Faldaprevir, BI 207127 and ribavirin
Boehringer Ingelheim studied the use of treatment
which combined faldaprevir with BI 207127 and ribavirin in different doses over different periods of time.8 The combination
that performed the best was in the group of participants who took faldaprevir
once a day and BI 207127 and ribavirin twice a day over 28 weeks. People with
G1b achieved a cure (SVR24) in 85% of cases but those with G1a only in 43% of
cases. This was the first interferon-free hepatitis C study that also included
people with cirrhosis – 9% of participants in this study had cirrhosis. As this
was only 33 individuals, not many conclusions can be drawn yet as to how
successful this treatment is in people with cirrhosis, but six out of nine
people who had cirrhosis, with G1a or with G1b, were able to eliminate their
hepatitis after 28 weeks of treatment. In the approval studies, this
interferon-free treatment will only be examined in people with G1b; people with
G1a will no longer be included, which may restrict this drug’s applicability.
Sofosbuvir and ribavirin
A year ago, ten out of ten previously untreated people
with G2 or G3 were cured after taking Gilead’s
protease inhibitor sofosbuvir with ribavirin for only twelve weeks. This caused
quite a stir, but hepatitis C is generally easier to treat in people with G2
and G3 who have not taken treatment before.
The hope that this relatively simple treatment regimen
could be effective for all other people with HCV such as people with G1,
especially null responders, has been dashed. In people with G1 being treated for the first time with sofosbuvir and
ribavirin, 84% were cured; in former null responders of genotype 1, however,
nine out of the ten people suffered a relapse shortly after completing
treatment.9 With difficult-to-treat virus, sofosbuvir obviously
needs to be combined with something stronger than ribavirin alone – ideally
another direct-acting antiviral substance.
Sofosbuvir and daclatasvir
A pioneering study was presented at the International
Liver Congress, the annual meeting of the European Association for the Study of
the Liver (EASL), in April 2012. Gilead’s
sofosbuvir, then called GS-7977, was combined with Bristol-Myers Squibb’s
daclatasvir, with and without ribavirin.10 After 24 weeks of
treatment in previously untreated people with genotypes 1, 2 and 3, cure rates
of over 93% were achieved. This was the first time cure rates like this had
been achieved in an interferon-free regimen, and the study received wide
publicity. However, co-operation between the two companies was only maintained
for the period of this study, and combination treatments like this are now
being followed up by both companies independently.
Indeed, what all companies are looking for is an
equally potent and tolerable version of this combination, using their own
drugs. Both sofosbuvir and daclatasvir have good chances of being approved
independently of one another, and so using this combination is not completely
out of the question if both drugs were available, could be combined ‘off-label'
in everyday clinical practice, and were affordable.
Daclatasvir, asunaprevir and BMS-791325
Bristol-Myers Squibb has drugs of three classes in
development and, at the AASLD meeting, reported on a study combining all three:
daclatasvir (an NS5A inhibitor), asunaprevir (a protease
inhibitor) and BMS-791325 (a non-nucleoside polymerase inhibitor), in a combination
therapy without interferon or ribavirin.11 The study treated 32
previously untreated people with genotype 1a or 1b and without cirrhosis for
either 12 or 24 weeks. Excitingly, twelve weeks of treatment with these three
drugs was sufficient to achieve a provisional cure (SVR12) in all 16 people. In
the group treated for 24 weeks, only SVR4 data are available: all are (so far)
virus negative, with one exception which may simply be missing data. Some
people reported headaches, diarrhoea and general weakness but no-one
discontinued the treatment. It is particularly encouraging that genotype 1a saw
the same cure rates.
Sofosbuvir, ledipasvir and ribavirin
Meanwhile, Gilead is
developing its own NS5A inhibitor, ledipasvir or GS-5885, and has started
studies combining it with sofosbuvir. At AASLD, results of a phase II study of these two drugs plus
ribavirin were presented,12 with
25 people with G1 who had not previously taken treatment, and nine people who
were former null responders. Everyone was still virus negative four weeks after
the completion of treatment (SVR4), and at the 20th Conference on Retroviruses
and Opportunistic Infections (CROI 2013) it was reported that all the
participants had achieved a successful SVR12 response.
ABT-450r, ABT-267 and ABT-333 with ribavirin
AbbVie (formerly Abbott Laboratories) also has drugs
of three different classes in development – a ritonavir-boosted protease
inhibitor, a non-nucleoside polymerase inhibitor, and an NS5A inhibitor (see
box). In a study called AVIATOR presented at AASLD, up to three of the new drugs, with or without ribavirin, were
administered over different periods of time.13
Previously untreated people and null responders were
both included in the study, all with G1 and the majority with the particularly
stubborn G1a, though there were no people with cirrhosis in the study. The
treatment duration varied in length depending on the patient group (8 to 24
weeks), and results were available for people treated for only eight to twelve
weeks.
A lot of tablets, relatively short treatment duration
– and impressive results. In 79 people given the three new drugs with ribavirin
for twelve weeks, 77 people (97.5%) treated for the first time had an SVR12 response, as did
42 out of the 45 previous null responders (93.3%).
Just two of the 448 trial participants discontinued
treatment due to side-effects but the virus was still cured despite the
curtailment of the treatment. This combination will soon also be explored in
licensing studies. AbbVie plans to reduce the number of tablets by combining
ritonavir, ABT-450 and ABT-267 into one tablet.