Pan-genotypic regimen for HCV effective in eight weeks for the majority of patients1
1. Puoti M. High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: an integrated analysis of HCV genotype 1–6 patients without cirrhosis. J Hepatol. 2018 Aug;69(2):293-300
Clinical studies
SURVEYOR 1 and 2: Phase II registration clinical study1
Methods.
SURVEYOR-I and SURVEYOR-II are dose-ranging (dosimetry), multicenter, open-label phase II studies that include patients with genotype 1-6 HCV infection not previously treated or previously treated with pegylated interferon plus ribavirin. Patients received a single administration of glecaprevir/pibrentasvir at different doses with or without ribavirin for 8 or 12 weeks.
*includes two patients who received GLE 200 mg + PIB 120 mg for 12 weeks
GLE: glecaprevir; HCV: hepatitis C virus; PIB: pibrentasvir; RBV: ribavirin; SVR4: Sustained virologic response at four weeks; SVR12: Sustained virologic response at 12 weeks; SVR12, mITT: sustained virologic response at one week, modified Intention to Treat.
Conclusions.
Glecaprevir plus pibrentasvir was well tolerated and led to an elevated rate of sustained virologic response in cirrhotic patients with genotype 1-6 HCV infection treated for 8 or 12 weeks.
The combination of glecaprevir/pibrentasvir, direct-acting antivirals, is an oral pan-genotypic treatment in a single administration for genotype 1-6 HCV infection. The article reports the results of the phase II study that analyzed a wide range of doses in 449 non-cirrhotic patients on treatment for 8 or 12 weeks.
Bibliography:
1. Kwo P.Y, Poordad F. et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. Journal of Hepatology 2017 vol. 67, 263-271. doi: http://dx.doi.org/10.1016/j.jhep.2017.03.039
SURVEYOR-II Part 3: Phase III registration clinical study2
SURVEYOR-II Part 3 is a partially randomized, multicenter phase 3 study that evaluated the effectiveness and safety of glecaprevir/pibrentasvir (G/P) in adult patients with chronic infection from the genotype 3 hepatitis C virus, including patients with compensated cirrhosis and/or those previously treated for HCV. In total 189 patients were analyzed and enrolled in the study, 132 patients with genotype 3 HCV infection, and 131 began treatment.
Study design.
The non-cirrhotic previously treated patients were randomized 1:1 to receive treatment with glecaprevir (GLE) - developed by Abbvie and Enanta - for 12 or 16 weeks and co-formulated with pibrentasvir (PIB) [G/P]. Treatment-naïve patients or those with compensated cirrhosis who were previously treated received G/P for 12 or 16 weeks, respectively. All patients received 3 tablets containing 100 mg/40 mg once a day by mouth, for a total dose of 300 mg/120 mg.
Treatment-naïve patients with compensated cirrhosis were treated with G/P for 12 weeks; patients with compensated cirrhosis who had been previously treated were treated for 16 weeks.
HCV: hepatitis C virus; CI: Confidence interval; GLE (G): glecaprevir; PIB (P): pibrentasvir; SVR12: Virologic response at 12 weeks post-treatment
Overall, the efficacy results from this study demonstrate that glecaprevir/pibrentasvir by mouth is a direct antiviral treatment with an elevated cure rate that does not require the co-administration of ribavirin in patients with genotype 3 HCV infection, independent of other typical negative predictive factors of response such as previous treatment experience or compensated cirrhosis.
TAKE HOME MESSAGES
- The SURVEYOR-II study, Part 3 enrolled and treated several of the patients with HCV infection who were most difficult to treat: those with genotype 3 and/or cirrhotic previously treated patients.
- Overall, the fixed-dose combination of glecaprevir/pibrentasvir without ribavirin in a single administration was well tolerated and demonstrated an elevated rate of SVR12 (95%) in cirrhotic treatment-naïve patients treated for 12 weeks and in cirrhotic and non-cirrhotic previously treated patients treated for 16 weeks.
- Glecaprevir/pibrentasvir thus provides a treatment option in a single administration without ribavirin, which is effective and well tolerated in patients with genotype 3 HCV infection and/or previously treated cirrhotic patients.
Bibliography:
2. Wyles D., Poordad F. et al. Glecaprevir/Pibrentasvir for Hepatitis C Virus Genotype 3 Patients With Cirrhosis and/or Prior Treatment Experience: A Partially Randomized Phase 3 Clinical Trial. Hepatology. Vol. 67, No.2, 2018.
doi: doi/10.1002/hep.29541
SURVEYOR II, Part 4 - ENDURANCE-4 - ENDURANCE-2: Phase III registration clinical studies3
Methods
SURVEYOR-II, Part 4 and ENDURANCE-4 studies: untreated or previously treated non-cirrhotic adult patients with genotype 2, genotype 4, genotype 5, or genotype 6 HCV infection, who received glecaprevir/pibrentasvir once a day by mouth (n=121 in ENDURANCE-4 and n=145 in SURVEYOR-II) for 12 or 8 weeks respectively. ENDURANCE-2 study: untreated or previously treated non-cirrhotic adult patients with genotype 2 HCV infection were assigned randomly (2:1) to groups that received glecaprevir/pibrentasvir once a day by mouth (n=202; 300 mg/120 mg) or placebo (n=101) for 12 weeks.
Primary endpoint
Sustained virologic response at 12 weeks post treatment (SVR12) in the intention-to-treat (ITT) population.
HCV: hepatitis C virus; ITT: Intention to Treat; SVR12: Sustained virologic response at 12 weeks post-treatment.
Effectiveness of G/P treatment
ENDURANCE-2
- In patients with genotype 2 HCV infection, naïve to treatment with SOF, G/P for 12 weeks achieved a rate of SVR12 of 99%
- The six patients previously treated with SOF excluded from the primary analysis, all with SVR12 rate achieved, had an overall SVR12 of 99.5%
ENDURANCE-4
- The overall rate of SVR12 in patients with genotype 4 HCV infection (n=76), 5 (n=26) or 6 (n=19) treated for 12 weeks was 99%
SURVEYOR-II, Part 4
- The rate of SVR12 in patients with genotype 2 HCV infection treated for eight weeks was 98%.
- Five of the six patients previously treated with SOF for eight weeks achieved the rate of SVR12.
G/P: glecaprevir/pibrentasvir HCV: hepatitis C virus; SVR12: Sustained virologic response at 12 weeks post-treatment; SOF: sofosbuvir
AE: adverse events; G/P: glecaprevir/pibrentasvir; GT1: genotype 1; GT2: Genotype 2; GT4-6: genotype 4-6; HCV: hepatitis C virus; mITT: Modified intention to treat; SOF: sofosbuvir; SVR12: Sustained virologic response at 12 weeks post-treatment
G/P: glecaprevir/pibrentasvir; HCV: hepatitis C virus; SVR12: Sustained virologic response at 12 weeks post-treatment
Bibliography:
3. Asselah T., Kowdley K.V., et al. Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients with HCV Genotype 2, 4, 5, or 6 Infection Without Cirrhosis. Clinical Gastroenterology and Hepatology (2017). doi: 10.1016/j.cgh.2017.09.027.
MAGELLAN-I: Phase II registration clinical study1
Overview of the study
MAGELLAN-1 is a multicenter, open-label, randomized, phase 2 study that evaluated the effectiveness and safety of glecaprevir/pibrentasvir in patients with genotype 1 HCV infection previously treated with direct antivirals.
HCV: hepatitis C virus
For the ITT and mITT population individual rates of SVR12 are provided for arm A (blue), arm B (green) and arm C (light blue). All patients in the ITT population received at least one dose of the study drug (n=50), while the mITT population did not include any patients who had failed to achieve SVR for reasons other than virologic failure. The vertical lines represent CI 95% evaluated using the Wilson score method. In both patients lost at follow-up HCV RNA was not detectable eight weeks post-treatment.
GLE: glecaprevir; CI: confidence interval; ITT: Intention To Treat; LTFU: lost at follow-up; mITT: Modified Intention To Treat; PIB: pibrentasvir; RBV: ribavirin; SVR12: Sustained virologic response at 12 weeks post-treatment
Bibliography:
1. Poordad F., Felizarta F. Et al. Glecaprevir and Pibrentasvir for 12 Weeks for Hepatitis C Virus Genotype 1 Infection and Prior Direct-Acting Antiviral Treatment. Hepatology, Vol. 66, No. 2, 2017. DOI 10.1002/hep.29081
MAGELLAN 1 part 2: Phase II registration clinical study 2
Methods
MAGELLAN-1, Part 2 is a phase 3, open-label, randomized study that evaluated the effectiveness and safety of glecaprevir/pibrentasvir treatment (G/P; 300 mg/120 mg) without ribavirin (RBV) in patients with chronic HCV infection who had no response to a previous regimen containing a NS5A inhibitor and/or a NS3/4A. inhibitor.
Conclusions
16 weeks of treatment with G/P led to an elevated rate of SVR12 in patients with genotype 1 HCV infection and who had no response to a previous regimen containing a NS5A and/or NS3 inhibitor. Patients naïve to treatment with NS5A inhibitor who had no response to a previous regimen with NS3/4A inhibitor (e.g. boceprevir, telaprevir and simeprevir) had a rate of SVR12 of 100%, independent of treatment duration. In this study, the combination of G/P without RBV was shown to be safe and well tolerated, independent of the duration of treatment (12 or 16 weeks).
G/P: glecaprevir/ pibrentasvir; GT1: genotype 1; HCV: hepatitis C virus; RBV: ribavirin; SVR12: sustained virologic response at 12 weeks post-treatment
Bibliography:
2. Poordad F., Pol S. et al. Glecaprevir/Pibrentasvir in Patients with HCV Genotype 1 or 4 and Prior Direct-acting Antiviral Treatment Failure.
doi: 10.1002/hep.29671
In total, 1,280 patients were treated. The sustained virologic response rate at 12 weeks in patients with genotype 1 HCV infection was 99.1% (CI 95%, 98 to 100) in the 8-week group and 99.7% in the 12-week group.
Patients with genotype 3 HCV infection who were treated for 12 weeks with glecaprevir-pibrentasvir achieved a response rate at 12 weeks of 95% (CI 95%, 93 to 98; 222 of the 233 patients) and 97% (CI 95%; 93 to 99.9; 111 of 115) for those on treatment with sofosbuvir-daclatasvir; treatment with glecaprevir-pibrentasvir for eight weeks demonstrated a rate of 95% (CI 95%; 91 to 98; 149 of 157 patients).
Treatment with glecaprevir-pibrentasvir in a single administration for 8 or 12 weeks achieved elevated rates of sustained virologic response in patients with genotype 1 or 3 HCV infection who did not have cirrhosis.
HCV: hepatitis C virus; Confidence Interval
HCV: hepatitis C virus; SVR12: Sustained virologic response at 12 weeks post-treatment Surveyor Magellan Endurance Expedition RWE Navigator II RWE Mistral
Bibliography:
1. Zeuzem S., Foster G.R. et al. Glecaprevir–Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection. N Engl J Med 2018;378:354-69. DOI: 10.1056/NEJMoa1702417
Study design
ITT: Intention-to-treat
* Both patients reached the sustained virologic response rate at 12 weeks post-treatment
The study enrolled 146 patients with compensated cirrhosis including:
- 48 (33%) patients with genotype 1a HCV infection
- 39 (27%) patients with genotype 1b HCV infection
- 34 (23%) patients with genotype 2 HCV infection
- 16 (11%) patients with genotype 4 HCV infection
- 2 (1%) patients with genotype 5 HCV infection
- 7 (5%) patients with genotype 6 HCV infection
HCV: hepatitis C virus
The majority of patients were white males and naïve to treatment. Of the 36 previously treated patients, 25 (69%) experienced virologic failure with the previous treatment containing interferon or pegylated interferon with or without ribavirin, while 11 (31%) had experienced virologic failure with a previous treatment containing sofosbuvir plus ribavirin with (n=2) or without (n=9) pegylated interferon.
HCV: hepatitis C virus; CI: Confidence interval; ITT: Intention-to-treat; SVR12: Sustained virologic response at 12 weeks post-treatment
The rate of SVR12 was demonstrated for each genotype and the total population.
The error bars (shown only for the groups with more than ten patients) are CI 95% of the Wilson score at 95% on two sides. The exact number of patients who reached SVR12 were 89 of 90 with genotype 1 HCV infection, 31 of 31 with genotype 2 infection, 16 of 16 with genotype 4 infection, 2 of 2 with genotype 5, 7 of 7 with genotype 6 and 145 of 146 patients total.
Bibliography:
1. Forns X., Lee S.S. et al., Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017. www.thelancet.com/infection - Published online August 14, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30496-6
EXPEDITION-II: Phase III registration clinical study2
Background
The single administration of glecaprevir in combination with pibrentasvir (glecaprevir/pibrentasvir) demonstrated elevated rates of sustained virologic response at 12 weeks after treatment (SVR12) in patients with genotype 1-6 hepatitis C virus infection (HCV) and co-infection from HIV-1, including patients with compensated cirrhosis.
Methods
The EXPEDITION-2, open-label, multicenter, phase 3 study evaluated treatment with glecaprevir/pibrentasvir (300 mg/120 mg) in adult patients with co-infection from genotype 1-6 HCV/HIV-1 with or without compensated cirrhosis for 8 and 12 weeks respectively.
Conclusions
Glecaprevir/pibrentasvir, administered for eight weeks in non-cirrhotic patients and for 12 weeks in cirrhotic patients, is a highly effective and well tolerated treatment for HCV/HICV-1 [sic: HIV-1] co-infection, independent of the viral load of HCV or previous treatment with interferon or sofosbuvir. The elevated rates of SVR achieved with oral therapy and a single administration of glecaprevir/pibrentasvir in patients co-infected by HCV/HIV-1, were similar to those obtained in patients with a HCV infection alone.
HCV: hepatitis C virus; HIV: human immunodeficiency virus; SVR12: Sustained virologic response at 12 weeks post-treatment.
Bibliography:
2. Rockstroh J.K, Lacombe K. et al. Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients Co-infected with Hepatitis C Virus and Human Immunodeficiency Virus-1: the EXPEDITION-2 Study. ©The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. DOI: doi/10.1093/cid/ciy220/4939381
EXPEDITION-IV: Phase III registration clinical study3
Background
Chronic hepatitis (from the hepatitis C virus) occurs more frequently in patients with chronic renal disease than those without. Patients with chronic renal disease with HCV infection are more at risk of progression towards the terminal stage of renal disease than those with chronic renal disease but no HCV infection. Patients with chronic renal disease associated with HCV infection have limited treatment options.
Results
Of the 104 patients enrolled in the study, 52% had a genotype 1 HCV infection, 16% had genotype 2, 11% genotype 3, 19% genotype 4 and 2% genotype 5 or 6. The rate of sustained virologic response was 98% (102 of 104 patients; CI 95%, 95 to 100).
Conclusions
Treatment with glecaprevir and pibrentasvir for 12 weeks achieved an elevated rate of sustained virologic response in patients with stage 4 or 5 chronic renal disease and HCV infection.
Many direct-acting antiviral regimens are not recommended for patients with advanced renal failure. Treatment without ribavirin, a combination with glecaprevir and pibrentasvir, led to an elevated virologic response rate; no patients experienced virologic failure, independent of the HCV genotype, presence or absence of cirrhosis or other baseline factors.
HCV: hepatitis C virus; CI: Confidence Interval
Bibliography:
3. Gane E., Lawitz E. et al. Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment. N Engl J Med 2017;377:1448-55. DOI: 10.1056/NEJMoa1704053
°89% of patients treated at eight weeks
**includes data on all patients treated with DAA in Lombardy starting in December 2014. This study analyzed all HCV+ patients treated with MAVIRET between October 2017 and January 2018
G/P = Glecaprevir/Pibrentasvir
Multicenter study to evaluate the effectiveness and safety of MAVIRET
Bibliography:
1. D’Ambrosio et al. Real-life effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C. JHEPAT 7163. https://doi.org/10.1016/j.jhep.2018.11.011
Endpoints:
• Effectiveness of treatment with GLE/PIB
• Safety
Conclusions
The MISTRAL study demonstrated the effectiveness of treatment with GLE/PIB in a real-life context in an area of southern Italy with a high rate of HCV. Significant differences were detected in the distribution of the genotype between subgroups of the most difficult to treat patients including those who use drugs.
G/P: glecaprevir/pibrentasvir; HCV: hepatitis C virus; PWID: patients who inject drugs.
Bibliography:
1. Persico M., Aglitti A. et al. Real-life glecaprevir/pibrentasvir in a large cohort of patients with hepatitis C virus infection: The MISTRAL Study. doi: 10.1111/liv.14170
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