Interim results from Trek Therapeutics' Phase 2 study show triple combination therapy achieves 100% SVR4 in genotype 4 HCV patients
Open-label Phase 2a study of faldaprevir (FDV) plus TD-6450 and ribavirin (RBV). The sustained viral response (SVR) rate four weeks after the completion of treatment (SVR4) was 100 percent (16 of 16) in treatment naïve patients with chronic genotype 4 (GT 4) hepatitis C virus (HCV) who received 120 mg of FDV and RBV in combination with 60 mg or 120 mg of TD-6450 for 12 weeks.
2015 Study-Faldaprevir, Deleobuvir and Ribavirin
Interferon-free Treatment of Chronic Hepatitis C With Faldaprevir, Deleobuvir and RibavirinSOUND-C3, a Phase 2b Study
Stefan Zeuzem, Jean-François Dufour, Maria Buti, Vicente Soriano, Robert J. Buynak, Parvez Mantry, Jawahar Taunk, Jerry O. Stern, Richard Vinisko, John-Paul Gallivan, Wulf Böcher, Federico J. Mensa
Disclosures Liver International. 2015;35(2):417-421.
Abstract and Introduction
Background & Aims The safety and efficacy of the interferon-free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored.
SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a (IL28B CC genotype only; n = 12) and genotype-1b (n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin. Patients with compensated liver disease, including cirrhosis, were eligible for inclusion in this study. The primary endpoint was sustained virological response 12 weeks after completion of therapy.
Sustained virological response rates 12 weeks after completion of therapy were 17% and 95% in patients infected with HCV genotype-1a and genotype-1b respectively. All four patients with cirrhosis achieved sustained virological response 12 weeks after completion of therapy. The most frequently reported adverse events of at least moderate intensity were anaemia (16%), nausea, vomiting and fatigue (9% each). Three (9%) patients discontinued because of adverse events.
The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated.
In treatment-naïve patients infected with chronic hepatitis C virus (HCV) genotype-1 (GT-1), Phase 3 clinical trials of direct-acting antivirals combined with pegylated interferon (PegIFN) plus ribavirin have achieved sustained virological response (SVR) rates of up to 89%.[1–5] However, PegIFN-based regimens are associated with serious side effects and toxicity-related premature discontinuations, and have a number of contraindications.[1–6]
The Phase 2b SOUND-C2 trial assessed the efficacy and safety of the interferon-free combination of once daily faldaprevir (an NS3/4A protease inhibitor) plus either twice or three times daily deleobuvir (BI 207127, a non-nucleoside NS5B polymerase inhibitor) with and without ribavirin for 16, 28 or 40 weeks in treatment-naïve patients infected with HCV GT-1. The regimen of deleobuvir 600 mg twice daily for 28 weeks was the most effective, driven by a favourable tolerability profile, with 43% of patients with GT-1a infection and 85% of patients with GT-1b infection achieving SVR 12 weeks after completion of therapy (SVR12). Rates of SVR12 were similar for the combination of faldaprevir, deleobuvir three times daily, and ribavirin irrespective of treatment duration (52–59%) but were lower in the arm without ribavirin (39%), indicating ribavirin is an important component of this regimen.
GT-1a-infected patients had lower SVR12 rates than GT-1b-infected patients in all arms of the SOUND-C2 study. However, an impact of the IL28B CC genotype (rs12879860) was observed in GT-1a-infected patients. Patients with the unfavourable IL28B CT and TT genotypes achieved low SVR12 rates (32–42% across the ribavirin-containing arms), while patients with the favourable IL28B CC genotype achieved response rates similar to those in GT-1b-infected patients (75% vs. 85%, respectively, in the ribavirin-containing twice-daily arm).[7,8]
While the SOUND-C2 study examined different drug combinations and different treatment durations, it did not examine the better tolerated twice-daily deleobuvir regimen at the shortest treatment duration (16 weeks). To inform the design of Phase 3 studies, we assessed the safety and efficacy of a 16-week regimen of daily faldaprevir, twice-daily deleobuvir and weight-based ribavirin in GT-1a-infected patients with the IL28B CC genotype, and in GT-1b-infected patients with any IL28B genotype.
Materials and MethodsStudy DesignThe SOUND-C program (clinicaltrials.gov, NCT01132313) consisted of three distinct parts, with the results of Parts 1 and 2 (SOUND-C1 and -C2) described previously.[7,9,10]
Part 3 (SOUND-C3) was a multicentre, open-label Phase 2b study. Patients with HCV GT-1a infection with the IL28B CC genotype or patients with HCV GT-1b infection (any IL28B genotype) were assigned to an exploratory treatment regimen of 16 weeks of combination therapy with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and ribavirin 1000 mg/day (<75 kg body weight) or 1200 mg/day (≥75 kg). The number of GT-1b patients was limited to 20.
Plasma HCV RNA levels were measured using the quantitative Roche COBAS® Taqman HCV/HPS assay and HCV RNA levels <25 IU/ml were analysed and reported as target detected or target not detected (TND).
Viral breakthrough was defined as a confirmed increase in HCV RNA: two consecutive measurements of HCV RNA ≥25 IU/ml in those with HCV RNA previously <25 IU/ml or ≥1 log10 IU/ml increase in those with HCV RNA previously ≥25 IU/ml. Relapse was defined as HCV RNA ≥25 IU/ml after HCV RNA <25 IU/ml TND at the end of planned treatment.
Patients who discontinued treatment because of lack of antiviral activity or an adverse event (AE) while receiving combination therapy were switched to PegIFNα-2a and ribavirin. Patients with HCV RNA <25 IU/ml TND who discontinued early after completing at least 12 weeks of combination therapy were switched to PegIFN and ribavirin only after documented virological relapse.
HCV GT-1 subtype (1a or 1b) was determined using Bayer Trugene® HCV genotyping assay or VERSANT HCV Genotype 2.0 assay if Bayer Trugene result was inconclusive. IL28B (rs12979860) genotype (CC or non-CC, allelic discrimination) was measured by TaqMan PCR, Applied Biosystems.
The main characteristics of eligible patients have been described previously. Briefly, treatment-naïve patients with chronic HCV GT-1 infection (1a or 1b), aged 18–75 years with compensated liver disease were recruited. Patients who were ineligible for treatment with interferon were included.
Study documentation was approved by the appropriate institutional review board and this study was carried out in accordance with the Declaration of Helsinki (October 1996) and International Conference on Harmonisation guidelines. All patients provided written informed consent before enrolment.
The sponsor designed and conducted this study in collaboration with the principal investigators, monitored this study, collected the data and performed the statistical analysis. The investigators, participating institutions and sponsor agreed to maintain confidentiality of the data. All the authors had access to the data and assume responsibility for the integrity and completeness of the data and for the fidelity of this report to this study protocol.
The primary efficacy endpoint was HCV RNA <25 IU/ml TND 12 weeks after completion of therapy (SVR12). Secondary efficacy endpoints were plasma HCV RNA level <25 IU/ml at Week 4 and 12, and HCV RNA <25 IU/ml TND 4 weeks after completion of all therapy.
HCV RNA was measured on Days 2, 4 and 12, at Week 1, 2, 3, 4 and 6 then every 2 weeks thereafter during treatment and 4, 8, 12, 24, 48 and 96 weeks after the end of treatment.
Biochemical and haematologic assessments were performed at each visit during the treatment and the follow-up periods. AEs were reported using the Division of AIDS (DAIDS) grading system and collected at each treatment visit and 4 weeks after the last dose of study drug. Complete physical examinations were performed at the screening visit, Week 4, Week 12 and the end of treatment visit and targeted physical examinations at each of the other study visits. An independent data and safety monitoring committee conducted regular planned reviews of the safety data.
No formal hypothesis testing was planned. The primary efficacy and safety analyses were based on the intent-to-treat population (all randomized patients who took at least one dose of study medication were included). The proportions of patients with plasma HCV RNA level <25 IU/ml TND was calculated and compared. To analyse the 4-week on-treatment results, one interim analysis was conducted after all patients had completed Week 4.
Of the 32 patients included in the trial, 12 were infected with GT-1a and 20 with GT-1b. Baseline patient demographics (other than IL28B genotype) and disease characteristics were similar between the two groups (Table S1
Over the first 2 weeks of treatment, no difference was observed in HCV RNA decline between patients with GT-1a (IL28B CC) and GT-1b (Fig. S1 http://onlinelibrary.wiley.com/store/10.1111/liv.12693/asset/supinfo/liv12693-sup-0001-FigS1.jpg?v=1&s=365db0317490ae81ffb1d71cb3572187b2762659). However, SVR12 rates were only 17% in patients infected with GT-1a but 95% in patients infected with GT-1b (Table 1).
Among the patients with GT-1a infection who did not achieve SVR12, one patient withdrew consent, one patient failed to achieve undetectable HCV RNA by Week 8, three patients had virological breakthrough, four had relapse and one discontinued because of an AE (moderate pruritus) on Day 98 (Table 1 and Fig. S2 http://onlinelibrary.wiley.com/store/10.1111/liv.12693/asset/supinfo/liv12693-sup-0002-FigS2a.jpg?v=1&s=1ee7dcf6c796797a550452c4f43b036115871756 http://onlinelibrary.wiley.com/store/10.1111/liv.12693/asset/supinfo/liv12693-sup-0003-FigS2b.jpg?v=1&s=3ff9575cb4bc3f7e35687af8beba6d2945b24bcc). Of patients with GT-1b infection, none had breakthrough or relapse. Two patients discontinued treatment early because of AEs: one patient on Day 41 (vomiting) and the other on Day 69 (dehydration). Both had HCV RNA <25 IU/ml TND at the time of discontinuation and at the end of treatment. The first patient achieved SVR12 and the second had HCV RNA detected during follow-up (Table 1 and Fig. S2 http://onlinelibrary.wiley.com/store/10.1111/liv.12693/asset/supinfo/liv12693-sup-0002-FigS2a.jpg?v=1&s=1ee7dcf6c796797a550452c4f43b036115871756 http://onlinelibrary.wiley.com/store/10.1111/liv.12693/asset/supinfo/liv12693-sup-0003-FigS2b.jpg?v=1&s=3ff9575cb4bc3f7e35687af8beba6d2945b24bcc). Four GT-1b-infected patients with cirrhosis were included in this study; all of them achieved SVR12.
Among the 32 treated patients, the most common AEs were nausea, vomiting and fatigue. Four patients experienced severe AEs, two of whom discontinued therapy; one patient had dehydration as a serious AE (associated with prerenal failure) and the other patient discontinued because of vomiting and a severe gastrointestinal disorder. One patient discontinued treatment because of moderate pruritus (Table 2). Four (13%) patients had rash and five (16%) patients had photosensitivity reactions. One case of photosensitivity was of moderate intensity but all other skin events were classified as mild, and none led to treatment discontinuation.
The median [interquartile range (IQR)] reduction in haemoglobin levels from baseline to the last value on treatment was 2.6 (1.8–3.6) g/dl; haemoglobin ≤10 g/dl and ≤8.5 g/dl was reported in seven (22%) and one (3%) patients respectively. Median (IQR) platelet levels increased from baseline to the last value on treatment [36 (–6–80) × 109/L]. Of the 14 patients who had bilirubin >2.6 times the upper limit of normal (ULN, ≥ DAIDS Grade 3; Table S2 http://onlinelibrary.wiley.com/store/10.1111/liv.12693/asset/supinfo/liv12693-sup-0004-TblS1-S2-FigLegends.docx?v=1&s=d1beff8dc6c7d2cba79f44dd15423ad8d92b7234), three patients had bilirubin >5 times the ULN (DAIDS Grade 4). All patients with elevated bilirubin had a predominance of unconjugated bilirubin and none had a concomitant alanine transaminase or aspartate aminotransferase elevation. Six (19%) patients had jaundice reported as an AE. One patient experienced severe neutropenia not considered to be related to study medication; this patient had received metamizole (dipyrone) for the treatment of epigastric pain from Day 14 to Day 22 and neutropenia was seen at visits on Days 30, 44 and 58. The neutrophil count returned to normal levels during uninterrupted treatment with faldaprevir, deleobuvir and ribavirin by Day 90.
In this Phase 2b study of treatment-naïve patients with HCV GT-1 infection, the interferon-free combination of faldaprevir, deleobuvir and ribavirin for 16 weeks was highly efficacious in patients infected with GT-1b, with 95% (19/20) achieving SVR12 including all four patients with compensated cirrhosis. The one patient with GT-1b infection who did not achieve SVR12 completed only nine of the 16 weeks of treatment. In contrast, 17% of patients with GT-1a infection and IL28B CC genotype achieved SVR12.
In SOUND-C2, 6/8 (75%) patients with an IL28B CC genotype and GT-1a infection achieved an SVR12 after 16 weeks of treatment with a ribavirin-containing combination of faldaprevir and twice-daily deleobuvir. In the present study, the SVR12 rate in GT-1a-infected patients was much lower (17%); however, caution should be exercised when comparing these results because of the small sample size and the possible imbalance of baseline factors. In addition, the SOUND-C3 study did not include a double induction dose of deleobuvir, while the SOUND-C2 study did. Nevertheless, the high relapse rate seen among GT-1a patients after 16 weeks of treatment in SOUND-C3 (71%) is consistent with the results from SOUND-C2 (41%).
The AE profile for the combination of faldaprevir, deleobuvir and ribavirin was in line with the findings of the twice-daily regimen in SOUND-C2: gastrointestinal and skin events were the most common but were predominantly mild and manageable. All rash and photosensitivity events were mild. The overall frequency and severity of AEs were comparable with those reported for other all-oral combinations.[12,13] Discontinuations for AEs (9%) were more frequent than reported for other all-oral combinations (2–5%)[12,13] but less frequent than reported for PegIFN-based triple therapy (13–14%).[14,15] No patients discontinued because of elevated bilirubin and no patient with elevated bilirubin had other signs of liver injury. The reduction in haemoglobin was expected as ribavirin was included in the treatment regimen.
In conclusion, this small Phase 2b study demonstrated that the interferon-free combination of faldaprevir, deleobuvir and ribavirin had an acceptable AE profile and was efficacious in treatment-naïve patients infected with HCV GT-1b. These results supported Phase 3 evaluation of this regimen in patients with GT-1b infection, including patients with cirrhosis. These results add to the growing body of evidence showing that patients with advanced liver disease can be cured from hepatitis C with shorter and better tolerated regimens than those that are interferon based.
- Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–87.
- Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.
- Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–206.
- Ferenci P, Asselah T, Foster GR, et al. Faldaprevir plus pegylated interferon alfa-2a and ribavirin in chronic HCV genotype-1 treatment-naive patients: final results from STARTverso1, a randomised, double-blind, placebo-controlled phase III trial. J Hepatol 2013; 58: S569–70.
- Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2014; doi: 10.1016/S0140-6736(14)60494-3. [Epub ahead of print].
- Ogawa E, Furusyo N, Kajiwara E, et al. Evaluation of the adverse effect of premature discontinuation of pegylated interferon a-2b and ribavirin treatment for chronic hepatitis C virus infection: results from Kyushu University Liver Disease Study. J Gastroenterol Hepatol 2012; 27: 1233–40.
- Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med 2013; 369: 630–9.
- Zeuzem S, Soriano V, Asselah T, et al. SVR4 and SVR12 with an interferon-free regimen of BI201335 and BI207127, +/- ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: interim results of SOUND-C2. J Hepatol 2012; 56: S45.
- Zeuzem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 2011; 141: 2047–55.
- Zeuzem S, Asselah T, Angus P, et al. Faldaprevir (BI 201335), deleobuvir (BI 207127) and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results. Antivir Ther 2013; 18: 1015–9.
- McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology 2010; 138: 2307–14.
- Kumada H1, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59: 2083–91.
- Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment- naive patients: the COSMOS randomised study. Lancet 2014; doi: 10.1016/S0140-6736(14)61036-9. [Epub ahead of print]
- Merck Sharp & Dohme Corp. Victrelis (boceprevir) prescribing information, Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA. Revised February 2013. (accessed 3 September 2014).
- Vertex Pharmaceuticals Inc. Incivek (telaprevir) prescribing information, Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA. Revised April 2013. (accessed 3 September 2014).