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Drug chirality is now a major theme inthe design, discovery, development,launching and marketing of new drugs[1–4]. Stereochemistry is an essentialdimension in pharmacology [1]. In past decades the pharmacopoeiawas dominated by racemates, but sincethe emergence of new technologies inthe 1980s that allowed the preparationof pure enantiomers in significantquantities, the awareness and interestin the stereochemistry of drug actionhas increased [1–4].
The advances in stereoselectivebioanalysis led to a new awareness of the importance of stereoselectivepharmacodynamics andpharmacokinetics, enabling thedifferentiation of the relativecontributions of enantiomers to overalldrug action. When one enantiomer isresponsible for the activity of interest,its paired enantiomer could be inactive,possess some activity of interest, be anantagonist of the active enantiomer orhave a separate activity that could bedesirable or undesirable [3–5].Considering these possibilities, thereappears to be major advantages inusing stereochemically pure drugs,such as a reduction of the totaladministered dose, enhancedtherapeutic window, reduction ofintersubject variability and a moreprecise estimation of dose–responserelationships [3,4]. These factors haveled to an increasing preference forsingle enantiomers in both industryand regulatory authorities. Regulatorycontrol of chiral drugs began in the US
with the publication in 1992 of formalguidelines on the development of chiraldrugs in a document entitled PolicyStatement for the Development ofNew Stereoisomeric Drugs [6] and wasfollowed in the European Union (EU)in 1994 by Investigation of Chiral ActiveSubstances [7]. Applicants mustrecognize the occurrence of chirality in new drugs, attempt toseparate the stereoisomers, assess the contribution of the variousstereoisomers to the activity of interestand make a rational selection of thestereoisomeric form that is proposedfor marketing [4].
Worldwide sales of chiral drugs insingle-enantiomer forms continue togrow. The market share of single-enantiomer dosage form drugsincreased annually from 27% (US $74.4 billion) in 1996, 29% (1997),30% (1998), 32% (1999), 34% (2000),38% (2001) to an estimate of 39%(US $151.9 billion) in 2002 [8–13].
The top ten single enantiomerblockbuster drugs (>US $1 billion salesper year) are: Atorvastatin calcium[Pfizer; http://www.pfizer.com](cardiovascular); Simvastatin [Merck;http://www.merck.com] (cardiovascular);Pravastatin sodium [Bristol-MyersSquibb; http://www.bms.com](cardiovascular); Paroxetinehydrochloride [GlaxoSmithKline;http://www.gsk.com] (CNS);Clopidogrel bisulfate [Sanofi-Synthelabo/Bristol-Myers Squibb;http://www.sanofi-synthelabo.com](hematology); Sertraline hydrochloride
[Pfizer] (CNS); Fluticasone propionateand salmeterol xinafoate[GlaxoSmithKline] (respiratory);Esomeprazole magnesium [AstraZeneca;http://www.astrazeneca.com](gastrointestinal); Amoxicillin andpotassium clavulanate [GlaxoSmithKline](antibiotic); and Valsartan [Novartis;http://www.novartis.com](cardiovascular) (Source: TechnologyCatalysts International) [13].
The previously reported surveys ofchiral and achiral drugs have beenlimited in scope, each covering onlyshort periods and a single jurisdiction.Examples include an informal analysisof the 95 submissions of newchemical entities (NCEs) assessed bythe UK Medicines Control Agency[MCA; now Medicines and Healthcareproducts Regulatory Agency (MHRA)]in 1996–2000 [14], and an analysis ofthe new molecular entities (NMEs)approved by the FDA in 1998–2001(http://www.fda.gov/cder/rdmt/) [15].
In this article we evaluate andprovide an insight into thedevelopment of chiral and achiraldrugs and examine the impact of thison industrial drug development anddrug regulation worldwide.
Methods of surveying approveddrugs according to chiralitycharacterTo survey the chirality character ofworldwide approved drugs, drugswere classified as being achiral, singleenantiomer or racemate. Racematesalso include diastereomeric mixtures
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Trends in the development of chiral drugsHava Caner, Efrat Groner and Liron Levy, Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel and Israel Agranat*, Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel and Division ofBiomedical Sciences, Faculty of Medicine, Imperial College, Sir Alexander Fleming Building, South Kensington, London SW72AZ, UK; *e-mail: [email protected]
for the purpose of this survey. Itshould be noted that racemates areconsidered to be chiral drugs. Thepresent analysis does not include newbiological entities (NBEs).
The following two databases ofapproved drugs were surveyedaccording to the chirality character ofthe drugs: (i) To Market, To Market inAnnual Reports in Medicinal Chemistry,in the years 1983–2002 [16]. Thisdatabase lists all the new drugslaunched each year in worldwide
markets; and (ii) new molecular entities(NMEs) also termed by the FDA as newchemical entities (NCEs), approved bythe FDA in the years 1991–2002(http://www.fda.gov/cder/da/da.htm).This database lists all new drugsclassified as Chemical Type 1 (NME).NMEs are defined as active ingredientsthat have never been manufactured inthe US. The FDA classifies investigationalnew drug applications (INDs) and newdrug applications (NDAs) to assignreview priority on the basis of the
Chemical Type (CHE) of the drug andpotential benefit (Box 1). According tothe FDA a chiral switch [4] is notclassified as a NME as it already containsa previously approved active moiety.
Chiral switches are drugs that havealready been claimed, approved and/ormarketed as racemates or as mixturesof diastereomers, but have since beenredeveloped as single enantiomers[4,17]. The essential criterion of a chiralswitch is a change in the status ofchirality [4]. Thus, the chiral switches,esomeprazole magnesium (Nexium)(CHE 2), levobupivacaine hydrochloride[Chirocaine; AstraZeneca/Celltech(http://www.celltechgroup.com)] (CHE 2),dexfenfluramine [Redux; Indevus/Wyeth (http://www.indevus.com andhttp://www.wyeth.com)] (CHE 3;withdrawn), levofloxacin [Levaquin;Daiichi/Aventis/Ortho-McNeil(http://www.daiichius.com;http://www.aventis.com; andhttp://www.ortho-mcneil.com] (CHE 3),levalbuterol [Xopenex; Sepracor(http://www.sepracor.com)] (CHE 3),dexmethylphenidate [Focalin; Novartis/Cellgene (http://www.celgene.com)](CHE 3), levocetirizine hydrochloride[Xyzal, Xusal; Sepracor/UCB Farchim SA(http://www.ucbpharma.com)] (CHE 3) and escitalopram oxalate
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Box 1. FDA classification of investigational new drugapplications (INDs) and new drug applications (NDAs)according to Chemical Type (CHE)
Chemical Type (CHE)1 New Molecular Entity (NME): an active ingredient that has never been
marketed in the US.2 New derivative: a chemical derived from an active ingredient already
marketed (a ‘parent’ drug).3 New formulation: a new dosage form or new formulation of an active
ingredient already on the market.4 New combination: a drug that contains two or more compounds, the
combination of which has not been marketed together in a product.5 Already marketed drug product, but a new manufacture: a product
that duplicates another firm’s already marketed drug product (same activeingredient, formulation or combination).
6 Already marketed drug product, but a new use: a new use for a drugproduct already marketed by a different firm.
7 A drug that is already legally marketed without an approved NDA.
Figure 1. (a) Distribution of worldwide-approved drugs according to chirality character in the period 1983–2002 (b) Distribution of FDAapproved drugs (NMEs) according to chirality character in the period 1991–2002. *Including diastereomeric mixtures.
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6%Single
33%Multiple
SingleEnantiomers
39%
Achirals38%
Racemates*23%
Chiral centers
Chiral centers
Racemates*14%
Achirals42% Single
Enantiomers44%
36%Multiple
8%Single
(a) (b)
[Cipralex/Lexapro; H. Lundbeck/ForestLaboratories (http://www.lundbeck.comand http://www.frx.com)] (CHE 3) arenot included among the NMEs (CHE 1).Most of the chiral switches appear inthe database of worldwide-approveddrugs [16].
It should be noted that most (>90%) of the FDA-approved drugs in 1991–2002 were also included inthe database of worldwide approveddrugs, although not necessarily in thesame year.
Figure 1a illustrates the totalworldwide distribution of 730 approveddrugs in 1983–2002 (including 382 in1991–2002) and the US distribution of304 FDA approved drugs (NMEs) in1991–2002 according to their chiralitycharacter. Table 1 and Figures 2–5describe the annual distributions ofworldwide approved drugs in theperiod 1983–2002 and of the FDA-approved drugs (NMEs) in the period1991–2002 and the corresponding fouryear (worldwide) and three year (FDA)range distributions.
Distribution of worldwideapproved drugs, according tochirality character*1983–2002An overall look at the 20-year periodfrom 1983–2002 (Figure 1a) indicatesthat single-enantiomers surpassedachirals whereas racemates representedthe minority category at 23% ofworldwide approved drugs. Thepreponderance of single-enantiomerswas probably driven by the tide ofapproved single-enantiomer drugs thatoccurred since 1998. In the four-yearperiod from 1983–1986 (Figure 3),more racemic drugs (32%) wereapproved compared with singleenantiomer drugs and achiral drugsexceeded both categories of chiral
drugs. However, even in this early timespan of the 1980s, single enantiomerswere not a minor component ofapproved drugs and of approvedchiral drugs. In subsequent years thepercentage of achiral drugs decreasedgradually from 43 to 34% of allapproved drugs. The achirals:chiralsratios were 43:57 (1983–1986), 36:64(1987–1990), 34:66 (1991–1994),41:59 (1995–1998) and 34:66(1999–2002) (Figure 3). Thepercentage of racemates droppeddramatically in the period 1999–2002to 8% compared with the earliergradual decreases. In 2001 there were no racemates approved whereastwo racemic drugs were approved in 2002 (in Japan and in South Korea).Single enantiomers reached 50% of all approved drugs for the first time
in 1998, rising to >60% between2000–2001.
These trends were probablyinfluenced considerably by theguidelines of the regulatory agencies inthe major jurisdictions, which favoredand encouraged, but did not force, the development of single-enantiomerdrugs over racemates [6,7], thusaccounting for the dramatic shift ofpharmaceutical company interest inmanufacturing the safer singleenantiomer and achiral drugs over theproblematic racemic drugs.
Distribution of FDA approveddrugs, according to chiralitycharacter1991–2002The distribution of FDA approved NMEsaccording to chirality character covers
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Table 1. Annual distribution of worldwide and FDA-approved drugs(NMEs) according to chirality character in the period 1983–2002
Year Racematesa Single enantiomers AchiralWorldwide FDA Worldwide FDA Worldwide FDA(%) (%) (%) (%) (%) (%)
1983 37 na 26 na 37 na
1984 28 na 26 na 46 na
1985 38 na 22 na 40 na
1986 26 na 26 na 48 na
1987 18 na 49 na 33 na
1988 26 na 39 na 35 na
1989 29 na 26 na 45 na
1990 33 na 35 na 32 na
1991 20 9 40 65 40 26
1992 21 33 44 42 35 25
1993 16 17 45 29 39 54
1994 38 5 38 57 24 38
1995 21 37 46 30 33 33
1996 9 14 41 43 50 43
1997 24 8 30 38 46 54
1998 15 9 50 41 35 50
1999 13 4 52 46 35 50
2000 9 19 62 37 29 44
2001 0 0 68 60 32 40
2002 6 0 55 53 39 47aIncluding diastereomeric mixtures; Abbreviations: na, not applicable
*The annual distribution in 1989–2000 and1989–2001, and for five-year distributions in theperiod 1983–2002 have recently been reported [4, 17, 20]
only 12 years (1991–2002) (Figure 1b).It does not include the decade beforethe publication of the FDA guidelines[6]. The distribution of FDA approveddrugs for the whole 12-year periodbears some similarity to the worldwidedistribution, in that 44% were singleenantiomers, 42% achiral drugs and aminority (14%) were racemic drugs.
In the three-year range distribution(Figure 5) the dominance of single-enantiomer drugs is obvious, startingwith 45% between 1991–1993. Thisfigure varied only slightly in the periodof 1991–2002 whereas racematesdropped significantly in the same period.Achirals fluctuated from 35% in1991–1993 to 52% in 1997–1999 and
then dropped slightly to represent 44%of FDA-approved drugs in 2000–2001.Single enantiomers took over as theleading category in 2001 (60%)compared with achirals (40%) andracemates (0%).
The case of the racemic drugthalidomide is worthy of comment.The thalidomide tragedy of 1961 was alandmark in drug regulation [4,18].Thalidomide was marketed outside theUS in the late 1950s and early 1960s asa sleeping pill and a treatment formorning sickness during pregnancy.This treatment resulted in the birth ofdeformed babies. At that timethalidomide had not been approvedby the FDA. However, in 1998 theFDA-approved racemic thalidomide[Thalomid (Celgene)] for the acutetreatment of the cutaneousmanifestations of moderate to severeerythema nodosum leprosum (ENL)and as maintenance therapy for theprevention and suppression of thecutaneous manifestations of ENLrecurrences. It was awarded orphandrug status and was classified as aNME (CHE 1). The proposal that thethalidomide tragedy could have beenavoided if the single enantiomer hadbeen used is misleading [4].
Conclusions• In the 1980s single enantiomers were a
significant and important componentof approved drugs even beforechanges in guidelines by regulatoryagencies encouraged (but did notforce) the development and marketingof enantiomerically pure drugs.
• The regulatory guidelines did notaffect significantly the chiral (singleenantiomers + racemates) to achiralratio. However, the guidelines didhave a major impact within thechiral drug category, resulting in thedramatic decline in the developmentof racemates in recent years.
• Changes in the attitudes of theregulatory agencies over the past
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Figure 2. Annual distribution of worldwide-approved drugs according to chirality in theperiod 1983–2002. * Including diastereomeric mixtures
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0
10
20
30
40
50
60
70
(%)
Per
cent
age
ofto
tal a
ppro
ved
drug
s
Racemates*
Year
Single enantiomers Achiral
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Figure 3. Distribution of worldwide-approved drugs according to chirality character infour-year ranges. *Including diastereomeric mixtures
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1983–19861987–1990
1991–1994
Year range
1995–19981999–2002
Racemates*
Single enantiomers
Achiral
43
3635
41
34
25
3942
41
58
32
2524
18
8
0
10
20
30
40
50
60
(%)
Per
cent
age
ofto
tal a
ppro
ved
drug
s
decade with respect to chiral drugshave affected the number ofsubmissions of single enantiomers.
• Of the single-enantiomer approveddrugs, the overwhelming majoritycontain multiple chiral centers (84%worldwide and 82% FDA) comparedwith those containing only one chiralcenter (16% worldwide, 18% FDA).
• The available data for 15 FDAapproved drugs in the periodJanuary–August 2003 indicate thefollowing distribution: 64% singleenantiomers, 14% racemates and22% achirals (http://www.fda.gov/cder/rdmt/NMECY2003.htm).
• In spite of the absence of anyFDA-approved racemates in 2001and 2002 and only two approvedracemates in 2002 (worldwide),racemic drugs should not bedeclared a dead option. It remainsto be seen whether or not racemateswill disappear from the drugapproval scene.
• The present study might shed light onaspects of intellectual property in chiralswitch scenarios [4,19], such as thatrelating to the pending litigation in theUS challenging the patents coveringthe oral anti-platelet chiral drug Plavix(clopidogrel bisulphate) [20].
• Finally, the data reported here verifiesthe conclusion that the debate aboutthe relative merits of racemates andsingle enantiomers has been resolvedemphatically in favor of singleenantiomer drugs [4].
AcknowledgementWe thank John Caldwell (Dean, Facultyof Medicine, University of Liverpool,UK) for a stimulating and fruitfulcooperation.
References1 Eichelbaum, M., Testa, B. and Somogyi A.,
eds (2003) Stereochemical Aspects of DrugAction and Disposition, Springer
2 Eichelbaum, M. and Gross, A.S. (1996)Stereochemical aspects of drug action anddisposition. Adv. Drug Res. 28, 1–64
3 Caldwell, J. (1999) Through the lookingglass in chiral drug development. ModernDrug Discov. 2, 51–60
4 Agranat, I., Caner, H. and Caldwell, J. (2002)Putting chirality to work: the strategy ofchiral switches. Nat. Rev. Drug Discov. 1,753–768
5 Shah, R.R. (2003) Improving clinicalrisk/benefit through stereochemistry. InStereochemical Aspects of Drug Action andDisposition (Eichelbaum, M., Testa, B. andSomogyi, A., eds), pp. 401–432, Springer
6 Food and Drug Administration (1992) FDA’spolicy statement for the development of new
stereoisomeric drugs. 57 Fed. Reg. 22 2497 Committee for Proprietary Medical Products
(1993) Working parties on quality, safety andefficacy of medical products. Note forguidance: investigation of chiral activesubstances. III/3501/91
8 Stinson, S.C. (1998) Counting on chirality.Chem. Eng. News 76 (38), 83–104
9 Stinson, S.C. (1999) Chiral drug interactions.Chem. Eng. News 77(41), 101–120
10 Stinson, S.C. (2000) Chiral drugs. Chem. Eng.News 78(43), 55–78
11 Stinson, S.C. (2001) Chiral pharmaceuticals.Chem. Eng. News 79(40), 79–97
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Figure 4. Annual distribution of FDA-approved drugs (NMEs) according to chirality in theperiod 1991–2002. * Including diastereomeric mixtures.
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0
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30
40
50
60
70
1991 1992 1993 1994 1995 1996Year
1997 1998 1999 2000 2001 2002
(%)
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Racemates* Single enantiomers Achiral
Figure 5. Distribution of FDA-approved drugs (NMEs) according to chirality character inthree-year ranges. *Including diastereomeric mixtures
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1991–19931994–1996
1997–1999
Year range2000–2002
Racemates*
Single enantiomers
Achiral
3539
52
4445
4241
50
2019
76
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Advancing in the face ofconventional wisdom
In recent issues of Drug Discovery Today[1,2], Jurgen Drews and David Cavalladiscussed the future productivity ofdrug discovery. Although they mademany insightful and valid comments,I would like to add some points to theoverall discussion.
My first point is that most smallbiotechnology companies are notfunded enough to enter a Phase IIIclinical study. Often, it is not even intheir business strategy to enter Phase IIIdevelopment without a major partneron board. Therefore, it might be that thelack of funding and increased discretionof the major pharmaceutical companiesplay the more important roles indetermining which products enterPhase III drug development. This wouldexplain many of David Cavalla’s
observations, including why there hasbeen an increase in Phase I and IIinvestigations, with a 71% increase in the time taken in Phase II between1997 and 2001 (Ref. [2] and referencestherein).
My second point is that drugdiscovery could blossom if werecognized the need both for moreaccurate descriptions of drug–receptorinteractions and for safer drugs. I believethat most readers would agree withthese two points, although when itcomes to Drews’ and Cavalla’s pointthat ‘…without the conviction basedon scientific rectitude to advance intouncharted areas in the face ofconventional commercial wisdom,medicine will advance little, and thefuture for the pharmaceutical industry islacklustre.’ [2], we enter a rather strangerealm in which we should promote theunusual and more creative scientific
ideas to develop better drugs. However,the drug discovery process is notconstructed to do this in a way thatencourages the funding of the morecreative young biotechnologycompanies or entrepreneurs. Muchinvestor money is risk adverse, so thisjob is handed over to the well-fundedpharmaceutical or biotechnologycompanies, or to the universities andNational Institutes of Health. This isslightly better, although they are allinvested in the conventional wisdom(which is often shaped by money andpower) and, therefore, have no desireto upset it.
Often, there are rather large egosinvolved in promoting and keepingscientific theories and ideas in press forpossible prestige and potential fame. Yetsome of the areas of most need are leftwanting for the necessary cutting-edgeresearch. Many diseases have onlypalliative treatments and many of thedrug therapies have serious side effectsthat have increased morbidity andmortality. Much has been made of theInstitute of Medicine report suggestingthat from 44 000 to 98 000 deathsoccur annually in the USA because ofmedical errors [3]. However, the sideeffects of drugs and drug combinationsincrease each year, despite increasedvigilance from the health carecommunity. Certainly, some of thereported medical errors are due to theimproper use of drugs. For the mostpart, the Food and Drug Administration
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The Discussion Forum provides a medium for airing your views on any issues
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Furthermore, the views provided are those of the authors and are not
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e-mail: [email protected]
12 Rouhi, A.M. (2002) Chiral roundup. Chem. Eng. News 80(23), 43–50
13 Rouhi, A.M. (2003) Chiral business. Chem. Eng. News 81(18), 45–55
14 Shah, R.R. and Branch, S.K. (2003)Regulatory requirements for thedevelopment of chirally active drugs. In Stereochemical Aspects of Drug Action andDisposition (Eichelbaum, M. et al., eds),pp. 379–399, Springer
15 Miller, S.P. (2001) FDA perspective on quality control for chiral pharmaceuticals.13th International Symposium on ChiralDiscrimination (abstract L/316)
16 Bristol, J.A. and Doherty, A.M. eds.(1984–2003) To Market, To Market. In Annual Reports in Medicinal Chemistry,19–38, Academic Press
17 Rouhi, A.M. (2003) Chirality at work. Chem. Eng. News 81(18), 56–61
18 Hilts, P.J. (2003) Protecting America’s Health:the FDA Business, and One Hundred Years ofRegulation. pp. 144–165. Alfred A. Knopf,New York
19 Agranat, I. and Caner, H. (1999) Intellectualproperty and chirality of drugs. Drug Discov.Today 4, 313–321
20 Anonymous (2003) Patent watch. A newtwist on the chiral switch. Nat. Rev. DrugDiscov. 2, 424
