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Reduction of Side Effects from Aromatase Inhibitors

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(19) & (11) EP 1 945 224 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/56 (2006.01) A61P 35/00 (2006.01) 02.05.2012 Bulletin 2012/18 A61K 31/4196 (2006.01) A61K 31/568 (2006.01) A61K 45/06 (2006.01) (21) Application number: 06804410.6 (86) International application number: (22) Date of filing: 18.10.2006 PCT/AU2006/001539 (87) International publication number: WO 2007/045027 (26.04.2007 Gazette 2007/17) (54) REDUCTION OF SIDE EFFECTS FROM AROMATASE INHIBITORS USED FOR TREATING BREAST CANCER VERRINGERUNG DER NEBENWIRKUNGEN VON AROMATASE-HEMMERN ZUR BEHANDLUNG VON BRUSTKREBS RÉDUCTION DES EFFETS SECONDAIRES DES INHIBITEURS DE L’AROMATASE EMPLOYÉS DANS LE TRAITEMENT DU CANCER DU SEIN (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-01/87334 WO-A-02/30355 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI WO-A-2005/011705 US-B1- 6 696 432 SK TR Designated Extension States: • ’The Merck Index’, vol. 13TH ED., 2001, MERCK & AL BA HR MK RS CO INC. XP008141946 • GOSS ET AL.: ’Anastrozole: A New Selective (30) Priority: 19.10.2005 AU 2005905768 Nonsteroidal Aromatase Inhibitor’ ONCOLOGY 03.11.2005 US 732662 P vol. 11, no. 11, 1997, pages 1697 - 1703, DISC. 08.05.2006 US 798308 P 1707-08, XP008080452 • SANTEN: ’Recent Progress in Development of (43) Date of publication of application: Aromatase Inhibitors’ J. STEROID BIOCHEM. 23.07.2008 Bulletin 2008/30 MOL. BIOL. vol. 37, 1990, pages 1029 - 1035, XP003012148 (73) Proprietor: Chavah Pty Ltd • WASAFF: ’Current Status of Hormonal Medindie SA 5081 (AU) Treatments for Metastatic Breast Cancer in Postmenopausal Women’ ONCOL. NURS. (72) Inventor: BIRRELL, Stephen, Nigel FORUM vol. 24, 1997, pages 1515 - 1520, Medindie, S.A. 5081 (AU) XP008080467 (74) Representative: Ritter, Thomas Kurt et al Jones Day Prinzregentenstraße 11 80538 München (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 945 224 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 945 224 B1 2 Description enzyme inhibitors have been developed, which specifi- cally inhibit the aromatase enzyme that converts testo- Cross-References To Related Applications sterone to estradiol. These compounds are known as aromatase inhibitors. They are used to block the conver- [0001] This application claims the priority benefit of the 5 sion of testosterone to estradiol, resulting in non-tissue- following applications: 1) Australian Provisional Serial specific enzymatic inhibition and almost complete abla- No. 2005905768, filed on October 19, 2005, 2) U.S. Pro- tion of testosterone conversion to estradiol. The relevant visional Serial No. 60/732,662, filed November 3, 2005, conversion pathways are shown in FIG. 1. and 3) U.S. Provisional Serial No. 60/798,308, filed May [0007] The development of these aromatase inhibi- 8, 2006. 10 tors, such as exemestane (Aromasin®), anastrozole (Ar- imidex®) and letrozole (Femara®) has brought about a Field of the Invention major change in the therapeutic approach to patients with hormone-sensitive breast cancer. In randomized clinical [0002] The present invention relates to the reduction trials, each of these aromatase inhibitors has demon- of side effects caused by aromatase inhibitors which are 15 strated efficacy in the adjuvant treatment of post-meno- used to treat subjects with breast cancer. In particular, pausal women with receptor-positive tumors. Although the present invention provides composition, methods, long-term follow up for safety and overall survival contin- and kits for reducing side effects in post-menopausal ues in each of these trials, currently available data sug- women with breast cancer already being treated with ar- gest that an aromatase inhibitor should now be included omatase inhibitor comprising administering an effective 20 as part of adjuvant endocrine therapy for the great ma- amount of an androgenic agent. Furthermore, the jority of receptor- positive post- menopausal patients. The present invention provides compositions, methods, and current strategy comprises at least five years of global kits for reducing side effects associated with aromatase estrogen deprivation with a tissue non-specific aro- inhibitor treatment in post-menopausal women with matase inhibitor. These aromatase inhibitors overcome breast cancer comprising administering a pharmaceuti- 25 the significant adrenal toxicity of the previous anti- estro- cal composition comprising an aromatase inhibitor and gen medications, and this has allowed them to now be- an androgenic agent. come the most widely prescribed hormonal therapy for breast cancer. Background of the Invention [0008] A significant problem with these aromatase in- 30 hibitors, however, is that they cause unwanted and sub- [0003] Breast cancer is the most common non-cuta- stantial short and long-term side effects. Examples of neous malignancy in women. It is estimated that there these side effects include, but are not limited to, vasodil- were 212,600 new cases in 2003 in the USA. It is esti- atation, osteoporosis, osteopenia, loss of libido, weight mated that at least 13% of women will develop breast gain, vaginal dryness, sleeping difficulties, night sweats, cancer at some time in their life, and this incidence is35 asthenia, painful intercourse, pain, arthritis, arthralgia, increasing. As more than 80% of breast tumors grow in breast pain, pharyngitis, depression, bloating, nausea, response to sex hormone stimulation caused by estro- rash, mood swings, headache, diminished cognitive gen, part of adjuvant therapy (i.e. therapy in addition to function, hypertension, insomnia, lymphoedema, back surgical removal of the tumor) is to administer an agent pain, peripheral edema, cold sweats, abdominal pain, to block this growth stimulation, including by means of 40 injury, constipation, coughing, diarrhea, fracture, hyper- blocking estrogen receptor activation or blocking estro- cholesteremia, infection, arthrosis, dizziness, dyspnea, gen production. paraesthesia, urinary tract infection, vulvovaginitis, anx- [0004] One such agent has been tamoxifen. Notwith- iety, bone pain, chest pain, dyspepsia, flu syndrome, gas- standing its success in adjuvant breast cancer therapy, trointestinal disorder, sweating and/or leukorrhea. tamoxifen has unwanted side-effects, which can be cat- 45 [0009] The present invention described herein differs egorized into estrogen receptor stimulating (uterine can- from other hormonal therapy methods for the treatment cer, deep venous thrombosis) and estrogen receptor an- of breast cancer. It provides the advantages of androgen tagonizing (vaginal dryness, hot flushes, mood swings) replacement therapy in combination with an aromatase and has led to the search for a better alternative. A more inhibitor. selective estrogen receptor regulator has so far not been 50 [0010] Current therapeutic circumstances in which an successful in taking the place of tamoxifen and the cur- aromatase inhibitor (e.g., Arimidex®) and an androgenic rent trend in hormonal therapy is to reduce the level of agent (e.g., testosterone) have been used in combination bio-available estrogen. previously are to reduce the estrogenic effect of testo- [0005] Another such agent has been aminoglutethim- sterone abuse in body building, in particular gynaeco- ide (Cash, Brough et al 1967). This drug was poorly tol- 55 mastia (Hoffmann J Raatamess N Journal of Sports Sci- erated and resulted in a marked adrenal suppression that ence and Medicine 5, 182-183 (2006), to reduce estro- limited the use of the drug. genic side-effects in hypogonadal men on T therapy [0006] Over the past 15 years, however, more specific (Leder et al. 2004, and Leder et al. 2005), and to explore 2 3 EP 1 945 224 B1 4 the safety issues (risk of cardiovascular disease) of an- breast cancer comprising administering to a subject a drogen replacement therapy, specifically in female to pharmaceutical composition comprising (a) an effective male transexuals undergoing testosterone therapy. amount of an androgenic agent and (b) an effective (Bunck et al. 2006). None of these circumstances of an- amount of an aromatase inhibitor, and, optionally, a phar- drogen replacement therapy, however, were for the treat- 5 maceutically acceptable excipient and/or carrier. ment of a woman diagnosed with breast cancer. In fact, [0017] Another aspect of the present invention is im- there has been a great reluctance by the medical profes- proving one or more side effects associated with aro- sion to prescribe hormone substrates to women who matase inhibitor treatment in a subject diagnosed with have hormonally active breast cancers. The use of an- breast cancer comprising administering to a subject a drogen replacement is controversial in post-menopausal 10 pharmaceutical composition comprising an effective women generally, and its use in women who have had amount of an androgenic agent and, optionally, a phar- breast cancer is almost universally contra- indicated. For maceutically acceptable excipient and/or carrier. example, a Proctor & Gamble application to the FDA for [0018] An additional aspect of the present invention is the
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  • Aromtase Inhibitors in Breast Cancer

    Aromtase Inhibitors in Breast Cancer

    한국유방암학회지：제5권 제4호 Aromtase Inhibitors in Breast Cancer Department of Surgery, Gachon Medical School, Incheon, Korea Woo-Shin Shim, M.D. INTRODUCTION gressions and to be associated with minimal side effects and toxicity. The second strategy, blockade of estradiol biosyn- Breast cancer is now the second most cancer in women after thesis, was demonstrated to be feasible using the steroido- stomach cancer in Korea, and is increasing continuously. In the genesis inhibitor, aminoglutethimide, which produced tumor year 2000, the crude incidence of breast cancer in Korea was regressions equivalent to those observed with tamoxifen.(3) estimated about 23 per 100,000 people.(1) However, side effects from aminoglutethimide were consid- For the process of inducing breast cancer, estrogens appear erable and its effects on several steroidogenic enzymes required to play a predominant role. These sex steroids are believed to concomitant use of a glucocorticoid. Consequently, tamoxifen initiate and to promote the process of the breast carcinogenesis became the preferred, first line endocrine agent with which to by enhancing the rate of cell division and reducing time treat ER-positive advanced breast cancer. However, the clinical available for DNA repair. A new concept is that estrogens can efficacy of aminoglutethimide focused attention upon the need be metabolized to catechol-estrogens and then to quinines that to develop more potent, better tolerated, and more specific directly damage DNA. These two process-- estrogen receptor inhibitors of estrogen biosynthesis. mediated, genomic effects on proliferation and receptor independent, genotoxic effects of estrogen metabolites-- can act INHIBITION OF ESTRADIOL BIOSYNTHESIS in an additive or synergistic fashion to cause breast cancer.(2) Breast cancers that arise in patients can be divided into Multiple enzymatic steps are involved in the biosynthesis of hormone dependent and hormone independent subtypes.(3) The estradiol and could potentially be used as targets for inhibition.