Global Strategies & Case Reports of Developing NME Leads to Human TrialsGlobal Strategies & Case Reports of Developing NME Leads to Human Trials

Diane Tang-Liu, PhDVice President, PreDevelopment,

Fast Track Development, and Clinical PharmacokineticsAllergan, Inc., Irvine, CA

Cost of developing a new drug increases to about $1.7 billion…Cost of developing a new drug increases to about $1.7 billion…

Wall Street Journal, December 8, 2003

Rev

enue

(in

billi

ons)

Rev

enue

(in

billi

ons)

Jackpots & Valuables

Jackpots & Valuables

0.60.6

a Med Ad News 20 (5), 7 May 2001.b Ash, R. The Top 10 of Everything 2001, Dorling Kindersley, New York, 2000.c Guiness World Records 2001, Guinness World Records LTD, London, 2000.

Hit MovieHit

Movie

5.25.2

Top Ten Artists

Top Ten Artists

4.24.2

OmeprazoleOmeprazole

6.266.26

Pharmaceuticals are a high-gain enterprise. In the year 2000, the worldwide pharmaceutical market was about 325 billiondollars There were forty-four drugs with world-wide sales over 1 billion dollars —a general threshold for blockbuster status—from among which omeprazole (Prilosec™) was the top moneymaker, at 6.26 billion dollars.a

Revenue in the year 2000 from this single drug exceeded the total cash intake from the top five-grossing movies of all time (Titanic, two Star Wars movies, Jurassic Park, and Independence Day)b as well as the combined retail value of all the known paintings of the top ten grossing artists (Picasso, Monet, Renoir, Degas, Cézanne, Chagall, Matisse, Pissaro, van Gogh, and Modigliani)b.

Finally, the combined value of the highest prices ever paid for the most expensive diamond, coin, clock, pen, piece of furniture, sculpture, book, baseball, manuscript, plus the biggest slot-machine and lottery jackpots is only about ten percent of the single-year revenue of omeprazole.c

Only 3 out of 10 marketed drugs produce revenues that match or exceed average R & D costs…

Only 3 out of 10 marketed drugs produce revenues that match or exceed average R & D costs…

Pharmacoeconomics, December 2002

A new medical compound entering Phase 1 testing is estimated to have only 8% chance of reaching the market…

A new medical compound entering Phase 1 testing is estimated to have only 8% chance of reaching the market…

Critical Path Report, FDA, March 2004

Managing the Attrition CurveManaging the Attrition Curve

10

8

6

4

2

0

# of

Com

poun

ds i

n D

evel

opm

ent

# of

Com

poun

ds i

n D

evel

opm

ent Phase 1Phase 1 Phase 2Phase 2 Phase 3Phase 3

Repeat Dose ToxRepeat Dose Tox

CarcinogenicityCarcinogenicity

Human Safety Human Safety Human Safety Human Safety Pivotal Safety Pivotal Safety AssessmentAssessment & Efficacy& Efficacy & Efficacy& Efficacy

Normals Controlled Pt. Groups Large Target Patient-Populations

CPK-Guided CPK-Guided CPK- CPK-PD: CPK-PD: Dose EscalationDose Escalation Patient Variables Special PopulationsSpecial Populations

CPK-BA Genetic Polymorphism Hepatic ImpairmentDose Proportionality Drug-drug interaction Renal ImpairmentHuman Metabolism Young vs. Elderly Drug-Drug Interaction

Food Effect BA of Final Formulation Pediatric PopulationPK Bridging Study Population PK

Therapeutic Drug Monitoring

Repeat Dose ToxRepeat Dose Tox

INDINDNDANDA

Reasons that Compounds FailReasons that Compounds Fail

ToxicityPoor PK Profile

Lack of EfficacyMarket

Reasons

Poor PK Profile

Toxicity

Lack of Efficacy

Market Reasons31 %

6 %

41 % 22 %

1964

1985

Discovery Pre-Clinical Development

ClinicalDevelopment

INDINDLeadLeadSelectionSelection

Prentis, et al, Br J Clin Pharmac, 25, 1988Data on 198 failures of 319 NCEs in UK, 1964-1985

Drug Withdrawal from the U.S. Market(Due to Unfavorable Drug Metabolism Profile)

Drug Withdrawal from the U.S. Market(Due to Unfavorable Drug Metabolism Profile)

Posicor® (BP)7/1997

Raxar® (antibiotic)8/1997 10/1999

6/1999

19971997 19981998 200020001999199919961996

7/2000

Rezulin® (Type 2 diabetes)1/1997

19951995

Hismanal® (allergy)1988…

Propulsid® (heartburn)1993…

Seldane® (allergy)1982…..

2/1998

3/2000

6/1998

Information on polymorphic ADME genes is the most advanced area in genomic regulatory submission and a high priority for regulatory agencies…

Information on polymorphic ADME genes is the most advanced area in genomic regulatory submission and a high priority for regulatory agencies…

Reasons That Compounds Fail—2001

Data provided by 25 companiesfor 166 of the 189 NASs Terminated in 2001

STRATTERA® (atomoxetine HCl)STRATTERA® (atomoxetine HCl)A selective norepinephrine reuptake inhibitor

Attention-Deficit/Hyperactivity Disorder

Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetinecompared with people with normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.

Laboratory tests are available to identify CYP2D6 PMs.

The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetineconcentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetineconcentration in EMs and 45% of atomoxetine concentration in PMs).

Drug Withdrawal from the U.S. Market(Due to “Safety” Issues)

Drug Withdrawal from the U.S. Market(Due to “Safety” Issues)

20022002 20032003 2005200520042004200120011997-20001997-2000

9/2004

Bextra® (arthritis)

2/2005Tysabri® (MS)

Vioxx® (arthritis)

11/2000Lotronex® (IBS)

2/2000

Baycol® (lipid-lowering)8/2001

Lotronex® (IBS)*6/2002

Duract® (pain)7/199 7 6/1998

Redux® (obesity)4/1996 9/1997

11/2004

11/2001 4/2005

1997

5/1999

*Restricted Marketing

Health CanadaHealth Canada

Clinical Trial Applications

30-day default review period7-day target for Phase 1 and comparative BA trials

The Investigational Medicinal Product Dossier (IMPD) The Investigational Medicinal Product Dossier (IMPD)

IMPD, IB, and the Clinical Protocol

The aim of this information is not the registration of the drug but rather its use in a particular clinical trial about which the EC/CA will give an opinion

Ethics Committee/Competent Authority

Compound A: FIM Dose SelectionCompound A: FIM Dose Selection

40 mgActual FIM Dose

1620 mgFIM Dose per Guidance

500 mg/kg/d X 28 dNOAEL, Dog

1000 mg/kg/d X 28 dNOAEL, Rat

40 80

160

320

480

640

800

960

0

100

200

300

400

500

600

700

800

900

1000

40 80

160

320

480

640

800

960

0

100

200

300

400

500

600

700

800

900

1000

2004 2005Sep-16

Sep-30Oct-14

Oct-28Nov-11

Dec-16Jan-06

Jan-27

IND Amendment

Compound A: Dose EscalationCompound A: Dose Escalation

Dosing Dates

Dos

e (m

g)

Compound A: FIM DosesCompound A: FIM Doses

40 mgActual FIM Dose

1620 mgFIM Dose per Guidance

500 mg/kg/d X 28 dNOAEL, Dog

1000 mg/kg/d X 28 dNOAEL, Rat

Highest Dose in FIM Study: 960 mg

Compound A: Comparative Exposure Between Animals and Man

Compound A: Comparative Exposure Between Animals and Man

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

Cmax AUC

Rat , NOAEL

Dog, NOAEL

Man, HighestDose

Compound B: FIM Dose SelectionCompound B: FIM Dose Selection

3 mgActual FIM Dose

3 mgFIM Dose per Guidance

30 mg/kgNOAEL, Dog

60 mg/kgNOAEL, Rat

Compound B: Dose EscalationCompound B: Dose Escalation

600

240180

12060

10

475

375

300

3030

100

200

300

400

500

600

700

600

240180

12060

10

475

375

300

3030

100

200

300

400

500

600

700

2004 2005Nov-16

Nov-30Dec-14

Jan-11Jan-25

Feb-08Feb-22

Mar-08Apr-26

IND Amendment

May-10May- 24

Dosing Dates

Dos

e (m

g)

Compound B: Comparative Exposure Between Animals and Man

Compound B: Comparative Exposure Between Animals and Man

0

20000

40000

60000

80000

100000

120000

Cmax AUC

Rat , NOAEL

Dog, NOAEL

Man, Highest Dose

Compound B: FIM DosesCompound B: FIM Doses

3 mgActual FIM Dose

3 mgFIM Dose per Guidance

30 mg/kgNOAEL, Dog

60 mg/kgNOAEL, Rat

Highest Dose in FIM Study: 600 mg

Compound C: FIM Dose SelectionCompound C: FIM Dose Selection

0.3 mgActual FIM Dose

1 mgFIM Dose per Guidance

10 mg/kg/d X 28dNOAEL, Dog

1 mg/kg/d X 28 dNOAEL, Rat

Compound C: Dose EscalationCompound C: Dose Escalation

180

120

90

60

30

20

10310.3

0

20

40

60

80

100

120

140

160

180

200

180

120

90

60

30

20

10310.3

0

20

40

60

80

100

120

140

160

180

200

2004 2005Dec-03

Dec-17Jan-07

Jan-21Feb-04

Feb-18Mar-04

Mar-18Apr-08

Apr-22

Dosing Dates

Dos

e (m

g)

Compound C: Comparative Exposure Between Animals and Man

Compound C: Comparative Exposure Between Animals and Man

0

500

1000

1500

2000

2500

3000

3500

4000

4500

Cmax AUC

rat , NOAEL

dog, NOAEL

man, MaxDose

Compound C: FIM DosesCompound C: FIM Doses

0.3 mgActual FIM Dose

1 mgFIM Dose per Guidance

10 mg/kg/d X 28dNOAEL, Dog

1 mg/kg/d X 28 dNOAEL, Rat

MTD Dose: 180 mg

Compound D: FIM DosesCompound D: FIM Doses

60 mg/m2/dDose Limiting Toxicity in man @

60 mg/m2/d up to 99dFIM Dose

540 mg/m2/d X 30dSTD, Dog

590 mg/m2/d X 30 dSTD, Rat

MTD Dose: < 30 mg/m2/d

Exploratory INDExploratory IND

“The agency believes that sponsors have not taken full advantage of that flexibility and often provide more supporting information in their INDsthan is required by regulations”

Clarifies preclinical/clinical/ CMC approaches for expIND for

Clinical pharmacokinetic or imagingHuman pharmacological studiesHuman mechanisms of action studies

Duration of dosing in man: no more than 7 days

FDA Draft Guidance, April 14, 2005

Exploratory IND Studies:Exploratory IND Studies:

For investigational new drugs and biological products

Including recombinant therapeutic proteins and monoclonal antibodiesDoes not apply to human cell or tissue products, blood and blood proteins, vaccines or devices

Very early Phase 1 studiesTypically prior to traditional dose escalation, safety, and tolerance studies

Very limited human exposureNo therapeutic intentLimited dose range and limited period of time

Assess feasibility for further development

For Human PharmacokineticsFor Human Pharmacokinetics

A microdose: < 1/100th of a pharmacologic effect dose and < 100 ug

For Pharmacologic Effect StudiesFor Pharmacologic Effect Studies

A starting dose no greater than 1/50 of the NOAEL from 2 week tox in a sensitive species on mg/m

Traditional vs. Exploratory INDTraditional vs. Exploratory IND

CMC;Guidance in development for cGMP

CMC:Graded nature as needed

AddressRationale of compound selection and investigation endpointSub-therapeutic or pharmacologic dose, thus lower risk to subjects

Provide Justification to AddressProposed clinical program and potential outcomeMaximal tolerated dose

Nonclinical Safety under GLP in general for microdosing in man:

Extended, single-dose toxicity, one species, using intended clinical route

For human pharmacology:2-week tox in rat and a non-rodentSafety pharmacologyGenotoxicity

For human MOA:Pharmacologic endpoints

Nonclinical Safety to AddressSelection of FIM doseTarget organ toxicityPharmacodynamics

One or More Related NMEsA Single NMEExploratory INDTraditional IND

ConclusionConclusion

Innovative early clinical evaluation of one or more NMEs will generate critical information in a timely and cost-effective manner.

Innovative early clinical evaluation of one or more NMEs will generate critical information in a timely and cost-effective manner.