A triple regimen
containing two experimental hepatitis C drugs – AL-335 and odalasvir –
simeprevir taken for either 6 or 8 weeks cured all participants with
previously untreated genotype 1 hepatitis C 1 who did not have cirrhosis
in a small study, while
a dual regimen without simeprevir cured 90%, according to findings
presented last month at New Perspectives in Hepatitis C Virus Infection – The
Roadmap for Cure in Paris. The conference was organised by the European Association for the Study of the Liver (EASL).
Direct-acting antiviral therapy that
combines drugs targeting different steps of the hepatitis C virus (HCV)
lifecycle – usually taken for 12 weeks – is highly effective, but researchers
continue to explore new combinations that can be used for a shorter duration,
thereby improving convenience and reducing cost. Ideally such therapy would be
pangenotypic, meaning it is active against all HCV genotypes and can be used
throughout the world without the need for prior genotypic testing.
Edward Gane of the University of Auckland and
colleagues evaluated the pharmacokinetics, safety and efficacy of regimens
containing the investigational HCV polymerase
inhibitor AL-335, being developed by Alios BioPharma (a subsidiary of Janssen),
Achillion's pangenotypic second-generation NS5A inhibitor odalasvir (formerly
ACH-3012) and Janssen's approved HCV protease inhibitor simeprevir (Olysio).
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
of a Latin term meaning once every day.
Early studies of AL-335 demonstrated
potent antiviral activity even against drug-resistant HCV, and viral load
reductions of up to 4.8 log10 IU/ml in a 7-day monotherapy study. In
2014 Prof. Gane reported high cure rates in a phase
2 trial evaluating odalasvir plus Gilead Sciences' approved HCV polymerase
inhibitor sofosbuvir (Sovaldi) in people with previously untreated genotype 1 HCV.
The current ongoing phase 2a study will include
up to 16 cohorts of 20 participants each, testing various dosing regimens of AL-335 plus odalasvir, with or without simeprevir,
taken for 6 or 8 weeks.
Last week's presentation covered the
first four cohorts, which enrolled an easier-to-treat population of people with previously
untreated genotype 1 HCV without liver cirrhosis. People with genotype 3
and those with compensated cirrhosis are included in later cohorts.
This interim analysis included 80 people with
chronic hepatitis C who had not taken hepatitis C treatment before
(treatment naive). About two-thirds were men, most were white and
the mean age was about 53 years. About 80% had harder-to-treat HCV
the rest 1b, with a mean baseline HCV viral load of about 6.2 log10
IU/ml. The average FibroScan liver
stiffness score was approximately 6.0 kPa, suggesting mostly mild to moderate
Participants in this open-label study received AL-335
at doses of 400 or 800mg once-daily (QD), odalasvir at 50mg once-daily or
every-other-day (QOD), and simeprevir at 75 or 100mg once-daily. They were
allocated to four cohorts:
- Cohort 1:
AL-335 400mg QD + odalasvir 50mg QD + simeprevir 100mg QD for 8 weeks;
- Cohort 2:
AL-335 800mg QD + odalasvir 50mg QOD for 8 weeks (no simeprevir);
- Cohort 3:
AL-335 800mg QD + odalasvir 50mg QOD + simeprevir 75mg QD for 8 weeks;
- Cohort 4:
AL-335 800mg QD + odalasvir 50mg QOD + simeprevir 75mg QD for 6 weeks.
In the three cohorts receiving triple therapy, 100% of
participants achieved sustained virological response at 12 weeks after
completing treatment (SVR12).
In the dual therapy cohort that did not receive
simeprevir, the SVR12 rate fell to 90%. The two people who experienced relapse in this cohort developed
NS5A mutations that confer resistance to odalasvir.
Treatment was generally safe and well tolerated. There
was one serious adverse event leading to treatment discontinuation: an
atrioventricular block (a type of heart rhythm abnormality) considered probably
related to the study drugs.
A majority of adverse events were mild, with the most
common being headache (18 reports), fatigue (15), respiratory tract infections
(11) and bruising (9). There were few grade 3 or higher laboratory
abnormalities and no clinically relevant echocardiogram changes.
Based on these findings, the researchers concluded
that AL-335 + odalasvir with or without simeprevir “was highly effective in
treatment-naive patients with HCV genotype 1 without cirrhosis”. They added
that these results support evaluation of triple combinations in people with
genotype 3 or cirrhosis.
A larger phase 2b trial (NCT02765490) evaluating 800mg AL-335 + 25mg odalasvir + 75mg simeprevir, all once-daily for 6 or 8
weeks, is expected to begin enrolment this autumn for treatment-naive and
treatment-experienced people without cirrhosis who have HCV genotypes 1, 2, 4, 5 and