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(12) United States Patent (10) Patent No.: US 9,533,022 B2 Mehta Et Al

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(12) United States Patent (10) Patent No.: US 9,533,022 B2 Mehta Et Al USO09533022B2 (12) United States Patent (10) Patent No.: US 9,533,022 B2 Mehta et al. (45) Date of Patent: *Jan. 3, 2017 (54) PEPTIDE ANALOGS FOR TREATING (56) References Cited DISEASES AND DISORDERS U.S. PATENT DOCUMENTS (71) Applicants: Nozer M. Mehta, Randolph, NJ (US); 4,764,589 A 8, 1988 Orlowski William Stern, Tenafly, NJ (US); Amy 9,006,172 B2 * 4/2015 Mehta .................... A61K 38.23 M. Sturmer, Towaco, NJ (US); Morten 514/1.1 Asser Karsdal, Kobenhavn (DK); Kim 2002/0065255 A1* 5/2002 Bay .................. A61K 47, 183 Henriksen, Hillerod (DK) 514,166 2010/0311650 A1* 12/2010 Mehta .................... CO7K 1400 (72) Inventors: Nozer M. Mehta, Randolph, NJ (US); 514,49 William Stern, Tenafly, NJ (US); Amy M. Sturmer, Towaco, NJ (US); Morten FOREIGN PATENT DOCUMENTS Asser Karsdal, Kobenhavn (DK); Kim Henriksen, Hillerod (DK) WO 2010O85700 A2 T 2010 (73) Assignee: KeyBioscience A/S, Stans (CH) OTHER PUBLICATIONS Lee et al., “Metformin Decreases Food Consumption and Induces (*) Notice: Subject to any disclaimer, the term of this Weight Loss in Subjects with Obesity with Type Il Non-Insulin patent is extended or adjusted under 35 Dependent Diabetes,” Obes. Res. 6:47-53 (1998).* U.S.C. 154(b) by 0 days. Feigh et al., “A novel oral form of Salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese This patent is Subject to a terminal dis rats' Diab. Obesity Metab. 13:911-920 (2011).* claimer. Unigene Laboratories Inc. Unigene Laboratories Inc. Corporate Overview 2010, URL: www.getfillings.com/sec-filings/100325/ (21) Appl. No.: 14/634,188 UNIGENE-LABORATORIES-INC 8-K/dex991.htm, whole document. (22) Filed: Feb. 27, 2015 Andreassen, et al. Oral formulation of UGP302, a novel amylin and calcitonin dual receptor agonist, exerts anti-obesity effects in diet Prior Publication Data induced obese (DIO) rats, Diabetologia 2013, vol. 56(Suppl1), p. (65) S344, Abstract 867. US 2015/O196617 A1 Jul. 16, 2015 Feigh, et al. A novel oral dual-action amylin and calcitonin receptor agonist (UGP302) rebalances insulin and glucagon hyperglycaemia in Zucker diabetic fatty rats, Diabetologia 2013, vol. 56(Suppl2), p. Related U.S. Application Data S405-S406, Abstract 1009. (63) Continuation-in-part of application No. 13/667,578, * cited by examiner filed on Nov. 2, 2012, now Pat. No. 9,006,172. Primary Examiner — Julie Ha Assistant Examiner — Kristina M Hellman (60) Provisional application No. 61/578,620, filed on Dec. (74) Attorney, Agent, or Firm — Benjamin Aaron Adler 21, 2011, provisional application No. 61/554,771, filed on Nov. 2, 2011. (57) ABSTRACT Provided herein are methods for the treatment of type I (51) Int. C. diabetes, Type II diabetes, metabolic syndrome, or obesity, A6 IK 38/00 (2006.01) or of appetite Suppression, or for mitigating insulin resis A6 IK 38/23 (2006.01) tance, or for reducing an undesirably high fasting serum A6IP3/04 (2006.01) glucose level, or for reducing an undesirably high peak C07K 5/00 (2006.01) serum glucose level, or for reducing an undesirably high A6 IK 38/16 (2006.01) peak serum insulin level, or for reducing an undesirably A6 IK3I/55 (2006.01) large response to a glucose tolerance test in Synergistic C07K 4/585 (2006.01) combination with metformin. Treatment is effected with a (52) U.S. C. combination therapy of metformin and a peptide with a CPC ............. A61K 38/16 (2013.01); A61K 31/155 sequence selected from SEQ ID NO: 11, SEQ ID NO: 12, (2013.01); A61K 38/23 (2013.01); C07K SEQID NO: 13, SEQ ID NO: 14, SEQID NO: 15, SEQ ID 14/585 (2013.01) NO: 16, SEQID NO: 17, SEQID NO: 19, SEQID NO: 20, (58) Field of Classification Search SEQID NO: 21, SEQID NO: 22, SEQID NO. 23, and SEQ None ID NO: 24 administered to a patient. See application file for complete search history. 22 Claims, 25 Drawing Sheets U.S. Patent Jan. 3, 2017 Sheet 1 of 25 US 9,533,022 B2 2 5 -O- Vehicle -er SC gikg -o- UGP3021 g/kg 5 9 5 O -One Vehicle SCT mg/kg 89 5O OO -o- UGP302 mg/kg 8 O O FIG. 1B U.S. Patent Jan. 3, 2017 Sheet 2 of 25 US 9,533,022 B2 Vehicle OO sCT mg/kg UGP3021 mg/kg 60 40 FIG. C Vehicle sCT 1 mgkg UGP302 1 mg/kg -4 O FIG. D U.S. Patent Jan. 3, 2017 Sheet 3 of 25 US 9,533,022 B2 2 -O- Vehicle SC1 mg/kg -o- UGP3021 mg/kg 8 4. -30 O 3O 6O 90 20 150 80 21 O 240 Time (min) FIG. 2A g 1500 Vehicle sCT 1 mg/kg S. UGP302 1 mg/kg (D - : OOO is 500 O () O 3. FIG. 2B U.S. Patent Jan. 3, 2017 Sheet 4 of 25 US 9,533,022 B2 s FIG. 3 () . it. e Vehicle sCT 2 mg/kg M UGP3022 mg/kg o 5. FIG. 4A s g 5 -20 sCT 0.5 mg/kg M. JGP302 0.5 mg/kg sCT 0.5 mg/kg M UGP302 0.5 mg/kg 5 FIG. 4B 1 O 5 U.S. Patent Jan. 3, 2017 Sheet 5 Of 25 US 9,533,022 B2 W2 O sCT 1 mg/kg M UGP302 1 mg/kg F.G. 5A 2 O sCT 1 mg/kg UGP302 1 mg/kg 1 5 O 5 O FIG. 5B U.S. Patent Jan. 3, 2017 Sheet 6 of 25 US 9,533,022 B2 -3 O sCT 2 mg/kg UGP3022 mg/kg F.G. 6A 15 sCT 2 mg/kg M UGP3022 mg/kg O FIG. 6B U.S. Patent Jan. 3, 2017 Sheet 7 Of 25 US 9,533,022 B2 12 8 -O- Vehicle (ppoied) sCT 1 mg/kg-04 UGP302 1 mg/kg 4 -30 O 3O 6O 90 120 50 18O 21 O 240 Time (min) FIG. 7A 500 Vehicle (poied) SC ing/kg UGP3021 mg/kg FIG. 7B U.S. Patent Jan. 3, 2017 Sheet 8 of 25 US 9,533,022 B2 1 2 1 O 8 -O- Vehicle -O- UGP3022 mg/kg SC 2 mg/kg -30 O 3O 60 90 120 150 18O 21 O 240 Time (min) FIG. 8A 1500 w SCT2gkg UGP3022 ring/kg FIG. 8B U.S. Patent Jan. 3, 2017 Sheet 9 Of 25 US 9,533,022 B2 sCT 0.5 mg/kg UGP302 0.5 mg/kg m UGP284 0.5 mg/kg UGP298 0.5 mg/kg FIG. 9A sCT 0.5 mg/kg 1 OO " UGP302 0.5 mg/kg O UGP284 0.5 mg/kg 8 O UGP298 0.5 mg/kg 6 O 4 O O FIG. 9B U.S. Patent Jan. 3, 2017 Sheet 10 of 25 US 9,533,022 B2 sCT 1 mg/kg M UGP3021 mg/kg M UGP2841 mg/kg UGP298 1 mg/kg ... 1 O -3-2 OO FIG. 9C sCT 1 mg/kg 2 O M UGP302 1 mg/kg 0 UGP2841 mg/kg f 5 UGP298 1 mg/kg 10 5 O FIG. 9D U.S. Patent Jan. 3, 2017 Sheet 11 of 25 US 9,533,022 B2 sCT 2 mg/kg M UGP3022 mg/kg O UGP2842 mg/kg UGP298.2 mg/kg FIG. 9E 5 sCT 2 mg/kg M UGP3022 mg/kg m UGP2842 mg/kg 10 UGP298.2 mg/kg k es ke FIG. 9F U.S. Patent Jan. 3, 2017 Sheet 12 of 25 US 9,533,022 B2 -O- Vehicle (pooled) UGP28 4 0.5 g/kg sCT 0.5 mg/kg -&- UGP298 0.5 mg/kg 1 2 -On UGP3O2 0.5 in gikg O 8 4. -30 O 30 60 90 120 150 18O 21 O 240 Time (min) FIG. OA " Vehicle (pooled) 9. 1500 sCT 0.5 mg/kg 8 M UGP302 0.5 mg/kg 5 UGP284 0.5 mg/kg ge 1000 UGP298 0.5 mg/kg E.O a () - 500 O (...) O s FIG. OB U.S. Patent Jan. 3, 2017 Sheet 13 Of 25 US 9,533,022 B2 re-Or Vehicle 2 SCT glkg -o- UGP3021 mg/kg -x- UGP284 mg/kg -x- UGP298 1 mg/kg 8 4. -30 O 30 SO 90 120 150 180 20 240 Time (min) FIG. OC 1500 Vehicle sC 1 mg/kg UGP302 1 mg/kg I UGP2841 mg/kg O O O UGP298 1 mg/kg e t 5 O O FIG. OD U.S. Patent Jan. 3, 2017 Sheet 14 of 25 US 9,533,022 B2 8 sCT 2 mg/kg 12, -C- VehicleUGP3022 mg/kg -o--()- UGP298.2UGP2842 mg/kg 8 6 4. -30 O 3O 6O 90 20 SO 80 21 O 240 Time (min) FIG. OE 1500- Vehicle UGP3022 mg/kg sCT 2 mg/kg UGP2842 mg/kg x UG-298 2. ng fkg FIG. OF U.S. Patent Jan. 3, 2017 Sheet 15 Of 25 US 9,533,022 B2 250 go s s s s s s x8% UGP302 (n=7) s sk---------------------------------------------------------------------------------'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''. s s s s a s UGP298 (n=4) 100. x: UGP284 (n-3) 8 a *.x*a- sCT (n-63) s s s s s s 50.3.s UGP306 (n=4) s s s s s s UGP283 (n=4) UGP303 (n=4) O 250 500 750 1 OOO Peptide (pg/ml) FG. 8 3 . ge 2 : s g a i FIG. 2A & a {} g & - ie:::ce - S -88 -x- 38°382.38 gikg 8 S rix.
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