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NOVEL, SOY-BASED SE5-OH CONTAINING NATURAL S-EQUOL SUPPLEMENT REDUCED HOT FLASH FREQUENCY BY NEARLY 59 PERCENT
Release date: 10/7/2009

Clinical trial data documenting improved menopause symptoms

Northridge, California SE5-OH containing Natural S-equol, a novel soy germ-based ingredient in a supplement, improved menopausal symptoms, including significantly reducing hot flash frequency by nearly 59 percent, according to a peer-reviewed study in Japanese women. This key study was presented in an oral presentation at the North American Menopause Society (NAMS) 20th annual meeting. A second oral presentation reported peer-reviewed data that documented for the first time the pharmacokinetics, or absorption and distribution in the body, in U.S. menopausal women of S-equol when taken as a supplement using SE5-OH containing Natural S-equol. Development and ongoing research of SE5-OH containing Natural S-equol is conducted by the Saga Nutraceuticals Research Institute of Otsuka Pharmaceutical Co., Ltd. Pharmavite LLC, the makers of NatureMade® vitamins and minerals and a subsidiary of Otsuka Pharmaceutical Co., Ltd., is studying SE5-OH containing Natural S-equol in supplement form for management of menopausal symptoms.

"Natural S-equol, a soy-derived compound that is thought to interact with specific estrogen receptors, has been studied for its benefits in relieving menopausal symptoms in both U.S. and Japanese women. The data presented at NAMS adds to this research and illustrates the potential that SE5-OH containing Natural S-equol has for management of menopausal symptoms. Pharmavite LLC and Otsuka Pharmaceutical Co., Ltd. have a rigorous program, including additional clinical studies, to develop a SE5-OH containing Natural S-equol supplement," said Belinda H. Jenks, Ph.D., director of Scientific Affairs & Nutrition Education at Pharmavite LLC.

Soybeans contain a compound daidzein that certain bacteria living within the digestive tract of some individuals can metabolize, or convert, into Natural S-equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman], a compound thought to act as a selective estrogen receptor modulator (SERM). SERMs can bind to the body's receptors for estrogen, the naturally occurring female sex hormone, and Natural S-equol has a selective affinity for the estrogen receptor beta. Not everyone can produce Natural S-equol after soy consumption, as the production depends on the types of bacteria present in the large intestine and may be influenced by the amount of soy consumed. About 50 percent of Asians and 20 to 30 percent of North Americans and Europeans, who in general consume less soy than Asians, have the ability to produce equol. Studies in Japan have documented an association between milder menopausal symptoms in equol producers as compared to non-producers, but efficacy studies of S-equol, and of SE5-OH containing Natural S-equol, have been limited.

Investigational SE5-OH Containing Natural S-equol Supplement Improves Menopause Symptoms

In the study of Japanese postmenopausal women who were equol non-producers and reported at the NAMS annual meeting, a supplement whose active ingredient was SE5-OH containing Natural S-equol had significant effects on improving several menopausal symptoms.

"Our clinical trial of SE5-OH containing Natural S-equol in Japanese post-menopausal women documented a significant reduction of their menopausal symptoms as measured in several ways, and the compound appears to have a promising future role in the management of women's menopausal symptoms," said study author Takashi Aso, M.D., Ph.D., of the Department of Obstetrics and Gynecology, Faculty of Medicine, Tokyo Medical and Dental University and past president of the Japanese Menopause Society. "Safe and effective alternatives to hormone replacement therapy are needed to help women who suffer from menopause symptoms."

In the study, women taking a daily oral dose of 10 milligrams (mg) of Natural S-equol via the supplement reduced their frequency of hot flashes by 58.7 percent after 12 weeks of treatment, significantly more than the 34.5 percent reduction experienced in women receiving a placebo (p=0.0092 ). The study's primary endpoint was individual menopause symptom scores after 12 weeks of treatment.

SE5-OH containing Natural S-equol also yielded positive improvements of other menopause symptoms, as measured by the study's several secondary endpoints, including total scores on menopausal symptom evaluations as assessed by a physician-administered 22-item menopausal symptom questionnaire and by a validated tool called the Visual Analogue Scale of five symptoms (hot flashes, sweating, light sleep insomnia, depression and shoulder muscle stiffness). Women in Japan in general experience less hot flashes than women in the United States but experience more neck and shoulder stiffness, the investigators noted.

The trial also evaluated safety and adverse treatment-related effects. No adverse events were reported in this study and the supplement was well tolerated. A complete report of the study data will be submitted for peer-review publication.

The trial, a randomized, double-blind, placebo-controlled, parallel-group study, evaluated 230 post-menopausal Japanese women aged 45 to 60 years. At enrollment, the women had at least one hot flash per day, did not produce equol after eating soy products, and did not take hormonal drugs or menopause symptom treatments. The postmenopausal enrollment criteria included estrogen levels of less than 21 picograms per milliliter (ml) and follicle stimulating hormone (FSH) values greater than 30 million international units/ml. Investigators randomized the women into two groups to receive either the placebo or the supplement, in the form of two daily tablets taken for 12 weeks.

The Natural S-equol used in this study and the pharmacokinetic study was in the form of SE5-OH containing Natural S-equol. The supplement tablets each contained 5 mg of Natural S-equol. The SE5-OH is the product of fermentation of soy germ by the bacterial strain Lactococcus garvieae 20-92 using a patented and proprietary process by the Otsuka Pharmaceutical Co., Ltd. The process results in the conversion of the daidzein to S-equol. SE5-OH is created under current Good Manufacturing Practices. Following fermentation, the bacteria undergoes heat denaturation and is deactivated. The process is designed to produce a Natural S-equol rich product, or nutraceutical ingredient.

SE5-OH Containing Natural S-equol Supplements Provide Very High Systemic Bioavailability

The S-equol in SE5-OH containing Natural S-equol supplement tablets was rapidly absorbed from the tablets and attained optimal concentrations in the blood stream, providing very high systemic bioavailability when given to healthy postmenopausal women. These findings were from a single-center, open-label, randomized, two-period crossover study conducted in white, non-Hispanic women. Bioavailability is a calculation of how much of a given dose of a test compound reaches the blood stream to circulate within the body, has a potential therapeutic effect and then is excreted in urine.

"These data are the first to report the pharmacokinetics of the S-equol when given in the SE5-OH containing Natural S-equol supplements to healthy U.S. postmenopausal women. This information is fundamental to determine the best dose of S-equol to use in the design of future clinical studies aimed at evaluating the effectiveness of S-equol in hormone-dependent conditions, such as menopause. We also documented that the SE5-OH Natural S-equol supplement offers a means of providing S-equol to those adults that do not produce it after ingestion of soy," said Kenneth D. R. Setchell, Ph.D., professor in the Division of Pathology and Laboratory Investigation, Department of Pediatrics, Cincinnati Children's Hospital Medical Center in Ohio. Dr. Setchell, an expert pharmacologist, evaluated the blinded data from the trial, which was conducted by Community Research in Cincinnati, Ohio, with support from Otsuka Pharmaceutical Development and Commercialization, Inc.

In the study, investigators randomly assigned 12 post-menopausal women, aged 48 to 65 years, to receive after fasting overnight either 10 mg or 30 mg of S-equol via SE5-OH containing Natural S-equol supplement tablets that each contained 5 mg of S-equol. Then 48 hours later, the women were switched to the other dosage. Following the 30 mg dose, the average peak plasma concentration, a calculation called Cmax, of Natural S-equol was 1,200 nanomoles per liter and was reached one hour after dosing.

Values for measures were similar for both doses of S-equol. Three of these measures included the calculation of Natural S-equol plasma concentration following each dosing, called an Area Under the Curve (AUC) calculation, and both Cmax and AUC calculated by dose. Also, S-equol from the SE5-OH containing Natural S-equol supplement was rapidly excreted in urine. The average half-life, the time for plasma concentrations to decrease by 50 percent, was eight hours but sustained concentrations were measureable through 48 hours after dosing. The fraction of the S-equol dose excreted in urine was more than 80 percent for both doses. A complete report of the study data will be submitted for peer-review publication.

Investigators determined that three of the 12 women (25 percent) were equol-producers, based on their equol levels after a soymilk challenge. This standard test for equol production in humans includes a three-day soy milk challenge followed by measures of urinary equol concentration on day four of the test. There were no observable differences in Natural S-equol pharmacokinetics between the equol-producers and non-producers in the study, the investigators note.

No serious adverse events were reported and nor were there any clinically important changes in the women's blood biochemistry, including FSH, triiodothyronine, thyroxine, and thyroid-stimulating hormone, or in hematology, urinalysis or vital signs after administration of the Natural S-equol supplements.

For this pharmacokinetics trial, the women's postmenopausal status enrollment criteria was serum estradiol values of less than 100 picomol per liter and FSH levels greater than 50 international units per liter. Participants could not take any prescription or over-the-counter estrogen, combination estrogen+progestin, or phytoestrogen products within 14 days before the Natural S-equol dosing. The women also had to abstain from consuming soy-, flax- or lignan-containing foods, beverages and supplements for seven days before the equol dosing.


Otsuka Pharmaceutical Co. Ltd. supported both studies.

NAMS Presentations

Friday, Oct. 2, 2009


Oral presentation

Pharmacokinetics of S-(-)-Equol Administered as SE5-OH Tablets to Healthy Postmenopausal Women Kenneth D. R. Setchell and Xueheng Zhao (Cincinnati Children's Hospital Medical Center and Cincinnati College of Medicine, Ohio); and Susan E. Shoaf and Karen Ragland (Global Clinical Development, Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Md.)

Oral presentation

The Physiological Effects of Natural S-Equol Tablets on Menopausal Symptoms of Japanese Post-Menopausal Women Takeshi Aso, (Tokyo Medical and Dental University); Masahiro Nozaki (Kyushu Central Hospital, Fukuoka, Japan); Hiroaki Ohta (Tokyo Women's Medical University, Japan); and Tomomi Ueno and Shigeto Uchiyama (Saga Nutraceutical research Institute, Otsuka Pharmaceutical Co. Ltd., Japan).

About Otsuka Pharmaceutical Co., Ltd.: Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment. Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group comprises 153 companies and employs approximately 36,000 people in 23 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned „955.9 billion (approx. US $9.7 billion*) in annual revenues in fiscal 2008. * Exchange rate as of March 31, 2009.

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