(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/048944 Al 15 March 2018 (15.03.2018) W !P O PCT (51) International Patent Classification: A61K38/1 7 (2006.01) C07K 14/575 (2006.01) A61P 3/00 (2006.01) A61K 38/22 (2006.01) (21) International Application Number: PCT/US2017/050334 (22) International Filing Date: 06 September 2017 (06.09.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/383,957 06 September 2016 (06.09.2016) US (71) Applicant: LA JOLLA PHARMCEUTICAL COMPA¬ NY [US/US]; 10182 Telesis Court, 6th Floor, San Diego, CA 92121 (US). (72) Inventors: TD3MARSH, George; 45 Tintern Lane, Porto- la Valley, CA 94028 (US). CHAWLA, Lakhmir; 10586 Abalone Landing Ter, San Diego, CA 92 130 (US). = (74) Agent: HALSTEAD, David, P. et al; Foley Hoag LLP, = 155 Seaport Boulevard, Boston, MA 02210-2600 (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, 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, CI, CM, GA, GN, GQ, GW, = KM, ML, MR, NE, SN, TD, TG). — Declarations under Rule 4.17: — of inventorship (Rule 4.1 7(iv)) < Published: — with international search report (Art. 21(3)) 00 © 00 (54) Title: METHODS OF TREATING IRON OVERLOAD © (57) Abstract: Provided herein are compositions and methods related to the use of hepcidin and/or hepcidin analogues for the treatment and/or prevention of iron overload in a subject (e.g., a human subject) and/or for reducing serum iron levels in a subject without inducing serum iron rebound. METHODS OF TREATING IRON OVERLOAD RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application serial number 62/383,957, filed September 6, 2 6, which is herein incorporated by reference in its entirety. BACKGROUND Iron is an essential element required for growth and survival of almost every organism. In mammals, the iron balance is primarily regulated at the level of duodenal absorption of dietary iron. Following absorption, ferric iron is loaded into apo-transferrin in the circulation and transported to the tissues, including erythroid precursors, where it is taken up by transferrin receptor-mediated endocytosis. Reticuloendothelial macrophages play a major role in the recycling of iron from the degradation of hemoglobin of senescent erythrocytes, while hepatocytes contain most of the iron stores of the organism in ferritin polymers. In the case of iron deficiency, the pathophysiological consequences of gene defects identified are well understood because they usually result in loss of function of proteins directly involved in the pathway of iron absorption. The proteins include the iron transporters DMT1 (also called Nramp2 or DCTl), ferroportin (also called IREG1 or MTPl), and copper oxidases coupled to ferroportin, namely ceruloplasmin and haephastin. Iron overload (also referred to as hemochromatosis) is the exact opposite of iron deficiency, and refers to the over-accumulation of iron in the body. Chronic iron overload can lead to a number of detrimental conditions, including cirrhosis of the liver, diabetes, cardiomyopathy and arthritis. The genetic disorder hereditary hemochromatosis (HHC) is a relatively common autosomal recessive genetic disease that results in the hyperabsorption of dietary iron leading to an iron overload in plasma and organs. The excess iron is stored in the body's tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. Once diagnosed, hemochromatosis is often treated by phlebotomy to rid the body of excess iron and to maintain normal iron stores. Phlebotomy, an invasive and inefficient therapy, remains the sole recommended treatment for hereditary hemochromatosis . Beta thalassemias (β thalassemias) are a group of inherited blood disorders caused by reduced or absent synthesis of the beta chains of hemoglobin that result in outcomes ranging from severe anemia to clinically asymptomatic individuals. Current treatments include repeated blood transfusions, which can result in transfusional iron overload. In many patients with β thalassemia, multiple blood transfusions, ineffective erythropoiesis, and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload impairs the immune system, placing patients at greater risk of infection and illness. To counter this iron overload, patients often undergo chelation therapy. Many common chelators used for treating iron overload are associated with toxicity and renal impairment, hepatic impairment and gastrointestinal hemorrhage . Thus, there is a need for new treatments for iron overload and related disorders that are safer and better tolerated. SUMMARY Provided herein are compositions and methods related to the use of hepcidin and/or hepcidin analogues for the treatment and/or prevention of iron overload in a subject (e.g., a human subject) and/or for reducing serum iron levels in a subject. The compositions and methods provided herein are related, in part, to the discover}' of serum iron level rebound following hepcidin therapy under some conditions. Following hepcidin administration at higher doses, some patients experience a serum iron level rebound, in which serum iron levels initially drop in response to hepcidin administration, but then paradoxically rise (or rebound) above baseline iron level (i.e., the level of serum iron prior to hepcidin administration). The compositions and methods described herein follow from the observation that this undesirable rebound in serum iron level can be avoided or mitigated by initially administering low doses of hepcidin (e.g., 1-20 mg, preferably 1- 0 mg, or even more preferably 1-5 mg), and/or increasing the frequency of administration of lower doses to heighten the effects of hepcidin therapy (rather than administer doses above 40 mg, or even above 30 mg or even above 20 mg). The need for increasing the frequency or dose of hepcidin administration can be identified from measurements of serum or tissue iron levels in the patient (for example, serum iron levels, ferritin levels, transferrin saturation, hemoglobin, or hematocrit) and comparing these measurements to predetermined target levels. In certain embodiments, the methods provided herein include administering to the subject hepcidin or a hepcidin analogue at an amount sufficient to reduce the serum iron concentration in the subject without inducing a serum iron level rebound following treatment. In some embodiments, the amount of hepcidin or hepcidin analogue is between about 0.1mg and about 40 mg. In some embodiments, the amount of hepcidin or hepcidin analogue is between 1 mg and about 3 mg (e.g.. between about 5 mg and about 3 mg, between about 10 mg and about 30 mg, between about 20 mg and about 30 mg, between about 1 mg and about 20 mg, between about 5 mg and about 20 mg, between about mg and about 20 mg, between about 1mg and about 10 mg, between about 5 mg and about mg). In some embodiments, the amount of hepcidin or hepcidin analogue is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, mg, mg, 12 mg, 3 rng, 14 mg, 15 mg, 16 rng, 17 mg, 18 mg, 19 rng, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 3 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg or 40 mg. Provided herein are methods of treating or preventing iron overload in a subject and/or reducing serum iron levels in a subject by administering to the subject a hepcidin or hepcidin analogue at an amount sufficient to reduce the serum iron concentration of the subject, wherein administering the hepcidin or hepcidin analogue comprises administering the hepcidin or hepcidin analogue at an initial dose below the threshold to induce serum iron rebound. In some embodiments, the methods further comprise administering to the subject an additional dose or doses of the hepcidin or hepcidin analogue, e.g., on a periodic basis (e.g., biweekly, weekly, semiweekly, daily), which doses may be the same as the initial dose or higher or lower depending on whether the patient has experienced the desired clinical response. The additional dose or doses may be below the threshold to induce serum iron rebound (e.g., 40 mg or less, preferably 30 mg or less, or even 20 mg or less). The additional dose or doses may be the same as the threshold dose to induce serum iron rebound.