drug development a multidisciplinary process - toxikologie.de · solvay pharmaceuticals, hannover...

Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 1

Drug DevelopmentA Multidisciplinary Process

Ulf Preuschoff/Siegfried SchäferSolvay Pharmaceuticals

Hannover


Solvay Pharmaceuticals R&D Sites

Brussels, Belgium Fournier, France

Hannover, Germany

Tokyo, Japan

Marietta, USAWeesp, The Netherlands


Solvay Pharmaceuticals Therapeutic Areas


Drug Development SchemeManagement Decision Points

Research Phase Development Phase Launch Phase

Move to phase IIa

(POC)

Drug candidate selected and move to Pre-Clinical stage

Validated HitsStart

ResearchProgramme

Decision to file submissionAMM/NDA

Launch per

countryMove to phase III

Leads identified and move to lead

optimisation and candidate selection

Decision to go into

manHits identified with

Potential foroptimisation

StrategicPlan

Move to phase IIb

Validate launch

sequence

Hits character-isation

& selectionHTS

Target ident-

ificationHits to Leads

Leads optimisation & candidate

selectionPre-

ClinicalIND/CTA

submission + Phase I

Phase IIaM8M7M6M5M4M3M2M1 Phase

IIbPhase

III M12 M14M9 M10Pre-

Launch 1

M11Phase III

+ pre-launch

Phase IV

First time in man = first administration of drug product in a healthy

volunteer

Production of GMP

1/10 commercial scale

LaunchMAA or NDA notification receivedKey events:


Research and Development

Sequence 1 : R to DSequence 1 : R to D Sequence 2 : mgs to tons

Sequence 3 : clinical to launchSequence 3 : clinical to launchToxicology/Safety developmentToxicology/Safety development


molekular-biologische,

biotechnologische,,

bioinformatische,protein-

kristallographische,medizinische u.a.

Disziplinen

Drug Discovery OrchestraPräklinische Phasen, Prozesse und beteiligte Disziplinen

TargetTargetValidationValidation

AssayAssayDevelopmentDevelopment

primary screeningprimary screeningCC/HTSCC/HTS

secondarysecondaryscreeningscreening

in vivoin vivoprofilingprofiling

ADMEADMEtoxicological teststoxicological tests

HitHitFindingFinding

““Hit Hit -- to to -- LeadLead””Lead FindingLead Finding

LeadLeadOptimizationOptimization

clinical candidateclinical candidateprofilingprofiling

Targ

et F

indi

ngTa

rget

Fin

ding

Target ClinicalCandidate

primaryAssay Hit Lead

ClinicalCompound

clin

ical

dev

elop

men

t: P

hase

I,II,

IIIcl

inic

al d

evel

opm

ent:

Pha

se I,

II,III

biologischebiologische, , pharmacologischepharmacologische, , toxicologischetoxicologische, , medizinischemedizinische, u.a. , u.a. DisziplinenDisziplinen

chemischechemische, , analytischeanalytische, , spectroskopischespectroskopische, , pharmazeutischepharmazeutische, u.a. , u.a. DisziplinenDisziplinen


Screening

Sekundär-screening

ChemischeChemische undundpharmazeutischepharmazeutische

EntwicklungEntwicklung

LeitstrukturLeitstrukturSubstanzanbieterNaturstoffbanken

rationale IdeeIntuitionAuswahl

AssayAssay

HTSPrimär-

screening

CADD

Synthese“Bibliotheken”

SpektroskopieAnalytik

CADD

N

N

O

N

O

Cl

Cl

Synthese“Substanzen”


Drug Development: A Multidisciplinary Process

1. Target selection2. Assay development and validation3. In silico chemistry, properties (ROF etc), in silico

ADME, structure based design4. Combinatorial Chemistry, compound selection

from available stock5. Medicinal Chemistry6. HTS, MTS 7. In-vitro Pharmacology: Receptor binding,

functional tests, isolated organs, &c &c8. In-vitro ADME: Solubility, Membrane passage,

Cytochromes, Metabolic Stability


Combinatorial Chemistry

A + B A-B

A + B + C D

NOT

A + B C + D


Mannich Chemistry:

NR1

R2H + CHO +

OH OH

NR1

R2

NR1

HH + O

O

+ RO OR

O OO

OCO2RRO2C

NR1


Combinatorial Chemistry

Core molecule

3 intermediary products

+ +

3 reagents of type

4 reagents of type

Result: library with 3 x 4 = 12 substitute core products


Solvay Arqule Alliance

RESULTS

• Arqule– Delivered 125,000 exclusive compounds– 20,000 exclusive compounds/year– 200,000 screening compounds/year

• TOTAL >1,000,000 COMPOUNDS– Diversified chemical input



• REMP Storage System

Type: “Mixed Warehouse”

• Size: length 17m; width: 3.8m; height: 5.5m

• Storage temperature: +4°C• humidity: < 20%• Stores standard deepwell plates,

microtiter plates, flasks and vials• Capacity: 5 million compounds in

96 well format.



Storage devices and Handling

PlatesPlates FlasksFlasks TubesTubes

65 P/h65 P/h 130 F/h130 F/h 160 T/h160 T/h



1. Target selection2. Assay development and validation3. In silico chemistry, properties (ROF etc), in silico

ADME, structure based design4. Combinatorial Chemistry, compound selection

from available stock5. Medicinal Chemistry6. HTS, MTS 7. In-vitro Pharmacology: Receptor binding,

functional tests, isolated organs, &c &c8. In-vitro ADME: Solubility, Membrane passage,

Cytochromes, Metabolic Stability



9. Early formulation work10. In-vivo Pharmacology

• Mechanistic model• Disease oriented model

11. In vivo ADME: PK/PD, Culex12. Orientating toxicology/safety,13. Toxicogenomics/pharmacogenomics14. Pharmaceutical Characterization

• Classic adjuvants• Nanosizing, Cyclodextrins, PEG, Liposomes

15. GLP Toxicology and GLP ADME16. Chemical and pharmaceutical development17. Clinical Phases 1 and 218. Full Development


Drug Discovery Paradigms in Pharmaceutical Industry

• Small Molecules with high oral bioavailability• Advantageous ADME profile, ROF compliance,

membrane passage• Good chemical and biological stability• Short and cheap synthesis, easy upscaling• No toxic or allergic reactions• Blockbuster potential

No Biopharmaceuticals !


Biopharmaceuticals

What is a Biopharmaceutical?


Biopharmaceuticals

Defined by Production:• Extraction from biological matrix, e.g.

growth hormone from human bodies• Proteins by chemical synthesis: Only for

small proteins• Fermentation: Most important

E.coliMammalian cells, CHO or BHK cellsInsect cellsYeast and fungi


Biopharmaceuticals or Bioproducts

• Natural products, extracts: Baldrian?• Pancreatic enzymes as Creon, Pancreatin?• Recombinant Lipase, Amylase, Proteases• Penicillins?• Erythromycin A and other macrolides?• Motilides, semisynthetic macrolides with 14

membered ring structure and 17 stereocentersfrom EA?

• Monoclonal antibodies• EPO• Vaccines


Biopharmaceuticals or Bioproducts

Bioproducts are derived from fermentationContracting of special problems for development:• Fragments originating from producing

microorganisms as potential impuritiesCell material as membrane proteins, sugars &c&cDNA fragments (picomolar!) Often mixtures: glycosylation structure, heterogeneity N-terminus

• Specific patent issues: Bioproduct has beeninvented already by nature, protection only fornewly identified product with provided production(isolation) process

• Upscaling often cumbersome, high COG


Biopharmaceuticals: Example Infliximab

• In 1994 Centocor offered Infliximab for licensing• Impressive efficacy against TNF-a and in arthritis

pharmacology models• Safety: 30mg/kg single dose infusion and 90mg/kg

multi dose infusions to chimpanzees are „safe“• Worst case patient selection, 10mg/kg as single dose• Dose scheme (twice weekly) decided upon based on

plasma levels in humans• 100% responders• Side effects: Urinary tract infections, bronchitis,

pharyngitis, urticaria, eczema, pruritis


Biopharmaceuticals: Infliximab

Would you buy it?

Today Blockbuster DrugMore than 1 Billion USD sales

Recently FDA approval for maintenance in UC


Biopharmaceuticals

• There is no investment in pharmaceuticalsjust from altruistic motives

• Without economic success there will be no sustainable advantage for the patient

• Biopharmaceuticals must offer high valuefor the patients

Often life prolongationGenerally used in „hard“ indicationsCancer, MS, Rheumathoid Arthritis, InfectionVaccines: Flu pandemia expected!


Therapeutic Indications forBiopharmaceuticals


Biopharmaceuticals: Market potential

• 50 BUSD sales worldwide• 80 NBE‘s approved• EPO with 9 BUSD sales blockbuster drug• Monoclonal AB‘s 5 BUSD• Interferon ß 3 BUSD• Ca 300 NBE‘s in clinical development• Ca 350 NBE‘s in preclinical development• Double digit growth rates


Biopharmaceuticals: Market potential

Year 2000 2001 2002 2003 2004

Biopharmaceuticalsales

23 27 33 40 48

Growth (%) 16 19 23 21 20


Example: Erythromycin AErythromycin A• antibiotic compound• stimulates upper GI-motility

and phase III activity (Itoh et al. 1984)

• erythromycin acts as a motilinagonist (Peeters et al. 1989)

O

OHO

O

OOH

N

O

O

OH

O

OH

OH

O

Motilin• 22 amino acid peptide• gut hormone involved in

stimulation of upper GI-motilityPhase III of Migrating Motor Complex

(Brown et al. 1966, 1972)


Erythromycin A• Macrolide antibiotic produced by certain

strains of streptomyces erythreus as defenseweapon against bacterial infections

• Long time medical use, safe compound • Well known GI side effects caused by motilin

agonistic effects• Natural compound with 17 stereocenters, 2

glycosidic linkages and 5 hydroxy functions• (3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-((2,6-Dideoxy-3-C-

methyl-3-O-methyl-a-L- ribo- hexopyranosyl) -oxy) -14- ethyl-7,12,13-trihydroxy - 3,5,7,9,11,13-hexa methyl-6- ((3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo- hexopyran osyl)oxy)oxacyclotetradecane-2,10-dione.


Erythromycin A

•Not „drug-like“, natural product

•Not compliant with Lipinsky‘s „Rule of five“

•Not stable in acid, poorly bioavailable in rats

•Complicated molecule, very complicated synthesis

•Active transport, orally bioavailable


Total Synthesis of Erytromycin AWoodward et al, JACS 1981

S S

OOO

O

H

O

S

O O

SHO

O

O

O

S S

OOO

H

O

OOO

O

O

S S

OOO

O

H

OOO

OO

O

H

OOOAcO

OO

O

HH

HH HHO

H

OO OHOAcO

OO

O

HH

HH H

H

H HS

O

H

+ 9 steps 2 steps

3 steps

9 steps

2 steps

2 steps


Total Synthesis of Erythronolide A

OO OHOAcO

OO

O

HH

HH H

H

H HS

O

H

OO OHO

OO

O

HH

HH H

H

H HO

O

H

OMs

OHOH OHOH

OHOH

HH

HH H

H

H HO

O

H

NH

O

O

O2N

OHO OO

OHOH

HH

HH H

H

H HS

O

H

NH

O

N

O

OH

O

NH

O

OH

O

O

O

OHO OO

OHO

HH

HH H

H

H H

OH

NH

OOH

NHO

O

OH

O

O OO= =

4 steps3 steps

4 steps


Total Synthesis of Erythromycin A

OH

NHO

O

OH

O

O OO

OH

NHOH

OH

O

O OHOH

O

OH

NHOH

OH

O

O OOH

O

ON

OH

OS

N

N

ON

OO

OH

NHOH

OH

O

O OO

O

ON

OH

O OH

O

OH

NH2OH

OH

O

O OO

ON

OH

O OH

O

OH

OHOH

O

O OO

ON

OH

O OH

O

O

O

O

O

O

SN

3 steps

2 steps

2steps

2steps


Erythromycin A

Erythromycin A is available in 25kg packs, 67USD/kg bulk


BiosynthesisBiosynthesis of of ErythronolideErythronolide BB

SO

OH

OH

OH

OH

O

SO

OH

OH

OH

O

SO

OH

OH

O

SO

O

OH

OH

SO

OH

OH

SO

OH

SO

SCoA

O OH SCoA

O O

DEBS1 DEBS2 DEBS3 TE

Deoxyerythronolide

B


Solvay Pharmaceuticals: Research

Past FutureStarting from compounds/experimentsmechanism of action unclear

Aiming at disease related targets validity hypothesis is to be tested

Progress inDrug discovery

“manufacturing”

Understandingof disease

Human genomegenetic origin of

disease

- Small molecules- Peptides

Combinatorialchemistry

70’S 80’S 90’S 2000

Combinationof diagnosisandtreatment

Molecular biology

Biotechnology

Chemistry-driven


Clinical Candidate Survival Rates

Drug Discovery Phase 1Clinical Trials

Phase 2Clinical Trials

Phase 3Clinical Trials

Priority Substance

60%40% 70% 50%Product

Registration

Probability of success in each phase

CN - O NH2

OCH3

F3C

Start with 100,000 chemicals in screeningOnly 8% survive after PS stage

Total R&D time 10 years or moreCost per product $US 800M


Clinical development

Phase III Total Phase III Total Phase IIPhase I

Mittlere Anzahl von eingereichten

Studien

Mittlere Anzahl von eingereichten

Studien35 5 10 20 35 5 10 20

Mittlere Anzahl von Individuen Mittlere Anzahl von Individuen

4323 3348 639 4323 427 3348 639 427

Aus: CMR Intern. 2000Aus: CMR Intern. 2000


0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Developmt time (years)

% of total developmentcosts spent/ compound

Full Development

Synthesis/Screening

Preclinical Testing

Clinical Testing

Pharmacology

Phase IPhase IIa

Phase IIbPhase III

Submission for Registration (1-3 years )Price (6 mths-1 year)Reimbursmt (1-5 years)Phase IV

800 M EUR

Subchronical Toxicology

Chronical Toxicology

Expiration Patenta) 20 yearsb) + 5 years SPC (E.U.)

(Supplemental Protection Certificate)0,25 1,5 10 30 90

100

The lenghthy process of drug development reduces the effective patent protection time

PoP,Value generation

Primary Screening, Library Synthesis,Natural CompoundsProprietary Libraries


Thank you very muchFor your attention!

drug development a multidisciplinary process - toxikologie.de · solvay pharmaceuticals, hannover...

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