is the edited text of a press release issued by drug developer
Kowa Company describing the trial and the subgroup analysis
Announces Subgroup Analyses of Peretinoin (NIK-333) Phase II/III
Trial in Patients Following Curative Therapy for Hepatocellular
Carcinoma (HCC) Indicate Populations Who May Gain Most Benefit
from Peretinoin Therapy
may reduce de novo carcinogenesis
at American Society of Clinical Oncology Gastrointestinal
Cancers Symposium 2011
-- January 24, 2011 -- Kowa Company, Ltd. announced today
that the results of subgroup analyses in the peretinoin (generic
name; code, NIK-333) Phase II/III clinical trial, which evaluated
its suppressive efficacy on recurrence of hepatocellular carcinoma
(HCC), were presented at the General Poster Session of the
American Society of Clinical Oncology Gastrointestinal Cancers
Symposium 2011 (ASCO-GI 2011) on January 21, 2011 in San Francisco,
USA (Abstract number #165).
The analyses were performed in two subgroups (patients with
mild [Child-Pugh A*] liver impairment or patients with Child-Pugh
A impairment with a major tumor diameter of less than 20 mm
prior to the curative therapy).
In these subgroups, peretinoin 600 mg/day showed a significantly
greater reduction in the risk of HCC recurrence or death (the
primary endpoint) compared to placebo. These results were
better than in the study as a whole and appear to indicate
subgroups of patients who may benefit from peretinoin therapy.
The observation gives a clue to its mode of action in that
it suggests that peretinoin may prevent the occurrence of
new liver tumors. These results reinforce the analysis in
the phase II/III study suggesting that peretinoin suppresses
[*Child-Pugh scoring system, which corresponds to A, B or
C, classifies hepatic impairment in patients with liver cirrhosis
and is used to assess the prognosis of the patients.]
About the subgroup analyses of the
Phase II/III trial
In these subgroup analyses, Child-Pugh A patients, who have
relatively preserved liver function, were selected to evaluate
the efficacy (recurrence free survival rate; RFS) of peretinoin.
The evaluation of the efficacy endpoints for HCC or HCC-related
disease (including overall survival and RFS) can be confounded
by the inclusion of patients with moderate or severe (Child-Pugh
B or C) hepatic impairment because these patients have higher
rates of adverse events, including death, due to the underlying
Recurrence of HCC is generally divided into two types: intrahepetic
metastasis and de novo (multicentric) carcinogenesis.
Almost all recurrences occurring among patients who have had
treatment for a major tumor with a diameter less than 20 mm
are due to de novo carcinogenesis, so patients with
a previous tumor diameter of less than 20 mm were selected
to assess the effect of peretinoin on de novo carcinogenesis.
Among the 401 patients in the Phase II/III trial, 310 patients
had Child-Pugh A liver impairment, and 144 patients had Child-Pugh
A liver impairment and a previous major tumor with a diameter
less than 20 mm. In the Child-Pugh A subgroup, peretinoin
600 mg/day (n=100) reduced the risk of HCC recurrence or death
approximately 40% compared to placebo (n=106) [HR=0.60 (95%
CI: 0.40-0.89)]. In the subgroup with Child-Pugh A and previous
major tumor size less than 20 mm, peretinoin 600 mg/day (n=49)
showed a 62% reduction in the risk of HCC recurrence and death
compared to placebo (n=49) [HR=0.38 (95% CI: 0.20-0.71)].
Adverse events considered related to peretinoin were mainly
albuminuria, hypertension, and headache, but all of these
The subgroup analyses in patients with Child-Pugh A hepatic
impairment showed a clearer suppressive effect on HCC recurrence
than in the phase II/III trial, which was greater in the subgroup
of patients who had previous had a major tumor with a diameter
less than 20 mm. It is considered that the efficacy may be
due to the suppression de novo carcinogenesis.
These results reinforced the suppressive effect of peretinoin
on HCC recurrence suggested by the phase II/III study.
About the phase II/III trial
This trial evaluated the ability of peretinoin to suppress
the recurrence of HCC in patients who had undergone curative
therapy for hepatitis C virus (HCV) positive HCC.
These results were also presented at ASCO 2010 held in Chicago,
USA, in June 2010 and ILCA 2010 held in Montreal, Canada,
in September 2010.
The results of the Phase II/III trial indicated that peretinoin
600 mg/day given daily for up to 96 weeks reduced the recurrence
of HCC after curative therapy when compared to placebo.
Expert comments on this trial
Dr. Kiwamu Okita (superintendent at Shimonoseki Kohsei Hospital,
and professor emeritus at Yamaguchi University), the chairperson
of the coordinating committee for the Phase II/III trial,
said, "In these subgroup analyses of our trial, we could
see clearer effect of peretinoin and it supports our Phase
II/III clinical trial data. And we strongly suggest that peretinoin
suppress de novo carcinogenesis of HCC. Considering
with this, we suppose that peretinoin can suppress not only
HCC recurrence but also carcinogenesis from cirrhosis."
Peretinoin is an oral acyclic retinoid with a vitamin A-like
structure, and its main targeting molecule is the retinoid
Kowa Company, Ltd. (Headquarters: Nagoya, Japan, President
& CEO: Yoshihiro Miwa, "Kowa") is a privately
held multinational company headquartered in Nagoya, Japan.
Established in 1894, Kowa is actively engaged in various manufacturing
and commercial activities in the fields of pharmaceutical,
life science, information technology, textiles, machinery
and various consumer products. In its ethical pharmaceutical
business section, the company offers the hypercholesterolemia
drug Livalo (pitavastatin), among other products, to the Japanese,
US and other markets worldwide, and is in the process of global
expansion of Livalo.
Kowa's US subsidiaries include Kowa Research Institute, Inc.,
for the research and development of pharmaceutical products,
and Kowa Pharmaceuticals America, Inc., which markets their
pharmaceutical products. European subsidiaries include Kowa
Research Europe, Ltd., for the research and development of
pharmaceutical products, and Kowa Pharmaceutical Europe Co.
Ltd., which markets their pharmaceutical products. Kowa is
organizing its global network from Japan-Europe-US trilateral
cancer begins in the cells of the liver. The most
common form of liver cancer begins in cells called
hepatocytes and is called hepatocellular
Company. Kowa Announces Subgroup Analyses of Peretinoin (NIK-333)
Phase II/III Trial. Press release. January 24, 2011.