ddc presentation r christopher jan 2013

7/28/2019 DDC Presentation R Christopher Jan 2013

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Ronald J. Christopher, Ph.D., D.A.B.T., FCP

Compound Selection & Preclinical Studies


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Preclinical Research & Development

Overview

Pharmaceutical R&D Paradigm Compound Selection Preclinical R&D Activities

Pharmacology Drug Metabolism & Pharmacokinetics Drug Safety

Case Example & Clinical Translation


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Discovery To Market The Economics

Time:Discovery IND: 1-5 yearsIND NDA/BLA: ~ 6 yearsReview/Approval Time: 1.1 years avg

Expense:

The cost of developing a new drug is higherthan ever about $1.3 billion


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Success Rate of Drug Development

Candidates for a new drug to treat a disease mightinclude from 5,000 to 10,000 chemical compounds.

On average about 250 of these show promise forfurther development

About 10 of these will progress to human clinicaltrials

Research to Market Success rate: ~1 in 1,000compounds


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R&D Focus on Validation State of Targets

In

Vivo

(animal)In Vitro(e.g. cell)

In Vivo(animal)

In

Vivo

(animal)

Clinical(e.g. Ph II)

In

Vivo

(animal)

LaunchedDrug

>70% of all marketed drugs result

from R & D efforts on previouslyclinically validated targets

Low validation state High validation state


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Compressing the Drug Discovery Process?

Target

Identification

(1 3 y)

Lead

Generation

(1 2 y)

Lead

Optimization

(1.5 2.5 y)

Pre-clinical

Development

(1 y)

Formal

Development

(4 8 y)

Average Industry R& D Timeline: >12 Years

Iteration (can add years)

Lead

Gen.

(0.7 y)

Lead

Opt.

(0.9 y)

Pre-clinical

Development

(1 y)

Formal

Development

(4 y)

Desired R& D Timeline: < 7 years


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We cant afford to collect extra data in the R&D Process Therefore, optimal efficiency in R&D is critical

Taking Shortcuts

CORPORATE FINANCE

You wanna spend WHAT?!?


8/51http://www.fda.gov/oc/initiatives/criticalpath/stanski/stanski.html

How Do We Improve?

Drug Co A

Drug Co E

Drug Co C

Drug Co D

Drug Co B


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Discovery Preclinical Clinical

The new paradigm for drug R&D

Input from Business Development, Regulatory Affairs, Project Management, Legal

Integration of skillsJoint ownership/responsibility


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Compound Selection


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11

Target Choice

A good target has distinctly different meaning to

biology and chemistry personnel

In a biology sense, a good target is a biologicalpathway that can be intercepted in some way to

give a useful therapeutic outcome

In a chemistry sense, a good target is a biologicalpathway that can be intercepted in a useful

sense by an orally active small organic molecule

Interplay of the disciplines leads to success


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Typical Compound Criteria in Research

v Focus on First-in-Class or Best-in-Classv Structurally unique moleculev Solid Pharmacology

vPotency that meets or exceeds Gold standardv

Target selectivity >1,000 fold selective vs. closely related targetvEfficacy in relevant animal models (durability of response important)vExcellent Drug Metabolism & Pharmacokinetic Properties

v No DDI liabilitiesv Suitable for Q.D dosing (if oral)v Limited metabolism, etc.

vRobust Efficacy in rodent autoimmune disease modelsvExcellent Safety profile (in vitro, in vivo)


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Scaffold Morphing

Biased libraries

Virtual screening

Novel TSD Leads

De Novo Design

Shapes & Fragments

In Vivo DMPK

In Vivo PD

Developability Criteria

(P450, hERG, etc)

Biochemical/Cell-based

Screening

Iterative

Structure-Based

Drug DesignCo-Crystal

Complexes

Drug Design &

Compound

Synthesis

Lead Generation Strategy

Known Inhibitors

Compound Screening


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First tier screens Receptor Binding [EC50 < 10 nM] Solubility [0.1 - 0.2 mg/mL aq pH7] HLM / MLM / RLM T1/2 stability > 60 hERG binding [3H]-Astemizole > 10 M HepG2 cytotoxicity panel IC50 > 100 M Human 5 major P450s [microsomal] Protein binding [human / rodent] < 95 % Mini AMES [+/- S9]

Second tier studies Oral efficacy & Dose Response [ED50 ~ 1 mpk] Mouse PK / PD Single dose iv/po, SD rat and mouse [PK/PD ) Cardiotox.: hERG CEREP panel Ames mutagenicity [+/- metabolic activation]

Third tier studies Primary disease model : Mouse, Rat efficacy in vitro metabolism, metabolite ID Dose escalation PK Single dose IV/PO dog, monkey PK/PD Dog CV / rodent telemetry Pharm. Sci. [solid state testing, preformulation]

Research Testing Cascade Metrics

Tier 11,000

Tier 2

100

Tier 3

5


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Chemistry Enzyme/Ligand Assays

Ligand Selectivity(off-targets or closely related targets)

IC50

< 100 nM

Rat/Dog Plasma DPP4 Inhibition Human/Rat/Dog microsome stability CYP450 inhibition Solubility Protein binding

Rat PK/PD (iv and po)Ligand inhibition (PD)Plasma conc. timecourse

Lead Series

Declaration

Safety pharmacologye.g., Cerep

initial rodent toxicologyNon-rodent PKhERG ChannelGenetic toxicity

CandidateSelection

Selectivity > 1000-fold

Typical Research Assay Flow Scheme

Development(IND enabling studies)

Target


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Case Example


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17

ActosNesina

GleevecViraceptAgenerase

An increasing role in understanding disease and inthe design of new medicines

Structural Biology in Drug Discovery

Reprinted with permission from Time magazine.Authorization expires April 18th, 2010


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Atomic Structure of DPP-4 Protein

Catalytictriad

Side opening

Propelleropening

-propeller domain

Peptidase domain


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Structural Biology adopts the use of X-rays in the design of new medicines

But how can X-rays be used to take apicture of a protein target involved in ahuman disease and then design a drug

for that target?


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Crystal Source

Diffraction Pattern

X-Rays

X-Ray Crystallography

+ PhasesStructure

X-Ray Wavelength: 1C C bond length: 1.5"


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Overall Goal: A Best-in-Class DPP-4 Inhibitor

DPP-4 Inhibitor Program Critical Success

Factors

Absolute Criteria: Highly selective and very potent No CYP450 interactions Once-daily dosing Orally active Superior Efficacy and safety profiles

Relative Criteria: Equivalence or superiority to best known competitor DPP-4

inhibitors on all significant parameters

Key comparator compounds: Novartis (Galvus) andMerck (Januvia)


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Vildagliptin Alogliptin


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Structures of DPP-4 Inhibitors

LAF-237 (Vildagliptin/Galvus)

MK-431 (Sitagliptin/Januvia)

BMS-477118 (Saxagliptin)

F

F

FO

N

NH2

N N

N

CF3N N

O

H3C

O N

CN

NH3+ PhCO2

-

N

O

HH

NCHO

NH2

HO

NHO

N

NC

non-covalent

covalent(cyanopyrrolidine)SYR-322

(Alogliptin benzoate)

launched Oct 2006

covalent(cyanopyrrolidine)

Alogliptin

Januvia (Sitagliptin)

Galvus (Vildagliptin)

Saxagliptin


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DPP-4 Related Enzymes

Inhibitors thought to be specific for DPP-4 may inhibit other enzymes in theDPP-4 activity and/or structural homologue (DASH) family

Include: FAP/Seprase DPP-2 DPP-8 DPP-9 PREP Tryptase

Biological role of related proteases: T-cell apoptosis Attenuating T-cell activation Inactivation of regulatory neuropeptides Pathogenesis of cancer (promoting growth & metastasis)


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Alogliptin: DPP-4 Potency & Selectivity Comparisons

Compound DPP-2 DPP-8 DPP-9 FAP PREP Tryptase

Alogliptin > 100,000 > 100,000 > 100,000 > 100,000 > 100,000 > 400,000

Galvus

(Vildagliptin)> 100,000 1,400 81.5 73,000 > 50,000 > 200,000

Januvia

(Sitagliptin)

> 50,000 19,000 62,000 > 100,000 > 100,000 > 400,000

Alogliptin is a potent DPP-4inhibitor with high selectivityagainst related serineproteases

DPP-8 and DPP-9 activityappear to correlate withtoxicities in animals and may

be a key liability

0

5

10

15

20

Alogliptin 6.9

Galvus 23.8

Januvia 12.1

DPP-4i

DPP4

Potency

++++

++

+

IC50 (nM) for each enzyme


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Plasma Concentrations and DPP-4 Inhibition in Monkeys

on Alogliptin (PO Dosing)

Dose linear pharmacokinetics T1/2 (PO) = 6 hours %F = >80%

Inhibition initiated at0.25 hours post dose

Maximum DPP-4inhibition at 2 to 3 hourspost dose (90% to 91%)

0 4 8 12 16 20 241

10

100

1000

10000

100,000 2 mg/kg10 mg/kg30 mg/kg

time (hour)

PlasmaConcentration

(ng/ml)

0 2 4 6 8 10 12 14 16 18 20 22 24-10

0

20

40

6080

100110

30 mg/kg10 mg/kg2 mg/kg

Time (hours)

%I

nhibitionof

DPP-4activity

21


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Pharmacology


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Non-Obese/Diabetic N-STZ-1.5 Rats

Alogliptin orally administered 1.5 h before meal load.Mean and SD, N=8, #P0.025

Alogliptin Reduces DPP-4 Activity andIncreases Active GLP-1 Levels

##

#

020406080

100120

Control 0.1 0.3 1

DPP-4Activity

(%)

Alogliptin (mg/kg)

##

#

010203040

5060

Control 0.1 0.3 1

ActiveGLP-1

(pM)

Alogliptin (mg/kg)

16


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Alogliptin Lowers Plasma Glucose and Increases PlasmaInsulin (OGTT in N-STZ-1.5 Rats )

Mean and SD, N=6, *P0.025

0

50

100

150

200

250

300350

0 60 120

Time (min)

PlasmaGlucose(mg/dL) Control

0.03 mg/kg0.1 mg/kg0.3 mg/kg

Pre

0.5.5.5

.5

-60 0 60 120Time (min)

PamannnmL

Control0.03 mg/kg0.1 mg/kg0.3 mg/kg

Pre00.5

1

1.5

22.5

3

3.5

4

0 60 120

Time (min)

PlasmaInsulin(ng/mL)

Control0.03 mg/kg0.1 mg/kg

0.3 mg/kg

Pre

*

0

2000

4000

6000

8000

10000

12000

14000

16000

Control 0.03 0.1 0.3

IncrementalGlucoseAUC

(0-120min)(mg/dL

min)

Alogliptin (mg/kg)

*

*

0

0.5

1

1.5

22.5

3

3.5

4

Control 0.03 0.1 0.3

PlasmaInsulina

t10min

(ng/mL)

Alogliptin (mg/kg)

17


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Effects on Fasting Plasma Glucose in NormalSD Rats

Fasting Sprague-Dawley rats (7 wks old,male) were orally administered alogliptin

or nateglinide at 0 min.Mean SD, N=6. *P0.025

Alogliptin30 mg/kg Alogliptin

100 mg/kg

Control

Nateglinide30mg/kg

Nateglinide

100 mg/kg

-5000

-4000

-3000

-2000

-1000

0

1000

2000

IncrementalGlucose

AUC

(mg/dL

0-120min

)

*

*

0

20

40

60

80

100

120

0 30 60 90 120

Time (min)

P

lasmaGlucose(mg/dL)

ControlAlogliptin 30 mg/kgAlogliptin 100 mg/kgNateglinide 30 mg/kgNateglinide 100 mg/kg

0

0.5

1

1.5

2

2.5

3

0 30 60 90 120

Time (min)

PlasmaInsulin(ng/mL)

18


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Alogliptin In Vivo

Pharmacology (multiple doses)


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Alogliptin in db/db mice

db/db (N=8) and db/+ (n=5) mice(8 week-old)

Dietary admixture:CE-2 powder diet

containing 0.01%,0.03%, 0.1% of

Alogliptin for2 days

0.01% 14 mg/kg0.03% 42 mg/kg0.1% 140 mg/kg

Plasma DPP-IV activity and GLP-1 levels


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Alogliptin on DPP-IV and GLP-1 in db/db Mice

0

5

10

15

20

25

30

35

40

0.01 0.03 0.1

Control SYR-322 (%) lean

Plas

maactiveGLP-1

(pM)

* * *

0

20

40

60

80

100

120

0.01 0.03 0.1

Control SYR-322 (%) lean

Plam

saDPP-4activity

(%ofcontroldb/dbmice)

**

*

DPP-IV activity GLP-1 level

Alogliptin dose-dependently inhibitedplasma DPP-IV activity.

*p 0.025 vs. control by one-tailed

Shirley-Williams test.

Alogliptin increased plasma activeGLP-1 levels.

*p 0.025 vs. control by one-tailed

Williams test.


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Study designControl ob/ob n=8 UntreatedSYR-322 ob/ob n=8 0.002% in dietSYR-322 ob/ob n=8 0.01% in dietlean ?/+ n=4

Study designControl ob/ob n=7 Untreated

SYR-322 ob/ob n=7 0.03% in dietlean ?/+ n=4

Study-1; Dose-dependent efficacy of Alogliptin

Study-2; High dose efficacy of Alogliptin

Mice; ob/ob/Crj and lean(Charles River Laboratories Jap

Four weeks treatment of Alogliptin admixture with diet.

Four weeks treatment of Alogliptin admixture with diet.

(2.80.3 mg/kg/d)(14.1 0.8 mg/kg/d)

(42.2 4.0 mg/kg/d)

Chronic (4 Week) Study in ob/ob (obese) mice


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0

20

40

60

80

100

120

Control 0.002% 0.01% ?/+

PlasmaDPP-IV

activity(%)

0

2

4

6

8

10

12

14

16

Control 0.002% 0.01% ?/+

PlasmaGLP-1(pM)

Plasma DPP-IV Activity and Active GLP-1 Levels after4-week Treatment of Alogliptin in ob/ob Mice

*

* #

#

Mean and SD, n=8*p


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0

2

4

6

8

10

12

14

16

Control 0.002% 0.01% ?/+

Plasma

GLP-1(pM)

#

#

ob/ob MiceMean and SD, n=8*p


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0

100

200

300

400

500

600

0.002% 0.01%

Control SYR-322 ?/+

Plasm

aglucagon(pg/mL)

0

20

40

60

80

100

120

140

0.002% 0.01%

Control SYR-322 ?/+

Plasmainsulin(ng/mL)

**

Mean and SD, n=8*p


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Pancreatic Insulin Content Restored with Drug

Intense insulin staining wasobserved in islets of ob/ob micetreated with alogliptin

Insulin staining in islets ofalogliptin-treated ob/ob mice wascomparable to that in vehicle-treated non-diabetic ?/+ mice

Moritoh et al, 511-P, ADA 2007

Control

Alogliptin Treated (Ob/Ob)

Control (Ob/Ob)


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Drug Metabolism &

Pharmacokinetics


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In Vivo Pharmacokinetic/Pharmacodynamic Profiles

Sprague-Dawley rats Beagle dogs Cynomolgus monkeys

Pl C t ti d DPP IV I hibiti i


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Plasma Concentrations and DPP-IV Inhibition inMonkeys for Alogliptin (po)

Dose linear pharmacokinetics

T1/2 (oral) = 6 hours

F = >80%

Inhibition Initiated at 0.25 hours post dose

Maximum DPP-IV inhibition at 2 to 3 hours post

dose (90% to 91%)

Inhibition still apparent at 24 hours post dose

(81% to 84%)

Plasma concentrations % Inhibition of DPP-IV activity

0 4 8 12 16 20 241

10

100

1000

10000

1000002 mg/kg

10 mg/kg

30 mg/kg

time (hour)

plasma

concentration

(ng/ml)

0 2 4 6 8 10 12 14 16 18 20 22 24-10

0102030405060708090

100110

30 mg/kg

10 mg/kg

2 mg/kg

Time (hours)

%In

hibitionof

DPP

IVactivity


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CYP Isoforms involved in metabolism CYP-2D6 (N-demethylated metabolite) CYP-3A4 also involved in metabolism

CYP induction/inhibition Minimal induction of CYP3A4/5 (up to 5.88X) Minimal inhibition of CYP2D6 (27% at 100 mol/L)

Low protein binding No drug-drug interactions (in vitro) when co-administered

with other diabetic agents

Drug Metabolism Profile


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Pharmacokinetic Profile

ParameterRats

(20 mg/kg)Dogs

(2 mg/kg)Monkeys

(10 mg/kg)

Cmax 1,192 278 3,208

AUC(0-) 2,821 699 15,859

T1/2 (hours)(IV)

1.4 2.9 5.7

Tmax (hours) 1.7 0.75 1.0

F (%) 42 71 87

ExcretionRoute

Urine, feces Urine, feces --

Pharmacokinetic Parameters Following a Single Oral Dose

Units: Cmax= ng/mL; AUC= nghr/mL


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Drug Safety Evaluation


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Alogliptin Drug Safety Profile Overview

Safety Pharmacology: No CNS, Cardiovascular orPulmonary toxicities noted.

Genetic Toxicology: Not mutagenic or clastogenic.

Chronic Toxicology: doses up to 900 mg/kg (rat) and 200mg/kg (dog)


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Clinical Translation

H S f t M i


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Human Safety MarginsExposureMultiples*EndpointsFrom Oral

ToxicityStudies Dose(mg/kg/day) AUC(nghr/mL) 12.5mg 25mg

6 Month Chronic Toxicity Study in RatsNOAEL 400 258,579 362 181

9 Month Chronic Toxicity Study in Dogs

NOAEL 200 400,140 560 280

*Plasma AUC0-24h values determined based on data obtained in the

multiple repeat dose (14 day) study in patients with type 2 diabetesmellitus.

NOAEL - No Observable Adverse Effect Level = nontoxic


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Single Dose in Healthy Volunteers: Pharmacokinetics

110

1001000

10000

0 10 20 30 40 50 60 70 80Time (hr)

2550100

200400800

Alogliptin Concentration vs Time

4


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Single Dose in Healthy Volunteers: DPPIV Inhibition

-20

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80Time (hr)

2550100200400800Placebo

DPP-4 Inhibition vs Time

5


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Alogliptin Single Dose in Healthy Volunteers:

Conclusions

No dose-limiting adverse events 25 mg to 400 mg to 800 mg

Alogliptin was absorbed rapidly Total exposure (AUC) and peak exposure (Cmax)

increased with increasing dose Pharmacokinetics consistent with once daily dosing DPP-4 inhibition consistent with once daily dosing No significant metabolites

Plasma and urine concentrations of M-I (N-demethylated) and M-II (N-acetylated) metaboliteswere


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ddc presentation r christopher jan 2013

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