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Douglas Dieterich, 1 Vicente Soriano, 2 Mark Nelson, 3 Jürgen Kurt Rockstroh, 4 Keikawus Arastéh, 5 Sanjay Bhagani, 6 Andrew Talal, 7 Cristina Tural, 8.

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Presentation on theme: "Douglas Dieterich, 1 Vicente Soriano, 2 Mark Nelson, 3 Jürgen Kurt Rockstroh, 4 Keikawus Arastéh, 5 Sanjay Bhagani, 6 Andrew Talal, 7 Cristina Tural, 8."— Presentation transcript:

1 Douglas Dieterich, 1 Vicente Soriano, 2 Mark Nelson, 3 Jürgen Kurt Rockstroh, 4 Keikawus Arastéh, 5 Sanjay Bhagani, 6 Andrew Talal, 7 Cristina Tural, 8 Richard Vinisko, 9 and Jens Kort 9 STARTVerso 4: High rates of early virologic response in HCV genotype 1/HIV-co-infected patients treated with faldaprevir plus pegIFN and RBV 1 Mount Sinai School of Medicine, New York, NY, USA; 2 Hospital Carlos III, Madrid, Spain; 3 Chelsea and Westminster Hospital, London, UK; 4 University of Bonn, Bonn, Germany; 5 EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin, Germany; 6 Royal Free Hospital, London, UK; 7 State University of New York, Buffalo, NY, USA; 8 Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013

2 Presenter disclosure I have had financial relationships within the last 12 months relevant to my presentation with: Boehringer Ingelheim Pharmaceuticals AND My presentation includes information on faldaprevir, which is an investigational compound and is not yet approved Douglas Dieterich, MD Mount Sinai School of Medicine, New York, USA

3 Introduction to faldaprevir Faldaprevir is a potent and selective inhibitor of the HCV NS3/A4 protease The pharmacokinetics of FDV allow oral once daily administration Phase IIb data demonstrated potent antiviral activity against HCV GT-1 for: Faldaprevir combined with pegIFN/RBV An IFN-free combination of faldaprevir with BI and RBV Phase III trials are ongoing for the iFree and iBased faldaprevir clinical development programs Llinàs-Brunet M, et al. J Med Chem 2010;53:6466–6476; Lemke CT, et al. J Biol Chem 2011;286:11434–11443; Sulkowski MS, et al. Hepatology 2013 Jan 28 [Epub ahead of print]; Zeuzem S, et al. AASLD Congress November 9–13, 2012 [Abstract No. 232]. GT, genotype; HCV, hepatitis C virus; IFN, interferon alpha; RBV, ribavirin; BI , a non-nucleoside inhibitor of HCV RNA polymerase Faldaprevir: Interaction with NS3/4A protease Green = hydrophobic Blue = mildly polar Purple = H bonding

4 Phase III open-label, sponsor-blinded study in treatment-naïve and relapser patients with chronic HCV GT-1 and HIV infection LLoQ, lower limit of quantification <25 IU/mL HCV RNA; pegIFN: pegylated interferon alfa-2a 180 µg once weekly; QD, once daily; SVR, sustained virologic response at 12 weeks after end of treatment.; ETS, early treatment success RBV: ribavirin 1000 or 1200 mg daily dose for body weight <75 kg or 75 kg, respectively Patients with HCV RNA below LLoQ, at Week 4, and HCV RNA below LLoQ target not detected at Week 8 (=ETS) will be re-randomized 1:1 at week 24 to stop treatment or continue pegIFN/RBV through week 48 Patients who did not achieve ETS will continue pegIFN/RBV through week 48 STARTVerso 4: Study design (1) Faldaprevir 120 mg QD + pegIFN/RBV Day 1Week 12Week 24Week 48 pegIFN/RBV Faldaprevir 240 mg QD + pegIFN/RBV pegIFN/RBV Randomization 1:1 Primary endpoint: SVR12Interim data

5 STARTVerso 4: Study design (2) No ART Raltegravir or maraviroc based 120 or 240 mg QD Efavirenz based Darunavir/ritonavir or atazanavir/ritonavir based ART regimen Faldaprevir dosage RANDOMIZED 120 mg QD240 mg QD ART, antiretroviral therapy; QD, once daily ALLOCATED HCV GT-1 infection, including compensated cirrhosis HCV treatment-naive or relapsers

6 STARTVerso 4: Patient disposition (Week 12 interim data) Allocated/Randomized (N=153/N=157) Screen failure (N=143) a Includes: viral rebound 1 log 10 HCV RNA from previous undetected level; lack of HCV RNA reduction from baseline by 2 log 10 at Week 12; lack of viral response at Week 24. b Includes: protocol violation, withdrawal by subject, or other reasons AE, adverse event; ATZ, atazanavir; DRV, darunavir; EFV, efavirenz; r, ritonavir Completed 12 weeks of treatment (N=176) Faldaprevir (120 or 240 mg QD) + pegIFN/RBV (N=308) Screened (N=453) Not treated (N=2) HCV treatment-naïve (N=239) Relapser (N=69) Not available (N=18) Discontinued (N=45) 15 Due to AE 12 Lack of efficacy a 18 Other reason b Not available (N=4) Discontinued (N=7) 3 Due to AE 1 Lack of efficacy a 3 Other reason b Completed 12 weeks of treatment (N=58)

7 STARTVerso 4: Baseline characteristics Treatment-naïve (N=239) Relapser (N=69) Total (N=308) Age, years (mean)47 Male, n (%)184 (77)64 (93)80 Race, n (%)White Black or African American Other a 179 (75) 39 (16) 21 (9) 63 (91) 2 (3) 4 (6) ART, n (%)EFV-based ATZ/r- or DRV/r-based Ral-based and other b No ART (ARV-naïve), n (%) 67 (28) 60 (25) 105 (44) 7 (3) 17 (25) 7 (10) 41 (59) 4 (6) 84 (27) 67 (22) 146 (47) 11 (4) Mean baseline CD4 + T cell count, cells/µL Baseline HCV RNA IU/mL, n (%)197 (82)49 (71)246 (80) HCV Genotype-1a, n (%)184 (77)55 (80) 239 (78) Cirrhosis F4 or FibroScan >13 kPa, n (%)40 (17)11 (16) 51 (17) a Includes Asian, Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and missing data. b Includes 1 patient taking maraviroc plus emtricitabine/tenofovir disoproxil fumarate, 1 patient taking emtricitabine/tenofovir disoproxil fumarate only. Ral, raltegravir

8 STARTVerso 4: Interim safety and tolerability Most frequent AEs in >20% of patientsNo. of patients (%) Nausea Fatigue Diarrhea Headache Asthenia 113 (37) 102 (33) 83 (27) 71 (23) 68 (22) Other AEs of interestNo. of patients (%) Anemia Neutropenia Rash Loss of HIV suppression a 55 (18) 49 (16) 55 (18) 0 Most frequent serious AEs (>1 patient)No. of patients (%) Pyrexia Abdominal pain Diarrhea Gastroenteritis Vomiting Anemia Rash Dehydration 4 (1) 3 (<1) 2 (<1) a Increase of HIV plasma RNA >200 copies/mL on two consecutive measurements from prior <40 copies/mL Three deaths: dyspnea; hemorrhage, cerebrovascular accident; Drug reaction with eosinophilia and systemic symptoms

9 Proportion of patients (%) 191/ / 239 Week 4 Week / / 239 Early virologic response in HIV/HCV co-infected patients: HCV treatment-naïve Treatment-naïve { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/1274391/3/slides/slide_8.jpg", "name": "Proportion of patients (%) 191/ 239 143/ 239 Week 4 Week 12 206/ 239 195/ 239 Early virologic response in HIV/HCV co-infected patients: HCV treatment-naïve Treatment-naïve

10 Proportion of patients (%) 191/ / 239 Week 4 Week / / 239 Early virologic response in HIV/HCV co-infected patients: HCV treatment-naïve and relapsers 64/ 69 63/ 69 63/ 69 51/ 69 Treatment-naïve { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/1274391/3/slides/slide_9.jpg", "name": "Proportion of patients (%) 191/ 239 143/ 239 Week 4 Week 12 206/ 239 195/ 239 Early virologic response in HIV/HCV co-infected patients: HCV treatment-naïve and relapsers 64/ 69 63/ 69 63/ 69 51/ 69 Treatment-naïve

11 Proportion of patients (%) a SILEN-C1 study arm of 240mg QD FDV plus pegIFN/RBV in HCV GT1 treatment-naïve monoinfected patients without cirrhosis; data on file 191/ / 239 Week 4 Week / / 239 Early virologic response in HIV/HCV co-infected patients: comparison with HCV mono-infected patients 64/ 69 63/ 69 63/ 69 51/ 69 Treatment-naïve { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/1274391/3/slides/slide_10.jpg", "name": "Proportion of patients (%) a SILEN-C1 study arm of 240mg QD FDV plus pegIFN/RBV in HCV GT1 treatment-naïve monoinfected patients without cirrhosis; data on file 191/ 239 143/ 239 Week 4 Week 12 206/ 239 195/ 239 Early virologic response in HIV/HCV co-infected patients: comparison with HCV mono-infected patients 64/ 69 63/ 69 63/ 69 51/ 69 Treatment-naïve

12 Proportion of patients (%) 184/ / 69 Response guided therapy criteria (ETS) in STARTVerso 4 Treatment-naïveRelapser ETS criteria: Wk 4 HCV RNA { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/1274391/3/slides/slide_11.jpg", "name": "Proportion of patients (%) 184/ 239 61/ 69 Response guided therapy criteria (ETS) in STARTVerso 4 Treatment-naïveRelapser ETS criteria: Wk 4 HCV RNA

13 Summary and conclusions AEs were comparable to those with faldaprevir and pegIFN/RBV in HCV mono-infected patients ETS was observed in 80% of patients Half of these patients will stop treatment at Week week data show high rates of early virologic response to faldaprevir + pegIFN/RBV Interim data compare well with early response rates in mono-infected patients Sustained virologic response data will be used to determine the feasibility of response-guided therapy with faldaprevir Overall reductions in HCV RNATreatment-naïveRelapsers Week 4 { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/1274391/3/slides/slide_12.jpg", "name": "Summary and conclusions AEs were comparable to those with faldaprevir and pegIFN/RBV in HCV mono-infected patients ETS was observed in 80% of patients Half of these patients will stop treatment at Week 24 12-week data show high rates of early virologic response to faldaprevir + pegIFN/RBV Interim data compare well with early response rates in mono-infected patients Sustained virologic response data will be used to determine the feasibility of response-guided therapy with faldaprevir Overall reductions in HCV RNATreatment-naïveRelapsers Week 4

14 Patients, and study investigators and site staff at 67 study centers: Boehringer Ingelheim for sponsoring the study and the Boehringer Ingelheim team The external Data Monitoring Committee Acknowledgments BrazilHans JägerJosep MallolasChloe OrkinMarina Nunez Carlos Eduardo Brandão MelloArastéh KeikawusJuan Antonio PinedaAlison UrielGerald Pierone Raymundo Ferreira FilhoHartwig KlinkerDaniel PodzamczerUnited StatesMichael Saag Paulo FerreiraJürgen Kurt RockstrohCristina TuralJohn BaxterMichael Somero Juvencio FurtadoItalyJorge VergasMaurizio BonaciniRichard Sterling Beatriz GrinsztejnGiacchino Angarano,SwitzerlandCynthia BrinsonMark Sulkowski Jose MadrugaAndrea AntinoriManuel BattegayDouglas DieterichAndrew Talal FranceGiovanni Di PerriEnos BernasconiRichard ElionKristen Marks Marc BourliereGaetano FiliceJan FehrJerome Ernst Laurent CotteFrancesco MazzottaAndri RauchDouglas G. Fish Pierre-Marie GirardPaola NastaUnited KingdomFederico Hinestrosa Caroline Lascoux-CombeMassimo PuotiKosh AgarwalMamta Jain Marc-Antoine ValantinSpainSanjay BhaganiAnthony LaMarca GermanyFrancisco BlancoMartin FisherEric Lawitz Johannes BognerManuel Crespo,Ranjababu KulasegaramCheryl McDonald Christian HoffmannJosep GuardiolaClifford LeenKaram Mounzer Patrick IngilizJuan Carlos LopezMark NelsonRonald Nahass


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