Single-Enantiomer Drugs

Poised for Further Market Growth

Sandra Erb

THE SINGLE-ENANTIOMER drug segment Single-enantiomer drugs account for nearly

is an important part of the overall
pharmaceutical market. Although the 40% of the global pharmaceutical market. The
iherapeutic value of a given medicinal
compound is the driving force behind
author analyzes the current market for single-
development, a large number of cur- enantiomer drugs, their role as a generic drug
rently marketed drugs and pipeline
candidates are chiral, and pharmaceuti- defense strategy, and forecasts for growth.
cal c(>mpa[iies generally seek to develop
these compounds as single enan- us FOOD AND DRUG ADMINISTRATION

tiomers. Single-enantiomer drugs not

only 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 pharmaceutical
company can extend the product's life
cycle.These factors provide the market
foundation for process research and
development teams within pharmaceu-
tical companies and custom manufac-
turers to continually advance chiral
technologies, including catalytic routes
in asymmetric synthesis.
Single enantiomers dominate
Single-enantiomer therapeutics had
sales of S225 billion in 2005, represent-
ing 37% of the total final formulation
pharmaceutical market of $602 billion
(Table I), based on estimates from
Technology Catalysts International
(Falls Church, VA) and 1K4S Health
{Plymouth Meeting, PA). The com-
Sandra Erb is the manager of chiral and
fine chemicals consulting, Technology
Catalysts International. 605 Park
Avenue, Falls Church. VA 22064, tel.
703.531.0247, fax 703.237.7967,
serb@technology-catalysts.com.
si4 Pharitfaceotical Technolosf TECHNOLOGY OUTLOOK, APIS. INTERMEDIATES, AND FORMULATION
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 five
years is 11%, which is on par with the
pharmaceutical 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 from
increased approvals for biologies,
small-molecule single enantiomers also
have played a significant role. The fu-
ture growth of single-enantiomer
products is expected to be strong based
on the following key market drivers;
• increased evidence and awareness of
improved therapeutic profiles;
• published policies and guidelines of
regulatory agencies;
• advances in chiral technologies;
• racemic switches as a generic defense
strategy;
• need for new and better anticancer
and antiviral drugs.
Key categories for single enantiomers
For 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 AstraZeneca
PLC is a major contributor to growth
in the GI category (see Figure 1). As-
traZeneca first launched the drug in
2000 and reported 2005 sales of $4.6
billion. This product exemplifies the
underlying rationale of deciding to
forward a racemic switch, namely:
• chemical feasibility of producing a
single enantiomer;
• obtaining a clinical advantage;
' obtaining a market advantage.
The launch of Nexium provided
AstraZeneca with a product that offset
generic competition that resulted in the
decline of sales of the racemate
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Chiral Chemistry and Pharmaceuticals

Table 1: Worldwide sales of single enantiomer pharmaceutical products final dine), and "Agenerase" (amprenavir).
formulation. The recent approval of "Atripla," a
2000 sales 2004 sales 2005 sales CAGR (%)*
once-daily, fixed-dose combination
Therapeutic category therapy will continue to add to the
(in $ billions) (in $ billions) (in $ billions) 2000-2005
growth of single-enantiomer sales in
Cardiovascular 27.650 34.033 36.196 6
Antibiotics and
the antiviral category. Atripla contains
25.942 32.305 34.298 6 three active pharmaceutical ingredi-
antifungals
Cancer therapies 12.201 21.358 27.172 17 ents (APIs): tenofovir, the API in
Hematology 11.989 20.119
Gilead Sciences's "Viread;" efavirenz,
22.439 13
Hormone and
the API in Bristol-Myers Squibb's
15.228 20.608 22.355 8 "Sustiva;"and emtricitahine, the API
endocrinology
Central nervous system 9.322 17.106 18.551 15
in "Emtriva." All three drugs are single
enantiomers, and the simplified dos-
Respiratory 6.506 12.827 14.708 18
ing of the combination therapy
Antiviral 5.890 11.654 14.683 20 should enhance patient compliance
Gastrointestinal 4.171 11.647 13.476 26 and, hence, market potential.
Ophthalmic 2.265 3.063 3.416 9
Other single-enantiomer drugs re-
Dermatological 1.272 1.486 1.561 4
cently approved or in development in
Vaccines 1.427 2.450 3.100 17 the antiviral class include "Prezista"
Other 7.128 10.400 13.268 13 (darunavir), a protease inhibitor de-
Total 130.991 199.056 225.223 11 veloped by lohnson & lohnson's Ti-
' CAGB is coiTipound annual growth rate botec, and tclbivudine, a reverse tran-
Source: Technology Catalysts Intemational
scriptase inhibitor under develop
ment by Indenix Pharmaceuticals
"Prilosec" {omeprazole). In addition, sition have occurred. Ranbaxy has and Novartis.
Nexium daims to heal the erosion in the tentative approval from the US Food Darunavir was approved by FDA in
esophagus caused by gastroesophageal and Drug Administration to market a lune 2006 in combination with a low-
reflux disease, thus providing a clinical generic version of tolterodine. dose of ritonavir and other active
advantage as well. Schwarz Pharma submitted a new anti-HIV agents. The compound has
Other single enantiomers contribut- drug application to FDA and a mar- .shown resistance repellence proper-
ing to growth in the Cll segment were keting authorization application to ties. This means that the compound
"Flomax"or"Harnar'(tamsulosin) and the European Medicines Agency suppressed the development of new
"Remicade" (infliximab). Tamsulosin (EMEA). Pfizer has acquired world- drug-resistant viral strains in addition
was developed hy Yanianouchi Pharma- wide rights to fesoterdine. Peak sales to inhibiting the replication of exist-
ceutical, which merged with Fujisawa are expected to be in the range of ing multidrug strains. The drug has
Pharmaceutical to form Astellas in $650-800 million range, according to also been submitted to the EMEA for
2005. Astellas markets the drug with industry estimates. approval in Europe. Peak sales of
Ahbott Laboratories and Boehringer Roche's "Tamiflu" (oseltamivir) is darunavir are expected in the range of
Ingelheim. The compound has patent an example of a single enantiomer $650-800 million, according to indus-
protection in the United States through drug contributing to growth in the try estimates.
2009, but the patent has been chal- antiviral segment. Interest in the Telbivudine has been submitted for
lenged by the Indian pharmaceutical product also has led to the develop- regulatory approval to EDA and EMEA
company Ranbaxy Laboratories. Remi- ment ot alternative synthetic routes for treating chronic hepatitis B. Several
cade, although originally launched for by researchers at Harvard University studies are underway to demonstrate
Crohn's disease, is approved for other (1) and the University of Tokyo (2) to clinical benefits In comparison with
indications, including rheumatoid avoid the use of (-)-shikimic or (-)- Gilead Sciences"'Hepsera" (adefovir
arthritis, which contributed to growth. quinic acids, starting materials in dipivoxil). A combination therapy with
Pfizer is developing fesoterodine limited supply. Idenix Pharmaceuticals' valtorcitabine,
with Schwarz Pharma for treating uri- Other single-enantiomer drugs another L-nucleoside analog, in Phase
nary incontinence and overactive contributing to growth in the antiviral I! development may be the optimal
bladder in response to the expected segment include: GlaxoSmithKline's therapy because of synergies between
loss of market exclusivity for Pfizer's "Valtrex" (valacyclovir), Abbott Labo- the two molecules. Peak sales of tel-
"Detrol" (tolterodine) in 2008. Al- ratories "Kaletra" (lopinavir and ri- bivudine are projected to be between
though the patent has not yet expired, tonavir), GlaxoSmithKline's "Trizivir" $225-275 million, according to indus-
court challenges to Pfizer's patent po- (abacavir, zidovudine, and lamivu- try estimates.

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

 Chiral Chemistry and Pharmaceuticals

GlaxoSmithKline's "Advair" (fluti-

Table II: Top-selling single enantiomer drugs, global 2005 sales
casone and salmeterol) and Merck &
Co.'s"Singulair" (montelukast) are Active
2005 sales
Company Brand name pharmaceutical
two single enantiomers leading (in $ billions)
ingredient
growth in the respiratory category. In
Pfizer, Astellas Lipitor 12.986
Advair, GlaxoSmithKline is gaining atorvastatin
patients from its older respiratory Sanofi-Aventis,
Plavix 6.345
Bristol-Myers Squibb clopidogrel
drugs, including "Serevent"(salme-
tcrol) and "Flixotide" or "Flovent" Amgen, Johnson & Johnson Epogen, Procrit 5.799
epoetin alfa
(fluticasone). GlaxoSmithKline's tluticasone 5.465
GlaxoSmithKline Advair, Seretide
strategy is to take advantage of the and salmeterol
longer patent life for the combination Genentech, Roche Rituxan. MabThera rituximab 5.166
product Advair. The patents for Ad- 4.633
AstraZeneca Nexium esomeprazole
vair are set to expire in 2010 in the
United States and in 2013 in the Eu- Merck & Co. Zocor simvastatin 4.382
ropean Union. The patents for Daiichi Sankyo, Mevalotin or
pravastatin 3.844
FHxotide or Flovent have expired in Bristol-Myers Squibb Pravachol
both the United States and the Euro- Novartis Diovan vatsartan 3,676
pean Union. The patents for Serevent
Amgen, Wyeth Enbrei etanercept 3.567
are set to expire in 2008 in the United
States. In Europe, the only patent Johnson & Johnson.
Remicade infliximab 3.477
Schering-Plough
protection is in France (2008) and
Italy (2009). Amgen Aranesp darbepoetin alfa 3.276

Sales increases tor cancer therapeu- Pfizer Zoloft sertraline 3.256

tics result from a combination of bio-
logics and small-molecule single enan-
tiomer products. These products
include: 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), and
Eli Lilly's "Gemzar" (gemcitabine).
Pipeline products for cancer thera-
peutics have focused on biologies,
mainly monoclonal antibodies. One
example is Amgen's panitumumab, for
which peak sales are estimated between
$1.3-1.6 billion.
Single enantiomers as blockbusters
The growth in single-enantiomer phar-
maceuticais has produced several
blockbuster compounds as shown in
Table 11. As would be expected, many
of the high-growth compounds men-
tioned earlier in this article are in-
cluded in this list. Others such as
Pfizer'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-
Merck & Co. Singulair montelukast 2.976
Lovenox 2.668
Sanoii-Aventis enoxaparin
Genentech, Roche Herceptin trastuzumab 2.469
Amgen Neulasta pegfilgrastim 2.288
Lundbeck, Forest Laboratories Cipralex or Lexapro escitalopram 2.043
Pfizer Zithromax azithromycin 2,025
Sanofi-Aventis Taxotere docetaxel 2.003
Sanofi-Aventis Eloxatin oxaliplatin 1.947
Source: Technology Catalysts International and company information
ing-drugs for several years. Many of these blockbusters, specifically 13
these products are at or nearing the Pharmaceuticals, are considered smali
end of their patent life, and innovator molecules rather than biologies. Thus,
drug companies are seeking ways to continued development of chiral tech-
protect themselves from sales de- nologies, including catalytic and enzy-
clines from generic competition. For matic synthesis routes, will be impor-
example, Amgen developed tant tor contract manufacturers and
"Aranesp" (darbepoetin alfa) as a sec- pharmaceutical companies. Moreover,
ond generation biologic to Epogen. the development of improved
Aranesp has been so successful that it processes will be needed as these com-
is also in the top 20 selling drugs. pounds come off patent.
For Zoloft, Pfizer developed a new
synthetic route to lower the cost of Generic competition
manufacture. AstraZeneca responded The maturing of the single-enantiomer
with the racemic switch from omepra- drug market is clearly seen by the ar-
zole to esomeprazoie. GlaxoSmithKline rival of generic competition. The
targeted a combination product, Ad- angiotensin-converting enzyme (AGE)
vair, to address patent expiries. inhibitors, the so-called "prils" are the
It should be noted that manv of first class of single-enantiomer com-
Ptiaimceuticai Teebmiogj/ TECHNOLOGY OUTLOOK- APIS, INTERMEDIATES, AND FORMULATION si 7
Chiral Chemistry and Pharmaceuticals

pounds to face such competition. The

Table III: Potential generic competition of select single enantiomer drugs.
following prils have had declining sales
in the doubte-digit range: Ptl7er's"Ac- US Food and Drug
Active
Company Brand name Marketed generics Administration
cupril" (quinapril); Novartis' ingredient
tentative approvals*
"Lotensin" (benazepril); Bristol-Myers
Sanofi-
Squibb's "Monopril" (fosinopril);
Aventis,
Merck & Co.'s "Vasotec" (enalapril); Piavix clopidogrel Apotex Not appiicabte
Bristol-Myers
and AstraZeneca's "Zestril" (lisinopril). Squibb
The statins are the next large class of Alpharma (now part of
Ivax (now part of Teva
single-enantiomer cardiovascular ther- AstraZeneca Nexium esomeprazole Actavis), Teva
Pharmaceuticals)
apies to see generic competition. Sig- Pharmaceuticals
nificant generic competition exists for Ivax (now part of Teva
Aurobindo, Cobalt
Merck & Co.'s "Mevacor" (lovastatin), Pharmaceuticals),
Pharmaceuticals.
and generic competition is increasing Merck & Co. Zocor simvastatin Ranbaxy Laboratories
Ranbaxy Laboratories,
has approval for an 80
for Merck's Zocor (simvastatin), as Teva Pharmaceuticals
mg formulation
shown in Table III. Ranbaxy is seeking
Apotex, Dr Reddy's,
to launch a generic atorvastatin prod-
Geneva
uct, but has lost court cases in the Daiichi Pharmaceuticals (part
United Kingdom and the United States. Mevaiotin
Sankyo, of Sandoz),
Of pravastatin Teva Pharmaceuticals
Ranbax}' is appealing both cases. Bristol-Myers
Pravachol
GenPharma, Lek (part
Squibb of Sandoz), Watson
Pfizer developed several combina-
Pharmaceuticals,
tion therapies to protect its position Zydus
in cholesterol-lowering therapeutics. Andrx, Aurobindo. Dr.
Caduet, a fixed-dosage formulation Reddy's, GenPharma,
Ivax (now part of Teva Ivagen. Mutual
combining atorvastatin and amlodip-
Pharmaceuticals) Pharmaceuticals,
ine, was approved in 2004 and treats Pfizer Zoloft sertraltne Ranbaxy Laboratories Mylan
both hypertension and hypercholes- has approval for an oral Pharmaceuticals,
terolaemia. Pfizer reported Caduet concentrate Purepac (now part of
sales of $185 million in 2005. In ad- Actavis), Roxane
dition, Pfizer is developing its single- Laboratories, Zydus
Lundbeck, Alpharma (part of
enantiomer compounds, atorvastatin Cipralex or Ivax (now part of Teva
Forest escitalopram Actavis), Teva
(40 mg) and torcetrapib (60 mg) as a Laboratories
Lexapro Pharmaceuticals)
Pharmaceuticals
fixed-combination therapy for pa-
tients with elevated cholesterol, espe- Abraxis Pharmaceutical
cially LDL-cholesterol, levels, and low Pfizer Zithromax azithromycin Products, Pliva, Sandoz, Not applicable
HDL-cholesterol levels. Phase III Teva Pharmaceuticals
clinical trials are in progress. A new
drug application is expected to he • Asof Juty2006
filed with FDA in 2007. Peak sales are Source: Technology Catalysts Intemational and US Food and Drug Administration
forecast at $1.3-1.6 billion, based on
small molecules in certain key classes vative treatments that will continue to
industry estimates.
such as cancer, arthritis, central nerv- drive the development of single-enan-
Other singie-enantionier, small mol- ous system, and antivirals will have sig- tiomer drugs.
ecules approved as abbreviated new nificant impact.
drug applications or with tentative ap- Several singie-enantiomer drugs in- References
provals from FDA are listed in Table 111. troduced in 2005 show ongoing drug 1. \. Vcung, S. Hong, and E.J. Corey, "A Short
innovation. Examples include Amylin Entantioselective Pathway for the Synthe-
sis of the Anti-Influenza Neuraniidase In-
Future of single-enantiomer drugs Pharmaceuticals' "Byetta" (exanatide),
hibitor Oseltamivir from 1.3-Butadiene
Overall, single-enantiomer drugs will a peptide for improved sugar control and Acrylic Acid," /. Am. Chem. Soc. 128
grow at a similar rate as the pharma- in patients with Type II diabetes; (9), 6310-6311 (Communication) (2006),
ceutical market. Higher growth in key Pfizer's "Macugen" (pegaptanih), an 2. M.Shibasaki et al, "De Novo Synthesis of
therapeutic categories will be offset hy aptamer for neovascular age-related Tamiflu via a Catalytic Asymmetric Ring-
the large and maturing markets in an- macular degeneration; and Sepracor's Opening of Meso-Aziridines with TMSN,
/, Am. Chem. Soc. 128 (19), 6312-6313
tibiotics and cardiovascular drugs. Part "Lunesta" (eszoplicone), the (S)-
(Communication) (2006). fT
of the higher growth will be from sales enantiomer of zoplicone for treating
increases in biologies, but the use of insomnia. It will be the push for inno-

si8 Phamaceatical lecltBOleg]/ TECHNOLOGY OUTLOOK: APIS. INTERMEDIATES, AND FORMULATION www.pharmtecti.com