Peretinoin Improves Hepatocellular Carcinoma in People with Mild Liver Impairment

	SUMMARY: The investigational liver cancer drug peretinoin, or NIK-333, appeared to reduce the risk of hepatocellular carcinoma (HCC) recurrence or death among people with Child-Pugh stage A, or mild liver impairment, in a Phase II/III clinical trial, even though it did not lead to significant improvement when looking at the study population as a whole. These results, reported at a medical conference last week, indicate that the drug may be effective for a selected subset of patients.

Kowa 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

	Peretinoin may reduce de novo carcinogenesis
	Presented at American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2011

Tokyo -- 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 HCC recurrence.

[*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 hepatic cirrhosis.

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 were tolerable.

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."

About Peretinoin

Peretinoin is an oral acyclic retinoid with a vitamin A-like structure, and its main targeting molecule is the retinoid nuclear receptor.

About Kowa

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 bases.

Liver cancer begins in the cells of the liver. The most common form of liver cancer begins in cells called hepatocytes and is called hepatocellular carcinoma.

1/28/11