Single-Enantiomer DrugsPoised for Further Market GrowthSandra Erb

THE SINGLE-ENANTIOMER drug segmentis an important part of the overallpharmaceutical market. Although theiherapeutic value of a given medicinalcompound is the driving force behinddevelopment, a large number of cur-rently marketed drugs and pipelinecandidates are chiral, and pharmaceuti-cal c(>mpa[iies generally seek to developthese compounds as single enan-tiomers. Single-enantiomer drugs notonly are critical in new drug develop-ment, but they also can he used as a de-fense strategy by innovator drug com-panies from generic drug competition.By developing racemic switches, or sin-gle enantiomers of previously ap-proved racemates, a pharmaceuticalcompany can extend the product's lifecycle.These factors provide the marketfoundation for process research anddevelopment teams within pharmaceu-tical companies and custom manufac-turers to continually advance chiraltechnologies, including catalytic routesin asymmetric synthesis.

Single enantiomers dominateSingle-enantiomer therapeutics hadsales of S225 billion in 2005, represent-ing 37% of the total final formulationpharmaceutical market of $602 billion(Table I), based on estimates fromTechnology Catalysts International(Falls Church, VA) and 1K4S Health{Plymouth Meeting, PA). The com-

Sandra Erb is the manager of chiral andfine chemicals consulting, TechnologyCatalysts International. 605 ParkAvenue, Falls Church. VA 22064, tel.703.531.0247, fax 703.237.7967,serb@technology-catalysts.com.

Single-enantiomer drugs account for nearly40% of the global pharmaceutical market. Theauthor analyzes the current market for single-enantiomer drugs, their role as a generic drugdefense strategy, and forecasts for growth.

us FOOD AND DRUG ADMINISTRATION

Figure 1 : Esomeprazole, the active pharmaceutical ingredient in AstraZeneca's Nexium and

the (5)-enantiomer of Prilosec (omeprazole), is an example of a successful racemic switch.

pound annual growth rate for single-enantiomer products over the past fiveyears is 11%, which is on par with thepharmaceutical market as a whole.

Sales growth in several key thera-peutic categories has been very robust.Although part of this increase, particu-larly In cancer therapy, has been fromincreased approvals for biologies,small-molecule single enantiomers alsohave played a significant role. The fu-ture growth of single-enantiomerproducts is expected to be strong basedon the following key market drivers;

• increased evidence and awareness ofimproved therapeutic profiles;

• published policies and guidelines ofregulatory agencies;

• advances in chiral technologies;• racemic switches as a generic defensestrategy;

• need for new and better anticancerand antiviral drugs.

s i 4 Pharitfaceotical Technolosf TECHNOLOGY OUTLOOK, APIS. INTERMEDIATES, AND FORMULATION

Key categories for single enantiomersFor the single enantiomer drug market,gastrointestinal (GI), antiviral, respira-tory, and cancer therapies are the ther-apeutic categories exhibiting above-average growth over the past five years.

The racemic switch product "Nex-ium" {esomeprazole) by AstraZenecaPLC is a major contributor to growthin the GI category (see Figure 1). As-traZeneca first launched the drug in2000 and reported 2005 sales of $4.6billion. This product exemplifies theunderlying rationale of deciding toforward a racemic switch, namely:

• chemical feasibility of producing asingle enantiomer;

• obtaining a clinical advantage;' obtaining a market advantage.

The launch of Nexium providedAstraZeneca with a product that offsetgeneric competition that resulted in thedecline of sales of the racemate

www.phdimtech.com

Custom Developmentand GMP Manufacturingof APIs, Intermediates and"Criticai" ExoipientsCUSTOM PEPTIDE MANUFACTURE

Solid and solution phasePre-clinical to commercial requirementsPseudoproiine dipeptides

SYNTHETIC LIPID DEVELOPMENTAND MANUFACTURE

PtiospholipidsSphingolipids

AMINO ACID DERIVATIVES

Custom and stondard amino acids availabieGram to multi-ton supply

DRUG DELIVERY TECHNOLOGIES

LipoBridge'̂ Delivery of drugs acrossthe blood brain barrier

LipoMask'" Increased circulation half liteTargeting ot iipid particies

Design tor Peptide Delivery'"'

COME VISIT US AT CPHI BOOTH 6C30

For research scale peptide synthesis

and libraries, ask us about the newly

formed Mimotopes-Genzyme

Pharmaceuticals Global Alliance

AmericasGenzyme Pharmaceuticals675 West Kendall StreetCambridge, MA 02142USATel *1 800 868 8208: +1 617 374 7248Fax+1 617 768 9765Email pharmaceuticals@genzyme.com

vrww.genzymepharmaceutlcolrcom

Rett of WorldGenzyme PharmaceuticalsEichenweg 1CH^MIO LlestaiSwitzerlandTel +41 (0)61 906 5959Fax +41 (0)61 906 5958Email pharmQceuticals,swiss@genzyme.com

Pharmaceuticols

Chiral Chemistry and Pharmaceuticals

Table 1: Worldwide sales of single enantiomer pharmaceutical products finalformulation.

Therapeutic category

CardiovascularAntibiotics andantifungalsCancer therapies

Hematology

Hormone andendocrinology

Central nervous system

Respiratory

Antiviral

Gastrointestinal

Ophthalmic

Dermatological

Vaccines

Other

Total

2000 sales(in $ billions)

27.650

25.942

12.201

11.989

15.228

9.322

6.506

5.890

4.171

2.265

1.272

1.427

7.128

130.991

2004 sales

(in $ billions)

34.033

32.305

21.358

20.119

20.608

17.106

12.827

11.654

11.647

3.063

1.486

2.450

10.400

199.056

2005 sales(in $ billions)

36.196

34.298

27.172

22.439

22.355

18.551

14.708

14.683

13.476

3.416

1.561

3.100

13.268

225.223

CAGR (%)*

2000-2005

6

6

17

13

8

15

18

20

26

9

4

17

13

11

' CAGB is coiTipound annual growth rateSource: Technology Catalysts Intemational

"Prilosec" {omeprazole). In addition,Nexium daims to heal the erosion in theesophagus caused by gastroesophagealreflux disease, thus providing a clinicaladvantage as well.

Other single enantiomers contribut-ing to growth in the Cll segment were"Flomax"or"Harnar'(tamsulosin) and"Remicade" (infliximab). Tamsulosinwas developed hy Yanianouchi Pharma-ceutical, which merged with FujisawaPharmaceutical to form Astellas in2005. Astellas markets the drug withAhbott Laboratories and BoehringerIngelheim. The compound has patentprotection in the United States through2009, but the patent has been chal-lenged by the Indian pharmaceuticalcompany Ranbaxy Laboratories. Remi-cade, although originally launched forCrohn's disease, is approved for otherindications, including rheumatoidarthritis, which contributed to growth.

Pfizer is developing fesoterodinewith Schwarz Pharma for treating uri-nary incontinence and overactivebladder in response to the expectedloss of market exclusivity for Pfizer's"Detrol" (tolterodine) in 2008. Al-though the patent has not yet expired,court challenges to Pfizer's patent po-

sition have occurred. Ranbaxy hastentative approval from the US Foodand Drug Administration to market ageneric version of tolterodine.Schwarz Pharma submitted a newdrug application to FDA and a mar-keting authorization application tothe European Medicines Agency(EMEA). Pfizer has acquired world-wide rights to fesoterdine. Peak salesare expected to be in the range of$650-800 million range, according toindustry estimates.

Roche's "Tamiflu" (oseltamivir) isan example of a single enantiomerdrug contributing to growth in theantiviral segment. Interest in theproduct also has led to the develop-ment ot alternative synthetic routesby researchers at Harvard University(1) and the University of Tokyo (2) toavoid the use of (-)-shikimic or (-)-quinic acids, starting materials inlimited supply.

Other single-enantiomer drugscontributing to growth in the antiviralsegment include: GlaxoSmithKline's"Valtrex" (valacyclovir), Abbott Labo-ratories "Kaletra" (lopinavir and ri-tonavir), GlaxoSmithKline's "Trizivir"(abacavir, zidovudine, and lamivu-

si 6 Pbamaceoticat TechBologf TECHNOLOGY OUTLOOK, APIS. INTERMEDIATES, AND FORMULATION

dine), and "Agenerase" (amprenavir).The recent approval of "Atripla," a

once-daily, fixed-dose combinationtherapy will continue to add to thegrowth of single-enantiomer sales inthe antiviral category. Atripla containsthree active pharmaceutical ingredi-ents (APIs): tenofovir, the API inGilead Sciences's "Viread;" efavirenz,the API in Bristol-Myers Squibb's"Sustiva;"and emtricitahine, the APIin "Emtriva." All three drugs are singleenantiomers, and the simplified dos-ing of the combination therapyshould enhance patient complianceand, hence, market potential.

Other single-enantiomer drugs re-cently approved or in development inthe antiviral class include "Prezista"(darunavir), a protease inhibitor de-veloped by lohnson & lohnson's Ti-botec, and tclbivudine, a reverse tran-scriptase inhibitor under development by Indenix Pharmaceuticalsand Novartis.

Darunavir was approved by FDA inlune 2006 in combination with a low-dose of ritonavir and other activeanti-HIV agents. The compound has.shown resistance repellence proper-ties. This means that the compoundsuppressed the development of newdrug-resistant viral strains in additionto inhibiting the replication of exist-ing multidrug strains. The drug hasalso been submitted to the EMEA forapproval in Europe. Peak sales ofdarunavir are expected in the range of$650-800 million, according to indus-try estimates.

Telbivudine has been submitted forregulatory approval to EDA and EMEAfor treating chronic hepatitis B. Severalstudies are underway to demonstrateclinical benefits In comparison withGilead Sciences"'Hepsera" (adefovirdipivoxil). A combination therapy withIdenix Pharmaceuticals' valtorcitabine,another L-nucleoside analog, in PhaseI! development may be the optimaltherapy because of synergies betweenthe two molecules. Peak sales of tel-bivudine are projected to be between$225-275 million, according to indus-try estimates.

www.pharmtech.fom

Chiral Chemistry and Pharmaceuticals

GlaxoSmithKline's "Advair" (fluti-casone and salmeterol) and Merck &Co.'s"Singulair" (montelukast) aretwo single enantiomers leadinggrowth in the respiratory category. InAdvair, GlaxoSmithKline is gainingpatients from its older respiratorydrugs, including "Serevent"(salme-tcrol) and "Flixotide" or "Flovent"(fluticasone). GlaxoSmithKline'sstrategy is to take advantage of thelonger patent life for the combinationproduct Advair. The patents for Ad-vair are set to expire in 2010 in theUnited States and in 2013 in the Eu-ropean Union. The patents forFHxotide or Flovent have expired inboth the United States and the Euro-pean Union. The patents for Sereventare set to expire in 2008 in the UnitedStates. In Europe, the only patentprotection is in France (2008) andItaly (2009).

Sales increases tor cancer therapeu-tics result from a combination of bio-logics and small-molecule single enan-tiomer products. These productsinclude: Genentech's and Roche's "Her-ceptin" (trastuzumab); "Rituxan" or"MabThera" (rituximab) by Roche,Genentech, and Biogen-Idec; Pfizer's"Gamptosar" (irinotecan); Sanofi-Aventis's "Eloxatin" (oxaliplatin), andEli Lilly's "Gemzar" (gemcitabine).

Pipeline products for cancer thera-peutics have focused on biologies,mainly monoclonal antibodies. Oneexample is Amgen's panitumumab, forwhich peak sales are estimated between$1.3-1.6 billion.

Single enantiomers as blockbustersThe growth in single-enantiomer phar-maceuticais has produced severalblockbuster compounds as shown inTable 11. As would be expected, manyof the high-growth compounds men-tioned earlier in this article are in-cluded in this list. Others such asPfizer's "Lipitor" (atorvastatin) and"Zoloft" (sertraline), Amgen's"Epogen" (epoetin alfa), Johnson &Johnson's "Procrit" (epoetin alfa),and Merck & Go.'s "Zocor" (simvas-tatin) have been among the top sell-

Table II: Top-selling single enantiomer drugs, global 2005 sales

Company

Pfizer, Astellas

Sanofi-Aventis,Bristol-Myers Squibb

Amgen, Johnson & Johnson

GlaxoSmithKline

Genentech, Roche

AstraZeneca

Merck & Co.

Daiichi Sankyo,Bristol-Myers Squibb

Novartis

Amgen, Wyeth

Johnson & Johnson.Schering-Plough

Amgen

Pfizer

Merck & Co.

Sanoii-Aventis

Genentech, Roche

Amgen

Lundbeck, Forest Laboratories

Pfizer

Sanofi-Aventis

Sanofi-Aventis

Brand name

Lipitor

Plavix

Epogen, Procrit

Advair, Seretide

Rituxan. MabThera

Nexium

Zocor

Mevalotin orPravachol

Diovan

Enbrei

Remicade

Aranesp

Zoloft

Singulair

Lovenox

Herceptin

Neulasta

Cipralex or Lexapro

Zithromax

Taxotere

Eloxatin

Activepharmaceutical

ingredient

atorvastatin

clopidogrel

epoetin alfatluticasone

and salmeterolrituximab

esomeprazole

simvastatin

pravastatin

vatsartan

etanercept

infliximab

darbepoetin alfa

sertraline

montelukast

enoxaparin

trastuzumab

pegfilgrastim

escitalopram

azithromycin

docetaxel

oxaliplatin

2005 sales(in $ billions)

12.986

6.345

5.799

5.465

5.166

4.633

4.382

3.844

3,676

3.567

3.477

3.276

3.256

2.976

2.668

2.469

2.288

2.043

2,025

2.003

1.947

Source: Technology Catalysts International and company information

ing-drugs for several years. Many ofthese products are at or nearing theend of their patent life, and innovatordrug companies are seeking ways toprotect themselves from sales de-clines from generic competition. Forexample, Amgen developed"Aranesp" (darbepoetin alfa) as a sec-ond generation biologic to Epogen.Aranesp has been so successful that itis also in the top 20 selling drugs.

For Zoloft, Pfizer developed a newsynthetic route to lower the cost ofmanufacture. AstraZeneca respondedwith the racemic switch from omepra-zole to esomeprazoie. GlaxoSmithKlinetargeted a combination product, Ad-vair, to address patent expiries.

It should be noted that manv of

these blockbusters, specifically 13Pharmaceuticals, are considered smalimolecules rather than biologies. Thus,continued development of chiral tech-nologies, including catalytic and enzy-matic synthesis routes, will be impor-tant tor contract manufacturers andpharmaceutical companies. Moreover,the development of improvedprocesses will be needed as these com-pounds come off patent.

Generic competitionThe maturing of the single-enantiomerdrug market is clearly seen by the ar-rival of generic competition. Theangiotensin-converting enzyme (AGE)inhibitors, the so-called "prils" are thefirst class of single-enantiomer com-

Ptiaimceuticai Teebmiogj/ TECHNOLOGY OUTLOOK- APIS, INTERMEDIATES, AND FORMULATION s i 7

Chiral Chemistry and Pharmaceuticals

pounds to face such competition. Thefollowing prils have had declining salesin the doubte-digit range: Ptl7er's"Ac-cupril" (quinapril); Novartis'"Lotensin" (benazepril); Bristol-MyersSquibb's "Monopril" (fosinopril);Merck & Co.'s "Vasotec" (enalapril);and AstraZeneca's "Zestril" (lisinopril).

The statins are the next large class ofsingle-enantiomer cardiovascular ther-apies to see generic competition. Sig-nificant generic competition exists forMerck & Co.'s "Mevacor" (lovastatin),and generic competition is increasingfor Merck's Zocor (simvastatin), asshown in Table III. Ranbaxy is seekingto launch a generic atorvastatin prod-uct, but has lost court cases in theUnited Kingdom and the United States.Ranbax}' is appealing both cases.

Pfizer developed several combina-tion therapies to protect its positionin cholesterol-lowering therapeutics.Caduet, a fixed-dosage formulationcombining atorvastatin and amlodip-ine, was approved in 2004 and treatsboth hypertension and hypercholes-terolaemia. Pfizer reported Caduetsales of $185 million in 2005. In ad-dition, Pfizer is developing its single-enantiomer compounds, atorvastatin(40 mg) and torcetrapib (60 mg) as afixed-combination therapy for pa-tients with elevated cholesterol, espe-cially LDL-cholesterol, levels, and lowHDL-cholesterol levels. Phase IIIclinical trials are in progress. A newdrug application is expected to hefiled with FDA in 2007. Peak sales areforecast at $1.3-1.6 billion, based onindustry estimates.

Other singie-enantionier, small mol-ecules approved as abbreviated newdrug applications or with tentative ap-provals from FDA are listed in Table 111.

Future of single-enantiomer drugsOverall, single-enantiomer drugs willgrow at a similar rate as the pharma-ceutical market. Higher growth in keytherapeutic categories will be offset hythe large and maturing markets in an-tibiotics and cardiovascular drugs. Partof the higher growth will be from salesincreases in biologies, but the use of

Table III: Potential generic competition of select single enantiomer drugs.

Company

Sanofi-Aventis,Bristol-MyersSquibb

AstraZeneca

Merck & Co.

DaiichiSankyo,Bristol-MyersSquibb

Pfizer

Lundbeck,ForestLaboratories

Pfizer

Brand name

Piavix

Nexium

Zocor

MevaiotinOf

Pravachol

Zoloft

Cipralex orLexapro

Zithromax

Activeingredient

clopidogrel

esomeprazole

simvastatin

pravastatin

sertraltne

escitalopram

azithromycin

Marketed generics

Apotex

Ivax (now part of TevaPharmaceuticals)

Ivax (now part of TevaPharmaceuticals),

Ranbaxy Laboratorieshas approval for an 80

mg formulation

Teva Pharmaceuticals

Ivax (now part of TevaPharmaceuticals)

Ranbaxy Laboratorieshas approval for an oral

concentrate

Ivax (now part of TevaPharmaceuticals)

Abraxis PharmaceuticalProducts, Pliva, Sandoz,Teva Pharmaceuticals

US Food and DrugAdministration

tentative approvals*

Not appiicabte

Alpharma (now part ofActavis), Teva

Pharmaceuticals

Aurobindo, CobaltPharmaceuticals.

Ranbaxy Laboratories,Teva Pharmaceuticals

Apotex, Dr Reddy's,Geneva

Pharmaceuticals (partof Sandoz),

GenPharma, Lek (partof Sandoz), WatsonPharmaceuticals,

ZydusAndrx, Aurobindo. Dr.Reddy's, GenPharma,

Ivagen. MutualPharmaceuticals,

MylanPharmaceuticals,

Purepac (now part ofActavis), Roxane

Laboratories, ZydusAlpharma (part of

Actavis), TevaPharmaceuticals

Not applicable

• Asof Juty2006Source: Technology Catalysts Intemational and US Food and Drug Administration

small molecules in certain key classessuch as cancer, arthritis, central nerv-ous system, and antivirals will have sig-nificant impact.

Several singie-enantiomer drugs in-troduced in 2005 show ongoing druginnovation. Examples include AmylinPharmaceuticals' "Byetta" (exanatide),a peptide for improved sugar controlin patients with Type II diabetes;Pfizer's "Macugen" (pegaptanih), anaptamer for neovascular age-relatedmacular degeneration; and Sepracor's"Lunesta" (eszoplicone), the (S)-enantiomer of zoplicone for treatinginsomnia. It will be the push for inno-

s i 8 Phamaceatical lecltBOleg]/ TECHNOLOGY OUTLOOK: APIS. INTERMEDIATES, AND FORMULATION

vative treatments that will continue todrive the development of single-enan-tiomer drugs.

References1. \. Vcung, S. Hong, and E.J. Corey, "A Short

Entantioselective Pathway for the Synthe-sis of the Anti-Influenza Neuraniidase In-hibitor Oseltamivir from 1.3-Butadieneand Acrylic Acid," /. Am. Chem. Soc. 128(9), 6310-6311 (Communication) (2006),

2. M.Shibasaki et al, "De Novo Synthesis ofTamiflu via a Catalytic Asymmetric Ring-Opening of Meso-Aziridines with TMSN,/, Am. Chem. Soc. 128 (19), 6312-6313(Communication) (2006). fT

www.pharmtecti.com