) ( (51) International Patent Classification: A61K 36/71 (2006.01) A61P 35/00 (2006.01) A61K 36/28 (2006.01) (21) International Application Number: PCT/EP20 19/086205 (22) International Filing Date: 19 December 2019 (19. 12.2019) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 18215929.3 31December 2018 (3 1. 12.2018) EP (71) Applicant: MAX ZELLER SOEHNE AG [CH/CH] ; See- blickstrasse 4, 8590 Romanshom (CH). (72) Inventors: DREWE, Jurgen; Weinbergstrasse 4, 8082 Kreuzlingen (CH). HASLER, Samuel; Amselweg 4A, 8500 Frauenfeld (CH). BOONEN, Georg: c/ Max Zeller Soehne AG Seeblickstrasse 4, 8590 Romanshorn (CH). (74) Agent: KASCHE, Andre; Resirain 1, 8125 Zollikerberg (CH). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW,KZ, LA, LC, LK, LR, LS, LU, LY,MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) (54) Title: COMBINATION OF CIMICIFUGA AND PETASITES EXTRACTS FOR ANTICANCER THERAPY AND PROPHY¬ LAXIS (57) Abstract: The present invention is directed to the novel use of an extract combination comprising extracts from a Cimicifuga species, e.g. Cimicifuga racemosa (also termed Actaea racemosa L; black cohosh) and a Petasites species, e.g. Petasites hybridus, for the therapeutic or prophylactic treatment of cancer. Also, the invention pertains to the use of such extract combinations for preparing a medicament, corresponding pharmaceutical compositions, comprising a combination of an extract from Cimicifuga sp. and an extract from Petasites sp., as well as a method for the therapeutic or prophylactic treatment of cancer, preferably by oral administration of the extract combination or pharmaceutical composition. Combination of Cimicifuga and Petasites extracts for anticancer therapy and prophylaxis The present invention is directed t o the novel use of an extract combination comprising extracts from a Cimicifuga species, e.g. Cimicifuga racemosa (also termed Actaea racemosa L; black cohosh) and a Petasites species, e.g. Petasites hybridus, for the therapeutic or prophylactic treatment of can cer. Also, the invention pertains t o the use of such extract combinations for preparing a medicament, corresponding pharmaceutical compositions, comprising a combination of an extract from Cimicifuga sp. and an extract from Petasites sp., as well as a method for the therapeutic or prophylactic treatment of cancer, preferably by oral administration of the extract combination or pharmaceutical composition. Cimicifuga racemosa extract is commonly used in the treatment of menopausal symptoms such as hot flashes and sweating due to hormonal changes, such as estrogen depletion. The extract has the benefits of hormonal replacement therapy without the increased risk for breast cancer or t hrom boembolic events. In fact, Cimicifuga racemosa extract is known for its positive benefit-risk profile and is listed in a monograph by the Herbal Medicinal Product Committee (HMPC) of the European Medicines Agency (EMA). WO 99/47149 describes the use of Cimicifuga extracts for use as medicaments for selective treatment of cardiovascular diseases and climacteric discomfort. Seidlova-Wuttke et al. (Phytomedicine, 19, 2012, 846-853) discloses the use of Cimicifuga racemosa extracts for reducing abdominal fat depots (hyperlipidemia) and thus preventing metabolic syndrome (MB) in ovariectomized (ovx) rats, mimicking a postmenopausal situation. WO 2005/002609 Al teaches methods for the preparation of plant extracts, in particular from Cimicifuga racemosa using extraction agents together with solution mediators such as organic po ly mers, in particular poly(vinylpyrrolidone). WO 98/26791 Al teaches the use of an extract of Cimicifuga racemosa for preparing a medi cament for treating estrogen-dependent tumors in combination with a medicament containing an ant i estrogenic active agent such as tamoxifen or genistein. Borrelli et al. (Eur. J. Clin. Pharmacol., 58, 2002, 235 - 241) provides a systematic review of the clinical efficacy of Cimicifuga racemosa in many medical indications. The Cimicifuga racemosa extract for Cimifemin ® uno (manufactured by Max Zeller Soehne AG, Romanshorn, Switzerland, also called Ze 450) is an extract produced by a procedure comprising root extraction by an aqueous-ethanolic solvent (60 % V/V) containing in minimum 6 % (m/m) triterpene glycosides, expressed as 27-deoxyactein and calculated with reference t o the native dried extract. The extract features over 20 triterpensaponines with actein and 27-deoxyactein being most prominent. It is approved for the treatment of peri-menopausal complaints in doses of 6.5 to 13 mg per day (1 tablet per day) in many European countries. The extract was also shown to increase AMPK phosphorylation in vitro and ameliorated metabolic disorders in ob/ob mice and in ovariectomized rats in vivo, thereby indicating beneficial metabolic effects. EP2874637 A1 discloses an extract from Cimicifuga racemosa for use in the therapeutic or prophylactic treatment of diabetes, in particular diabetes mellitus type 2. C. Speirs etal. (2018, Pharmacol Res, 128, 88-100) provide a review on the potential use of AMPK activators t o treat several haematological malignancies containing mutationally activated JAK, such as myeloproliferative neoplasms or acute lymphoblastic leukemia. The plant Petasites (Petasites hybridus (L.) Gaertn., B. Mey. etScherb.) is commonly also referred t o as Butterbur and Petasites extracts can be obtained from the plant, in particular from the leaves and/or the rhizome. The production of Petasites extracts is well known in the art. However, depending on the extraction protocol the extracts can comprise pyrrolizdine-alkaloids which can be hepatotoxic, mutagenic and carcinogenic. Petasites extracts are known t o display spasmolytic and analgesic properties. DE-A1 198 38 848 discloses Petasites extracts for use in the treatment of gastrointestinal diseases, asthma, pol linosis, dysmenorrhoea, eczemas, migraine, psoriasis, high blood pressure and/or spasms. EP 1 499 334 B1 describes the use of a polar Petasites extract for use in the treatment of pains. S. A. Steiert et. al. (2017, Biofactors, 43, 388-399) describes the anti-inflammatory effects of the petasin phytodrug Ze 339 involving inhibition of the STAT signalling pathway. The use of Petasites extracts for treating allergic rhinitis has been clinically verified and is described in the art. For further information on the medical utility of Petasites extracts reference is made to, e.g. Schapowal et al., 2002, BMJ, 324, 144-6; Thomet et al., 2002, Intern. Immunopharmacol.; Brattstrom et al., 2003, Phytomedicine, 10, Suppl 4, 50-2; Schapowal et al., 2004, Arch. Otolaryngol. Head Neck Surg., 130, 1381-6; Schapowal et al., 2005, Phytother. Res., 19, 530-7; Keusch et al., 2004, Ars Medici; Kaufeler et al., 2006, Adv. Ther., 23, 373-84; Brattstrom et al., 2010, Phytother. Res., 24, 680-5; Dumitru et al., 2011, J. Allergy Clin. Immunol., 127, 1515-21; and Nebel et al., 2014, Planta Med., 80). The active ingredients in Petasites include mainly sesquiterpenes, in particular petasin, isope- tasin and neopetasin that feature high lipophilicity and good bioavailability. The P. hybridus leaf native extract in Tesalin ® of Max Zeller Soehne AG (Romanshorn, Sw it zer land), also called Ze 339, is a "new herbal entity" since extracts from Petasites leaves have not yet been used medically. The extract is prepared by means of subcritical carbon dioxide extraction from the leaves of a chemovariant of Petasites hybridus (Petasites hybridus (L.) Gaertn., B. Mey. et Scherb.). It is standardized for petasins (sum of petasin, isopetasin and neopetasin) and each Tesalin ® tablet contains 8 mg petasins. The daily dosage is 2 t o 3 tablets. In 2017 Tesalin ® was switched from list B (Rx product) to list C (OTC) in the Swiss list of approved medicines. Tesalin ® / Ze 339 is one option among suitable Petasites alternatives and is the most preferred extract and pharmaceutical composition for practicing the present invention. Metformin, a methylated biguanide, is mostly known for its anti-diabetic effect for the t reat ment of type 2 diabetes based on the reduction of blood sugar levels. In recent years metformin has been investigated for possible cancer prevention and therapy due t o the observation of a decreased risk of the occurrence of various types of cancers, especially of pancreas, colon and hepatocellular cancer, which led t o the further investigation of several mechanisms underlying the proposed ant i cancer effect of metformin as well as its activity against various types of cancer both in diabetic and non-diabetic populations (Kasznicki et al, Ann. Transl. Med. 2014 June; 2(6): 57). Metformin leads t o indirect AMPK-activation, which is related t o the direct inhibition of complex I of the mitochondrial respiratory chain (Viollet et al., Clin. Sci. (Lond.) 2012, 122 (6): 253-270T; Kawashima & Kirito, Expe ri mental Hematology 2016, 44(12):1156-1165).