Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 1
Drug DevelopmentA Multidisciplinary Process
Ulf Preuschoff/Siegfried SchäferSolvay Pharmaceuticals
Hannover
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 2
Solvay Pharmaceuticals R&D Sites
Brussels, Belgium Fournier, France
Hannover, Germany
Tokyo, Japan
Marietta, USAWeesp, The Netherlands
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 3
Solvay Pharmaceuticals Therapeutic Areas
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 4
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:
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 5
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 6
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 7
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”
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 8
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 10
Combinatorial Chemistry
A + B A-B
A + B + C D
NOT
A + B C + D
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 11
Mannich Chemistry:
NR1
R2H + CHO +
OH OH
NR1
R2
NR1
HH + O
O
+ RO OR
O OO
OCO2RRO2C
NR1
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 12
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 Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 13
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 14
Drug Development: A Multidisciplinary Process
• 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.
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 15
Drug Development: A Multidisciplinary Process
Storage devices and Handling
PlatesPlates FlasksFlasks TubesTubes
65 P/h65 P/h 130 F/h130 F/h 160 T/h160 T/h
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 16
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 17
Drug Development: A Multidisciplinary Process
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 18
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 !
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 19
Biopharmaceuticals
What is a Biopharmaceutical?
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 20
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 21
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 22
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 23
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 24
Biopharmaceuticals: Infliximab
Would you buy it?
Today Blockbuster DrugMore than 1 Billion USD sales
Recently FDA approval for maintenance in UC
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 25
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!
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 26
Therapeutic Indications forBiopharmaceuticals
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 27
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 28
Biopharmaceuticals: Market potential
Year 2000 2001 2002 2003 2004
Biopharmaceuticalsales
23 27 33 40 48
Growth (%) 16 19 23 21 20
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 29
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)
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 30
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.
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 31
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 32
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 33
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 34
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 35
Erythromycin A
Erythromycin A is available in 25kg packs, 67USD/kg bulk
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 36
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, Hannover AK Reg Tox Martinsried 2005 37
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 38
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 39
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
Solvay Pharmaceuticals, Hannover AK Reg Tox Martinsried 2005 40
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