All- Orl 12- Week Combin3on Tretment With Dcltsvir nd Sofosbuvir in P3ents Infected With HCV Genotype 3: ALLY- 3 Phse 3 Study Nelson DR, 1 Cooper JN, 2 Llezri JP, 3 Lwitz E, 4 Pockros P, 5 Freilich BF, 6 Younes ZH, 7 Hrln W, 8 Ghlib R, 9 Oguchi G, 10 Thuluvth P, 11 OrQz- Lsnt G, 12 Rbinovitz M, 13 Bernstein D, 14 BenneT M, 15 Hwkins T, 16 Rvendhrn N, 17 Sheikh AM, 18 Vrunok P, 19 Kowdley KV, 20 Hennicken D, 21 M c Phee F, 21 Rn K, 21 nd Hughes EA 21 on behlf of the ALLY- 3 Study Tem 1 University of Florid, Ginesville, FL; 2 Inov Firfx Hospitl, Flls Church, VA; 3 Quest Clinicl Reserch, Sn Frncisco, CA; 4 Texs Liver InsQtute, University of Texs Helth Science Center, Sn Antonio, TX; 5 Scripps Clinic, L Joll, CA; 6 Knss City Reserch InsQtute, Knss City, MO; 7 Gstro One, Germntown, TN; 8 Asheville Gstroenterology Assocites, Asheville, NC; 9 Texs Clinicl Reserch InsQtute, Arlington, TX; 10 Midlnd Florid Clinicl Reserch Center, DeLnd, FL; 11 Mercy Medicl Center, BlQmore, MD; 12 Fundción de InvesQgción de Diego, Snturce, Puerto Rico; 13 University of PiTsburgh, PiTsburgh, PA; 14 Hofstr North Shore- Long Islnd Jewish School of Medicine, Mnhsset, NY; 15 Medicl Assocites Reserch Group, Sn Diego, CA; 16 Southwest CARE Center, Snt Fe, NM; 17 DigesQve Disese Assocites, BlQmore, MD; 18 GstrointesQnl Specilists of Georgi, MrieT, GA; 19 Premier Medicl Group of Hudson Vlley, Poughkeepsie, NY; 20 Swedish Medicl Center, SeTle, WA; 21 Bristol- Myers Squibb Reserch nd Development, Princeton, NJ The Liver Mee*ng AASLD 2014 Boston, MA November 7 11, 2014 HCVDE14NP10149-01 Nov 2014
Bckground HCV genotype (GT) 3 is common worldwide nd remins significnt disese burden 1 GT 3 infecqon is ssocited with incresed risk of fibrosis progression, stetosis, nd heptocellulr crcinom in pqents with cirrhosis 2-4 Current therpies for pqents with GT 3 infecqon include: US nd Europe 24- week sofosbuvir (SOF) + ribvirin (RBV) 5 12- week SOF + peginterferon/rbv 5 Europe 24- week dcltsvir (DCV) + SOF ± RBV 6 1 Pol S, et l. Liver Int 2014;34(suppl 1):18-23. 2 Nkontchou G, et l. J Virl Hept 2011;18:e516-522. 3 Lrsen C, et l. J Med Virol 2010;82:1647-1654. 4 Bochud PY, et l. J Heptol 2009;51:655-666. 5 SOVALDI (sofosbuvir) prescribing informqon. 2014. 6 DAKLINZA (dcltsvir) summry of product chrcterisqcs. 2014. 2
Dcltsvir nd Sofosbuvir Dcltsvir (DCV) Potent, pngenotypic NS5A inhibitor Once dily with low potenql for drug drug intercqons Sfe nd well tolerted in > 6000 subjects DCV in combinqon is pproved in Jpn nd Europe; currently under regultory review in the US Sofosbuvir (SOF) Pngenotypic nucleoqde NS5B inhibitor Once dily with low potenql for drug drug intercqons Sfe nd well tolerted Approved in combinqon with other HCV gents in the US, Europe, nd Cnd Pngenotypic: GT 1 6 in vitro nd GT 1 4 in clinicl trils. 3
ALLY Phse 3 Progrm All- Orl DCV + SOF in PQents With High Unmet Medicl Need ALLY- 1 N = 113 PQents with cirrhosis or post- liver trnsplnt GT 1 to 6 DCV + SOF + RBV, 12 weeks ALLY- 2 N = 203 PQents with HIV coinfecqon GT 1 to 6 DCV + SOF, 8 or 12 weeks ALLY- 3 N = 152 PQents with GT 3 infecqon Tretment- nive or tretment- experienced DCV + SOF, 12 weeks 4
ALLY- 3: Study Design GT 3 Tretment- nive N = 101 Tretment- experienced N = 51 DCV 60 mg + SOF 400 mg QD DCV 60 mg + SOF 400 mg QD Follow- up Dy 1 Week 12 Week 24 Week 36 Primry endpoint: SVR12 SVR12 HCV RNA < lower limit of ssy qunqtqon (LLOQ) t postretment Week 12 Eligible pqents Age 18 yers with chronic GT 3 infecqon nd HCV RNA 10,000 IU/mL Tretment- nive or - experienced (prior tretment filures), including pqents with cirrhosis Those who received prior tretment with NS5A inhibitors were excluded Assessed using the Roche HCV COBAS TqMn Test v2.0 (LLOQ 25 IU/mL). 5
Demogrphic nd Bseline Disese Chrcteris3cs Prmeter Tretment- Nive N = 101 Tretment- Experienced N = 51 Age, medin yers (rnge) 53 (24-67) 58 (40-73) Mle, n (%) 58 (57) 32 (63) Rce, n (%) White 92 (91) 45 (88) Blck 4 (4) 2 (4) Asin 5 (5) 2 (4) Other 0 2 (4) b HCV RNA, n (%) < 800,000 IU/mL 31 (31) 13 (25) 800,000 IU/mL 70 (69) 38 (75) Cirrhosis, n (%) c 19 (19) 13 (25) IL28B genotype, n (%) CC 40 (40) 20 (39) Non- CC 61 (60) 31 (61) Prior tretment filure, n (%) Relpse 31 (61) Null response 7 (14) PrQl response 2 (4) Other (intolernt, VBT) 11 (22) PQents who previously filed tretment with sofosbuvir (n = 7) or lisporivir (n = 2) were included. b Americn Indin/Alsk nqve. c Cirrhosis determined by liver biopsy (METAVIR F4; n = 14), FibroScn (> 14.6 kp, n = 11), or FibroTest score 0.75 nd APRI (sprtte minotrnsferse to pltelet rqo index) > 2 (n = 7). VBT, virologic brekthrough. 6
SVR12: Primry Endpoint Tretment- nive Tretment- experienced 100 90 86 80 SVR12, % 60 40 20 0 HCV RNA < LLOQ (25 IU/mL); error brs reflect 95% confidence intervls. 7
On- Tretment Virologic Response 100 94 98 99 100 Virologic response, % 80 60 40 20 Tretment- nive, undetectble Tretment- nive, < LLOQ Tretment- experienced, undetectble Tretment- experienced, < LLOQ 0 Week 4 b End of Tretment Undetectble HCV RNA or HCV RNA < LLOQ (25 IU/mL). b SVR12 rtes bsed on Week 4 HCV RNA levels: < LLOQ, trget detected, 86%; < LLOQ, trget not detected, 91%. 8
SVR12 by Bseline Fctors 100 94 86 90 70 91 88 92 87 80 SVR12, % 60 40 20 0 Mle Femle < 65 65 < 800K 800K CC Non- CC Gender Age, yers HCV RNA levels, IU/mL IL28B genotype 9
SVR12 in P3ents With Cirrhosis 100 80 Overll Tretment- nive Tretment- experienced 96 97 94 69 63 58 SVR12, % 60 40 20 0 Absent Present Absent Present Absent Present Cirrhosis,b Among pqents with cirrhosis, 34% (11/32) hd bseline pltelet counts < 100,000/mm 3 Cirrhosis sttus determined in 141 pqents by liver biopsy (METAVIR F4), FibroScn (> 14.6 kp), or FibroTest score 0.75 nd APRI (sprtte minotrnsferse to pltelet rqo index) > 2. b Cirrhosis sttus for 11 pqents ws inconclusive (FibroTest score > 0.48 to < 0.75 or APRI > 1 to 2). 10
SVR12 in P3ents by FibroTest Score 100 80 Overll Tretment- nive Tretment- experienced 93 95 91 73 63 70 SVR12, % 60 40 20 0 F0- F3 F4 F0- F3 F4 F0- F3 F4 FibroTest,b Per protocol, FibroTest ssessments (scores determined by BioPredicQve) were performed during screening; dt not vilble for 3 pqents. b FibroTest F4 defined s 0.75; F0- F3 defined s < 0.75. 11
Virologic Filure 100 Tretment- nive Tretment- experienced Non- SVR12, % 80 60 40 20 0 0 0 1 0 Virologic Brekthrough Other On- Tretment Filure 14 9 9/100 7/51 Relpse b Of the 16 pqents with relpse, 11 hd cirrhosis 1 / 16 relpses occurred between post- tretment weeks 4 nd 12 Resistnce- ssocited vrints (RAVs) tht emerged t relpse NS5A- Y93H emerged in 9 / 16 pqents One tretment- nive pqent with cirrhosis who hd detectble HCV RNA t the end of tretment. b Percentges bsed on the number of pqents with undetectble HCV RNA t the end of tretment. 12
On- Tretment Sfety nd Tolerbility Prmeter, n (%) All p3ents N = 152 Deth 0 Serious dverse events 1 (1) b Adverse events leding to discon3nu3on 0 Grde 3 dverse events 3 (2) c Grde 4 dverse events 0 Adverse events in 10% of p3ents (ll grdes) Hedche 30 (20) FQgue 29 (19) Nuse 18 (12) Grde 3/4 lbortory bnormli3es Hemoglobin < 9.0 g/dl 0 Absolute neutrophils < 0.75 10 9 /L 0 Absolute lymphocytes < 0.5 10 9 /L 1 (1) Pltelets < 50 10 9 /L 2 (1) InternQonl normlized rqo > 2 ULN 2 (1) Lipse > 3 ULN 3 (2) On- tretment events for deth nd dverse events; tretment- emergent events for Grde 3/4 lbortory bnormliqes. b One event of gstrointesqnl hemorrhge t Week 2, considered not relted to study tretment. c Arthrlgi in 1 pqent; food poisoning, nuse, nd vomiqng in 1 pqent; nd serious dverse event of gstrointesqnl hemorrhge in 1 pqent. 13
Summry DCV + SOF for shorter 12- week durqon chieved high SVR12 rtes in pqents with GT 3 infecqon (tretment- nive, 90%; tretment- experienced, 86%) High SVR rtes of 96% were chieved in pqents without cirrhosis No virologic brekthroughs DCV + SOF in combinqon ws sfe nd well tolerted Further opqons for opqmizing tretment outcome with DCV + SOF in GT 3- infected pqents with cirrhosis re currently being evluted 14
Acknowledgments The uthors thnk the pqents nd their fmilies for their support nd dedicqon, nd invesqgtors nd reserch stff t ll study sites BenneT, Michel Ghlib, Reem Nelson, Dvid R. Rune, Peter BMS Personnel Bernstein, Dvid Gitlin, Normn Oguchi, Godson Sheikh, Asim M. Colby, Susn Box, Terry Hrln, Willim OrQz- Lsnt, Grisell Siddique, Asm Dun, To Cooper, Jmes Hwkins, Trevor Pockros, Pul Thuluvth, Pul Hernndez, Dennis Dest, Tddese Kowdley, Kris Poleynrd, Gry Tong, Myron J. Mhoney, Michelle Fllh, Mrc Llezri, Jcob P. Rbinovitz, Mordechi Vrunok, Peter Mrin, Jclyn Fink, ScoT Lwitz, Eric Rvendhrn, Ntrjn Webster, Lynn Vellucci, Vincent Freilich, Brdley L. Mills, Anthony Rojter, Sergio Younes, Zid H. CliniclTrils.gov, registrqon number NCT02032901 (Study AI444-218) Editoril support ws provided by J Loh of ArQculte Science nd funded by Bristol- Myers Squibb 15