—Alan Franciscus, Editor-in-Chief
This month’s HCV Drugs column includes information about a variety of studies recently published in the New England Journal of Medicine
(NEJM)—AbbVie’s 3D drug combination to treat genotype 1, and Gilead’s
sofosbuvir, ledipasvir with and without ribavirin to treat genotype 1
and sofosbuvir plus ribavirin to treat genotypes 2 and 3. In addition,
there were applications for marketing of AbbVie’s 3D combination in
the European Union and Janssen’s supplemental application to the FDA
for marketing approval of Sovaldi and Olysio for genotype 1 in the U.S.
Finally, there is a short recap of the results of a study
presented at the Digestive Disease Week conference to treat HCV
A summary of the information from the NEJM will also be
included in the Drugs in Development section of the HCSP Fact Sheets on
our website. Additional EASL conference coverage will also be
available in our blog.
PEARL III & IV:
In an article in the New England Journal of Medicine
(NEJM) the results of the PEARL-III and PEARL-IV studies were
reported. The studies included HCV genotype 1a (305) and 1b (419)
patients without cirrhosis who were treated with ABT-450/r, ombitasvir, dasabuvir with and without ribavirin for 12 weeks.
The patients were somewhat similar between the arms:
- Genotype 1a—male 63-70%; White 83-86%; age ~51yo; fibrosis F0/F1–63 to 64%, F2–7 to 21%, F3–16 to 19%.
- Genotype 1b—male 41-51%; White 94%; age ~48-49yo; fibrosis F0/F1–68 to 71%, F2–18 to 23%, F3–10 to 11%.
Overall cure rates were 90 to 99% (see Table below which includes results from all of AbbVie’s Phase 3 clinical trials).
The majority of the side effects were mild. The
most common side effects in all the studies were headache and
fatigue. Two patients in the study discontinued therapy due to side
The authors of the study noted that the cure
rates were higher in the ribavirin containing arm of the group of
patients with HCV genotype 1a—90 % vs. 97% in the ribavirin containing
arm. In the HCV genotype 1b arms there was no difference in the
ribavirin vs. no ribavirin arms—99-100%.
AbbVie has completed their Phase 3 studies and
submitted their data to the Food and Drug Administration (FDA) for
approval. It is likely that the AbbVie 3D (without ribavirin)
combination for a treatment period of 12 weeks will be approved by the
FDA to treat HCV genotype 1b. The 3D combination will also be approved
to treat HCV genotype 1a, but it is unclear if the approval will
stipulate that ribavirin will be necessary. A 7% difference in cure
rates between the arms with and without ribavirin is not statistically
different (at least in my opinion).
At any rate it is likely that the FDA will
approve these ‘breakthrough therapies’ by the end of 2014 or the
beginning of 2015.
AbbVie also announced that it had applied to the
European Medicines Agency (EMA) for marketing approval of their 3D
combination. It was also noted that the 3D combination had been
granted Accelerated Assessment designation that will speed up the
Note: Please see HCSP Fact Sheet Drugs in Development: Phase 3–AbbVie’s 3 Drug Combination Therapy for more information about the phase 3 studies.
AbbVie-Phase 3 Clinical Trial Results
|Phase 3 Studies – Genotype 1 – ABT-450/r, ombitasvir, dasabuvir
– with and without ribavirin
|Study name/ Treatment Period||Ribavirin Y/N||TX Naïve/
|Number of Patients||Cure Rates Overall||Cure Rates Genotype 1a||Cure
AbbVie table adapted from: Doi:10.1056/NEJMoa1402338
There were three medications used in the study:
- Sovaldi (sofosbuvir) – polymerase inhibitor, 400 mg
- Ledipasvir – NS5A inhibitor, 90 mg
- Ribavirin – dosed twice a day based on body weight
A total of 647 treatment naïve patients without cirrhosis were randomly assigned to 3 treatment arms:
- Arm 1: Sovaldi (sofosbuvir) and ledipasvir (215 pts) treated for 8 weeks,
- Arm 2: Sovaldi, ledipasvir, ribavirin (216 pts) treated for 8 weeks,
- Arm 3: Sovaldi and ledipasvir ( 216 pts) treated for 12 weeks
Note: Sofosbuvir and ledipasvir are co-formulated into one pill, taken once a day. Ribavirin is dosed twice a day.
The patient population was similar across all
treatment arms: male (54% – 60%), mean age (51-53 yo), White (76% –
81%), genotype 1a (80%), genotype 1b (20%). F0-F2 (50-59%), and F-3
The overall cure rates were 93 to 95%. The table
below lists the drug combination and treatment duration for all of the
|Genotype 1 – ledipasvir, sofosbuvir with and without ribavirin|
|Ribavirin Y/N||Number of Patients||Cure Rates Overall||Cure Rates Genotype 1a||Cure Rates
|ION-1: Treatment Naïve|
|ION-2: Treatment Experienced|
|ION-3: Treatment Naïve|
Gilead table adapted from: Doi:10.1056/NEJMoa1402338
Fatigue, headache and nausea were the most common
side effects especially in the ribavirin containing group. There were 3
treatment discontinuations, but there were no treatment
discontinuations in the 8-week sofosbuvir/ledipasvir (no ribavirin).
The overall cure rates were similar among the three
groups of treatment-naïve patients without cirrhosis. The researchers
concluded that “no additional benefit was associated with the inclusion
of ribavirin in the regimen or with the extension of the duration of
treatment to 12 weeks.” But it is important to know that this study
only included treatment-naïve patients and excluded people with
cirrhosis—people who are treatment-experienced and who have cirrhosis
may require longer treatment duration.
The VALENCE study was recently published in the New England Journal of Medicine.
It is the same study data that was submitted to the Food and Drug
Administration (FDA) for marketing approval in 2013. The information
from the FDA on this study is already listed on our HCSP Fact Sheet Genotypes 2 and 3: Sovaldi (Sofosbuvir) plus Ribavirin Therapy.
This article is a short recap of the results.
There were a total of 419 patients—genotype 2 (73 pts); genotype 3 (261
pts). The genotype 2 patients were treated for 12 weeks; genotype 3
for 12 weeks (11 pts) and 24 weeks (250 pts). Note: there was a total of 85 patients (genotypes 2 & 3) who were in the placebo arms.
The cure rates by genotype and treatment duration are listed below:
- Genotype 2 (12 weeks) – 93% cure rate
- Genotype 3 (12 weeks) – 27% cure rate
- Genotype 3 (24 weeks) – 85% cure rate
The most common side effects were headache, fatigue, and pruritus (itching).
It is not a surprise that the treatment duration for genotype 3 was
pushed to 24 weeks since 12 weeks of treatment cure rates were so low.
The 24-week treatment duration was more than 3 times higher than 12
weeks and it’s an interferon-free therapy.
Note: Please see HCSP Fact Sheet Drugs in Development: Genotype 1 – Sofosbuvir/Ledipasvir for more information about the phase 3 studies.
On May 8, 2014 Janssen announced that it is seeking
supplemental marketing approval for the combination of Sovaldi
(sofosbuvir) and Olysio (simeprevir). The application is for approval
to treat HCV genotype 1 patients —treatment naïve with advanced
fibrosis (F3-F4) and prior null responders (all stages of liver
disease). A supplemental application, if approved, will allow the use
of a previously FDA approved medication(s) to be used for another
indication—in this case with sofosbuvir for a selected patient
Janssen has completed Phase 2 studies of the
Sovaldi/Olysio combination with and without ribavirin that resulted in
79% to 100% cure rates in people with HCV genotype 1, either
treatment-naïve or treatment-experienced, and either with little or no
fibrosis (F0-F2) or with moderate to severe fibrosis (F3-F4).
Janssen has recently initiated two Phase 3
studies of Sovaldi plus Olysio with and without ribavirin for 8 or 12
weeks to treat HCV genotype 1 treatment-naïve and treatment-experienced
patients. All stages of liver disease will be tested. The company
press release did not state an expected approval date.
Bristol-Myers Squibb has an extensive drug
development portfolio with their HCV inhibitors daclatasvir,
asunaprevir and BMS-791325 (BMS “triple therapy”) as well as
combinations of their HCV drugs with drugs from other pharmaceutical
companies such as sofosbuvir (Gilead), and simeprevir (Janssen). The
combinations are being tested in HCV genotypes 1, 2, 3 and 4. These
studies include monoinfected people and those coinfected with HIV.
BMS has submitted their data to the Food and Drug
Administration for approval of the triple therapy for the treatment of
genotype 1b. BMS is also conducting studies with other HCV drugs and
will seek regulatory approval for a wide range of indications, both
with their drugs, and with combinations of their drugs with HCV drugs
from other companies.
At the recent Digestive Disease Conference there
was data presented on the combination of daclatasvir, asunaprevir and
BMS-791325 to treat HCV genotype 4. Genotype 4 worldwide is prevalent
in Egypt, other parts of Africa, and the Middle East. In the United
States genotype 4 is usually found in immigrant populations.
There was a total of 21 patients in the study.
Twenty-one patients received the triple combination therapy but with
different doses of BMS-791325—75mg in 11 patients and 150mg in 10
patients. The majority of the patients were male (62%), White (91%),
non-cirrhotic (F-0, F-1, F-2 (80%)). The treatment duration was 12
At the end of treatment, 100% of the trial
participants were HCV RNA undetectable. At 12 weeks post- treatment
the cure rates were 91% (10 of 11 pts) in the BMS-79134 75mg group and
90% (9 of 10 pts) in the 150mg group. The side effects were mild. The
most common side effects were headache, insomnia, pain and nausea.
There were no treatment discontinuations. Additional studies are being