HORIZON SCANNING
2019

AMINO ACIDS

IASDA Annual Week
Sydney, Australia
April 12, 2019

Horizon Scanning:
Amino Acids
Kyowa Hakko Bio Co., Ltd.
Karen E. Todd, RD
Yoko Kawada, PharmDCompany Overview
Date of incorporation

February 23, 1907

Number of Group companies

281

Number of employees

40,097

Kirin Holdings Company, Ltd.
KYOWA HAKKO KIRIN
CO., LTD.

KYOWA HAKKO BIO
CO., LTD.
Kyowa Pharma
Chemical Co. Ltd

Company Overview
Date of incorporation

February 23, 1907

Number of Group companies

281

Number of employees

40,097

Kirin Holdings Company, Ltd.
KYOWA HAKKO KIRINCO., LTD.

KYOWA HAKKO BIO
CO., LTD.

KYOWA HAKKO BIO
CO., LTD.

Kyowa Pharma
Chemical Co. Ltd

On April 24th ,2019, Kirin Holdings is planned to acquire 95 % of
KHB share, in order to strengthen “Health and Well-being”
business.

Kyowa Hakko Timeline

Kyowa Hakko Bio Co., Ltd.
Based on Fermentation Technology
Proteins

L-Glutamic Acid Production
by Fermentation

All L-Amino Acids

Digested Proteins

Oligosaccharides
Glutathione

Isolated Amino Acids

1956

Dipeptides

L-Lysine

Citicoline

1958

1993

2000

2004

Food Additives
Feed Additives
Infusions
Health Foods
Infant Formula
Sports NutritionDietary Supplements
Drugs
Cosmetics
Cell Culture MediaA Variety of Applicationsof L-Amino Acids

Table of contents
What are amino acids?
Functions of Amino acids① Basic nutrition② Sensory function (Flavor and taste)③ Bioregulation

Various functions of amino acids
Role of amino acids in society in the futureWhat are amino acids?

Arginine

Glutamine

AlanineAspartic acid

Table of contents
What are amino acids?
Functions of Amino acids① Basic nutrition② Sensory function (Flavor and taste)③ Bioregulation

Various functions of amino acids
Role of amino acids in society in the future

Amino acids as nutrients
Essential components that support our daily activities

StressSeasonings② Sensory Function

Fatigue③ Bioregulation function

Metabolic Syndrom

Amino acid
Basic ① Basic nutritional function Medicalfoodnutrition
Body① Amino acids as basic nutrients
Amino acids works as building blocks of proteins.
・Brain・Hair
Proteins Create the Body All over ・Eyes
the bodies ・Nails
・Skin・BonesRaw materials are・Musclesamino acids!
・BloodAbout 20% of the body is made of amino acids.

AAs are distributed
to the body.

ProteinDigestedinto AALiverAbsorbedfromintestine

Proteins are broken down into amino acids
that are absorbed in the digestive tract

20 amino acids that make up proteins
Glycine
AlanineTyrosine

Serine Nonessential
Asparagine
amino acid
Arginine
Aspartic acid
ProlineGlutamine

ValineLysineThreonine

LeucineGlutamic acid
Isoleucineamino acid
Tryptophan
Essential
Cysteine
Methionine

Histidine

Phenylalanine

②Sensory functions
Amino acids greatly affect taste
・ Glutamic acid, an ingredient that imparts a umami taste
・ Ingredients that confer bitterness... BCAA, methionine
・ Ingredients that confer sweetness... alanine, glycinee.g., shrimp/crab sweetness → glycine
Sea urchin bitterness to methionine
Tomato flavor, sourness → glutamic acid, aspartic acidBy ripening and fermentation, enhancement of umami taste→ Proteins are degraded and amino acids are increased.

③ Amino acids as bioregulatory functions
・ Improvement in liver function, anti-fatigue effect,
ornithine
・ Vascular and blood flow improvement... citrulline
・ Relax... GABA, theanine
・ Energy production... creatine

Free amino acidNot a Raw Material for Protein but Acts Alone in the Body

Table of contents
What are amino acids?
Nutrition and amino acids① Basic nutrition and amino acids② Flavor and amino acids③ Bioregulation and amino acids

Various functions of amino acids
Role of amino acids in society in the futureWhat are Amino Acids?
Healthy skinAnti-stress/
fatigue

Muscle building/Fat burning

Liver health

About 20 %is AminoAcidsSleep✓Non-essential amino acids✓Essential amino acids✓Free amino acids

Brain health

Immune system

Lifestyle-related diseaseVarious functions of amino acidsMuscle and amino acids
Diet and amino acids
Blood vessels, blood flow,and amino acids
Liver and amino acids

Beauty & Better Quality of LifeSports

BCAA
Glutamine
Ornithine
AlaGlnCitrulline

Fatigue

Ornithine
Citrulline

Nitric Oxide

Citrulline
Arginine
Brain
Eye

Anti-aging

Skin

Sleep

Ornithine

Glutathione
Ornithine
Glutathione
Ornithine
Citrulline
AlaGlnOrnithineOptimal HealthImmune

Anti-oxidation

Detoxification

Glutathione
Ornithine
AlaGlnGlutamine
Arginine

Liver

Hypertension

Citrulline

Heart

Arginine
Citrulline

Appetite

Histidine

Glutathione

Glutathione
Ornithine

Glutathione
OrnithineNitric oxide for Health
L-Citrulline is a non-protein amino acid
Structure of L-Citrulline
Molecular formulaFW

C6H13N3O3
175.19

OH2NNHNH2CO2H
Scientific name: L-2-amino-5-ureidovaleric acid
CAS No. 372-75-8

Name is derived from Citrullus, watermelon in Latin word.
KYOWA’s L-Citrulline is produced by fermentation method with high quality.

Nitric oxide for Health
Nitric Oxide is produced from Amino Acids in NO cycle

Conversion from L-Arginine to L-Citrulline produces NO in NO cycle
Nitric Oxide cycle
eNOS

L-Arginine

L-CitrullineNO
Argininosuccinic acid
eNOS: endothelial nitric oxide synthetase

Nitric oxide for Health
What is Nitric Oxide ?
 Is naturally produced in our body Works as signaling molecule in many physiological processes
 Contributes to increase blood flow and lower blood pressure throughvasodilation.
Endothelial Cells

Endothelial Cells

L-Citrulline

Cross-section ofblood vessel

Cross-section ofblood vessel

Cross-section ofblood vessel

L-Citrulline Intake

NO production

Vasodilation

Sports Performance
Improves exercise performance
Design: Double-blind randomized placebo-controlled 2-way crossover study
Subjects: Twenty-two trained healthy Japanese(mean age 29 ± 8.4 years, body mass index 24 ± 3.3 kg/m2)
Samples: 2.4 g of L-citrulline or placebo
Administration term: 8 days
Measurement: Cycling time trial completion times, power output (PO), Oxygen
utilization rate (PO/VO2), plasma nitrite and nitrate (NOx), visual analog scale (VAS)
scoresL-citrulline (8 days)
Placebo (8 days)

Washout(3 weeks)

Placebo (8 days)
L-citrulline (8 days)

Day 8
Collect
Breakfast :a rice ball
Administrationblood(Rest 60 min)(Rest and warm up 60 min)samples

4-km TT*

Collectblood
samples*4-km TT: 4-km cycling time trial by cycle ergometerSuzuki T.et. al., Journal of the International Society of Sports Nutrition. 13:6, 2016

Sports Performance【Result 1】

In-house data

Correlation between plasma NOx andoxygen utilization rate in the L-citrulline group

Completion times of the 4 km TT
600

P<0.05*No signification correlation in Placebogroup (R=0.30, p=0.17)
Time (sec)

590
580

570

560

Mean±SE,
n=220Placebo

L-Citrulline• Significantly reduced completion time compared with placebo•A positive correlation between NOx levels and Oxygen utilization rate was observed
Suzuki T.et. al., Journal of the International Society of Sports Nutrition. 13:6, 2016

Sports Performance
Subjective feelings immediately after exercise(VAS)【Result 2】Power Output (W)Mean power output of the 4 km TT
200
P<0.05195

Subjective feeling score

80190

P<0.05

Placebo
L-Citrulline

P<0.160
P<0.0540200

Mean±SE,
n=220

Placebo L-Citrulline• Significant Increased mean power output compared with placebo• VAS : Significant improved [Muscle fatigue][Cibcebtration] and trend improved[Easiness of pedaling] compared with placebo
Suzuki T.et. al., Journal of the International Society of Sports Nutrition. 13:6, 2016

Table of contents
What are amino acids?
Functions of Amino acids① Basic nutrition② Sensory function(Flavor and taste)③ Bioregulation

Various functions of amino acids
Role of amino acids in society in the futureApplication of Amino Acids andPeptides• Infusion• Medicine• Medical Food
• Food & Beverages• Flavor(s)• Sports Nutrition• Dietary Supplement• Cosmetics & Toiletry• Industrial, and etc.

Old Thinking - Treat Disease: Drugs
New Thinking - Prevent Disease: Diet
Given the future aging society,
The role of diet may increase even moreThank you!

NOTE Intention
Although this document is based on academic data,Please observe the relevant laws and regulations such as the Health
Promotion Law and the Pharmaceutical Affairs Law with regard to thewording of amino acids used in consumer products presented here.

Kyowa Hakko Bio Co., Ltd.
http://www.kyowahakko-bio.co.jp/

OMEGA 3

“The Heart of the Omega-3 Industry”• 200 member companies throughout omega-3 supply chain• Promote consumption of EPA and DHA globally• Members adhere to quality standard as condition of membershipDescribe the category in 1-3 words• Scientifically-based• Global (in terms of sources and markets)• Confusing at the consumer level37,000 published papers

4000 clinical trials in humans

Source: Pubmed, 2018

Describe the category in 1-3 words• Scientifically-based• Global (in terms of sources and markets)• Confusing at the consumer level

Describe the category in 1-3 words• Scientifically-based• Global (in terms of sources and markets)• Confusing at the consumer levelUS Media Headlines: VITAL StudyDevelopments in the past few years• Evolution of the science• Three large-scale human clinical trials published last year
• ASCEND, VITAL and REDUCE-IT• Solidified science around several cardiovascular outcomes• Definitive paper on omega-3s
reducing the risk of pre-term birth

Developments in the past few years• Evolution of product sources and forms

What are three major barriers?
• Resistance at the Codex level for an NRV, as well as no recommended intakes inUS and Canada• Negative consumer media headlines around neutral science• Design of scientific studies not supportive of positive outcomes• Not taking into consideration pharmaceutical interventions• No measurement of baseline omega-3 levels• Study not significantly powered to achieve stated result

Is the category recognized in policy?
Depends on the geography• No DRI in US, Canada• Recommended intakes from many individual scientific bodies or government organizations• No Codex NRV• Retracted intake in some areas• Ie., Japan eliminated recommendation for EPA/DHA intake for cardiovascular healthAre there initiatives to promote the category?

For consumers: alwaysomega3s.com
For practitioners: fatsoflife.com

Are there initiatives to promote the category?

How is the market evolving?
• New developments in sources (algae, calanus, green shelled mussel)• New product forms (gummies, fish oil/olive oil combination)• Rapid growth in China and Asia Pacific region

How is the market evolving?
• New developments in sources (algae, calanus, green shelled mussel)• New product forms (gummies, fish oil/olive oil combination)• Rapid growth in China and Asia Pacific region

How is the market evolving?
• New developments in sources (algae, calanus, green shelled mussel)• New product forms (gummies, fish oil/olive oil combination)• Rapid growth in China and Asia Pacific region

Growth Rates by Percent Change from 2016 to 2017

Source: GOED Proprietary Research, 2018

Science: what are the game changers?
STUDY
Cochrane Review
ASCEND
VITALREDUCE-IT

DATE PUBLISHED
July 2018
August 2018
November 2018
November 2018

OUTCOME
Negative
Mixed
Mixed but more positive than expected
Positive

Take home message:
The science is much better than what you read in the popular press.

VITAMINS & MINERALSDietary Supplements
A Vitamin & Mineral perspective
Consumer insight-driven solutionsInspiring people to better heGerhard Gans,DSM, VP RA/QM

Global VDS Market Size

30,000.0

105,000.0
101,318.7

25,000.0

100,000.0

20,000.0
95,000.0
15,000.0
90,000.0
10,000.087,394.0
85,000.0

5,000.0
0.0

80,000.0
2018

Global1

2019
USA

2020
China

2021

2022
Japan

2023
South Korea

ItalyPutting the fish on the table…

…We are deficient !

Such a simple solution, yet…
Q. Do you currently take dietary supplements? *YESNOPage 3*Source: DSM IPSOS survey 2017, 7000 respondents in multiple markets

There are two overarching Themes
MORE
ENGAGING
How can new science and technology create contact points tothe consumer

THE RIGHT
SUPPLEMENTS
What attributes of an ingredient can make a difference inthe consumer´s perception
4

INNOVATION FOR THE FUTURE – FOCUS AREAS
***
*Page

5
NNIs = new nutritional ingredients

MORE ENGAGING
Measuring yourpersonal nutrient status

THE RIGHT SUPPLEMENTS
Example: Introducing Ampli-D™ The Naturally Active Form ofVitamin D!
Ampli-D™ 10-Week Bioequivalence
Study: Randomized, Double-Blind,
Placebo-Controlled Trial• Ampli-D™ is much faster at raising Vitamin D levels than Vitamin D!
• The Vitamin D3 group did not reach desirable Vit. D blood level, even with 20mcg over 10 weeks• The Ampli-D group easily reach the desired levels in about 3 weeks!
7THE RIGHT SUPPLEMENTS

Page 8

Conclusions
DS is a growing consumer segment
New science can provide new talking
points for the consumer

New analytical techniques (noninvasive spot testing or big dataanalysis) will create new consumer
needs“side factors” like sustainability willcreate differentiation and fulfill
specific customer expectations
9