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Startverso4 PHASE III TRIAL of FALDAPREVIR PLUS PEGYLATED INTERFERON Α-2A and RIBAVIRIN in PATIENTS with HIV and HCV GENOTYPE-1 CO-INFECTION

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Startverso4 PHASE III TRIAL of FALDAPREVIR PLUS PEGYLATED INTERFERON Α-2A and RIBAVIRIN in PATIENTS with HIV and HCV GENOTYPE-1 CO-INFECTION STARTVerso4 PHASE III TRIAL OF FALDAPREVIR PLUS PEGYLATED INTERFERON α-2a AND RIBAVIRIN IN PATIENTS WITH HIV AND HCV GENOTYPE-1 CO-INFECTION JK Rockstroh1, M Nelson2, V Soriano3, K Arastéh4, J Guardiola5, S Bhagani6, J Mallolas7, C Tural8, M Puoti9, P Ingiliz10, M Battegay11, MK Jain12, M Núñez13, K Marks14, J Kort15, JO Stern15, R Vinisko15, M Manero16, D Dieterich17, on behalf of the STARTVerso4 Study Group 1University of Bonn, Bonn, Germany; 2Chelsea and Westminster Hospital, London, UK; 3Hospital Carlos III, Madrid, Spain; 4EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin, Germany; 5Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6Royal Free Hospital, London, UK; 7Hospital Clínic, Barcelona, Spain; Jürgen K. Rockstroh 1099 8Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9AO Ospedale Niguarda Cà Granda, Milan, Italy; 10Medizinisches Infektiologiezentrum Berlin (MIB), Berlin, Germany; 11Division of Infectious Diseases and Hospital Epidemiology, Basel, Switzerland; 12UT Southwestern Medical Center, Dallas, TX, USA; 13Wake Forest University, Winston-Salem, NC, USA; 14Weill Cornell Medical College, New York, NY, USA; 15Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 16Boehringer Ingelheim España S.A., Barcelona, Spain; 17Mount Sinai School of Medicine, New York, NY, USA [email protected] BACKGROUND RESULTS EFFICACY FIGURE 4e. SVR4 by ART (total population) TABLE 5. AE summary ●● SVR4 was achieved by 74% of patients overall (Figure 3). FDV 120 mg FDV 240 mg + PR + PR Total ●● Faldaprevir (FDV) is a potent inhibitor of HCV NS3/4A.1 PATIENTS - SVR4 rates were comparable across FDV doses and durations of treatment. 24 weeks Total FDV + PR a ●● 1 n (%) (N=123) (N=185) (N=308) FDV has antiviral activity against HCV genotypes (GT) 1, 4, 5, and 6 in vitro. ●● Of 310 randomized patients, 308 received at least 1 dose of study medication and ●● The most frequent reason for not achieving SVR4 was on-treatment breakthrough 100 Any AE 119 (97) 182 (98) 301 (98) ●● FDV pharmacokinetics support oral, once-daily administration.2 were evaluable for SVR4 (Figure 2). (Table 4). Drug-related AEs 114 (93) 172 (93) 286 (93) ●● ●● Three Phase III trials of FDV + pegylated interferon α-2a and ribavirin (PR) in HCV Overall, demographic and baseline disease characteristics were balanced across 80 DAIDS Grade 3 or 4 AEs 24 (20) 33 (18) 57 (19) ●● SVR4 rates were high in all patient subgroups, regardless of HCV genotype, IL28B GT-1 are complete. the treatment groups (Tables 1–3). 80 75 genotype, presence of compensated cirrhosis, and ART regimen (Figures 4a–e). 73 DAIDS Grade 4 AEs 5 (4) 5 (3) 10 (3) - In STARTVerso1, FDV + PR resulted in sustained virologic response 12 weeks after 69 67 67 AEs leading to discontinuation of FDV only 1 (1) 1 (1) 2 (1) completion of treatment (SVR12) rates of 79% (FDV 120 mg QD) and 80% (FDV ●● ETS was achieved by 80% of patients (Figure 5a) and 88% of these patients AEs leading to discontinuation of all FIGURE 2. Patient disposition 9 (7) 13 (7) 22 (7) 3 achieved SVR4 (Figure 5b). 60 medication 240 mg QD) in treatment-naïve patients with chronic HCV GT-1 infection. c Serious AEs 17 (14) 15 (8) 32 (10) b ●● FDV is also being investigated in Phase III interferon-free trials. - Among patients with ETS, SVR4 rates were comparable at both FDV doses and Resulting in death 0 1 (1) 1 (<1) Randomized N=310a Life threatening 1 (1) 1 (1) 2 (1) ●● STARTVerso4 (NCT01399619) is an ongoing Phase III trial evaluating the safety and in patients randomized to 24 or 48 weeks of PR (Figure 5c). 40 Required hospitalization 15 (12) 12 (6) 27 (9) efficacy of FDV + PR in patients co-infected with HCV and HIV. Treated Two patients not treated Otherd 4 (3) 4 (2) 8 (3) aIncludes additional patients from 240 mg treatment group who discontinued prior to week 12. FIGURE 3. SVR4 overall population bDeath from SJS with onset 145 days after discontinuing treatment while on systemic antibiotics. cA subject may be counted in 20 more than one seriousness criterion. dOther serious AEs include those that persist or cause significant disability/incapacity, or FDV 240 mg + PR, N=185 Proportion of patients with SVR4 (%) other medically important serious events. METHODS FDV 120 mg + PR, DAIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events. b 100 24 weeks, N=123 12 weeks, N=84c 24 weeks, N=86d DC prior 58/84 37/55 9/12 115/143 2/3 8/11 to week 12 h 84 0 STUDY DESIGN N=15 79 TABLE 6. Most frequent AEs (≥20% overall) 80 76 EFV DRV/r ATV/r RAL Other No ART ●● Multicenter, open-label, sponsor-blinded, Phase III study in patients co-infected 72 74 FDV 120 mg FDV 240 mg Completed FDV DC FDV Completed FDV DC FDV Completed FDV DC FDV + PR + PR Total with HCV GT-1 and HIV-1 (N=310; Figures 1a and 1b). e f g n=98 n=25 n=83 n=1 n=74 n=12 24 weeks Total FDV + PR ●● Patients randomized (1:1) or assigned to: 60 n (%) (N=123) (N=185)a (N=308) ART, antiretroviral therapy; ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; EFV, efavirenz; RAL, raltegravir. Nausea 34 (28) 81 (44) 115 (37) - FDV 120 mg QD combined with PR for 24 weeks DC PR DC PR DC PR DC PR DC PR DC PR n=11i n=25i n=16j n=1j n=1k n=11k 40 Fatigue 39 (32) 65 (35) 104 (34) - FDV 240 mg QD + PR for 12 weeks followed by re-randomization to continue to Diarrhea 31 (25) 52 (28) 83 (27) week 24 or stop FDV and continue PR alone through week 24. Completed Completed Completed Headache 29 (24) 47 (25) 76 (25) ●● 20 At week 24, patients who achieved early treatment success (ETS; HCV RNA PR PR PR FIGURE 5a. ETS FIGURE 5b. SVR4 in patients who achieved ETS Asthenia 32 (26) 39 (21) 71 (23) <25 IU/mL at week 4 and undetectable at week 8) were randomized to an additional oportion of patients with SVR4 (%) Decreased appetite 30 (24) 36 (20) 66 (21) Completed Completed Pr 89/123 66/84 72/86 140/185 229/308 a 24 weeks of PR or to stop all treatment. 24 wks 48 wks 24 wks 48 wks 24 wks 48 wks PR 48 wks PR 48 wks 0 Includes additional patients from 240 mg treatment group who discontinued prior to week 12. n=42 n=45 n=26 n=41 n=38 n=35 n=1 n=1 FDV 120 mg FDV 240 mg FDV 240 mg FDV 240 mg TOTAL - Patients who did not achieve ETS received PR through week 48. a 24 weeks 12 weeks 24 weeks Total 100 100 TABLE 7. Grade ≥3 laboratory abnormalities ●● Randomizations (day 1, week 12, and week 24) were stratified by HCV GT-1 subtype FDV 120 mg FDV 240 mg (1a, 1b, and non 1a/1b). DC, discontinued; FDV, faldaprevir; PR, pegylated interferon α-2a and ribavirin; wks, weeks. 89 87 88 aIncludes additional patients from 240 mg treatment group who discontinued prior to week 12. + PR + PR Total aDisposition as of 7th October 2013; bTreatment-naïve (100), relapser (23); cTreatment-naïve (62), relapser (22); dTreatment-naïve 81 80 (%) 77 b 24 weeks Total FDV + PR (63), relapser (23); eReasons: adverse event (10), lack of efficacy (9), withdrawal by subject (6); fReasons: lack of efficacy (1); 80 80 a gReasons: adverse event (4), lack of efficacy (5), withdrawal by subject (3); hReasons: adverse event (10), protocol violation (1), n (%) (N=123) (N=185) (N=308) FIGURE 1a. STARTVerso4 study design withdrawal by subject (4); iReasons: adverse event (9), lack of efficacy (13), lost to follow-up (1), withdrawal by subject (12), Total patients with Grade ≥3 j 50 (41) 87 (47) 137 (44) reason not stated (1); Reasons: adverse event (3), lack of efficacy (8), protocol violation (1), withdrawal by subject (4), other (1); TABLE 4. Summary of reasons for not achieving SVR4 laboratory abnormalities kReasons: adverse event (4), lack of efficacy (5), withdrawal by subject (2), other (1). 60 60 FDV 120 mg FDV 240 mg FDV 240 mg FDV 240 mg Hemoglobin decreased 2 (2) 3 (2) 4 (2) PR (RGT) Arm A Faldaprevir + PR + PR + PR + PR White blood cell count 8 (7) 11 (6) 19 (6) (N=123)a 120 mg QD + PR 24 weeks 12 weeks 24 weeks Total Total Platelets decreased 13 (11) 13 (7) 23 (7) Primary a 40 40 TABLE 1. Baseline demographics n (%) (N=123) (N=84) (N=86) (N=185) (N=308) Neutrophil, absolute 24 (20) 31 (17) 55 (18) endpoint Without SVR4 34 (28) 18 (21) 14 (16) 45 (24) 79 (26) ALT increased 3 (3) 3 (2) 6 (2) Faldaprevir SVR12 FDV 120 mg FDV 240 mg FDV 240 mg FDV 240 mg + PR + PR + PR + PR Creatinine increased 0 0 0 Arm B Faldaprevir 240 mg QD + PR PR (RGT) b Non-response 10 (8) 2 (2) 2 (2) 11 (6) 21 (7) oportion of patients with ETS (%) 20 20 b a (N=187) 240 mg QD + PR PR (RGT) 24 weeks 12 weeks 24 weeks Total Total oportion of patients with SVR4 Total bilirubin 17 (14) 43 (23) 60 (19) a Pr PR Pr (N=123) (N=84) (N=86) (N=185) (N=308) Breakthroughc 11 (9) 8 (10) 7 (8) 15 (8) 26 (8) aIncludes additional patients from 240 mg treatment group who discontinued prior to week 12. b Male, n (%) 103 (84) 66 (79) 68 (79) 145 (78) 248 (81) 95/123 150/185 245/308 85/95 131/150 216/245 Worst DAIDS grade on-treatment.
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