NATURAL INGREDIENTS TO SUPPORT HEART HEALTH a focus on Mediterranean botanical extracts

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1 NATURAL INGREDIENTS TO SUPPORT HEART HEALTH a focus on Mediterranean botanical extracts Yannick Capelle Product Manager Frutarom Health

2 Cardiovascular Health Risk factors Health conditions with high prevalence For example in England: Hypertension : 1 in 3 adults have high blood pressure Dyslipidemia : 50% in adult population have raised cholesterol Prediabetes : 35% in adult population 2

3 Cardiovascular Health Phytochemicals from Mediterranean plants Alliin Oleuropein Hydroxytyrosol Naringin Neohesperidin Anthocyanins Transreveratrol 3

swollen legs, varicose veins, a feeling of heaviness, pain, tiredness, itching, tension and

4 Cardiovascular Health Health claims examples in DS & OTC Well-established use Herbal medicinal product for treatment of chronic venous insufficiency, which is characterized by swollen legs, varicose veins, a feeling of heaviness, pain, tiredness, itching, tension and cramps in the calves. Art 13.1 on hold Red vine leaf contributes to a good blood flow in the legs 4 4

the top reasons why consumers aged 55+ use functional

regarding cardiovascular health Only 1% of new

5 Cardiovascular Health Health claims examples in functional foods Maintaining heart health is one of the top reasons why consumers aged 55+ use functional foods Limitations : health claims regulation regarding cardiovascular health Only 1% of new products make a cardiovascular health claim (Mintel report, April 2017) 5

7 Characteristics Produced using EFLA HyperPure technology: Solubility, stability, purity Multicomponent system, develops its activity profile by synergic effects of its components Extract form Powder Recommended dosage mg/day Standardization Oleuropein (16-24%) Polyphenols ( 30%) Efficacy and safety confirmed by proprietary studies 7

8 Tradition Olive leaf : traditional remedy & supplement Mediterranean region: Against hypertension, diabetes, atherosclerosis Against rheumatism, fever As part of daily diet: spices and infusion 8

9 Activity Beneficial blood pressure range Healthy cholesterol level Healthy blood sugar level Coronary & vascular protection (antioxidant) 9

10 Mode of action Blood pressure Appropriate olive leaf preparations may combine at least two mechanisms: 1. Increased Nitric Oxide (NO) production 2. Angiotensin converting enzyme (ACE) inhibition 10

11 In-vivo Study Efficacy of Benolea to reduce blood pressure Oral treatment with L- NAME (nitro-l-arginine methyl ester) induced hypertension 8 weeks L-NAME + Benolea (prophylactic effect) 6 weeks, then concomitant Benolea administration for a further 6 weeks (therapeutic effect) Benolea has prophylactic effect in preventing the increase of blood pressure Benolea is capable of reducing established hypertension Excellent tolerance Khayyal MT et al. (2002). Arzneimittelforschung 52 (11) 11

12 Blood pressure in mm Hg In-vivo Study Prophylatic effect of Benolea L-NAME Prophylactic antihypertensive effect of Benolea Start of Benolea L-NAME + Benolea 100 mg/kg BW Control week Khayyal MT et al. (2002). Arzneimittelforschung 52 (11) 12

Blood pressure in mm Hg In-vivo Study Therapeutic effect of Benolea 210 Start of Benolea 190 L-NAME Antihypertensive action for therapeutic effect

13 Blood pressure in mm Hg In-vivo Study Therapeutic effect of Benolea 210 Start of Benolea 190 L-NAME Antihypertensive action for therapeutic effect L-NAME + Benolea 100 mg/kg BW Control week Khayyal MT et al. (2002). Arzneimittelforschung 52 (11) 13

14 Clinical Study 1 Efficacy of Benolea to reduce blood pressure and LDL cholesterol Effective, safe & well tolerated Herbal extract with clinically proven blood-pressure lowering activity German trial involving 20 monozygotic twin pairs with borderline hypertension*: 8 weeks mg Benolea / day vs. control group (no treatment) significant antihypertensive effect significant lowering of LDL-Cholesterol excellent tolerance Perrinjaquet-Moccetti T et al, Phytotherapy Research 2008 vol 22 (9) 14

15 Clinical Study 1 Protocol 20 twin pairs 10 twin pairs Group 1 10 twin pairs Group 2 Dosage-grouping analysis twin 1 0 mg twin mg twin mg twin mg Difference Difference Perrinjaquet-Moccetti T et al, Phytotherapy Research 2008 vol 22 (9) 15

16 Clinical Study 1 Efficacy of Benolea to reduce blood pressure Significant blood pressure lowering effect of Benolea 6 mmhg 13 mmhg 5 mm Hg 5 mm Hg * Statistically significant within pairs difference, p < 0.05 Perrinjaquet-Moccetti T et al, Phytotherapy Research 2008 vol 22 (9) 16

17 Difference form start value (mmol/1) Clinical Study 1 Efficacy of Benolea to reduce LDL cholesterol Effects of Benolea on mean LDL cholesterol, after 4 and 8 weeks. Data represent mean differences within twin pair groups. After 4 weeks After 8 weeks 0,0 Significant cholesterol lowering effect -0,1-0,2-0, ,5 * Control vs. 500 mg. Benolea /day 500 mg. Vs mg Benolea /day (*statistically significant difference p < 0.05) -0,6 * Perrinjaquet-Moccetti T et al, Phytotherapy Research 2008 vol 22 (9) 17

18 Clinical Study 2 Protocol Participants: 232 volunteers with stage-1 hypertension (SBP mmhg; DBP mmhg) Benolea Group Captopril Group B P P C B C Benolea Captopril Active-controlled: 116 on Benolea P Placebo 116 on Captopril 2 x 500mg Benolea/day 2 x 12.5 mg Captopril/day Randomized, double-blind, double-dummy design Susalit E et al, Phytomedicine 2011 vol 18 18

19 Change from baseline (mmhg) Clinical Study 2 Efficacy of Benolea to reduce blood pressure (*p < 0.05) - 6 Blood pressure-reducing effect of Benolea is similar to Captopril * Benolea Captopril * Duration of treatment (weeks) Susalit E et al, Phytomedicine 2011 vol 18 19

20 Change from baseline (mg/dl) Change from baseline (mg/dl) Clinical Study 2 Efficacy of Benolea to improve blood lipids Total cholesterol Triglycerides 0 0 Blood lipid-lowering effect of Benolea, compared to Captopril Duration of treatment (weeks) Benolea Captopril 4 8 Duration of treatment (weeks) Benolea Captopril Susalit E et al, Phytomedicine 2011 vol 18 20

its components Patented blend citrus and olive leaf extract Extract form

22 Characteristics Efficacy and safety confirmed by proprietary studies Multicomponent system, develops its activity profile by synergic effect of its components Patented blend citrus and olive leaf extract Extract form Powder Recommended dose 400 mg/day Standardization Oleuropeosides 18% Flavonoids 12% 22

23 Mode of action Digestive enzyme inhibition + blocking of the association of fatty acids with bile salt micelles Antioxidant activity Antioxidant activity Prostacyclin NO Triglycerides Ox-LDL Vessel wall integrity Vascular elasticity Anti-atherosclerotic action Vasoprotective action 23

24 Atherosclerosis Lumen Most cardiovascular diseases results from complications of atherosclerosis Major initiating event is the oxidation of LDL 24

Clinical Study Efficacy of Citrolive TM to reduce triglyceride levels and ox-ldl Triglyceride levels Ox-LDL Participants: 23 volunteers 18-65 years-old Inclusion criteria: total cholesterol > 200

25 Clinical Study Efficacy of Citrolive TM to reduce triglyceride levels and ox-ldl Triglyceride levels Ox-LDL Participants: 23 volunteers years-old Inclusion criteria: total cholesterol > 200 mg/dl and/or LDL-C > 130 mg/dl mg/dl % U/L % 43 Treatment : Citrolive TM 500 mg/day double blind trial, 3 month study 95 Placebo Citrolive 0 Placebo Citrolive Baseline levels Post-treatment levels 25

Characteristics Appreciated as culinary ingredient worldwide and long tradition of medicinal use Efficacy and safety confirmed by proprietary

27 Characteristics Appreciated as culinary ingredient worldwide and long tradition of medicinal use Efficacy and safety confirmed by proprietary studies Extract form Recommended dosage Powder 180 mg/day Multifunctional ingredient with triple mode of action on blood glucose metabolism 27

Tradition Purslane herb: a cosmopolitan plant Fast growing herb, with thick, fleshy, oval leaves Originating from Southern Asia Growing wild or cultivated in tropical and temperate regions worldwide

28 Tradition Purslane herb: a cosmopolitan plant Fast growing herb, with thick, fleshy, oval leaves Originating from Southern Asia Growing wild or cultivated in tropical and temperate regions worldwide including Mediterranean region Traditional use in folk medicine Used by ancient Egyptians for a variety of conditions including headache and stomach pain Usage as antidiabetic herb in Near East, Northern Africa, Mexico, China 28

29 Activity Reduced glucose absorption from intestine into blood stream Increased glucose uptake from blood stream into cells Triple mode of action of Portusana confirmed by in-vitro studies Modulation of cell sensitivity to Insulin 29

30 HbA1 mean changen (%) Clinical Study Efficacy of Portusana to keep glucose on track 12 Weeks Randomized, double-blind placebo-controlled trial Participants: 63 subjects 31 with portusana extract 32 with placebo Effect of Purslane extract on HbA1c 6 weeks 12 weeks 0 3 CAPSULES. OF 60MG/DAY Responders subgroup (participants whose HbA1c was less than baseline) 41 subjects - Systolic blood pressure - serum cholesterol group Placebo Purslane extract * p < 0.05 Significant reduction of HbA1c by 0.85, outperforming placebo by 44 % 16 with portusana extract 25 with placebo Wainstein, J., et al.. Journal of Medicinal Food, 2016, 19(2):

31 In vitro Study Portusana induces the translocation of glucose transporter 4 (GLUT4) from intracellular storage to the plasma membrane in an insulin-like manner 31

32 Thanks for your attention 32

Contact us for more information: GENERAL CONTACT: health@frutarom.com BELGIUM Ambachtsstraat 6 1840 Londerzeel +32 52 319 534 SPAIN Camino Viejo de Pliego Km.

33 Contact us for more information: GENERAL CONTACT: BELGIUM Ambachtsstraat Londerzeel SPAIN Camino Viejo de Pliego Km. 2, Alcantarilla, Murcia GERMANY Blyinghausen Stadthagen +49 (0) SWITZERLAND Rütiwisstrasse Wädenswil SLOVENIA Nova vas pri Markovcih Markovci USA 55 Railroad Ave Ridgefield, NJ Whatever can be natural should be natural

Managing High Blood Pressure Naturally. Michael A. Smith, MD Life Extension s Healthy Talk Series

Managing High Blood Pressure Naturally Michael A. Smith, MD Life Extension s Healthy Talk Series Part 1 What is Blood Pressure? Blood Pressure Systole Systolic Forward Pressure 110 mmhg 70 mmhg Diastole