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H3C -SO3H Patent Application Publication Apr US 20190099429A1 ( 19 ) United States ( 12) Patent Application Publication ( 10 ) Pub . No. : US 2019 / 0099429 A1 Lefebvre (43 ) Pub. Date : Apr. 4 , 2019 ( 54 ) CENICRIVIROC FOR THE TREATMENT OF A61K 45 / 06 (2006 .01 ) FIBROSIS A61K 9 /00 (2006 .01 ) A61K 4738 ( 2006 .01 ) (71 ) Applicant : Tobira Therapeutics, Inc . , South San A61K 38 /21 ( 2006 .01 ) Francisco , CA (US ) A61K 31 / 7072 ( 2006 . 01 ) A61K 38 / 13 ( 2006 . 01 ) ( 72 ) Inventor: Eric Lefebvre , South San Francisco , A61K 31 / 194 (2006 .01 ) CA (US ) A61K 31/ 427 ( 2006 .01 ) A61K 31 /513 (2006 . 01 ) ( 73 ) Assignee : Tobira Therapeutics , Inc ., South San A61K 31 /536 ( 2006 . 01 ) Francisco , CA (US ) ( 52) U . S . CI. CPC . .. .. A61K 31 /55 ( 2013 . 01 ) ; GOIN 33 /6893 ( 21 ) Appl. No. : 16 /148 , 749 ( 2013 .01 ) ; A61K 2300 / 00 ( 2013 .01 ) ; A61K 47 / 12 (2013 . 01 ) ; A61K 45 / 06 (2013 . 01 ) ; A61K (22 ) Filed : Oct . 1 , 2018 9 /0053 (2013 .01 ) ; GOIN 2800 / 52 ( 2013 .01 ) ; Related U . S . Application Data GOIN 2800 / 7052 (2013 . 01 ) ; A6IK 47 / 38 (2013 .01 ) ; A61K 38 / 212 ( 2013 .01 ) ; A61K (63 ) Continuation of application No. 15 / 127, 720 , filed on 31 / 7072 (2013 . 01 ) ; A61K 38 / 13 (2013 . 01 ) ; Sep . 20 , 2016 , now abandoned , filed as application A61K 31/ 194 ( 2013 .01 ) ; A61K 31/ 427 No. PCT /US2015 / 021828 on Mar. 20 , 2015 . ( 2013 .01 ) ; A61K 31/ 513 ( 2013 .01 ) ; A61K ( 60 ) Provisional application No. 61/ 968 , 829 , filed on Mar. 31/ 536 (2013 .01 ) ; A61K 38 / 12 ( 2013 .01 ) 21, 2014, provisional application No . 62 /024 ,713 , filed on Jul . 15 , 2014 , provisional application No . ( 57 ) ABSTRACT 62 / 114 , 304, filed on Feb . 10 , 2015 . or a fibrotic disease or condition in a subject in need thereof Publication Classification comprising administering to the subject a therapeutically (51 ) Int. CI. effective amount of cenicriviroc or a salt or solvent thereof. A61K 31 /55 ( 2006 .01 ) The fibrosis or fibrotic disease may be liver fibrosis , renal GOIN 33 / 68 ( 2006 . 01 ) fibrosis , non - cirrhotic hepatic fibrosis , associated with non A61K 38 / 12 ( 2006 .01 ) alcoholic steatohepatitis (NASH ) , non - alcoholic fatty liver A61K 47/ 12 ( 2006 . 01 ) disease (NAFLD ), or emerging cirrhosis . 19TX 7 H3C -SO3H Patent Application Publication Apr. 4 , 2019 Sheet 1 of 70 US 2019 / 0099429 A1 Figure 1 AANS *H3C -SO3H Patent Application Publication Apr. 4 , 2019 Sheet 2 of 70 US 2019 / 0099429 A1 Figure 2 UKAKAMALUKANNAL INMAMA,MAMAAnnawannamannammawinnaaminnn. Awwwwwwwwwwwww . %FractionAbsorbed . ni . 1 . s ' . w Penanamandawbananamatamson . ???????? . X SANAAN KANAKARTKANLALUKANNALTAMAALUKANA . fumaric citric maleic sodium TA . 1 solution acid acid acid bisulfateS . Patent Application Publication Apr. 4 , 2019 Sheet 3 of 70 US 2019 / 0099429 A1 . m cX . Totalimpurities(%). Wom UMWA . TVM wynx ? Womewomen we w wowo wo wwwwww warm www na w w w ?? Example 1b O Example 4 Examples 2b ht A Example 5 6 8 10 12 Time (weeks ) Patent Application Publication Apr. 4 , 2019 Sheet 4 of 70 US 2019 / 0099429 A1 . Figure 4 . UUUUUIKESEVALLS F mamRREKTURREKTYKARREKET ARREKESISYYRIRKISTYY565 . - Example TI5 - Sorption /Desorption - O - Example 3 - Sorption /Desorption Fine Cenicriviroc Mesylate - Sorption / Desorption WYMYIMTMwamTM INT INNGANCHO M WeightChange%w/) . 000- 6 -8 -8 -8 - 8- 8 -8 .- 8 -8 -8 - brane ???????????????????????? ??????????????????????????????? . 0 10 20 30 . 40 50 60 70 80 90 100 . WWWwwvwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww Relative humidity. (% ) at 25°C . Patent Application Publication Apr. 4 , 2019 Sheet 5 of 70 US 2019 / 0099429 A1 poobond yoon . YANYAANWAwNwYXVmanian NaWynARNWAARVAN . Cenicriviroc mesylate in a gelatin capsule . Example 3 . TUTTI . wwwwwwwwwwinninwiwit . )Dogs(%FBioavailabilityinAbsolute wwwwwwwww . EVRANM Pentagastrin No Pretreatment Famotidine · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ph 1 . 2 - 2 . 5 ) ( pH 3- 4 0 } { B 6 . 0 - 7 . 0 ) Dog Gastric Conditions Patent Application Publication Apr. 4 , 2019 Sheet 6 of 70 US 2019 / 0099429 A1 Figure 6 STROOKED O 'T KARGO SK . .wwwwwwwwww . ).Dogs(%FBioavailabilityinAbsolute wwwwww . VROUE 5 Ad L glaspassani . YTDOWN . Example12b CVC Example 120 CVC Example .12b . .3TC . Example . 12c. 3TC. Patent Application Publication Apr. 4 , 2019 Sheet 7 of 70 US 2019 / 0099429 A1 . FIGURE 7A . Full. Length DNA . FoldChangefromBaseline . Novny . Y O X , W WWYM 0 CVC 100 CVC 200 E FIGURE 7B Strong Stop DNA . FoldChangefromBaseline . mamman V ERVIEW . MY CVC 100 CVC 200 EFV Patent Application Publication Apr. 4 , 2019 Sheet 8 of 70 US 2019 / 0099429 A1 FIGURE 8A MVC 20x1010. ORT- PCR CVC MUZIA No Cells 1. 5x1010 _ . FAZER . RNACopiesImi. 1 . MA ratan murhan UTAKACHUKWU AMWAYWWOWA Hours FIGURE 8B MVC WANAMUZI No Cells . No Drug wouozd WE . X X . 3 : : : : : : : : XX . V WWVEULEVARE Hours Patent Application Publication Apr. 4 , 2019 Sheet 9 of 70 US 2019 / 0099429 A1 Figure 9 w wwwwww p = 0 .029 its AR ANVELYN FoldChangefromNoDrug ww. wwwwwwwwwwwwwwwww - LLORAR LANN Hmmmmmmmmmm w TV My wwwwwwwwwwwwwwwwwwwww · · · · · · · · · · · · · · · · · · · · · · · · · · DAN 2010 NoVirus NoDrug Treatment Patent Application Publication Apr. 4 , 2019 Sheet 10 of 70 US 2019 /0099429 A1 Figure 10A ? *. 1 % . : : A : ??1 *. ?, -?? ? 4.41 . htt *** ? iniste* 17: ?, r #= tel # ???:? : # . ? RSS . ??? : . EN , #? ??? ? ?” ? , . : : : : : : : : : : : : : : : : , , , , , , , , , , ASRSS Figure 10B . ECL2 . w . 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