NattoPharma ASA...Nov 20, 2018 · 12th Feb 2013: Osteoporosis International published a three-year clinical study evaluating the bone health benefits of Vitamin K2 as MK-7 This is

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Our Science. Your Trust™

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Hogne Vik, MD, PhD, MBA

Chief Medical Officer

NattoPharma ASA

Vitamin K2: The vitamin securing healthy bones and physiological arteries across the lifespan

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Introduction

The Western population has a greater life expectancy than ever before,

which also means we are more frequently experiencing negative age-related

medical conditions.

• The World Health Organization (WHO) reports that millions of people around the

world are vulnerable to poor bone metabolism, making both women and men

susceptible to life-threatening fractures.

• Meanwhile, heart disease remains the No. 1 global cause of death, with 17.3 million

deaths each year.

But what if we could vastly change these statistics with an

essential vitamin — Vitamin K2 — proven to simultaneously

protect cardiovascular health while supporting bone health?

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Question?

Q: Are OSTEOPOROSIS and ATHEROSCLEROSIS

normal by-products of aging?

Age-related hardeningof the arteries

A: NO! This is evidence of a vitamin deficiency, or

insufficiency.

Loss of bone increasing fracture risk

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Vitamin K2 for All of Life’s Stages

• Maintaining the best possible cardiovascular and bone

health are two of the most critical areas allowing

individuals to age in a healthy way.

• Laying the foundation for healthy ageing begins in

childhood.

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Key Indication Areas for Vitamin K2

BONE

• Bone loss statistically inhibited in MK-7 group vs placebo

• Implication: Higher bone density; reduction in fractures

CARDIOVASCULAR HEALTH

• Clinical trials indicated at reversal of arterial stiffness

• Implication: Improved arterial flexibility; reduction in ”biological” age

CHILDREN’S HEALTH

• Young bone is highly active; osteocalcin levels are 8-10x higher as compared to adults

• Implication: High vitamin K required for peak bone mass in a population typically deficient

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Vitamin K2 as MK-7

Puts Calcium In The Right Place

• Calcium is important for bone health, but it needs to be properly utilized

• Vitamin K2 as MK-7 is essential for proper calcium utilization

• By activating K-dependent proteins already present in the body,

Vitamin K2 as MK-7

o Directs calcium to the bones and teeth (where it is needed)

o Stops calcium from depositing in arteries and soft tissues

(where it can do harm)

Unfortunately, most Western populations are Vitamin K2 deficient,

which can negatively impact both bone and cardiovascular health.

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Henrik Dam

Edward Doisy

• Discovered in 1929

• K stands for “koagulation”

• Fat-soluble vitamin (A, D, E, and K)

• Essential Vitamin

• Activates vitamin K-dependent proteins

• Current RDI is 90 µg/day

Vitamin K

1943 Nobel Prize

Dam and Doisy shared the

1943 Nobel Prize for their

work on Vitamin K

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K Vitamins

MK-4

MK-7

K2 menaquinones

K1 phylloquinone

K f

am

ily

K1

• Fat soluble vitamin

• K1 Phylloquinone

o Source: green leafy vegetables

o Effect: Mainly hepatic effect

(coagulation)

• K2 Menaquinone

o Source: fermented foods

o Effect: contributes to coagulation,

but available beyond liver for other

systems (i.e., bone and vasculature)

MK-7 longer sidechain; responsible for longer half-life and reach beyond the liver.

Menaquinones shown to be the most bioavaiable form.

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K1 K2

Main function:Maintains blood

Clotting

Removes calcium from

arteries and transports it

to bones

Forms: PhylloquinoneMenaquinone 4 (MK-4)

Menaquinone 7 (MK-7)

Primary

sources:Green leafy vegetables

Bacterial fermentation

(natto, cheeses, intestinal

bacteria)

Half-life: 1.5 hrs ≥3 days (MK-7)

Vitamin K1 vs K2

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Two Vitally Important Proteins

Need Vitamin K2

Osteocalcin

Essential for bone

remodelling

Matrix Gla Protein (MGP)

Essential for transporting

calcium out of the

vessel walls

Studies show that the

majority of the

population has insufficient

levels of activated

Osteocalcin and MGP.

Require Vitamin K2 for sufficient activation

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Vitamin K2 as a Complementary

Nutrient

• Vitamin K2 is an essential nutrient because it helps the body to properly

utilize Calcium.

• In the interest of preserving bone (and heart) health, few vitamins pair better

than Vitamin K2 and Vitamin D3.

o K2 activates K-dependent proteins

o D3 is needed for the creation of these proteins

• Ideally, Vitamin K2 would be taken in tandem with Calcium and Vitamin D3.

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Deficiency

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In order to obtain just 45 mcg of Vitamin K2 daily from DIET alone, one would have to consume:

• Vitamin K2 is available in certain foods in very small amounts,

making it difficult to obtain enough K2 daily from diet alone.

• Hence, supplementation is a wise and viable solution.

Vitamin K & Diet

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Vitamin K Deficiency

• Non-activated bone and cardiovascular biomarkers signal Vitamin K deficiencies.

I.e. circulating levels of uncarboxylated Osteocalcin (OC) and Matrix Gla-protein

(MGP).

• The levels of undercarboxylated Osteocalcin are highest in early age. Osteocalcin

levels in children are 8–10 fold higher as compared to adults and stabilize after 30

years of age at still elevated levels. Especially in women. The levels of

undercarboxylated Matrix Gla increase with age.

• High levels of non-activated biomarker call for activation; for bone and

cardiovascular effect, respectively.

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MenaQ7® Vitamin K2 as MK-7

Based in Science

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Vitamin K2 as MK7 – Science

• MenaQ7® is only clinically validated MK-7 for real health benefits

• 19+ Human Studies - Performed by scientists at the University of Maastricht

observing all regulations for clinical studies and working under full academic

independence

• Key Trials include 3-year studies published in:

o Bone: Osteoporosis International (2013)

o CVD: Thrombosis and Haemostasis (2015)

• Trials completed with healthy and patient populations, adults and children

o Children (Deficiency): Food & Function (2014)

o Children (Bone): British Journal of Nutrition (2009)

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Age-related Bone Loss and

Osteoporosis

• Bone mass peaks around the age of 30. Thereafter, it

drops gradually with increasing age.

• Postmenopausal woman are particularly exposed to age-

related bone loss and subsequent risk of osteoporosis.

• Osteoporosis affects 75 million people in Europe, US and

Japan.

• 45% of women and 20–25% of men over the age of 50

will experience fractures.

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MenaQ7® In the News– Bone Health Breakthrough:

• First long-term intervention trial on MK-7 supplements

and bone health benefits

• Three-year Supplementation with MenaQ7® preserved

both bone mineral content and bone mineral density

• The study used a nutritional dose of 180 μg/day

• Calculated bone strength remains constant in MenaQ7®

group; strong beneficial effect on compression strength

12th Feb 2013: Osteoporosis International published a three-year clinical

study evaluating the bone health benefits of Vitamin K2 as MK-7

This is the first time in

history that such effect

was reached with low dose

of vitamin K (any form)

Knapen et al., Osteoporosis International (2013)

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Bone Health Results

Calculated bone strength remains

constant in MenaQ7® group; strong

beneficial effect on compression

strength.

• In the MenaQ7® group bone loss was

statistically significantly slower than in

the placebo group.

• The biggest difference between

placebo and MenaQ7® was obtained

after 3 years of intake.

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Age-related Vascular Calcification

• Cardiovascular disease is the most common cause of

death in the Western world.

• Excess calcium builds up in the vessel walls, causing

stiffening of the walls and build-up of plaque in the arteries.

• Arterial constriction in the body cause increased blood

pressure, increased workload for the heart and may end in

chronic heart failure.

• Constriction of the coronary areteries cause reduced blood

supply to the heart and may lead to coronary infarction.

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MenaQ7®

– Cardiovascular Breakthrough

• First intervention trial on MK-7 supplements and

cardiovascular endpoints

• Three-year supplementation with MenaQ7® decreased

arterial stiffness in healthy postmenopausal women (this

benefit was not observed with K1)

• The study used a nutritional dose of 180 μg/day

• While prior observational data had suggested a link

between Vitamin K2 as MK-7 and cardiovascular health,

up until this clinical study trial data was lacking

19th Feb 2015: Thrombosis and Haemostasis published a three-year

clinical study evaluating cardio benefits of Vitamin K2 as MK-7

This study unambiguously

showed improvement in

arterial stiffness, a

significant CV risk factor

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Heart Health Results

This is the first time ever that any

substance has been shown to

reverse arterial stiffness.

No existing compound can do this.

After 3 years of daily

supplementation with

180 mcg MenaQ7®,

the MenaQ7® group

had on average a

reduction in pwv*

corresponding to

around 3x the normal

age-related increase

in the placebo group.

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Knapen et al., Thrombosis and Haemostasis (2015)

*PWV = pulse wave velocity

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Children’s Health

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K Vitamin Status &

Bone Health in Children

• The higher the “peak” bone mass the more protection

from osteoporosis development later in life. Peak at 30.

• Young bone is highly active:

o Osteocalcin levels are 8–10 fold higher as

compared to adults

o Thus, vitamin K requirement is also higher

• New study shows that low vitamin K status correlates

with children’s low-energy fracture incidents

Theuwissen et al. Food & Function (2013) 5(2):229-34.

Popko J et al. Nutrients, 2018,10(6),734.

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This study shows that

Vitamin K2 as MK-7 safely

and effectively improves

BMD in children.

MenaQ7® Vitamin K2 as MK-7 Children’s Health Breakthrough

2009: British Journal of Nutrition published a clinical study evaluating

bone benefits of Vitamin K2 as MK-7 in healthy prepubertal children

• Randomized, placebo-controlled, double-blind study in healthy children

o 60 children, 6-10 years of age (equal boys / girls)

• Measured ratio of inactive to active osteocalcin (UCR) to:

o Assess the vitamin K status

o Test the effect of MK-7 on osteocalcin carboxylation in healthy children

• 45 µg/d of MenaQ7® for 8 weeks

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Children’s Bone Health Results

van Summeren et al. Br J Nutr (2009) 102(8): 1171-8.

• Ratio of inactive to

active osteocalcin

(UCR) reduced after 8

weeks MenaQ7®

supplementation.

• Results showed that

more osteocalcin is

working to grow bone.

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Ongoing Clinical Trials

Cardio Potential of K2 as a

Therapy for Patient Populations

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Ongoing Clinical Trials

VitaK-CAC Study

Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients

with Coronary Artery Disease

End points: primary = progress of coronary calcification secondary = vascular stiffness and biomarkers

BASIK2

Bicuspid Aortic Valve Stenosis and the Effect of vitamin K2 on Calcium

metabolism

End points: primary = active valve mineralization secondary = progress of valve coronary calcification tertiary = vascular stiffness and Matrix Gla-protein

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Significance

Both the VitaK-CAC and BASIK2 trials are

significant

• Driven by the medical community using

populations that exhibit heavy calcification

• Examining Vitamin K2 as a potential therapy for

these patient populations because no other

compound has been shown to provide the

specific cardiovascular support K2 does

• Should be completed in 2019

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Most Important MenaQ7 Clinical Studies

• Knapen et al. Thrombosis and Haemostasis. 2015;19;113(5).

• Knapen et al. Osteoporosis International. 2013 Sep;

24(9):2499-507.

• Knapen et al. European Journal of Clinical Nutrition. 2016: 1-

6.

• Knapen et al. Journal Nutritional Science. 2015;4:e35.

• Knapen et al. European Journal of Clinical Nutrition. 2017; 1-

6.

• Mansour et al. Journal American Society of Hypertension.

2017; Pii: S1933-1711(17)30255-3.

• Knapen et al. Journal of Clinical Trials. 2014; 4:160.

• Theuwissen et al. Food & Function. 2014;5(2):229-34.

• Aoun et al. BMC Nephrology. 2017;18:191.

• Caluwé et al. Nephrology Dialysis Transplant. 2014;29;1385-

90.

• Kurnatowska et al. Polish Archives of Internal Medicine. 2015

Jul 15.pii:AOP_15_066.

• Theuwissen et al. Thrombosis and Haemostasis.

2013;11(6):1085-92.

• Ozdemir et al. Journal of Pediatric Hematology Oncology.

2013;35(8):623-7.

• Theuwissen et al. British Journal of Nutrition. 2012;

28;108(6):1017-24.

• Westenfeld et al. American Journal Kidney Disease.

2012;59(2):186-95.

• van Summerena et al. British Journal of Nutrition.

2009;102(8):1171-8.

• Kanellakis et al. Calcified Tissue International. 2012;90(4):251-

62.

• Emaus et al. Osteoporosis International. 2010;21(10):1731-40.

• Shiraki et al. Journal of Bone Mineral Metabolism.

2009;27(3):333-40.

• Knapen et al. Osteoporosis International. 2007; 18(7); 963-72.

• Schurgers et al. Biochim Biophys Acta. 2002; 1570(1):27-32.

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Conclusion – We All Need Vitamin

K2 MK-7

• Vitamin K2 is needed across the whole lifespan – to secure

strong bones and healthy arteries

• Vitamin K2 as MK-7 has been clinically shown to be

superior to Vitamin K1 and Vitamin K2 as MK-4

• K2 deficiency is widespread, impacting the bone and heart

health of the global population … adults as well as children

• All claims for health benefits of vitamin K2 are based on

research sponsored by NattoPharma, which used MenaQ7®

as the actual source material

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Thank you!

Documents

NattoPharma ASA...Nov 20, 2018 · 12th Feb 2013: Osteoporosis International published a three-year clinical study evaluating the bone health benefits of Vitamin K2 as MK-7 This is