—Alan Franciscus, Editor-in-Chief
drugs in clinical development to treat hepatitis C. It was a very busy
month, with two studies published in the prestigious New England Journal of Medicine—AbbVie
and Gilead/BMS. Other news included the approval of Sovaldi in Europe
and BMS’s European submission for approval of their HCV medication.
In addition there were preliminary results from a couple of
cross-company trials. I think, however, that the most fascinating news
of the month is about a drug that may cure hepatitis C with just one
infusion—at least that is what the study will eventually evaluate in
people with HCV.
AbbVie’s HCV interferon-free combination therapy is
currently in Phase 3 studies. The article that appeared in the New England Journal of Medicine gives the final results from their Phase 2b study.
ABT-450/r (protease inhibitor)boosted with ritonavir,
ABT-333 (polymerase inhibitor) or ABT-267 (NS5A inhibitor) or both,
Ribavirin (one arm did not contain ribavirin)
8, 12, or 24 weeks.
14 treatment arms—total of 571 patients
Genotype 1, treatment naïve & treatment experienced—no patients had cirrhosis
88% among those who received the therapy for 8 weeks
95% among those who received the therapy for 12 weeks
83% to 100% among all the groups including treatment -naïve and treatment-experienced patients.
(side effects) were fatigue, headache, nausea, and insomnia. The cure
rates were similar among people who had positive and negative
predictors of treatment response (HCV subtype 1a, race, HCV RNA, non-cc
discontinued treatment due to adverse events (side effects). ABT-450/r
and ABT-267 were dosed once daily; ABT-333 and ribavirin were dosed
The high response rates and shorter treatment
duration all point to a very effective therapy to treat hepatitis C.
Although this was a Phase 2b study, the fact that this trial had a
large patient population with similar cure rates among all groups is
significant. In fact, the Phase 3 studies that have been released so
far have reported similar cure rates.
The final results from a clinical trial of the
combination of sofosbuvir and daclatasvir (with and without ribavirin)
was also published in the New England Journal of Medicine.
Daclatasvir (NS5A inhibitor)
Sofosbuvir (polymerase inhibitor)
Ribavirin (included study arms with and without ribavirin)
12 – 24 weeks (some patients received 1 week lead-in with sofosbuvir followed by 23 weeks with daclatasvir/sofosbuvir)
10 groups – 211 patients
Genotype 2 = 26 patients
Genotype 3 = 18 patients
Genotype 1 (treatment naïve) = 126 patients
Genotype 1 (treatment
experienced) = 41 patients—prior treatment experienced patients who
were previously treated with HCV protease inhibitors (boceprevir or
Genotype 1 treatment naïve = 98%
Genotype 1 treatment experienced = 98%
Genotype 2 treatment naïve = 92%
Genotype 3 treatment naïve = 89%
treatment response (genotype 1a, and 3, non-CC Il28B genotype, race)
did not affect the cure rates. The cure rates were also similar between
the groups that did and did not receive ribavirin. Both drugs are
This study has been the focus of a lot of noise in
2013. While the study has a relatively small patient population the
cure rates are very impressive. Below I have listed the recently
announced Phase 3 studies of daclatasvir and sofosbuvir (with and
without ribavirin) that BMS is sponsoring.
ALLY 1: daclatasvir and
sofosbuvir with and without ribavirin for 12 weeks. The study has 4
arms that will include genotypes 1 through 6 to test the drugs in
people with cirrhosis who may need a liver transplant.
ALLY 2: daclatasvir and
sofosbuvir for 12 weeks to treat HCV in people who are coinfected with
HIV—treatment naïve and treatment experienced. The trial will include
genotypes 1 through 6.
ALLY 3: daclatasvir and
sofosbuvir for 12 weeks to treat HCV genotype 3. The study will include
treatment-naïve and treatment-experienced patients.
BMS & Vertex
The first data from a Phase 2a study of the
combination of Vertex’s VX-135 (200 mg) plus daclatasvir for 12 weeks to
treat HCV treatment-naïve patients were released. Eighty-three percent
(83%—10 of 12 patients) achieved an SVR4.
first dose due to a serious adverse event of vomiting/nausea, but the
majority of the adverse events reported were mild.
produced SVR4 results of 73% (8 of 11 patients).
The preliminary data (SVR4) from a small study of 150
mg simeprevir, 50 mg samatasvir (IDX719) and ribavirin were released.
In this part of the study, HCV genotypes 1b and 4 (treatment-naïve,
non-cirrhotic patients) were treated with the triple combination for 12
weeks. Eighty-five percent (85%—17 of 20 patients) achieved SVR4.
Both drugs are dosed once-daily.
arms contained the triple therapy but the dose of samatasvir was either
50, 100 or 150 mg—those results have not yet been released.
Simeprevir and samatasvir are dosed once daily.
Probably the most fascinating news item that I have
seen in quite a while was a recent news release about a new therapeutic
technology that hopes to cure hepatitis C (and other diseases) with one
shot! The technology is based on gene-silencing. The drug is named
TT-034 and it is infused once. The first in-human trial of TT-034 has
been cleared by the Food and Drug Administration (FDA) for human
medicine is infused into the body—it will travel through the
bloodstream to the liver where it will enter any hepatitis C virus.
Once inside the virus TT-034 releases molecules that interfere with and
stop the hepatitis C virus from replicating. Not only that, but the
medicine will continue to replicate in the liver so that it can prevent
any further HCV from replicating. Now, wouldn’t that be something!
therapy could be the key to curing many diseases including hepatitis B,
HIV and many other potentially life-threatening diseases.
On January 17, 2014 Gilead announced that Sovaldi
combination therapy had been approved by the European Medicines Agency
(EMA) to treat HCV genotype 1 through 6. The EMA also approved
all-oral Sovaldi for HCV patients who can not take interferon and for
those awaiting liver transplantation (to prevent HCV recurrence).
application to the EMA for daclatasvir to treat HCV genotypes 1, 2, 3,
and 4 in Europe. BMS commented that they expect the approval will
enable daclatasvir to be prescribed with other HCV medications….which
drug? Hint – Sovaldi (sofosbuvir).
Boehringer Ingelheim (BI) announced on January 17,
2013 that it had halted the clinical development of
deleobuvir-containing therapies. The company commented that the
combination of deleobuvir (with faldaprevir, ribavirin) was halted
because the combination showed a higher rate of premature
discontinuation of treatment which suggested that the effectiveness is
not comparable to other interferon-free therapies.
BI is currently conducting STARTVerso trials (faldaprevir, pegylated
interferon plus ribavirin) that are expected to be completed soon and
the trial results will be submitted to the Food and Drug Administration
(FDA) for marketing approval.