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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,[email protected].
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
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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.
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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.
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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
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