Introduction Original Drugs Generic Drugs Case Study I

SELECTED ASPECTS OF THE RESEARCH AND DEVELOPMENT OF ORIGINAL vs GENERIC DRUGS

OSTEO

Stanislav Rádl

Introduction Original Drugs Generic Drugs Case Study I – ATORVASTATIN

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1

Introduction

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MedChemBio, Prague Dec 3rd, 2009

BASICS

The driving force of the Pharma Industry is profit, not ethical

dimensions Pharma Industry is highly profitable (profit) Pharma Industry is overregulated (expenses) Pharma Industry is highly competitive Pharmaceutical R&D is extremely costly Investment into the Pharma R&D is unusually long‐term


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ORGANIZATIONS INVOLVED IN THE PHARMA INDUSTRY

p Research Based = Brand‐name = Innovative companies Generic Drug Producers High‐Tech companies (Genentech, Selectide) CRO = Contract Research Organizations API (Active Pharmaceutical Ingredients) and PhI

(Pharmaceutical Intermediates) producers – India, China


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Original Drugs


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DISCOVERY AND DEVELOPMENT OF A NEW DRUG

Launch Clinic Development Get the Candidate Get the Lead Get the Screen Get the Idea

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DRUG DISCOVERY

Serendipitous discovery Identification from traditional medicines/natural sources Selective Optimization of Side Activities (SOSA) Utilization of metabolic studies Chiral switch

High‐Throughput Screening (HTS) ( ) Rational Drug design


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AVERAGE NEW ORIGINAL DRUG

12 Years in R&D Costs $897 M to discover and develop 1000 Applications within a year

2007 – Generic Initiative for Value and Efficiency (GIVE) issued by FDA to streamline the ANDA process

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LEGISLATIVE REQUIREMENTS Patent protection 9 20 years 9 + up to 5 years of SPC (Supplementary Protection Certificate) Data Exclusivity ‐ EU – registration of a generic drug is allowed after 6 (10) years after registration in the country From 2004 8 + 2 + 1 rule 9 8 years after 1st registration in EU ‐ registration 9 additional 2 years y ‐p production 9 additional 1 year ‐ significant clinical benefit


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REQUIREMENTS FOR GENERIC DRUGS EU – Essential similarity

Identical API (Active Pharmaceutical Ingredient), excipients may vary Identical in strength, dosage form and route of administration Identical indication Bioequivalent with the original drug Identical or very similar specification as the original drug (identical impurity profile) Manufactured under GMP (Good Manufacturing Practice)

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LIMITS OF IMPURITIES AND DEGRADATION PRODUCTS

Max. DD

Disregard limit

Unknown impurity

Known impurity

≤2g

0.05 %

0.10 % or 1.0 mg

0.15 % or 1.0 mg

> 2g

0.03 %

0.05 %

0.05 %

Identification limit for most APIs is 0.10 % Qualification limit for most APIs is 0.15 % For impurities over the QL For impurities over the QL, the safety must be proved by: the safety must be proved by: ‐ toxicological study ‐ for generics by proving that the original drug has a similar impurity profile


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PIPELINE CONCEPT – „OLD DAYS“ DRUG DISCOVERY

DRUG DEVELOPMENT

DRUG MARKETING DRUG EXPANSIONS

LAUNCH NDA BASIC PATENT FILLING

DATA EXCLUSIVITY

BASIC PATENT EXCLUSIVITY BASIC PATENT EXCLUSIVITY

GENERIC DRUG DEVELOPMENT

GENERIC DRUG MARKETING

LAUNCH ANDA

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CHANGES IN PATENT SITUATION

Prolongation of patent protection (evergreening) 9 new processes 9 new salts, polymorphs and pseudopolymorphs 9 new galenic forms 9 new use

Real patent situation is not known, mainly due to the patent activities off generic i companies i


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PIPELINE CONCEPT – CURRENT SITUATION DRUG DISCOVERY

DRUG DEVELOPMENT

DRUG MARKETING DRUG EXPANSIONS

LAUNCH NDA BASIC PATENT FILLING

DATA EXCLUSIVITY

BASIC PATENT EXCLUSIVITY BASIC PATENT EXCLUSIVITY PROCESS PATENT EXCLUSIVITY POLYMORPH PATENT EXCLUSIVITY GENERIC DRUG DEVELOPMENT

A = New process, new polymorph B = New polymorph C = No innovation

GENERIC DRUG MARKETING

GENERIC PROCESS PATENT FILLING

LAUNCH A

LAUNCHLAUNCH B C

ANDA GENERIC PATENTS EXCLUSIVITY


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Case Study – ATORVASTATIN


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BIOSYNTHESIS OF CHOLESTEROL

HO C H2C −

CH2

C O

2NADP + HSCoA HO C H2C

geranyl pyrophosphate farnesyl pyrophosphate

HMG-CoA

squalene

CH3 CH2

C

O

isopentenyl i t l pyrophosphate h h t

SCoA

HMG-CoA Reductase

+

−

C O

O

2NADPH

5‐pyrophosphomevalonate

CH3

H2 C OH

2,3‐oxidosqualene

mevalonate

O

19 steps HO

HO

lanosterol

cholesterol

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BIOSYNTHESIS OF CHOLESTEROL

HO C H2C −

CH2

C O

C H2C O

SCoA

HMG-CoA HMG-CoA Reductase

2NADP+ + HSCoA HO

−

C

enzyme that catalyzes the h l h conversion of HMG‐CoA to mevanolate.

O

O

2NADPH

HMG‐CoA reductase is the

CH3

This reaction is the rate‐

determining step in the synthetic pathway.

CH3 CH2

C O

H2 C OH

mevalonate

HMG-CoA - 3‐Hydroxy‐3‐methylglutaryl‐ coenzyme A MedChemBio, Prague Dec 3rd, 2009

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HISTORY OF STATINS

95 e c –mevalonic e a o c ac d was as isolated so a ed a d identified de ed as a 1956 – Merck acid and as an intermediate of the cholesterol biosynthesis. 1959 – Max Planck – enzyme HMG CoA‐reductase was discovered. 1971 – Endo a Koroda (Sankyo) – tested > 6000 bacterial strains – mevastatin (Penicillium citrinum) was found to reduce serum cholesterol levels in rats. 1971 1971 – Brown et al. (Beecham) al (Beecham) – compactin (Penicillium brevicompactum). brevicompactum) 1976 ‐ Merck discovered similarly mevinolin = lovastatin (Aspergillus terreus).

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HISTORY OF STATINS 1980 – Mevastatin development was stopped and due to its similarity to lovastatin, also its development was terminated. 1982 – Clinical trials were re‐started (only limited number of critical patients). 1987 – Lovastatin was launched.

Other statins were approved and launched (simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, itavastatin).

2001 – After about 50 fatalities (rhabdomyolysis) cerivastatin was withdrawn.


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HISTORY OF STATINS MEVASTATIN = COMPACTIN, R = H MEVINOLIN, LOVASTATIN, R = Me HO

O

O

β Hydroxy δ lactone of mevastatin is structurally β‐Hydroxy‐δ‐lactone similar to HMG‐CoA and its inhibition effect is based on this similarity.

O

The affinity to the enzyme is 104 higher than for HMG‐CoA

O H

In general, statins are competitive inhibitors of HMG CoA reductase. They are bulky and HMG‐CoA reductase The are bulk and literally get “stuck” in the active site preventing the enzyme from binding with its substrate, HMG‐CoA.

R

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NATURAL AND SEMISYNTHETIC STATIN STATINS S HO

HO

O

O

O

O O

O

O

O H

H

Mevastatin

Lovastatin HO

HO

O

COONa O

OH O

O

O

O

H

HO

Pravastatin Pravachol (Bristol-Myers Squibb) Mevastin (Sankyo) MedChemBio, Prague Dec 3rd, 2009

Simvastatin

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FULLY SYNTHETIC STATIN STATINS S F

F

OH

OH OH

OH

CO2 Ca

CO 2Na N

N

i-Pr

Pitavastatin

Fluvastatin

F F OH

OH CO 2Ca1/2

N

OH i-Pr HN

O

Me

OH CO2

N N

i-Pr

N SO 2Me

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ATORVASTATIN F

OH

N

OH

O

O

-

Ca2+ HN

O

2

Polymorphism ‐ > 50 crystalline forms described, form I x amorphous

Chemical purity

Chiral purity

Stability – chemical, chiral, polymorphic


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PATENT SITUATION Process patents

9 Process patents by Warner‐Lambert (Pfizer): EP 244 364; EP 247 633; EP 330 172; EP 409 281 US 4 611 067; US 4 681 893; US 5 003 080; US 5 097 045; US 5 103 024; US 5 124 482; US 5 149 837; US 5 155 121; US 5 155 251; US 5 216 174; US 5 245 047; US 5 248 793; US 5 273 995; US 5 280 126; US 5 342 952; US 5 397 792; US 5 686 104; US 5 969 156; US 6 121 461 WO 2002/055519; WO 2005/0145039; WO 2006/097909

9 In SciFinder – 167 process patents for atorvastatin (2009)

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PATENT SITUATION General patent Warner‐Lambert EP 247 633 (Priority 30.5.1986) 9 Structure generally claimed 9 Acid, lactone and salts claimed 9 Disadvantageous process, cis‐racemate 9 Nothing about polymorphism

F

F

F

OH Ph

Ph

O O

N

Ph

O COOMe

N

O

O O

O

NHPh

NHPh

NHPh

F

F

OH

OH

H Ph

N

O

O

Ph

N

OH COOMe

O NHPh


O

NHPh

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PATENT SITUATION Specific patent Warner‐Lambert EP 409 281(Priority 21.7.1989) 9 Structure specifically claimed 9 Acid, lactone and salts claimed 9 Disadvantageous process 9 Nothing about polymorphism Mg

F -

O

F

2+

F

Ph O

-

O Ph

OH

Ph Ph

Ph

N

OH COOMe

N

Ph

O

O

COOt-Bu

O NHPh

NHPh

O

N

O

NHPh

F

F

OH

OH

OH

H Ph

N

Ph O

O

COOt-Bu

N

O

O NHPh

NHPh

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PATENT SITUATION Specific patent Warner‐Lambert US 5 155 251 (Priority 1.10.1991) 9 Convergent synthesis 9 Nothing about polymorphism

NaCN EtOH, H2O

OH O Br

OEt

MeCOOt-Bu, LDA THF, - 50 °C

OH O NC

OH O

O

NC

OEt

Ot-Bu

Et2BOMe, NaBH4 MeOH, -97 °C

O NC


O

Me2C(OMe)2 aceton

O

OH OH O NC

Ot-Bu

Ot-Bu

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PATENT SITUATION Specific patent Warner‐Lambert EP 848 704, EP 848 705 (Priority 17.7.1995)

y p I and III 9 Polymorphs 9 „Amorphous atorvastatin is obtained using the original procedures.„ Formulation patent Warner‐Lambert EP 680 320 (Priority 19.1.1993) 9 Stabilized composition containing basic inorganic salts of Ca, Mg or Li, …

Basic patent: Particular molecule : Real process: Formulation Real polymorph:

Priority 30.5.1986 Priority 21.7.1989 Priority 1.10.1991 Priority 19.1.1993 Priority 17.7.1995

2011 2013 2015

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PATENT SITUATION Actavis Patent WO 2008/096377 (Priority 9.2.2007) 9 List of 5 degradation products (without synthesis). 9 15 Claims covering stable formulations containing ATV and at least 1 of the mentioned impurities. O OH O O HO HN

O

O HN

F

F I

II

IV


O

O

III

V

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ZENTIVA ATORVASTATIN PROJECT Facts 9 Basic patent and relevant process patents are not valid in CE. 9 Atorvastatin with amorphous API or own crystalline form could be launched in most CE in 2005 (data exclusivity). 9 The same product could be launched in WE in 2011 without using inorganic bases in the formulation (x form I in 2015). Decision 9 To develop atorvastatin amorphous (> 10 crystalline forms were known). 9 To develop own process for the atorvastatin amorphous API without isolating any crystals.

Risks 9 Atorvastatin was known to be chemically unstable. 9 Amorphous APIs are known to be less stable than crystaline ones. 9 Amorphous APIs are known to be more soluble – different formulation should be developod for bioequivalency. 9 Polymorphic stability of amorphous atorvastatin was not known. 39


ATORVASTATIN SYNTHESIS – ZENTIVA

O OH

i, ii, iii

iv O

91 %

O

O

NC

ix

O OH

70 %

90 %

O NC

O

O

I

75-80 %

v

O

O

vi or vii,viii

O CHO

65 -70 %

O

I

NC

i, BuLi/THF; ii, CO2 ; iii, I 2; iv, p-TsOH,aceton, r.t.; v, KCN/DMSO, 40 oC; vi, OsO4 -NaIO4 /dioxan-H2 O; vii, O3 ; viii, Me 2S; x, CrO3 -H 2SO 4/aceton, 0 oC;

S. Rádl, J. Stach: Tetrahedron Lett. 43 (11) 2087-2090 (2002). MedChemBio, Prague Dec 3rd, 2009

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ATORVASTATIN AMINE SYNTHESIS – ZENTIVA

O

i

O

HO

CO2t -Bu

O

ii

O

O

85-95 %

CO 2t-Bu

O

95 %

O CO 2t-Bu

O2N OH

iii

O

v

O CO2t-Bu

H 2N

O

100 %

iv

O

O CO2t -Bu

O2N

90 %

O

85-92 %

CO 2t-Bu

O 2N O

Me O

i, DMSO, ClCOCOCl, CH2Cl2, Et3N; ii,MeNO2, KF, Me2CHOH; iii, Ac2O, Et2O, DMAP; iv, NaBH4, EtOH; v, H2, Pd/C or Ra-Ni

S. Rádl: Synth. Commun. 33 (13) 2275-2283 (2003). 41


ATORVASTATIN SYNTHESIS – WL Procedure

F

F O

O

O

N

HN

OH O

OH

N

HCl, THF

O

HN

O O

O

1. NaOH 2. HCl F

F

OH OH

OH

O

H N

O

N

O

O OH

Δ HN


O

HN

O

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ATORVASTATIN SYNTHESIS – ZENTIVA Procedure

F

F O

O

N

HN

F

O

OH O

OH

O

N

HCl, THF

O

HN

O

OH O

OH

O

N

NaOH

+ HCl

HN

O

ONa

+ NaCl + NaOH

1. heptane extraction 2. ethyl acetate extraction F

F OH

precipitation into pentane

OH

N

O

OH OCa 1/2

OH

O

N

1. aqueous Ca(OAc)2

heptane solution of starting material and impurities

ONa

Atorvastatin amorphous 2. water extraction HN

O

Atorvastatin ethyl acetate solution

HN

O

in ethyl acetate

removal of NaOAc


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HISTORY OF THE ZENTIVA ATV PROJECT

Selected process failed. Alternate process developed, but Kaneka had an exclusive contract. Supplier of the penultimate intermediate was found. Triethylammonium salt process developed – Et3N impurity. Extractive process developed. Stability problems (oxidations). Oxygen scavengers solved the problem (price). Pakaging under nitrogen used.


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LIPITOR X TORVACARD

http://www.torvacard.cz MedChemBio, Prague Dec 3rd, 2009

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ORIGINAL VS GENERIC DRUG BUSSINESS

pp y g g p y Innovator firms have been supplying generic products for years. FDA estimates that innovative pharma companies manufacture over 50% of generic products. Most inovative pharma companies are involved in generic business in many ways. Owning stock of generic companies. Having own generic branch (Pfizer – Greenstone; Novartis – Sandoz; sanofi‐aventis – Winthrop, Zentiva; Daiichi Sankyo ‐ Ranbaxy). Licencing generics from generic companies (Pfizer – Aurobindo).


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DĚKUJI ZA POZORNOST


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DĚKUJI ZA POZORNOST

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Thank you for your kind attention


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