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W O 2019/067145 Al 04 April 2019 (04.04.2019) W IPO I PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property (1) Organization11111111111111111111111I1111111111111ii111liiili International Bureau (10) International Publication Number (43) International Publication Date W O 2019/067145 Al 04 April 2019 (04.04.2019) W IPO I PCT (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K47/40 (2017.01) A61K 9/08 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K9/00(2006.01) Rule 4.17: (21) International Application Number: Declarations under be granted a PCT/US2018/048414 - as to applicant's entitlement to applyfor and patent (Rule 4.17(i)) (22) International Filing Date: - as to the applicant'sentitlement to claim the priority ofthe 28 August 2018 (28.08.2018) earlier application (Rule 4.17(iii)) (25) Filing Language: English Published: (26) Publication Language: English with internationalsearch report (Art. 21(3)) (30) Priority Data: 62/565,053 28 September 2017 (28.09.2017) US 62/573,658 17 October 2017 (17.10.2017) US 62/586,826 15 November 2017 (15.11.2017) US 62/551,193 04 December 2017 (04.12.2017) US 62/643,694 15 March 2018 (15.03.2018) US 62/679,912 03 June 2018 (03.06.2018) US (71) Applicant: ASDERA LLC [US/US]; 220 E. 70th Street, #5C, New York, NY 10021 (US). (72) Inventor: WITTKOWSKI, Knut, M.; 220 E. 70th Street, #5C, New York, NY 10021 (US). (74) Agent: ZURAWSKI, John, A. et al.; BALLARD SPAHR LLP, 1735 Market Street, 51st Floor, Philadelphia, PA 19103 (US). (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, Fl, 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 regionalprotection 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, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, T (54) Title: USE OF CYCLODEXTRINS IN DISEASES AND DISORDERS INVOLVING PHOSPHOLIPID DYSREGULATION I (57) Abstract: The present disclosure provides certain compositions and methods that may be useful in the treatment and/or preven tion of a malignant, neurodegenerative, cardiovascular, metabolic, inflammatory, autoimmune, or viral disease or disorder, such as carcinomas, Alzheimer's and Parkinson's disease, multiple sclerosis, Paget's disease, or other aspects of aging, such as atherosclerosis or type-2 diabetes. In some such embodiments, compositions are provided that contain at least one cyclodextrin active agent, such as alpha-cyclodextrin, or an analogue or derivative thereof. In some embodiment the composition is a clathrate of HP-aCD and sodium CA caprate or caprylate. WO 2019/067145 PCT/US2018/048414 USE OF CYCLODEXTRINS IN DISEASES AND DISORDERS INVOLVING PHOSPHOLIPID DYSREGULATION RELATED APPLICATIONS [001] This application claims the benefit of priority to U.S. Provisional Application No. 62/679,912, filed June 3, 2018, U.S. Provisional Application No. 62/643,694, filed March 15, 2018, U.S. Provisional Application No. 62/586,826, filed November 15, 2017, U.S. Provisional Application No. 62/573,658, filed October 17, 2017, and U.S. Provisional Application No. 62/565,053, filed September 28, 2017, and U.S. Provisional Application No. 62/551,193, filed August 28, 2017. The entire contents of the aforementioned applications are incorporated by reference in their entireties. BACKGROUND [002] As the human population is aging, the prevalence of age-related conditions, Error! Reference source not found. cancers and neurodegenerative diseases increases, yet interventions to prevent or treat these conditions are lacking or have undesirable side effects. Currently, about 5 million US individuals have Alzheimer's disease and about 1 million have Parkinson's disease. As life expectancy increases, the prevalence of neurodegenerative diseases or disorders also increases. Ten percent of people age 65 and older and 15% of people age 75 or older have Alzheimer's disease. Alzheimer's disease also disproportionately affects women, who comprise two thirds of Americans with Alzheimer's disease. Alzheimer's disease is also more likely to affects members of African American and Hispanic communities than Caucasian communities. Patients with Alzheimer's disease have few treatment options. Three recent phase 3 studies of BACE1 inhibitors have failed. Similarly, patients with Parkinson's disease initially benefit from treatment of motor symptoms (levodopa), but become non-responsive over time. [003] Treatments of malignant diseases or disorders are also limited and suffer from numerous drawbacks. Treatments generally include local therapy (for instance: surgery with or without radiation in breast cancer, surgery or radiation in prostate cancer) and adjuvant systemic therapy (hormonal therapy, chemotherapy, and biologic agents) for cancer cells that may have spread. Radiation and chemotherapy often cause substantial side-effects including, but not limited to nausea and hair loss. Hormone therapy for prostate cancer includes anti androgens. For some hormone-receptor-positive forms of breast cancer, selective estrogen 1 WO 2019/067145 PCT/US2018/048414 receptor modulators (SERM), such as tamoxifen and raloxifene, and aromatase inhibitors, such as exemestane and anastrozole, can interfere with disease progression. Monoclonal antibodies, such as trastuzumab and pertuzumab, are approved for the treatment of HER2 positive cancer. For patients with triple-negative (absence of estrogen, progesterone, and the Her2/neu receptor), treatment options are limited. [004] A common thread between neurodegenerative disorders and malignancies are lysosomal dysfunction. Lysosomal dysfunction is implicated in a diverse range of disorders and diseases, including genetic diseases. In some cases, high levels of endocytosis have been suggested as a pleiotropic factor in the etiology underlying malignant and neurodegenerative processes, including, but not limited to a role of endocytosis in cancer, and "deranged" endocytosis in Alzheimer's disease, where endocytic pathway abnormalities precede AP deposition and inhibition of endocytosis reduces amyloid precursor protein ("APP") internalization and immediately lowers A levels in vivo. [005] While beneficial in early life, high levels of endocytosis may become detrimental with age. Enlarged macrophages have been identified in atherosclerosis, stearohepatitis, and cyctic fibrosis, and impaired phospholipid efflux increases accumulation of lipids in macrophages. Activation of the early endocytic pathway has been observed in autoimmune-diseases, such as systemic lupus erythematosus (SLE), inflammatory bowel disease, and arthritis. Attenuation of phosphoinisitides restrains autoimmune disease. Inhibition of P13K signaling has been shown to benefit inflammatory/autoimmune diseases and hematological malignancies. Overall, dysregulation of the lipid raft have been linked to poor quality of life with aging. [006] Phosphoinisitides (PIPs), which regulate endocytosis, have been mentioned in genetic diseases, In particular, P13K inhibitors have been shown to be effective in a variety of inflammatory and autoimmune diseases. Several attempts to inhibit or activate individual phosphatases or kinases, however, have failed to result in successful therapies. Hence, in spite of this strong evidence for involvement of endo-/pinocytosis in all these diseases and for involvement of PIPs, effective modulators of endocytosis are lacking. [007] Because "derailed endocytosis" has been linked to cancers, neurodegenerative diseases, and other "pathological conditions", the same treatment that prevents metastases in cancer is expected to also prevent accumulation of undegraded macromolecules in neurodegenerative diseases and other many other age-related conditions, including formation of foam cells in atherosclerosis via macropinocytosis. Yet, effective treatments to regulate 2 WO 2019/067145 PCT/US2018/048414 endocytosis are lacking. Therefore, there is a need for effective treatments for the symptoms of disorders and diseases that involve dysfunction in lysosomal pathways. [008] Broadly acting [cyclin-dependent kinase (CDK)] inhibitors yielded largely disappointing results, and only a small number of patients benefit from phosphoinositide 3 kinase (P13K) inhibitors. Recently, HP--CD has been proposed for the treatment of cancers, but extracting cholesterols not only from cancer, but also from outer hair cell, may cause permanent hearing loss. [009] 2-Hydroxypropyl-3-cyclodextrin (HP-3-CD) is "generally recognized as safe" (GRAS) as food additives and frequently used as an excipient with parenteral use to form water soluble compounds with lipophilic drugs. Parenteral and intrathecal HP-3-CD has been used for the treatment of Niemann-Pick disease type C (NPC), where its function is to extract excess cholesterol, a lipid molecule, from lysosomes. As cholesterol is implicated in many other processes,
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