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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.