. Manuscripts and supporting publications can be uploaded in
the appendix.

Current State of Project
1. Replace text with the requested information Projects of interest will be at one of the following
stages: (1) lead optimization including clear structure-activity relationships (SAR) in at least two
structurally distinct chemical series or well defined biological lead, reproducible activity in
Public
 reporting
 burden
 for
 this
 collection
 of
 information
 is
 estimated
 to
 average
 one
 hour
 per
 response,

including
 the
 time
 for
 reviewing
 instructions,
 searching
 existing
 data
 sources,
 gathering
 and
 maintaining

the
 data
 needed,
 and
 completing
 and
 reviewing
 the
 collection
 of
 information.

 An
 agency
 may
 not

conduct
 or
 sponsor,
 and
 a
 person
 is
 not
 required
 to
 respond
 to,
 a
 collection
 of
 information
 unless
 it

displays
 a
 currently
 valid
 OMB
 control
 number.

 Send
 comments
 regarding
 this
 burden
 estimate
 or
 any

other
 aspect
 of
 this
 collection
 of
 information,
 including
 suggestions
 for
 reducing
 this
 burden,
 to:
 NIH,

Project
 Clearance
 Branch,
 6705
 Rockledge
 Drive,
 MSC
 7974,
 Bethesda,
 MD
 20892-­‐7974,
 ATTN:
 PRA

(0925-­‐XXXX).

 Do
 not
 return
 the
 completed
 form
 to
 this
 address.

Applicant’s last name, first initial

Abbreviated title

Submission deadline

primary and orthogonal assays, efficacy in an accepted animal model (or when not available,
cellular model) of the disease, and initial indications of favorable Absorption, Distribution,
Metabolism, and Excretion (ADME) properties, (2) high-quality New Molecular Entity (NME)
lead(s) with clear efficacy, good DMPK properties and initial non-GLP safety studies
demonstrating absence of gross toxicities, (3) NME clinical candidates with incomplete INDenabling PK/PD/toxicology/formulation studies; or (4) a drug previously approved for another
indication by FDA with efficacy in an animal (or when not available, cellular) model of a rare or
neglected disease, making it a candidate for repurposing but in need of formulation, dosefinding, disease-specific toxicology, or other studies to allow clinical testing to commence. As
appropriate for the stage of the program, please describe:

a. Compound or biologic optimization status and strategy, including the assays and
efficacy studies used to guide medicinal chemistry optimization and define structureactivity relationships (SAR), including evidence of their robustness, reproducibility, and
relevance to the human disease or symptom. Include results of molecular pharmacology
assays, including in vitro functional activity, potency, and pharmacology, including
evaluation of efficacy in biochemical, cellular, and model organism assays, and
justification of the relevance of those assays to the human symptom/disease to be
treated
b. Medicinal chemistry optimization performed to date, including questions remaining and
potential for further optimization.
c. Evaluation of Absorption, Distribution, Metabolism, and Excretion (ADME) properties in
vitro and in vivo, including routes and products of metabolism, microsomal stability, and
related studies
d. Evaluation of pharmacokinetics (PK), pharmacodynamics (PD), and efficacy, including
oral bioavailability and half-life in serum and other relevant fluids/tissues
e. Toxicology studies in rodents and non-rodents, including IND-directed toxicology, with
correlative pharmacology and histopathology
f.

Definition or optimization of dose and schedule for in vivo activity in animal models

g. Pharmacodynamic measures in animals, and their applicability as biomarkers in human
studies
h. Acquisition of bulk substance (Good Manufacturing Practices - GMP and non-GMP),
and availability of protocols for scale-up production from lab-scale to clinical-trials lot
scale, and analytical methods
i.
2
 |
 P a g e

Development of suitable formulations

Applicant’s last name, first initial

j.

Abbreviated title

Submission deadline

Production and stability assurance of dosage forms

k. Projected dose, dose regimen, length of treatment and duration of therapeutic response
in humans, if known
l.

Biomarkers developed, and evidence of their utility and predictive value in the clinical
setting

m. Determination of clinical endpoints, and whether these are accepted by regulatory
agencies
n. Describe natural history studies of the disease and their relevance to the indication of
the candidate therapy
o. Status of biobanks and registries of patients with the disease and which organizations
maintain them
p. Potential clinical trial designs and evidence of feasibility
q. Results of consultations with FDA or other regulatory agencies, if any, on the project
r.

Results of assessments you have received from impartial clinical experts in the field on
why modulation of the target/pathway/phenotype is expected to decrease the morbidity
or mortality of the disease.

s. Results of discussions and assessments with potential drug development partners that
would support this drug candidate to FDA registration and market launch.
t.

For projects with clinical data: provide a summary of clinical efficacy, safety, and PK/PD
data. Describe the clinical trial strategy (e.g., primary and secondary study objectives,
endpoints, patient population, eligibility criteria, estimated sample size, treatment
arms/regimens, statistical endpoints, correlative studies, and patient samples required to
perform correlative studies). Describe availability of clinical trial support, infrastructure
resources, and experts available. If available, the Investigator's Brochure should be
uploaded in the appendix.

Proposed Development Strategy
Replace text with requested information. Describe what is needed to advance the program to IND
status for the rare or neglected disease indication, what the current roadblocks to development are,
and the stage that the project will need to be taken to in order to attract outside development
resources. If the development plans are not established or clear, please indicate this. Include specific
3
 |
 P a g e

Applicant’s last name, first initial

Abbreviated title

Submission deadline

details as necessary to demonstrate that the project has been well thought out (for example, the
availability of appropriate cellular and animal models, patent searches on the compounds and
components of the assays used to evaluate efficacy, etc.). Address the scientific feasibility of the
proposed development strategy, and whether and why proof-of-concept human studies are likely to be
needed for the project to be licensed.
Justification
Replace text with requested information. Address how the resulting drug from this collaboration will
change standard of care and impact the practice of medicine for this rare or neglected disease. Provide
a statement that the applicant team will engage and collaborate for the length of this drug development
project and what expertise and/or resources the applicant will bring to the project team. Describe the
likelihood of the drug candidate being adopted at the completion of preclinical development (i.e., once
an IND is approved), and why another organization (biotechnology companies, venture capital firms,
pharmaceutical companies) is presently unwilling to fund or develop this drug project as it currently
stands.

Timeline and Milestones
Replace text with requested information. Outline a potential timeline for conducting the collaborative
research with NCTT. Include potential milestones. Describe potential challenges and go/no go decision
points (a timeline chart is acceptable). (Note: Following acceptance the project, a project team of NCTT
investigators and applicant investigators will establish a new timeline, milestones, and go/no go
decisions points based on the evaluation recommendations.)

4
 |
 P a g e

Applicant’s last name, first initial

Abbreviated title

Appendix 1:
Provide data on the proposed lead compound using the following tables:

I.

Compound Properties Profile:

Lead Compound
Structure or
Composition

Calculated
Properties

Value

Goal

Compound
ID

Provide
data

N/A

MW

Provide
data

< 500

Log D7.4,
cLog P

Provide
data

1-3, 1-4.5

TPSA

Provide
data

< 140 (oral),
< 90 (CNS)

Ligand
Efficiency
(LE, LELP)

Provide
data

> 0.29, <10

Rotatable
Bonds

Provide
data

≤ 10

N+O
(HBA)

Provide
data

≤ 10

NH + OH
(HBD)

Provide
data

≤5

5
 |
 P a g e

Submission deadline

Applicant’s last name, first initial

Abbreviated title

Submission deadline

In Vitro Properties

Units

Value & Class

Goal

Compound ID

N/A

Provide data

N/A

Solubility (pH, media )

(µg/mL)

Provide data

> 60

t1/2 (min)

Provide data

> 30

CLint (mL/min/mg)

Provide data

< 10

t1/2 (min)

Provide data

> 120

CLint, µL/min/10 cells

Provide data

<5

Stability – Plasma (species)

% Remaining at 3 hr

Provide data

> 80%

Stability – Solution (media)

% Remaining at 24 hr

Provide data

> 80%

% Inhibition at 3 µM

Provide data

< 15%

IC50 (µM)

Provide data

> 10

Cmax at MED / Ki

Provide data

< 0.1

Fu, plasma (%)

Provide data

Fu, tissue (%)

Provide data

Provide data

>1

Provide data

>4

Papp (a-b, 10 cm/s)

Provide data

> 10

Efflux Ratio

Provide data

<3

Papp (a-b, 10 cm/s)

Provide data

> 20

Pgp Efflux Ratio

Provide data

<2

IC50 (µM)

Provide data

> 10

IC50 / Free Cmax

Provide data

> 30

Free Cmax - Plasma

Total Cmax (µM) * Fu, plasma

Provide data

Free Cmax - Tissue

Total Cmax (µM) * Fu, plasma

Provide data

Screening Ames

Positive / Negative

Provide data

Stability - Microsomes (species)

Stability – Hepatocytes (species)

CYP450 Inhibition (isozymes)

Plasma Protein & Tissue Binding
(species)
Permeability - PAMPA
Permeability - PAMPA-BBB

6

-6

Pe (10 cm/s)
-6

Pe (10 cm/s)
-6

Permeability - Caco-2

-6

Permeability - MDR1-MDCKII

hERG - (method)

6
 |
 P a g e

Negative

Applicant’s last name, first initial

II.

Abbreviated title

Submission deadline

Compound Efficacy Profile:

In Vitro Biology
Compound ID
Activity

Units

Value & Class

N/A

Goal
N/A

(Assay 1) - IC50

nM

Provide data

< 1000

(Assay 1) - Ki

nM

Provide data

< 1000

(Assay 2) - IC50

nM

Provide data

< 1000

(Assay 2) – Ki

nM

Provide data

< 1000

Selectivity
(Assay 1) - IC50 / Fold selectivity

nM

Provide data

> 100

In Vivo Biology

Units

Value & Class

Goal

Compound ID

N/A

(Species, dose, route) – MED

nM

Provide data

(Species, dose, route) - MED

nM

Provide data

(Species, dose, route) - MED

nM

Provide data

Other Biology

7
 |
 P a g e

Units

Value & Class

Goal

Applicant’s last name, first initial

Abbreviated title

Submission deadline

Dose (mpk), Dose (mpk),
Route,
Route,
Species
Species

PK Properties

Units

Goal

Compound ID

N/A

t1/2

hr

Provide data

Provide data

AUC0-∞, total,

hr*ng/mL

Provide data

Provide data > 500 (PO)

mL/min/kg

Provide data

Provide data < 25% HBF

N/A
>3

unbound

CL

Cmax, total, unbound ng/mL (nM) Provide data
Tmax

hr

Provide data

Provide data

Vd

L/kg

Provide data

Provide data

F

%

Provide data

Provide data

8
 |
 P a g e

Provide data

> 20%

Applicant’s last name, first initial

Abbreviated title

Submission deadline

Appendix2:

References for In Vitro ADME Assays and In Vivo Pharmacokinetics
General References
1. “Drug-Like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity
Optimization”, E. H. Kerns, L. Di (2008), Elsevier.
2. “Pharmacokinetics and Metabolism in Drug Design”, Smith, D.A., et al., (2001), Wiley-VCH
3. “Experimental and computational approaches to estimate solubility and permeability in drug disc.
and development settings.” Lipiniski, C.A., et al., (1997), Adv. Drug Delivery Rev. 23, 3-25.
4. “Application of pharmaceutical profiling assays for optimization of drug-like properties.” Di, Li; et
al., Current Opinion in Drug Discovery & Development (2005), 8(4), 495-504.
5. “High Throughput Physicochemical Profiling for Drug Discovery”, E.H. Kerns; J. Pharm. Sci.
(2001) 90, 1838-1858.

Solubility
1. “Solution Stability – Plasma, Gastrointestinal, Bioassay”, Li Di, et al., Current Drug Metabolism
(2008), 9(9), 860-868.
2. “In Vitro Solubility Assays in Drug Discovery”, Edward H. Kerns, et al., Current Drug Metabolism
(2008), 9(9), 879-885.

Stability – Microsomes, Hepatocytes, Plasma, Solution
1. “High Throughput Microsomal Stability Assay for Insoluble Compounds”; L. Di, et al., International
Journal of Pharmaceutics (2006) 317(1), 54-60.
2. “Metabolic Stability: Main Enzymes Involved and Best Tools to Assess It”, R. Laine, Current Drug
Metabolism (2008), 9(9), 9210-927.
3. “Development and Application of High Throughput Plasma Stability Assay for Drug Discovery”, L.
Di, et al., International Journal of Pharmaceutics (2005) 297(1-2) 110-119.
4. “Development and Application of an Automated Solution Stability Assay for Drug Discovery”, L.
Di, et al., Journal of Biomolecular Screening (2006) 11(1), 40-47.

CYP450 Inhibition
1. “Comparison of Cytochrome P450 Inhibition Assays for Drug Discovery Using Human Liver
Microsomes with LC-MS, rhCYP450 Isozymes with Fluorescence, and Double Cocktail with LCMS”; L. Di, et al., International Journal of Pharmaceutics (2007), 335(1-2), 1-11.
2. “In Vitro Cytochrome P450 Inhibition and Induction”, R.L. Walsky, et al., Current Drug Metabolism
(2008), 9(9), 928-939.

Plasma Protein, Tissue Binding, and Free Cmax – Plasma, Tissue
1. “Plasma / Serum Protein Binding Determinations”, M.J. Banker, et al., Current Drug Metabolism
(2008), 9(9), 854-859.
2. “The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery”,
Dennis A. Smith, Li Di, Edward H. Kerns, Nature Reviews Drug Discovery (2010), 9(12), 929-39.

Permeability – PAMPA
1. “Physicochemical high throughput screening: Parallel artificial membrane permeability assay in
the desc. of passive absorp. processes”, Kansy, M., et al., (1998), J. Med. Chem. 41, 1007-1010.
2. “High-throughput permeability pH profile and high-throughput alkane/water log P with artificial
membranes.” Wohnsland, F.; Faller, B. (2001), J. Med. Chem. 44, 923-930.

Permeability – PAMPA-BBB
9
 |
 P a g e

Applicant’s last name, first initial

Abbreviated title

Submission deadline

1. “High Throughput Artificial Membrane Permeability Assay for Blood-Brain Barrier”, L. Di, et al.,
Eur. J. Med. Chem. (2003) 38, 223-232.
2. “Comparison of blood-brain barrier permeability assays: in situ brain perfusion, MDR1-MDCKII
and PAMPA-BBB”, Li Di, et al., Journal of Pharmaceutical Sciences (2009) 98(6):1980-1991.

Permeability – Caco-2
1. “Caco-2 monolayers in experimental and theoretical predictions of drug transport”, Artursson, P.,
et al., (2001) Adv. Drug Deliv. Rev., 46, 27-43.
2. “Assessing the absorption of new pharmaceuticals”, Hidalgo, I.J., (2001), Curr. Topics Med.
Chem., 1, 385-401.

Permeability – MDR1-MDCKII
1. “Rational use of in in vitro P-glycoprotein assays in drug discovery”, Polli JW, et al. (2001), J
Pharmacol. Exper. Therapeutics 299, 620-628.
2. “Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain
barrier and to increased sensitivity to drugs”, Schinkel, A.H., et al., (1994), Cell 77, 491-502.

hERG
1. “Relationship between preclinical cardiac electrophysiology, clinical QT interval prolongation and
torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug
development”, Redfern, W.S. (2003), Cardiovascular Res. 58, 32-45.
2. “Patch clamping by the numbers”, Wood, C., et al., (2004), Drug Discovery Today, 9, 434-441.

Ames Test
1.

“Methods for detecting carcinogens and mutagens with the salmonella/mammalian-microscope
mutagenicity test”, Ames, B.N., et al., (1975), Mutation Research 31, 347-363.
2. “Improvement of the Ames test using human liver S9 preparation”, In: Yan, Z. and Caldwell, G.W.
(eds.), Optimization in Drug Discovery: In vitro Methods”, Totowa, Humana Press, pp. 325-336.

In vivo Pharmacokinetics
1.

“Rapid determination of pharmacokinetic properties of new chemical entities: in vivo
approaches”, Cox, K.A., et al., (2002), Combinatorial Chem. and H.T.S., 5, 29-37.
2. The simultaneous determ. of mixtures of drug candidates by liquid chrom./APCI mass spectrum.
as an in vivo drug screening procedure”, (1997), Rapid Comm. Mass Spectrom., 11, 17-23.

10
 |
 P a g e