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(12) Patent Application Publication (10) Pub. No.: US 2016/0166583 A1 Zukiwski Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0166583 A1 Zukiwski Et Al US 2016O166583A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0166583 A1 Zukiwski et al. (43) Pub. Date: Jun. 16, 2016 (54) ONAPRISTONE EXTENDED-RELEASE Publication Classification COMPOSITIONS AND METHODS (51) Int. Cl. (71) Applicant: ARNOTHERAPEUTICS, INC., A613 L/567 (2006.01) Flemington, NJ (US) A619/20 (2006.01) (52) U.S. Cl. (72) Inventors: Alexander Zukiwski, Clarksburg, MD CPC ................. A6 IK3I/567 (2013.01); A61 K9/20 (US); Stefan Proniuk, Austin, TX (US) (2013.01) (21) Appl. No.: 14/942,809 (57) ABSTRACT 1-1. Onapristone extended-release formulations and methods of (22) Filed: Nov. 16, 2015 administering onapristone extended-release formulations are O O provided. Onapristone extended-release formulations pro Related U.S. Application Data vide Sufficient therapeutic activity as compared to immediate (60) Provisional application No. 62/080,868, filed on Nov. release formulations with reduced potential for adverse side 17, 2014. effects. Patent Application Publication Jun. 16, 2016 Sheet 1 of 4 US 2016/O166583 A1 Figure Onapristone C vs Dose 7000 sood sood 4000 3ood 2000 338g .338g 388g ${}: 8:::::g it::g : & : & :: Patent Application Publication Jun. 16, 2016 Sheet 2 of 4 US 2016/O166583 A1 Figure 2 Onapristone AUC vs Dose 2300000 2000000 1sooooo 1000000 sooooo 88: it::gBreg $83.88ER 23rg E838E8 3rg 888 $g:::::::::::::::: 88 sig 8 1g:::::::: Patent Application Publication Jun. 16, 2016 Sheet 3 of 4 US 2016/O166583 A1 Figure 3 8 trig 8 it rig ER 28 ring £8 38 mg ER 48 trig ER 50 mg 88 .. 38 y 8 x 3y 38 83 y 3 Patent Application Publication Jun. 16, 2016 Sheet 4 of 4 US 2016/O166583 A1 Figure 4A Figure 4B exerts rig tid Regeneral pig & Er too US 2016/0166583 A1 Jun. 16, 2016 ONAPRSTONE EXTENDED-RELEASE ONA does not allow the PR complex to bind to DNA, does not COMPOSITIONS AND METHODS or minimally modulates PR-mediated genes, and inhibits ligand-induced PR phosphorylation, in contrast to other anti PRIORITY CLAIM progestins Beck 1996; Alfhippe 2009. Preclinical activity has been shown in several models, including endometrial 0001. This application claims priority to U.S. Provisional cancer Mueller 2003 and the clinical anticancer activity of Patent Application Ser. No. 62/080,868, filed Nov. 17, 2014. ONA has been previously documented in patients with hor The above referenced application is incorporated herein by mone therapy-naive Robertson 1999 or tamoxifen-resistant reference as if restated in full. The above referenced applica Jonat 2002 breast cancer. tion and all references cited herein, including but not limited 0007 Transcriptionally activated PR (APR) can be to patents and patent applications, are incorporated by refer detected by observational evaluation of the subnuclear distri ence in their entirety. bution pattern using immunohistochemistry (IHC). Using this method, APR can be used as a potentially predictive IHC BACKGROUND biomarker in endometrioid cancer of the uterus. See U.S. Pat. 0002 Onapristone (ONA) is an anti-progestin drug and No. 9,046,534. APR detection is being developed as a com progesterone receptor antagonist which was originally devel panion diagnostic to identify patients more likely to respond oped for potential contraceptive use and the use in benign to ONA Bonneterre 2015. gynecological disorders such as the treatment of uterine lei 0008 Early clinical studies employing the original imme omyomas. However, onapristone has demonstrated Substan diate release (IR) formulation of ONA have shown that ONA tial activity in advanced breast cancer. It is thought that ONA is well-tolerated with the exception of abnormalities in liver binds to the progesterone receptor (PR), preventing the PR function tests (LFTs) Cameron 1996, Cameron 2003, Crox from binding to DNA and thereby inhibiting or eliminating atto 1994, Jonat 2002, Robertson 1999. Studies with the PR-induced DNA transcription. See, e.g., Klijn et al., Proges original IR formulation were discontinued due to these LFT terone antagonists and progesterone receptor modulation in abnormalities. Id. the treatment of breast cancer, Steroids, V. 65, pp. 825–830 0009 Previously, onapristone was provided to patients (2000); Jonat et al., The clinical efficacy of progesterone with cancer (e.g., breast, endometrial, others) in an immediate antagonists in breast cancer, Endocrine Therapy of Breast release formulation of 100 mg and provided QD (once per Cancer, pp. 117-124. day). Onapristone has also been given to patients in endocri 0003) Onapristone is a type I progesterone receptor (PR) nology studies, at immediate release doses of 1 and 10 mg antagonist, which prevents PR-induced DNA transcription. doses resulting in a dose-dependent effect of onapristone on Presence of transcriptionally activated PR (APR) in tissue Suppression of gonadotrophin (luteinizing hormone LH and samples from a cancer patient, measured using, for example, follicle-stimulating hormone IFSH) secretion. Cameron an immunohistochemistry companion diagnostic procedure, 2003. However, these studies used immediate release formu indicates Susceptibility to treatment with onapristone anti lations of onapristone of unknown purity. Importantly, these cancer activity. Onapristone anti-cancer activity is docu studies addressed the dose and formulation of onapristone mented in multiple pre-clinical models and clinical studies in suitable for potential contraceptive use rather than the dose patients with hormone therapy-naive or tamoxifen-resistant and formulation Suitable for treating a disease such as cancer. breast cancer. Despite promising activity in breast cancer 0010 What is needed is an improved formulation of models, the development of onapristone as an oncology drug onapristone which allow for a continuous Suppression of the was terminated due to liver function test abnormalities. See, PR and methods of administering the same resulting in Suf e.g., Robertson et al., Eur J Cancer. 35(2):214-8 (Feb. 1999). ficient bioavailability to provide clinical benefit to cancer 0004 Expression of the progesterone receptor (PR) has patients at doses which result in less toxicity than the previous been described in breast Mote 2000, Lange 2008, endome clinical experience with onapristone. trial Kim 2013, Mortel 1984), prostate Lange 2007, Bonkhoff 2001, ovarian Sieh 2013, and several other can SUMMARY cers Yin 2010, Ishibashi 2005, Blankenstein 2000. Anti 0011 Aspects described herein provide extended-release progestins have been shown to have an inhibitory effect on the pharmaceutical compositions comprising onapristone as the growth of different type of cancer cells, and antiprogestin active ingredient in an amount from about 2 mg to about 100 treatment has been studied in breast Jonat 2013, endome mg. The extended-release pharmaceutical compositions (also trial Thigpen 1999, prostate Taplin 2008 cancers and uter referred to herein as ER formulations) further comprise ine sarcomas Koivisto-Korander 2007. excipients suitable for the desired dosage form (e.g., tablet, 0005. The effects of progesterone are mediated by two capsule, etc.) and for delaying the release of the active ingre distinct nuclear receptor proteins, PRA and PRB, two tran dient. Scriptional isoforms of the single PR gene. In luminal epithe 0012. Further aspects provide onapristone ER formula lial cells of the normal breast and in normal endometrium, tions utilizing highly purified onapristone (e.g., at least about both PR isoforms are expressed and are required to mediate 98%). In another aspect, the ratio of onapristone to inactive the physiological effects of progestin ligands Mote 2002, excipients in the ER formulations is about 0.05 to about 5%. Arnett-Mansfield 2004. The two PR isoforms have both been 0013 Inafurther aspect, the AUC (area under the curve) of detected in malignant tissues, such as breast, endometrial, onapristone is at least about 1578 ngh/ml over about an 8-12 ovarian and prostate cancers Cottu 2015. hour period after administration of a 10 mg dose BID (i.e., 0006 ONA is a type I antiprogestin which prevents PR twice per day) to a patient. monomers from dimerizing, inhibits ligand-induced phos 0014 Inanother aspect, the Cmax (maximum plasma con phorylation, prevents association of the PR with its co-acti centration) of onapristone is at least about 240 ng/ml over vators, and thus prevents PR-mediated DNA transcription. about an 8-12 hour period after administration of a 10 mg US 2016/0166583 A1 Jun. 16, 2016 dose BID to a patient. In yet another aspect, a steady state tical compositions or drug formulations that do not have a plasma concentration of onapristone is achieved at about 8 mechanism for delaying the release of the active ingredient days following the initial dose of the extended release following administration of the formulation to a patient. onapristone pharmaceutical composition. In another aspect, Exemplary extended release formulations are provided, for the extended-release onapristone pharmaceutical composi example, in Table 4 herein. The terms “treat,” “prevent,” or tion comprises at least about 10 mg to about 50 mg of onapris similar terms, as used herein, do not necessarily mean 100% tOne. or complete treatment or prevention. Rather, these terms refer to various degrees of treatment or prevention of a particular BRIEF DESCRIPTION OF THE DRAWINGS disease (e.g., 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 0015 FIG. 1 shows the exemplary Cmax (maximum 20%, 10%. 5%, or 1%) as recognized in the art as being active ingredient concentration) levels
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