—Alan Franciscus, Editor-in-Chief
In this month’s column I will discuss many news
stories related to HCV drugs in development, including a study from
Japan on Gilead’s combination of sofosbuvir/ledipasvir to treat HCV
genotype 1, and, also from Japan, BMS’s combination of daclatasvir plus
asunaprevir to treat HCV genotype 1b. There is more information from
AbbVie: The 3-D combination to treat HCV genotype 1, the FDA priority
review and AbbVie’s collaboration with OraSure Technologies. Also in
the news was Merck’s acquisition of Idenix and Achillion’s resurrection
of one of their HCV drugs that was on clinical hold and on another
Achillion drug that is about to begin a proof of concept study.
Hepatitis C is a disease with a largely
unmet need for drugs to treat it. But in Japan this need is even more
pressing since the HCV epidemic began earlier there and, as a result,
the impact of hepatitis C on the health system is much worse in Japan
than in the United States and Europe. The newer interferon and
ribavirin-free therapies can slow the expected severe health-care crisis
and prevent deaths related to hepatitis C in Japan. The results from
two studies on interferon and ribavirin-free treatments conducted in
Japan were recently released: Gilead’s ledipasvir plus sofosbuvir and
BMS’s daclatasvir plus asunaprevir.
Gilead reported on a Phase 3 study using a
once-a-day fixed-dose combination of ledipasvir (NS5A inhibitor – 90 mg)
plus sofosbuvir (polymerase inhibitor – 400 mg) with and without
ribavirin. The treatment period was 12 weeks for all groups treated.
All of the patients in the study were genotype 1; 166 treatment- naïve;
175 treatment-experienced; 76 had compensated cirrhosis. The cure
rates (SVR12) are listed below.
The most common side effects in
the non-ribavirin containing arms were nasopharyngitis (inflammation
of the nasal passages), headache and malaise. In the groups that
received ribavirin the additional side effects included anemia,
pruritus (itching) and rash.
100% (83 of 83 pts)
96% (80 of 83 pts)
100% (88 of 88 pts)
100% (87 of 87 pts)
ledipasvir (LDV); sofosbuvir (SOF); ribavirin (RBV)
results with and without ribavirin are excellent. Gilead indicated in
their press release that they plan to submit a New Drug Application to
the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by the
end of 2014.
Bristol-Myers Squibb (BMS) has multiple HCV drug
regimes in clinical development for the treatment of HCV. This article
will discuss the data from a recent article published in Hepatology
on a Phase 3 trial for the treatment of HCV genotype 1b with the
combination of daclatasvir (NS5A inhibitor – 60 mg dosed once-a-day)
plus asunaprevir (HCV protease inhibitor – dosed twice a day). A
journal article provides the best type of information since it is
peer-reviewed and, in this case, has been published in a prestigious
BMS has submitted the Phase 3
data to the Food and Drug Administration (FDA) for approval. The
treatment period was 24 weeks.
There were two groups in the study:
Group 1: 135
patients who were either interferon-ineligible or intolerant: 100
medically ineligible for interferon, and 35 intolerant to interferon.
The median age was 64 yo, male (28%), IL28B cc genotype (70%),
cirrhosis (8%), interferon intolerant (26%).
Group 2: 87
patients who were non-responders: 48 null responders, 36 partial
responders, and 3 who were previously treated but their treatment
status was undetermined. The median age was 60 yo, male (45%), IL28B cc
genotype (18%), cirrhosis (13%), prior null response (55%).
The sustained virological response rates (SVR 24) or cure rates were 80.5% to 87.4% (see table).
results are encouraging and relatively high for people with HCV
genotype 1b, a patient population that is typically difficult to
treat. It is important to know that this is a relatively small
population of patients so once this combination is approved and given
to a larger population of people we will get a better picture of the
effectiveness and safety of the combination of these two medications.
(Daclatasvir / Asunaprevir)
(Daclatasvir / Asunaprevir)
(118 of 135 patients)
(70 of 87)
The most common side effects were nasal congestion, elevated liver enzymes, headache, diarrhea and fever.
In June AbbVie announced that their New Drug
Application (NDA) had been accepted by the Food and Drug Administration
(FDA) and that it had been granted priority review. In addition, it
was noted earlier that AbbVie submitted marketing authorization
applications (MAAs) for regulatory approval in the European Union and
that these applications and priority review had been accepted. AbbVie
is seeking marketing approval for their 3D combination of HCV
medications to treat HCV genotype 1 patients.
In a related story, OraSure
Technologies announced that it had reached an agreement with AbbVie on a
co-promotion agreement for an OraQuick HCV Rapid Antibody test. The
agreement will provide OraSure $75 million in payments for the
exclusive use of its HCV tests through December 31, 2019. This means
that AbbVie will be sponsoring mass testing to identify the other 50%
to 75% of people with hepatitis C who don’t know they are infected. It
is definitely going to be a very interesting coming decade.
Acquisitions seem to be a permanent part of the HCV
treatment landscape. In June, Merck announced that they had offered
3.85 billion dollars in a bid to acquire Idenix Pharmaceuticals Inc.
The offer goes to Idenix stockholders, but I can’t imagine that any
sane stockholder would turn this down! In the news, however, there
have been stories about the bid being undervalued and overvalued. Who
Idenix has three HCV inhibitors
in Phase 1 and Phase 2 clinical development—IDX21437 and IDX21459
(polymerase inhibitors) and samatasvir (NS5A inhibitor). Merck has its
own MK-5172 plus MK-8742 with and without ribavirin in Phase 3 clinical
development. If and when these drugs come to market it will be
interesting to see how they are priced since the acquisition price tag
is a bit hefty for the Idenix pipeline.
In June, Achillion announced that the FDA removed a
clinical hold on their HCV protease inhibitor—sovaprevir—at doses of
200 mg once daily and that they have completed Phase 2 clinical trials
of this drug. Additionally, Achillion announced that they have begun a
proof of concept study in people with HCV genotype 1 on a new drug
candidate—ACH-3422—an HCV polymerase inhibitor.
Source: HCV Advocate Newsletter – July 2014
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