(19) TZZ __T (11) EP 2 916 856 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 38/12 (2006.01) 19.09.2018 Bulletin 2018/38 A61P 15/00 (2006.01) C07K 7/64 (2006.01) (21) Application number: 13851014.4 (86) International application number: PCT/US2013/068386 (22) Date of filing: 05.11.2013 (87) International publication number: WO 2014/071339 (08.05.2014 Gazette 2014/19) (54) USES OF BREMELANOTIDE IN THERAPY FOR FEMALE SEXUAL DYSFUNCTION VERWENDUNG VON BREMELANOTID IN DER THERAPIE VON WEIBLICHER SEXUELLER DYSFUNKTION UTILISATIONS DE BRÉMÉLANOTIDE DANS UNE THÉRAPIE DE DYSFONCTIONNEMENT SEXUEL FÉMININ (84) Designated Contracting States: • "Palatin Technologies Presents Positive Results AL AT BE BG CH CY CZ DE DK EE ES FI FR GB for Phase 2B Bremelanotide Female Sexual GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Dysfunction Trial", PRNewswire , 8 November PL PT RO RS SE SI SK SM TR 2012 (2012-11-08), XP002757483, Retrieved from the Internet: (30) Priority: 05.11.2012 US 201261722511 P URL:http://www.palatin.com/investors/press 28.02.2013 US 201361770535 P -releases/ [retrieved on 2016-05-09] • ROSEN R C ET AL: "Evaluation of the safety, (43) Date of publication of application: pharmacokineticsand pharmacodynamic effects 16.09.2015 Bulletin 2015/38 of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male (73) Proprietor: Palatin Technologies, Inc. subjects and in patients with an inadequate Cranbury NJ 08512 (US) response to Viagra(R)", INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH, (72) Inventors: STOCKTON, BASINGSTOKE, GB, vol. 16, no. 2, 1 • SPANA, Carl April 2004 (2004-04-01), pages 135-142, West Harrison, NY 10604 (US) XP002531555, ISSN: 0955-9930, DOI: • JORDAN, Robert 10.1038/SJ.IJIR.3901200 Hamilton, NJ 08610 (US) • PALATIN TECHNOLOGIES, INC.: ’Bremelanotide • EDELSON, Jeffrey, D. in Premenopausal Women With Female Sexual Berwyn, PA 19312 (US) Arousal Disorder and/or Hypoactive Sexual Desire Disorder’ CLINICALTRIALS.GOV (74) Representative: Bassil, Nicholas Charles et al (NCT01382719 20 March 2012, page 1, Kilburn & Strode LLP XP008179351 Retrieved from the Internet: Lacon London <URL:http://clinicaltrials.gov/archive/NCT0 84 Theobalds Road 1382719/ 2012-03 20> [retrieved on 2014-02-10] London WC1X 8NL (GB) (56) References cited: WO-A1-2011/060352 WO-A2-2009/151714 US-A1- 2005 222 014 US-A1- 2011 065 652 US-B2- 6 794 489 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 2 916 856 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 916 856 B1 • SAFARINEJAD, MR.: ’Evaluation of the Safety • PALATIN TECHNOLOGIES, INC.: ’Reports and Efficacy of Bremelanotide, a Melanocortin Positive Bremelanotide Study; Improved Safety Receptor Agonist, in Female Subjects with Profile with Subcutaneous Administration’ PR Arousal Disorder: A Double-Blind NEWSWIRE. 12 August 2009, XP008179369 Placebo-Controlled, Fixed Dose, Randomized Retrieved from the Internet: Study’’.’ INTERNATIONAL SOCIETY FOR <URL:http://www.thefreelibrary.com/Palatin SEXUAL MEDICINE. vol. 5, 2008, pages 887 - 897, +Technolo9ies,+Inc.+Reports+Positive+Bremel XP009109612 anotide+Study%38...-a020561 3302> [retrieved on 2014-02-10] 2 EP 2 916 856 B1 Description Field of the Invention (Technical Field): 5 [0001] The present invention relates to formulations and methods for treatment of sexual dysfunction, including female sexual dysfunction, by administration of selected doses of a melanocortin agonist In particular, the present invention relates to methods for the treatment of female sexual dysfunction while reducing or minimizing side-effects, or adverse effects, associated with the administration of melanocortin agonists. More specifically, the invention relates to the phar- maceutical compositions in which the melanocortin agonist is bremelanotide and methods in which these pharmaceutical 10 compositions are administered to patients for the treatment of female sexual dysfunction, including specifically female sexual dysfunction in premenopausal women, while reducing or minimizing side effects. Description of Related Art: 15 [0002] It is known that agonists of the melanocortin receptor, and particular melanocortin 4 receptor (MC4-R) agonists, may be employed for treatment of sexual dysfunction. See. for example. L.H.T. Van der Ploeg, W J Martin, A D Howard R P Nargund et al., A role for the melanocortin 4 receptor in sexual function. Proc. Natl. Acad. Sci. USA 99:11381-86 (2002) The cyclic. heptapeptide melanocortin receptor agonist Ac-Nle- cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, with the USAN adopted name bremelanotide and formerly known as PT-141, as further disclosed in U.S. Patent Nos. 6,579,968 20 and 6,794,489, has been employed in clinical trials for sexual dysfunction, including both male erectile dysfunction (ED) and female sexual dysfunction or disorder (FSD). [0003] There has been substantial progress in the definition and classification of the range of disorders that comprise FSD The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) recognizes four major disorders that define FSD: decreased sexual desire, decreased sexual arousal, dyspareunia, and difficulty in achieving orgasm 25 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed. text revision ed. Wash- ington, DC: American Psychiatric Publishing, Inc . 2000. In the United States approximately 43% of adult women expe- rience some form of female sexual arousal disorder (FSAD) and/or hypoactive sexual desire disorder (HSDD), with approximately 22% of these women reporting being distressed by their sexual dysfunction. E.O. Laumann. A Palk and R.C. Rosen. Sexual dysfunction in the United States: prevalence and predictors JAMA 281:537-544 (1999); and. J L. 30 Shifren, B U Monz, P A Russo, A Segreti and C B. Johannes, Sexual problems and distress in United States women: prevalence and correlates Obstet Gynecol 112:970-978 (2008). The current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), released in May 2013 by the American Psychiatric Association, revised the classification of female sexual dysfunction, replacing FSAD and HSDD with a new diagnosis of female sexual interest and arousal disorder (FSI/AD), and expanding the current concept of FSD to include receptivity to and initiation of sexual activity as 35 part of the diagnostic heuristic. However, definitions of FSAD and HSDD remain in use, and are consistent with the description of female sexual dysfunction in the current version of the international Classification of Diseases (ICD-10). [0004] Sexual therapy and education presently form the basis of treatment for FSAD and/or HSDD Pharmaceutical treatments are limited; no drug is currently approved in the United States and one drug was approved in the European Union but subsequently withdrawn (INTRfNSA® a testosterone transdermal patch previously marketed by Warner Chil- 40 cott). [0005] The female sexual response cycle is complex and dependent on physiological, psychological. and social factors. For many women, spontaneous desire is not the motivating factor to engage in sexual activity. Frequently, desire is a consequence of subjective arousal caused by a variety of sexual stimuli. An understanding of the female sexual response cycle provides a basis for the design and development of pharmacological interventions for treating FSAD and/or HSDD. 45 [0006] The mechanisms and corresponding pharmaceutical therapies underlying female sexual response are different from those underlying male sexual response. For instance, male sexual response involves both central nervous system function as well as nitric oxide production leading to an increase in blood flow to the penis. Conversely, female sexual responseis dominatedby centralnervous system function, whilethe nitricoxide production pathway is of minor importance compared to results in men. Therefore, while therapies for treatment of male sexual dysfunction can be targeted to either 50 or both mechanisms of action, therapies for treatment of female sexual dysfunction typically must be targeted to and must rely on the central nervous system function. A.M. Shadiack, S.D. Sharma, D.C Earle, C Spana and T J Haltam. Melanocortins in the Treatment of Male and Female Sexual Dysfunction. Current Topics in Medicinal Chemistry 7.1137-1144 (2007). Thus phosphodiesterase 5 (PDE-5) inhibitors such as sildenafil, tadalafil or vardenafil are effective in men with erectile dysfunction through a mechanism involving selective inhibition of PDE-5, thereby preventing the 55 hydrolysis of cyclic guanosine monophosphate, resulting in increased blood flow to the penis. However, in women with female sexual dysfunction while PDE-5 inhibitors have some effect on genital vasocongestion, the drugs have little or no effect on treatment of female sexual dysfunction, including treatment of sexual arousal problems M.L. Chivers and R C Rosen, Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J. Sex. 3 EP 2 916 856 B1 Med. 7:858-72 (2010). [0007] Both animal and human studies have suggested that bremelanotide has central nervous system effects unre- lated to local genital vasocongeslion. In animal studies utilizing female rats, a selective pharmacological effect on ap- petitive sexual behavior was observed, with subcutaneous injections of bremelanotide inducing the immediate-early 5 gene product Fos in a variety of limbic and hypothalamic structures, and increasing dopamine release in the medial preoptic area J G Pfaus, A Shadiack, T. Van Soest, M. Tse and P. Molinoff, Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl. Acad. Sci. USA 101:10201-4 (2004); J. Pfaus, F. Giuliano and H.