IHA UN TORN DATUKUMUMUS 20170258927A1 MUNDIAL MONTH ( 19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0258927 A1 Johnston (43 ) Pub . Date : Sep . 14 , 2017 ( 54 ) FORMULATIONS AND DOSES OF Publication Classification PEGYLATED URICASE (51 ) Int . CI. A61K 31/ 4355 ( 2006 .01 ) (71 ) Applicant : Selecta Biosciences , Inc ., Watertown, A61K 9 /00 ( 2006 . 01) MA (US ) A61K 31/ 436 (2006 . 01 ) A61K 38 / 44 ( 2006 .01 ) ( 72 ) Inventor: Lloyd Johnston , Belmont, MA (US ) A61K 9 / 16 ( 2006 . 01 ) (21 ) Appl. No. : 15 /456 , 520 A61K 39 / 00 (2006 . 01) (52 ) U .S . CI. (22 ) Filed : Mar. 11 , 2017 CPC . .. .. .. A61K 47/ 48215 ( 2013 .01 ) ; A6IK 38 / 44 (2013 .01 ) ; A61K 9 /0019 (2013 .01 ) ; A61K Related U . S . Application Data 9 / 1647 (2013 . 01 ) ; A61K 31/ 436 (2013 .01 ) (60 ) Provisional application No . 62 /442 , 948 , filed on Jan . 5 , 2017 , provisional application No . 62/ 430 , 547 , filed (57 ) ABSTRACT on Dec . 6 , 2016 , provisional application No. 62 / 403 , 664, filed on Oct. 3 , 2016 , provisional application No. Provided herein are methods and compositions and kits 62 /398 , 422 , filed on Sep . 22 , 2016 , provisional appli related to uricase compositions and /or compositions com cation No. 62 /397 ,832 , filed on Sep . 21 , 2016 , pro prising synthetic nanocarriers comprising an immunosup visional application No . 62 / 346 , 348 , filed on Jun . 6 , pressant . Also provided herein are methods and composi 2016 , provisional application No . 62 /339 , 944 , filed tions and kits for the treatment of subjects , including on May 22 , 2016 , provisional application No . 62/ 307 , subjects with hyperuricemia , gout or a condition associated 412 , filed on Mar. 11 , 2016 . with gout, and for preventing gout flare. Patent Application Publication Sep . 14, 2017 Sheet lof9 US 2017 / 0258927A1 Fig . 1 Patent Application Publication Sep . 14 , 2017 Sheet 2 of 9 US 2017 /0258927 A1 Fig. 2 wwwwwwwwwwwSVP . Rapamycinw wwwwwwwww Pegsiticase Rapamycin Pro try Hyttines PLA + PLA -PEG * " # SPAN 40 Patent Application Publication Sep . 14 , 2017 Sheet 3 of 9 US 2017 /0258927 A1 Fig . 3 Treatment Challenge Empty Nanoparkle Brescicax easticas SVA 230myon oix Dessiticase ogsittcase SVK 28axias D osien Festa?? ?? ???? ?? ?? ???? * * * * TI* Osy 1 29 53 13 341 * ** ** BOLVO¥sweds **** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * wiwiwinin miningnan nimiiniin Qays Patent Application Publication Sep . 14 , 2017 Sheet 4 of 9 US 2017 /0258927 A1 Fig . 4 Cose love cohorts pbupovouUKS 11.16 th ** lothing min www o . .. .. .. Days post infusion Patent Application Publication Sep . 14 , 2017 Sheet 5 of 9 US 2017 /0258927 A1 Fig . 5 Subject Phase 1a Cohort # 3 Wocid AOA :289 ADA ADA BO ABAT AON TEC Criteris 1398 miten se (Tan s k ( item and Mon 920NA 32853 NA ??????? Phase 1b Cohort # 9 Suseet O ADA ADA U XOA 104 ADA ( htenstein und in einen hohen * * * * * * * * * * * * * * 44444444 VA 33 3330 ha n nsson Barine Day 7 Day 14 Day 2 Day 1 Subiec Phase 1b Cohort # 4 200gr AQA osigade 80 % e com ADA AQA AOA * ** ** * * ** * * * NA 9180 2836 Subject Day 7 Or 39 Day 2 Day 30 wie AOA AOA ADA ORADA 204 Phase 1b Cohort # 6 www Tisno od mene titen Tong Tilen wwwww Soubound Nagu Negative: Na . = Sample not available ) Patent Application Publication Sep . 14 , 2017 Sheet 6 of 9 US 2017 /0258927 A1 Fig . 6 Phase 1a Cohort # 3 and Phaseja Cohort3 aosudoues #Boko Phase 1a1b CohortCohort #39 and Pegsiticage only Phase 1b Cotorts # 1 , # 3 and # S (SVR -Rapamyon only ) wwwwwwwwwwwwwwwwwwwwwwwwwwwww Phase 10 cohort # 2 S * * * * * (SEL - 212 ) Phase1bCohorts#1,2345and SerumUrloadd(mooL Phase 16 Cohort 4 ?????????????????????? . W * (SEL - 212 ) ? Phase 1o Cohort # 6 Bom (SEL212 ) wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww . 12 Patent Application Publication Sep . 14 , 2017 Sheet 7 of 9 US 2017 /0258927 A1 Fig . 7 Krystexxa Pegsiticase SEL -212 * Piacevo neck- ofesyoxdur Rasadnia SVP papaixo Meanuricadd,midi Down finnst y Cat 5 * brand innovativeanesquisa Resets Fogsitinn . *wwwwwww Rom . + + + + + + + . *** * Weeks Weeks WERKS s exceptions O to me to site dose rossowy 22 Cms Koema 38 Smye AKA 208 V 30877 Patent Application Publication Sep . 14 , 2017 Sheet 8 of 9 US 2017 /0258927 A1 Fig . 8 Serum Uric Acid Levels by Cohort SVP -Rapamycin only $ ( 0 .038 , 0 . 1 , and 0 . 3 amg/ kg ) * * Pegsiticase only * ** ** * * * ( 0 . 4mg/ kg ) ** * * * ** * * SerumUricAcid(mg/dL) SEL - 212 ( 0 .03mg / kg SVP -Rapamycin + 0 .4mg / kg pegsiticase ) . .. SEL- 212 (0 . 1mg/ kg SVP -Rapamycin .. .. .. .. .. .. .. + 0 .4mg / kg pegsiticase ) * . - - - - - - - SEL - 212 ( 0 . 3mg/ kg SVP -Rapamycin . .. .. .. + 0 . 4mg/ kg pegsiticase ) O 7 14 21 30 Day Day 30 SUA levels and ADA levels Pegsiticase alone SEL - 212 SEL - 212 ( 0 . 4 mg/ kg ) 0 . 3 mg/ kg SVP -Rapamycin 0 . 3 mg/ kg SVP -Rapamycin + 0 . 4 mg/ kg Pegsiticase + 0 . 4 mg/ kg Pegsiticase Day 30 Subject Day 30 Subject Day 30 Subject Unic acid ADA Uric acid ADA number Unc acid ADA number med (Titer ) number mad ) (Titer ) (mg / dL ) ( Titer) 108 -0010 N 1080 107 - 0018300018 : Neo 107 -0027 0 Neo 103- 0015 6 9720 107 -0021 Nec 107 - 0028 Mag 104 -0032 19 1080 104 - 0027 64 29160 104 - 0050 Neg 109- 0012 1080 108 - 0008 0 : 1 104 - 0060 120 | 104 -0036 880 9720 | 102- 0005 | < 0 . 1 Nes 103 - 0019 Neg (Neg = Negative ) Patent Application Publication Sep . 14 , 2017 Sheet 9 of 9 US 2017 /0258927 A1 Fig. 9 Cohort SEL - 110 SEL -037 junto NA 10. 2 mg/ kg 0 .4 mg/ kg N 0 . 05mg/ kg | 0 . 2 mg/ kg 0 .05mg kg 0 . 4 mg / k & 0 .08mg / kg 0 . 2 mg/ kg 0 .08mg / kg 0 . 4 mg / kg www US 2017 /0258927 A1 Sep . 14 , 2017 FORMULATIONS AND DOSES OF ing uricase provided herein alone or in combination with any PEGYLATED URICASE one of the compositions comprising synthetic nanocarriers comprising an immunosuppressant provided herein . In one RELATED APPLICATIONS embodiment of any one of the methods provided herein , the compositions comprising uricase provided herein alone or in [0001 ] This application claims the benefit ofpriority under combination with any one of the compositions comprising 35 U . S . C . $ 119 of U . S . provisional applications 62 /307 ,412 synthetic nanocarriers comprising an immunosuppressant filed Mar . 11 , 2016 ; 62 / 339 , 944 filed May 22 , 2016 ; 62 / 346 , may be repeatedly administered to the subject. The subject 348 filed Jun . 6 , 2016 ; 62 /397 ,832 filed Sep . 21 , 2016 ; may be one in need thereof. The subject may be any one of 62 /398 ,422 filed Sep . 22 , 2016 ; 62/ 403 , 664 filed Oct. 3 , the subjects described herein . 2016 ; 62 /430 ,547 filed Dec . 6 , 2016 ; and 62/ 442 ,948 filed [0006 ] In one aspect, a method of treating a human subject Jan . 5 , 2017 , the entire contents of each of which are with gout or a condition associated with gout, comprising incorporated herein by reference . administering to the subject a composition comprising FIELD OF THE INVENTION uricase and a pharmaceutically acceptable carrier is pro vided . In one embodiment, the administration is via a [ 0002 ] Provided herein are methods and compositions and non - intramuscular mode of administration . In one embodi kits related to uricase compositions and /or compositions ment, the composition comprising uricase and a pharmaceu comprising synthetic nanocarriers comprising an immuno tically acceptable carrier is administered more than once to suppressant. Also provided herein are methods and compo the subject . In one embodiment, the composition comprising sitions and kits for the treatment of subjects , including uricase and a pharmaceutically acceptable carrier is admin subjects with hyperuricemia , gout or a condition associated istered more than twice , more than thrice , or more than four with gout, and for preventing gout flare . times to the subject. In one embodiment, the composition comprising uricase and a pharmaceutically acceptable car SUMMARY OF THE INVENTION rier is administered every two to four weeks . In one embodi [0003 ] The development of anti - drug antibodies (ADAS ) ment, the composition comprising uricase and a pharmaceu is a common cause for biotherapeutic treatment failure and tically acceptable carrier is administered monthly. In one adverse hypersensitivity reactions . It has been demonstrated embodiment, the composition comprising uricase and a that synthetic nanocarriers comprising an immunosuppres pharmaceutically acceptable carrier is administered con sant are capable of inducing immunological tolerance to a comitantly with a composition comprising an immunosup composition comprising uricase , resulting in improved effi pressant. cacy of the uricase - comprising composition . The improved [ 0007 ] In one aspect, a method of treating a subject with efficacy has been demonstrated at least with a significantly gout or a condition associated with gout, comprising con higher rate of reduction in serum uric acid levels over time comitantly administering to the subject a composition com as compared to other treatments . It has also been demon prising synthetic nanocarriers comprising an immunosup strated that synthetic nanocarriers comprising an immuno pressant and a composition comprising uricase is provided . suppressant, when administered concomitantly with a com [0008 ] Also provided herein are methods of treating a position comprising uricase , are capable of significantly subject that may experience gout flare comprising adminis reducing the incidence of gout flare as compared to other tering any one of the compositions