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KYOWA HAKKO BIO’S NEWS FROM AROUND THE GLOBE • SUMMER 2016

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Message from our President & CEOThe global demand for high-value amino acids has continued to increase over the years, due in part to rising levels of healthcare in emerging countries and a greater need worldwide for generic drugs. At Kyowa Hakko Bio, we have made—and continue to make—substantial contributions to the well-being of people around the world by commercializing an array of health-promoting biochemical substances, including various amino acids, nucleic acid-related substances, vitamins, bioactive substances, and pharmaceutical products, as well as oligosaccharides and dipeptides.

As pioneers in the development and application of fermentation technology, we maintain an ongoing commitment to research, developing innovative new products, and quality management. Our quality-first approach to doing business means that our customers receive reliable, high-quality products that perform as promised.

In an effort to fully support our expanding global network, we have recently established a Global Brand Marketing Center. Comprised of members from Kyowa's headquarters in Japan and regional offices in North America, Europe, and Asia Pacific, the Marketing Center will help us leverage the investment we've made in clinical science behind our branded ingredients and ensure consistent branding activities around the globe.

Chikakuni KotaniPresident and Chief Executive OfficerKyowa Hakko Bio Co., Ltd.

Our quality-first approach to doing business means that our customers receive reliable, high-quality products that perform as promised.

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Product News ............................. 3

Science Updates......................... 4

BioKyowa.................................... 7

Regulatory Updates ................... 9

Employee News.......................... 9

Contents

3 AMINOSCOPE SUMMER 2016

Product NewsCognizin® Named as Finalist for Ingredient of the Year by NutraIngredients at Vitafoods Europe 2016

Cognizin® Citicoline was one of three finalists for NutraIngredients’ Ingredient of the Year at Vitafoods. Nominated in the Healthy Aging category, finalists were chosen for their innovation, scientific merit, efficacy, safety and market potential. The 2016 NutraIngredients Awards took place Wednesday, May 11, at the Starling Hotel in Geneva, Switzerland where Cognizin was announced a runner-up.

Cognizin® was introduced into the US market in the early 1980s and achieved Self-affirmed Generally Recognized as Safe (GRAS) status in 2009. Cognizin® Citicoline can be found in many well-respected North American dietary supplement brands and functional foods such as sports drinks and bars.

Cognizin® Citicoline can also be found in several European products. Agave Farmaceutici produces Assonal™ with Cognizin®, a supple-ment meant to support the conduc-tion of nerves and protect neurons from free radicals.

Bionops Laboratory offers Biomacula with Cognizin®, a daily supplement that supports eye health. FB Health offers Vivifast® with Cognizin® for optimal cognitive health.

A Look Back at Vitafoods 2015: Exhibitor Presentation on Cognizin®

Kyowa's affiliate group, Kyowa Hakko Bio Italia S.R.L., gave a presentation on Cognizin® Citicoline at Vitafoods 2015 titled “A brain- health nutrient clinically tested to support mental energy, focus attention and recall.”

As the first company to successfully achieve Novel Food Ingredient (NFI) status for its citicoline, Kyowa received authorization for Cognizin® to be placed on the market as of July 2014. Kyowa is excited to report that Vitafoods attendees from Europe, the Middle East, and other neighboring counties continue to

show significant interest in the market potential of this ingredient.

Cognizin® Citicoline meets United States Pharmacopeia (USP) Convention Standards and is available as a dietary supplement in the United States, Canada, Mexico, and select countries in Europe and Asia.

Cognizin Presentation given by Karen Todd, Sr. Director of Global Marketing, Kyowa Hakko USA.

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Science UpdateResearch on Kyowa’s L-Citrulline/Setria® Glutathione Combination Shows Potential for Sports Nutrition MarketA recently-conducted study reported that Kyowa’s L-Citrulline and Setria® Glutathione supplementation (2 g/day and 200 mg/day, respec-tively, for 7 days) resulted in long- lasting increases in Nitric Oxide (NO) levels in resistance-trained males (Figure 1). The combination was measured against placebo and L-citrulline alone and showed not only increased levels of nitrite and NOx, but that these levels were sustained post-exercise for a longer period of time.

L-citrulline is known to impact NO levels as it’s converted to L-arginine, which synthesizes NO when ingested. However, L-citrulline supplementation alone has shown conflicting results in reference to improving exercise performance. Previous studies have indicated that NO is correlated with intracellular glutathione. Glutathione reacts with NO to form S-nitrosoglutathione (GSNO) which acts as a slow releaser of NO. These results suggest that it may play a role in preventing oxidative reaction and sustaining the release of NO (Figure 2) however; its effective-ness–particularly in combination with L-citrulline–had not been determined prior to this study. The results of this first-of-its-kind study indicate that glutathione and L-citrulline may play a role in muscle protein synthesis and muscle performance when combined with resistance exercise.

Many athletes who want to build strength look for effective ways to boost NO because it increases blood flow, which helps build muscle tissue. Sustained NO levels post workout could also lead to reduced muscle fatigue and speedier recovery times.

Recognizing the market potential of a blend that optimizes the benefits of boosting NO levels, Kyowa has created a "Setria® Performance Blend" with Setria® Glutathione and Kyowa’s L-Citrulline, and filed an international patent application. Additional clinical trials are also being planned.

Reference: McKinley-Barnard S, Andre T, Morita M, Wiiloughby DS. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. J Int Soc Sports Nutr. 2015 Jun 10;12:27.

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2

0

-2

-4

∆Pla

sma

NO

x le

vels

(µM

)

Pre Ex

Placebo L-citrulline 2gL-citrulline 2g+ Setria 0.2g

Post

30 minPost Pre Ex

Post

30 minPost Pre Ex

Post

30 min Post*

N=15,*P<0.05 vs PlaceboMcKinley-Barnard S et al. J Int Soc Sports Nutr. (published online: 6/10, 2015)

Figure 1: Effects of Citrulline and Glutathione on NO production (McKinley-Barnard S et al. 2015)

Figure 2: Mechanism of action

CIT

NO GSNO

ONOO

Inactivated

Stabilized

Releasing

Sustained release

*NO half-life is about 3-5 sec.

NO

NO

X

ROS

GSH

Prolongs the half-life*GSH

CIT= L-CitrullineGSH= GlutathioneGSNO= S-Nitroso-L-Glutathione

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ScienceUpdateKyowa Hakko holds first meeting for Glutathione Sciences in Japan

Glutathione is the most abundant antioxidant in the body and plays a major role in detoxification of reactive oxygen species (ROS). The biosynthesis, metabolism, and physiological functions of gluta-thione have been extensively investigated since the 1980s. It has been shown that the maintenance of glutathione levels in the body is critical for maintaining health. Recently, physiological effects of oral glutathione supplementation have been reported in some clinical studies and much focus is being placed on its health benefits.

In an effort to stimulate more interest in the study of glutathione, Kyowa Hakko held its first meeting for glutathione sciences in Japan and invited researchers to share their work and findings. Held on April 28th in Tokyo, presentations were made to a group of 48 attend-ees on topics that included the latest findings of physiological functions and a novel assay method for glutathione in vivo.

The meeting was co-chaired by Junichi Fujii, Ph.D. Professor, Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, and Hideyo Sato, Ph.D., Professor, Department of Medical Technology, Faculty of Medicine, Niigata University.

Topics and speakers included:

Physiological function and metabolism of Glutathione, presented by Masahiko Morita, Researcher, Kyowa Hakko Bio.

Protective effects of oral glutathi-one on fasting-induced intestinal atrophy, presented by Hiroyuki Uchida, Ph.D., Associate Professor, Division of Pathophysiology, Depart-ment of Clinical Dietetics and Human Nutrition, Faculty of Pharma-ceutical Science, Josai University.

Electrochemical application for in vivo GSH measurement on boron-doped diamond electrodes, presented by Yasuaki Einaga, Ph.D., Professor, Depart-ment of Chemistry, Faculty of Science and Technology, Keio University.

Dynamics and neuroprotective action of glutathione in the cerebral infarction, presented by Kohji Fukunaga, Ph.D., Professor, Department of Pharmacology Tohoku University Graduate School of Pharmaceutical Sciences.

The intent of this meeting was to bring glutathione-minded scientists together to share knowledge, and inspire new approaches to expand our understanding of glutathione's health supporting potential. Given the success and enthusiasm generated by this event, Kyowa looks forward to hosting a similar glutathione summit every year going forward, and to eventually expand the meeting internationally.

Research on L-Citrulline's Ability to Boost Sports Performance Published in JISSNKyowa's randomized, double-blind, placebo-controlled, human clinical trial was recently published in the Journal of the International Society of Sports Nutrition investigating the effect of L-citrulline oral supplementation in healthy trained men.

Results of 2.4 g/day for 7 days showed significantly increased plasma L-arginine levels and a reduction in time to complete a cycle ergometer exercise trial. With increasing consumer interest in sports nutrition, this study is a welcome addition to a growing body of research on L-citrulline’s ability to support sports performance benefits.

Science Update

AMINOSCOPE SUMMER 2016

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BioKyowa BioKyowa, Inc. is a wholly owned subsidiary of Kyowa Hakko Bio Co., Ltd.

At the BioKyowa facility in Cape Girardeau, MO., thirteen different amino acids are produced for use in the pharmaceutical, dietary supple-ment, cosmetic, functional food and beverage industries. Thousands of metric tons of product are made annually in bulk via advanced fermentation and purification processes. All raw materials which are purchased from approved sources, are analyzed upon receipt. No animal origin raw materials are used in the process. This facility has been in continuous operation since 1984 producing amino acids. Operational stability is enhanced with 14 of the current 178 employ-ees having been at the site since its first year of operations.

BioKyowa operates 24/7 year round to supply customers worldwide. Approximately half of their products are sold outside the USA. Capacity at the plant has increased by 50% in the past five years to keep up with growing demand, specifically by the burgeoning global middle class, for its products. BioKyowa’s facility was showcased on the Fox Business News nightly feature on American manufacturing in April 2016. The video shown by Fox can be viewed on the BioKyowa website (www.biokyowa.com.) In this video one can see many facets of the operations including laboratory analysis of raw material and finished

products, fermentation equipment, product purification equipment, packaging of final product, ware-house activity and waste water treatment.

BioKyowa operates in strict compli-ance with US safety and environ-mental regulations. Their waste water plant utilizes a state of the art membrane filtration system to meet current discharge regulations. Residual solids from amino acidproduction and from the waste water treatment plant are recycled via land application by local farmers as a fertilizer under permit approval by the Missouri Department of Natural Resources.

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BioKyowacont.

At BioKyowa, product quality is strictly regulated. Food grade products meet USP standards. All products are Kosher and Halal certified. The plant is ISO 9001 and HACCP accredited. Many customer and regulatory audits are conducted each year at the facility. In the past two years audits and inspections have been conducted by the following regulatory authorities: AIB (HACCP), MNCA (ISO), FDA (ingredient manufacturer) and EPA (waste water operations). The FDA inspection resulted in no 483s being issued.

Regulations and customer expecta-tions continue to evolve and become more complex. BioKyowa is constantly improving their operations to keep up with the marketplace and with government regulations. Two notable continuous improvement activities underway in

2016 are: First – updating programs and practices to comply with the new FDA Food Safety Moderniza-tion Act (FSMA). Second – installing an ICP (Inductively Coupled Plasma Spectrometer) to measure heavy metals down to ppb levels in final products. This is to meet customer requests for more detailed product analysis and to comply with new USP test methods.

BioKyowa is very active in its efforts to meet customer needs for quality products. Their 30 plus year track record combined with a continuous improvement approach has them well positioned to be the premier US supplier of amino acids for the next generation.

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RegulatoryUpdatesSetria® Glutathione Now Available in AustraliaAustralia’s Therapeutics Goods Administration (TGA) has approved the use of Setria® Glutathione “as a therapeutically active ingredient in adults”. TGA approval was received in October 2014 after a milestone clinical trial of the master antioxidant showed positive results, which were published in the European Journal of Nutrition. Setria® also meets the current United States Pharmacopeia (USP) Convention Standards and is available as a dietary supplement in the United States, Canada, Mexico, and select countries in Europe and Asia.

Cognizin® Obtains Novel Food Registration Status in EuropeFollowing a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA) delivered a scientific opinion on Citicoline as a novel food ingredient (NFI), concluding on October 2013 that Citicoline is safe under the proposed uses and use levels.

The Commission Implementing Decision 2014/423/EY of July 2014 autho-rized the placing of Citicoline as a novel food ingredient under Regulation (EC) No 258/97 of the European Parliament and of the Council.

Citicoline is the generic name for CDP-choline (choline cytidine 5’-pyrophos-phate), organic molecule produced endogenously and found in all living cells. It’s a source of choline and a precursor for the synthesis of phospholipids that are essential constituents of cell membranes, including phosphatidylcho-line, phosphatidylserine, and phosphatidyl-ethanolamine.

Kyowa has been marketing Citicoline in the United States since the early 1980s as a dietary supplement under the Cognizin® brand name. The trademark name Cognizin® was created in 2004 and received self-affirmed GRAS status in 2009. Citicoline is certilfied as a safe food ingredient for use at levels of 250 mg per serving in products such as dietary supplements, beverages, breakfast cereals, chewing gum, pastas, hard candies, milk products, fruit juices, and soft candy.

Oksana Ritchie hired asMarketing Manager Kyowa Hakko Europe GmbH

Oksana comes to Kyowa with a wealth of international experience. She holds a Master’s Degree in International Business Commerce from the University of Moscow, and has worked for a variety of global multinational companies in Russia, Germany and the U.K.

With expertise in B2B and B2C business development and market-ing communications, Oksana will be able to make an immediate impact in Kyowa Hakko Europe. Passion-ate about health care and natural remedies she believes it is the responsibility of every individual to provide both their bodies and minds with the best possible nutrition.

EmployeeNews

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IFT Chicago – July 2016

This years' Institute of Food Technologists tradeshow from July 16–19, held in Chicago, brought together more than 23,000 top food science and technology experts from more than 90 countries, representing the most prominent organizations in the global food sector. In addition to having a booth at the show, Kyowa participated in a symposium that presented the science and unique benefits of Cognizin® Citicoline.

The symposium, Functional Ingredients for Cognitive Health in Food & Beverage Applications, took place on Monday July 18th and included the following speakers:

Dr. Rob Paul, PhDBoard Certified Clinical Neuropsychologist, Co-founder of Nawgan® energy drink

Michael McBurney, PhD, FACNVP Science, Communications and Advocacy, DSM

Danielle Citrolo, Pharm.D.Technical Services Manager, Kyowa Hakko USA

Karen Todd, RD, CSCS, HFSSr. Director Global Marketing, Kyowa Hakko USA

Functional foods and beverages that support cognitive performance are one of the hottest categories in the global Food and Beverage industry. We are excited to see that the interest in Cognizin® Citicoline continues to grow.

Tradeshows & ConferencesNutraceutical and Functional Food Asia Pacific Summit Singapore – June 2016

At the Nutraceutical and Functional Food Asia Pacific Summit, June 30th–July 1st in Singapore, Dr. Toshikazu Kamiya, Research Fellow, Kyowa Hakko Bio, gave a presentation titled: Creating New Nutraceutical Values with Innovative Amino Acid-, Peptide-, Oligosaccharide- Fermentation Technologies.

Dr. Kamiya discussed the innovative manufacturing technologies behind Kyowa’s top-quality ingredients that deliver improved nutritional values, along with dipeptide applications. Dr. Kamiya also shared recently published research on the health benefits of oral glutathione supple-mentation, and noted that Setria® is the first clinically studied glutathione to show an increase in blood levels. He cited Kyowa’s proprietary fermentation process as key to creating glutathione that is ultra- pure and high quality.

More on how Kyowa’s innovative technologies are able to bring advanced health products to market will be covered in future Amino-Scope issues.

Upcoming Events

Pharma AsiaSeptember 20-22, 2016Karachi, Pakistan – Booth A-62, 63Co-exhibit with Health Care Products Pakistan

IFT Longhorn Suppliers’ NightSeptember 22, 2016Frisco, Texas

SupplySide WestOctober 4–8, 2016 Las Vegas – Booth LL 135PANEL DISCUSSION: Cognitive Health Throughout the Lifespan, Danielle Citrolo, Pharm.D., RPh

FAPA 2016November 9-13, 2016Bangkok, Thailand

HIE 2016November 29 – December 1, 2016Frankfurt, Germany – Stand C78

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