The nonstructural (NS)5B polymerase inhibitor,

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1 RAPID COMMUNICATION Ledipasvir-Sofosbuvir Plus Ribavirin for Patients With Genotype 1 Hepatitis C Virus Previously Treated in Clinical Trials of Sofosbuvir Regimens David Wyles, 1 Paul Pockros, 2 Giuseppe Morelli, 3 Ziad Younes, 4 Evguenia Svarovskaia, 5 Jenny C. Yang, 5 Phillip S. Pang, 5 Yanni Zhu, 5 John G. McHutchison, 5 Steven Flamm, 6 and Eric Lawitz 7 Patients who fail to achieve sustained virological response (SVR) after treatment with sofosbuvir (SOF) plus ribavirin (RBV) with or without pegylated interferon (Peg-IFN) do not have established retreatment options. We conducted an open-label trial to assess the efficacy and safety of ledipasvir (LDV)-SOF plus RBV in patients with genotype 1 hepatitis C virus (HCV) who did not achieve SVR after treatment in phase II and III trials of SOF regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed-dose combination tablet of LDV-SOF once-daily plus weightbased RBV (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received SOF plus Peg-IFN-RBV, 20 (39%) had received SOF-RBV, 5 (10%) had received SOF placebo plus Peg-IFN-RBV, and 1 (2%) received GS-0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non-cc interleukin-28b genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received SOF in earlier treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and diarrhea. One patient discontinued treatment because of an unrelated AE (bipolar disorder). Conclusion: Twelve weeks of LDV-SOF plus RBV was an effective and safe treatment for patients who have not achieved SVR with earlier regimens that included SOF. (HEPATOLOGY 2015;61: ) The nonstructural (NS)5B polymerase inhibitor, sofosbuvir (SOF), was approved for treatment of patients chronically infected with hepatitis C virus (HCV) in In the phase II and III clinical trials leading up to the approval of SOF, patients with genotype 1 HCV received several regimens: SOF with pegylated interferon (Peg-IFN) and ribavirin (RBV), SOF with RBV, and the purine (guanidine) nucleotide analog polymerase inhibitor, GS-0938, which was formerly in development as a potential complementary oral antiviral agent for use with SOF. 2-6 Although rates of response were high in these trials, a number of patients did not achieve sustained virological response (SVR). Retreatment options for these patients have not yet been established. Abbreviations: AEs, adverse events; CI, confidence interval; DAAs, direct-acting antiviral agents; HCV, hepatitis C virus; IL, interleukin; LDV, ledipasvir; LLOQ, lower limit of quantification; NS, nonstructural; PCR, polymerase chain reaction; Peg-IFN, pegylated interferon; RAV, resistance-associated variant; RBV, ribavirin; SAEs, serious adverse events; SOF, sofosbuvir; SVR, sustained virological response; SVR12, SVR 12 weeks after the end of treatment; VF, virological failure. From the 1 University of California, San Diego, CA; 2 Scripps Clinic, La Jolla, CA; 3 University of Florida Health, Gainesville, FL; 4 Gastro One, Germantown, TN; 5 Gilead Sciences, Inc., Foster City, CA; 6 Northwestern University Feinberg School of Medicine, Chicago, IL; 7 Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX Received February 23, 2015; accepted March 26, Additional Supporting Information may be found in the online version of this article at onlinelibrary.wiley.com/doi/ /hep.27814/suppinfo. This analysis was supported by Gilead Sciences, Inc. (Foster City, CA). 1793

2 1794 WYLES ET AL. HEPATOLOGY, June 2015 The once-daily, single-tablet regimen of SOF with the HCV NS5A inhibitor ledipasvir (LDV) was approved in 2014 for treatment of patients chronically infected with genotype 1 HCV. 7 We conducted an open-label trial to evaluate the efficacy and safety of 12 weeks of the fixed-dose combination of LDV and SOF plus RBV in patients with genotype 1 HCV infection who did not achieve SVR in previous clinical trials of SOF-containing regimens. The primary efficacy endpoint was SVR (HCV RNA <15 IU/mL) 12 weeks after the end of treatment (SVR12). Patients and Methods Study Design and Participants. This was an openlabel study conducted at 24 sites in the United States. We enrolled patients with chronic genotype 1 HCV infection who did not achieve SVR after treatment in one of five clinical trials that evaluated regimens containing SOF: P (NCT ); QUANTUM (NCT ); PROTON (NCT ); AT OMIC (NCT ); or NEUT-RINO (NCT ). Full eligibility criteria for those studies may be found in the Supporting Information. Therewasno upper limit on the enrollment of patients with cirrhosis, which was defined as previous diagnosis of cirrhosis by biopsy or FibroTest score of >0.75 and an aspartate aminotransferase to platelet ratio index of >2 during screening. All patients provided written informed consent before any study procedures were undertaken. The study was conducted in accord with the principles of the Declaration of Helsinki and good clinical practice. Study Procedures. All patients received the fixeddose combination tablet of LDV-SOF once-daily plus weight-based RBV in a divided dose for 12 weeks. Dosage of RBV was determined by body weight (1,000 mg daily in patients with a body weight of <75 kg and 1,200 mg daily in patients with a body weight of 75 kg). HCV RNA was measured with the COBAS Taq- Man HCV Test (v2.0) for use with the Ampliprep System (Roche, Indianapolis, IN) with a lower limit of quantification (LLOQ) for HCV RNA of 15 IU/mL. HCV genotype and subtype were determined using the Siemens VERSANT HCV Genotype INNO-LiPA 2.0 Assay (Siemens AG, Munich, Germany). Interleukin (IL)28B genotype had been determined by polymerase chain reaction (PCR) amplification and sequencing of the rs single-nucleotide polymorphism. Deep sequencing of NS5A and NS5B regions of HCV RNA was performed at baseline for all patients and at the time of virological failure (VF) for all patients who did not achieve SVR12. The resulting sequences were compared with reference sequences or sequences from baseline samples in order to determine the prevalence and kinetics of resistance-associated variants (RAVs). RAVs present at greater than 1% of sequence reads were considered significant. All patients were assessed for safety by means of physical examination and review of adverse events (AEs) and clinical laboratory testing of blood samples. The primary safety endpoint was any AE leading to permanent discontinuation of study drugs. Use of hematological stimulating agents (e.g., erythropoiesisstimulating agents, granulocyte-colony stimulating factor, and thrombopoietin were prohibited during the screening period and for a minimum of 28 days preceding the baseline/day 1 visit through the end of treatment). Statistical Analysis. Sample size was determined by the number of patients who did not achieve SVR in previous Gilead-sponsored studies of SOFcontaining regimens and were eligible for enrollment in this study. Statistical analysis was performed on all enrolled and treated subjects. We calculated a point estimate of SVR12 rate and the two-sided 95% exact confidence interval (CI) based on Clopper-Pearson s Address reprint requests to: David Wyles, M.D., University of California, San Diego, CA, 9500 Gilman Drive, MC 0711, La Jolla, CA dwyles@ucsd.edu; fax: Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Dr. Wyles received grants from Gilead. Dr. Pockros consults for, advises for, is on the speakers bureau for, and received grants from Gilead, AbbVie, and Janssen. Dr. Younes advises for, is on the speakers bureau for, and received grants from Gilead. He is on the speakers bureau for and received grants from AbbVie. He received grants from Bristol-Myers Squibb and Janssen. Dr. Flamm consults for, is on the speakers bureau for, and received grants from Gilead, AbbVie, and Janssen. He consults for and received grants from Bristol-Myers Squibb. He consults for Merck. Dr. Lawitz consults for, advises for, is on the speakers bureau for, and received grants from AbbVie, Gilead, and Janssen. He consults for, advises for, and received grants from Achillion, Bristol-Myers Squibb, Idenix, Merck, Novartis, Santaris, Theravance, and Vertex. He consults for and advises for BioCryst, Biotica, Enanta, and Regulus. He received grants from Boehringer Ingelheim, GlaxoSmithKline, Presidio, Roche, and Salix. Drs. Zhu, Yang, Pang, McHutchison, and Svarovskaia are employed by and own stock in Gilead.

3 HEPATOLOGY, Vol. 61, No. 6, 2015 WYLES ET AL method. SVR12 rate was also examined in subject subsets defined by key demographic and baseline characteristics. Safety data were assessed descriptively. Formal statistical hypothesis testing was not conducted. Role of the Funding Source. The study sponsor oversaw trial management, data collection, statistical analyses, and the writing and review of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Results Baseline Characteristics. A total of 51 patients were enrolled and received at least 1 dose of study treatment (Fig. 1). Table 1 provides demographic characteristics for the population. Most patients were male (61%) and white (84%). Fourteen patients (27%) had documented cirrhosis by either biopsy or noninvasive assessment when screened for participation in previous Gilead studies. Twenty-five patients (49%) had previously received SOF plus Peg-IFN-RBV, 20 (39%) had received SOF plus RBV, and 5 (10%) had received SOF placebo plus Peg-IFN-RBV, and 1 (2%) received GS-0938 alone. Forty-seven (92%) patients had, virological failure (VF) after previous treatment, 2 (4%) discontinued before treatment because of AEs, and 2 (4%) had discontinued treatment because the trial (QUANTUM) was halted. Six of the fifty-one patients had NS5A resistant-associated variants at baseline at positions Q30H, L31M, A92T, or Y93H. At baseline, no patient harbored the S282T variant, which has been associated with phenotypic resistance to SOF. Fig. 1. Patient disposition. Abbreviation: HCC, hepatocellular carcinoma. Table 1. Baseline Characteristics Mean age, years (SD) 54 (8.7) Male sex, n (%) 31 (61) Race, n (%) White 43 (84) Black 8 (16) Mean body mass index, kg/m 2 (SD) 30.4 (5.4) Mean log 10 HCV RNA, IU/mL (range) 6.2 (4.4, 7.3) HCV RNA, IU/mL, n (%) <2 million 25 (49) 2-6 million 17 (33) >6 million 9 (18) Genotype, n (%) 1a 30 (59) 1b 20 (39) 3a 1 (2) Cirrhosis Yes 14 (27) No 37 (73) IL28b, n (%) CC 4 (8) CT 33 (65) TT 14 (27) Previous treatment regimen (by SOF exposure in weeks), n (%) SOF1Peg-IFN1RBV For 4 weeks 1 (2) For 12 weeks 22 (43) For 24 weeks 2 (4) SOF1RBV For 12 weeks 6 (12) For 24 weeks 14 (27) Without SOF 6 (12) Outcome with previous treatment VF 47 (92) Discontinuation from AE 2 (4) Study terminated by sponsor 2 (4) Abbreviation: SD, standard deviation. However, 2 patients had the L159F SOF treatmentemergent variant at baseline. Efficacy. By week 4 of treatment, 50 of the 51 patients (98%) had HCV RNA <15 IU/mL. By week 8 of treatment, all 51 patients (100%) had HCV RNA <15 IU/mL. No patients experienced virological breakthrough or nonresponse during treatment. Of the 51 patients enrolled and treated, 50 (98%) achieved SVR12 (Table 2). All patients with genotype 1 HCV, as well as all patients with cirrhosis, achieved SVR12. The patient who had detectable HCV RNA at week 4 of treatment achieved SVR12. Among the 45 patients who received SOF in previous therapy, 44 (98%) achieved SVR12. Overall, 1 patient experienced virological relapse. This patient, a 53-year-old white woman without cirrhosis, relapsed by post-treatment week 4. Upon viral sequencing of samples drawn at the time of VF, it was

4 1796 WYLES ET AL. HEPATOLOGY, June 2015 determined that this patient, who was recorded on enrollment in the previous trial as having genotype 1b HCV, was, in fact, infected with genotype 3a HCV before her original therapy. Both patients with the L159F treatment-emergent variant at baseline achieved SVR12, as did all 6 with NS5A Q30H, L31M, A92T, or Y93H resistanceassociated variants at baseline. No S282T was detected in any patient at any time point. Safety. The most common AEs were fatigue (25%), headache (22%), and diarrhea (14%; Table 3). One patient discontinued study treatment because of an unrelated AE. This patient, a 50-year-old black woman, experienced a worsening of her bipolar disease Parameter, n (%) Table 2. Response During and After Treatment Table 3. Safety Adverse events leading to discontinuation of LDV-SOF Bipolar disorder 1 (2) SAEs 2 (4) Anemia 1 (2) Bipolar disorder 1 (2) Chest pain 1 (2) Cholecystitis infective 1 (2) Any treatment-emergent AE 41 (80) Common AEs* Fatigue 13 (25) Headache 11 (22) Diarrhea 7 (14) Insomnia 6 (12) Rash 6 (12) Nausea 5 (10) Constipation 4 (8) Arthralgia 3 (6) Depression 3 (6) Influenza 3 (6) Irritability 3 (6) Pruritus 3 (6) Sinusitis 3 (6) Vomiting 3 (6) *AEs occurring in at least 5% of patients. Treatment week 4 <LLOQ, n (%) 50 (98) Treatment week 12 <LLOQ, n (%) 51 (100) SVR4, n (%) 50 (98) SVR12*, n (%) 50 (98) 95% CI VF, n (%) During treatment 0 Relapse 1 (2) *Of the 45 patients who received SOF in earlier therapy, 44 (98%) achieved SVR12 (95% CI: ). Abbreviation: SVR4, sustained virological response 4 weeks after end of treatment. in the 10th week of treatment and received the last dose of study medication on day 74 of treatment. She achieved SVR12. Two patients experienced treatment-emergent serious AEs (SAEs). One of the patients was the above-mentioned woman with worsening of bipolar disorder. The other was a 68-year-old white man who experienced SAEs of chest pain on day 34 of treatment, anemia on day 59 of treatment, and gangrenous cholecystitis on post-treatment day 25. Chest pain and anemia were attributed by the investigator to study treatment. Upon subsequent evaluation, it was determined that this patient s chest pain was noncardiac in origin, but instead the result of a gastrointestinal issue, possibly caused or exacerbated by study medication. This patient achieved SVR12. Two patients (4%) had hemoglobin nadirs of <10 g/dl, consistent with the use of RBV. Median change in hemoglobin from baseline to treatment week 12 was 22.2 g/dl. One patient with a history of Gilbert s syndrome had grade 3 and 4 hyperbilirubinemia. Two patients had transient asymptomatic grade 3 elevations of lipase. No other clinically significant laboratory abnormalities were observed. Discussion In this open-label study, all patients with genotype 1 HCV who had previously failed SOF and RBV or SOF plus Peg-IFN-RBV achieved SVR after 12 weeks of treatment with the fixed-dose combination of LDV- SOF plus RBV. The only patient not to achieve SVR was a patient with genotype 3 HCV who had been mistakenly enrolled. This trial included a number of patients with characteristics that have historically been associated with poor response to treatment cirrhosis, earlier treatment failure, non-cc IL28B genotypes, and presence of baseline RAVs. All of these patients achieved SVR12. We accordingly could not identify any characteristics that might be associated with treatment failure. A concern of clinicians considering retreatment of patients who have not achieved SVR after earlier treatment with direct-acting antiviral agents (DAAs) is the possible presence of resistant viral variants. For these particularpatients,theconcernwouldberesistancetosof, to which they had been previously exposed. For the clinician considering retreatment, even the lack of an S282T mutation, the signature RAV known to confer phenotypic resistance to SOF, does not rule out the possibility of other, less well-characterized mutations in or outside the NS5B polymerase gene. This study demonstrates that patients who have previously been exposed to SOF can

5 HEPATOLOGY, Vol. 61, No. 6, 2015 WYLES ET AL be successfully retreated with an SOF-based regimen of LDV-SOF and RBV for 12 weeks. This is consistent with a previously published study, in which 14 of 14 patients who failed SOF and RBV, including 1 patient who developed the S282T mutation, were successfully retreated with LDV-SOF for 12 weeks. 8 The limitations of this study are that it is a relatively small study without a control arm. One question that it does not address is the importance of RBV for optimal efficacy, though, as noted above, in another study, patients who did not achieve SVR after treatment with SOF and RBV were successfully treated with LDV-SOF without RBV. In conclusion, patients who were unsuccessfully treated in previous trials of SOF-containing regimens achieved a high rate of SVR12 when retreated with the fixed-dose combination of LDV-SOF with RBV. Acknowledgment: The authors thank the staff and patients who participated in the study; Reena Chhatre (Gilead Sciences) for clinical operations support; and David McNeel (Gilead Sciences) for writing and editorial assistance during the development of the manuscript. References 1. Sovaldi (sofosbuvir) tablets. U.S. prescribing information. Foster City, CA: Gilead Sciences; December Lalezari JP, Nelson DP, Hyland RH, Lin M, Rossi SJ, Symonds WT, et al. Once-daily sofosbuvir plus ribavirin given for 12 or 24 weeks in treatment-na ıve patients with HCV infection: the QUANTUM study. J Hepatol 2013;58(Suppl 1):S Rodriguez-Torres M, Lawitz E, Kowdley KV, Nelson DR, Dejesus E, McHutchison JG, et al. Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-na ıve patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial. J Hepatol 2013;58: Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013;13: Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013;381: Lawitz E, Mangia S, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368: Harvoni (ledipasvir and sofosbuvir) tablets. U.S. prescribing information. Foster City, CA: Gilead Sciences; October Available at: harvoni_pi.pdf. Accessed on February 12, OsinusiA,KohliA,MartiMM,NelsonA,ZhangX,MeissnerEG,etal. Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study. Ann Intern Med 2014;161: Supporting Information Additional Supporting Information may be found in the online version of this article at onlinelibrary.wiley. com/doi/ /hep.27814/suppinfo.