Wilmore Labs LLC.

Developer and Patent HolderBuccal Delivery of Resveratrol

Summary

• US Patent #9,125,858• Proven Vasodilator • Initial Bench Formulation Success (Sample size 4)

• Seeking $350,000 for mid-size Pre-Clinical Study for Proof of Delivery Effectiveness

Potential Clinical Market

• Primary: – Angina– 10 Mil patients in USA & increasing– Angina avg. 1 yr (2011). all-cause per-patient cost:

$28,590.00

• Secondary: – Atherosclerotic Cardiovascular Disease (CVD)– 335 Mil prescriptions yr in USA– 83 Mil patients living with some form of CVD disease in

USA– CVD avg. 1 yr. all-cause per-patient cost: $14,334.00

over 12 months

Image via: Ian Furst

Oral Transmucosal 3,5,4'-trihydroxystilbene/ Resveratrol (OMTR)

•Scientific name 3,5,4’ – trihydroxystilbene/ common name Resveratrol

•First published method for oral-transmucosal Resveratrol delivery in humans

• USA patent for method for delivery (Issued 9/8/2015) : Patent # 9,125,858

•USA Patent pending composition of matter patent : Application # 12/955,810

Virtual Academic Advisory Board• The following have been involved, and would like to continue their

involvement, with development for clinical applications.

– James M Smoliga DVM, PhD, School of Pharmacy, High Point University

– Eva M Rzucidlo MD, Dartmouth Medical School– Ole Vang PhD, Roskilde University, Denmark– Joseph Baur PhD, Perelman School of Medicine, U.

Pennsylvania

There is a clinical need for new novel acute angina therapeutics as alternatives to nitrates• Multiple side effects of Nitrates.

– Rebound effect with overuse can induce ischemic event– poor prognosis for long term use

• As stated by Munzel and Gori (2013)*, the current findings show that long-term therapy with organic nitrates has been associated with a worsening in the prognosis of patients with ischemic heart disease

• And continued “prolonged exposure to organic nitrates induces tolerance, sympathetic activation, and endothelial dysfunction in patients with cardiovascular disease & healthy volunteers.”

* Thomas Munzel and Tommaso Gori (2013) Nitrate therapy and nitrate tolerance in patients with coronaryartery disease Current opinion in Pharmacology

The four barriers to using oral dosing of 3,5,4'-trihydroxystilbene (resveratrol) as a vasodilator for chronic & sudden onset cardiovascular conditions.

1) Therapeutic concentrations (C ≥228ng/ml or 1uM) requires oral dosage >\= 2.5g + oral dosage

2) Gastrointestinal side effects with an oral dosage of 1.0g or larger

3) High cost/ benefit for active ingredient per relevant dosage vs. current therapeutics

4) Long time to achieve therapeutic concentration for an acute therapeutic (Tmax 45-90+ min)

Barriers to Oral Resveratrol as an acute angina

therapeutic

OTMR dosing addresses these barriers to further development. The three points here address therapeutic levels, side effects, and benefit/cost

• We have shown plasma levels [Blue box] that have restored myocardial perfusion in a swine model.

1. The 325ng/ml levels from buccal dosing support the potential of for the treatment of angina and CVD conditions.

2. The dosage of 0.14g is below the 1.0g + oral dosage shown to cause gastrointestinal side effects

3. The 0.14g dosage is comparable in cost to nitrates and has potential for improved clinical outcomes and no expectations of rebound effect

In Vivo Therapeutic Range

OTMR

As with buccal nitrates, buccal 3,5,4'-trihydroxystilbene (resveratrol) rapidly achieves dose delivery to potentially provide relief for angina.

4. Therapeutic levels occur near or before 12-15 minutes from OTMR dosing compared with 45-90 minutes for oral dosing with 2.5g-5.0g.

OTMR

Resveratrol has been shown to restore cardiac blood flow at plasma concentrations of approximately 228ng/ml and greater

• The representative swine hearts shown here all have surgically implanted blockage to a cardiac artery.

• The Resveratrol in Swine Heart “C” restored blood flow around the implanted blockage (via proximal collaterals).

• Our prototype buccal delivery resveratrol lozenge had rapid delivery of 325ng/ml plasma in humans.

Strong support to explore the potential for OTMR in humans for acute angina.

Figure & swine data from:

Summary of therapeutics for chronic stable angina & CVD

• Nitrates: – relief of sudden onset attacks – patches may have dual use as prophylactics

• Serious side effects

• ACE inhibitors, calcium channel blockers, Nicorandil, ranolazine, ivabradine, diuretics, etc.

– Prophylactic interventions– Limit heart capacity or plasma volume for effect

• Angioplasty, stent placement, heart bypass– Surgical interventions

• Long term risk factor modification including smoking cessation, daily anti-platelet agent, and statin therapy

Image: Blausen.com staff

Clinical Market: additional potential indications• Peripheral artery disease (PAD)

– Underserved by therapeutic market– Stents are broadly utilized– Expected $3B market by 2017– 10 million affected patients US 2017

• Friedreich’s ataxia – Disabling & Fatal Orphan Disease– Mutations affecting FXN– No current treatment

• Mild to Moderate Erectile Dysfunction – Unique mechanism to PDE5 inhibitor (i.e. Viagra)– Issues with efficacy with low Nitric Oxide production

Image: National Heart Lung and Blood Institute

At a Glance: Clinical Market Development• Abundant animal activity and toxicity studies are available for safety

and therapeutic range.

• Prior Phase I clinical trials completed with 5000mg bid dosages– GlaxoSmithKline completed multiple Phase I trials with their proprietary formulation for

increased gastrointestinal absorption of resveratrol, SRT-501 (with Resveratrol as only active molecule), which was an oral dosage of 2.5g-5.0g of Resveratrol blended with a 12oz-16oz water + detergents per dosage in 2006 & halted in Phase II in 2010.

• Moderate positive therapeutic effect on blood sugar levels in humans, but poor tolerance (GI side effects) and poor patient compliance, w/ SRT-501.

– SRT-501 Phase II development for cancer & diabetes (positive physiological effect), halted w/ poor patient compliance (poor taste, high costs (~$10k/yr+), & poor gastrointestinal tolerance.

Featured Publications• Blanchard OL & Smoliga JM (2015) Translating dosages from animal models to

human clinical trials - revisiting body surface area scaling, Federation of American Societies for Experimental Biology (FASEB) Journal pii: fj.14-269043. PMID: 25657112

• Smoliga JM & Blanchard OL (2014) Enhancing the Delivery of Resveratrol in Humans: If Low Bioavailability is the Problem, What is The Solution? Molecules19(11):17154-17172 PMID: 25347459

• Blanchard OL, Friesenhahn G, Javors MA, Smoliga JM. (2014) Development of a Lozenge for Oral Transmucosal Delivery of Trans-Resveratrol in Humans: Proof of Concept PLoS ONE 9(2): e90131. PMID: 24587240

Supplemental: Mini-Resumes and CV’s for Academic Advisors, etc.

• The following have been involved, and would like to continue their involvement, with development for clinical applications. – Joseph Baur PhD, Perelman School of Medicine, U.

Pennsylvania – Eva M Rzucidlo MD, Dartmouth Medical School– Ole Vang PhD, Roskilde University, Denmark– James M Smoliga DVM, PhD, School of Pharmacy, High

Point University– Otis Blanchard

Scientific Genealogy: in Brief• Dr Joseph Baur et al. (2006) published “Resveratrol improves health and survival of mice on a high-calorie diet.” in

the journal Nature which was featured in the NY Times, etc.

• Another notable work by Dr Joseph Baur from his post-doctorial training at Harvard was “Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice”., also with Dr Martin Javors at the Health Science Center in San Antonio’s Barshop institute for aging research.

• Dr Joseph Baur went on to train Dr James Smoliga where they published two reviews and one work of original research. One example includes authorship by Dr Ole Vang, Challenges of translating basic research into therapeutics: resveratrol as an example.

• Dr James Smoliga allowed Otis Blanchard to work in his new lab, if he paid all expenses and executed all guidelines for human, starting in October 2011 building our professional research relationship over the years.

• Otis Blanchard and Dr James Smoliga were introduced to Dr Martin Javors at the Health Science Center in San Antonio to perform the blood analysis for the pilot work. The collaboration enabled Otis’ research work Development of a Lozenge for Oral Transmucosal Delivery of Trans-Resveratrol in Humans: Proof of Concept to be completed and published in early 2014.

Joseph Baur, PhD – Philadelphia, PAAssistant Professor of Physiology at Perelman School of Medicine at the University of

Pennsylvania.

• When at Harvard University, Dr. Baur was the first to show resveratrol is able to improve insulin sensitivity with high dosages in obese mice.

• The Baur Lab explores the basic mechanisms of aging. – Age is the most important risk factor for many of the diseases affecting

industrialized society today, including cardiovascular disease and neurodegenerative disorders.

Featured Publications: Joseph A Baur• Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, An SS, Santhanam L, Martin B,

Faulkner S, Morrell C, Baur JA, Peshkin L, Sosnowska D, Csiszar A, Herbert RL, Tilmont EM, UngvariZ, Pearson KJ, Lakatta EG, & de Cabo R (2014) Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab 20, 183-190 PMID: 24882067

• Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis, J. G., Varamini, B., Hafner, A., Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, & Sinclair DA (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15, 675-690 PMID: 22560220

• Baur JA, & Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5, 493-506 PMID: 16732220

• Baur JA et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-342 PMID: 17086191

Eva M Rzucidlo, M.D. – Lebanon, NH Associate Professor of Surgery, Heart and Vascular Research Center, Department of

Vascular Surgery, Geisel School of Medicine

• Among other interests in cardiovascular disease, Dr Rzucidlo’s lab is investigating the role of Resveratrol in vascular smooth muscle cell phenotypic modulation which would have implication in therapy for the treatment of intimal hyperplasia and atherosclerosis regression.

• Practice specializing in Cerebrovascular Disease, Endovascular and Minimally Invasive Vascular Surgery, Peripheral Arterial Disease, Renal Artery Disease, Venous Disease

Featured Publications: Eva M Rzucidlo• Thompson AM, Martin KA, & Rzucidlo EM (2014) Resveratrol induces vascular smooth muscle cell

differentiation through stimulation of SirT1 and AMPK. PLoS One 9, e85495 PMID: 24416418

• Rzucidlo EM (2009) Signaling pathways regulating vascular smooth muscle cell differentiation. Vascular 17 Suppl 1, S15-20 PMID: 19426604

• Rzucidlo EM, Martin KA, & Powell RJ (2007) Regulation of vascular smooth muscle cell differentiation. J Vasc Surg 45 Suppl A, A25-32 PMID: 17544021

• Fillinger MF, Racusin J, Baker RK, Cronenwett JL, Teutelink A, Schermerhorn ML, Zwolak RM, Powell RJ, Walsh DB, & Rzucidlo EM (2004) Anatomic characteristics of ruptured abdominal aortic aneurysm on conventional CT scans: Implications for rupture risk. J Vasc Surg 39, 1243-1252 PMID: 15192565

Ole Vang, PhD – Roskilde, DenmarkAssociate Professor, Department of Science, Systems and Models at Roskilde

University

• Experienced in long term investigations of resveratrol on management of metabolic syndrome, osteoporosis, inflammation, and identification of plant derived anti-inflammatory compounds.

• Vang Lab is focusing on the cellular mechanism of action of resveratrol and resveratrol derivatives.

• Organizes the international conferences on Resveratrol and Health

Featured Publications: Ole Vang• Widlund AL, Baur JA , Vang O (2013), mTOR: more targets of resveratrol?, Expert Rev.Mol.Med., 15

(2013) e10. PMID: 24060150

• Vang, O. (2013) What is new for resveratrol? Is a new set of recommendations necessary? Ann N Y Acad Sci 1290, 1-11, Food Chem., 101, 449-457. PMID: 23855460

• Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM, (2011) What is new for an old molecule? Systematic review and recommendations on the use of resveratrol, PLoS One, 6, e19881. PMID: 21698226

James Smoliga, DVM, PhD – High Point, NCAssociate Professor, School of Pharmacy, High Point University

• Translational pharmacology of resveratrol to identify the difficulties which surround bringing basic research to clinic. This interest expands to the effects of resveratrol on cardiovascular disease in humans, as reflected by recent studies.

Featured Publications: James M Smoliga• Hausenblas HA, Schoulda JA, and Smoliga JM (2015) Resveratrol treatment as an adjunct to

pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Mol NutrFood Res 59, 147-159 PMID: 25138371

• Smoliga JM, Colombo ES, and Campen, M. J. (2013) A healthier approach to clinical trials evaluating resveratrol for primary prevention of age-related diseases in healthy populations. Aging 5, 495-506 PMID: 24073437

• Smoliga JM & Blanchard OL (2014) Recent data do not provide evidence that resveratrol causes ‘mainly negative’ or ‘adverse’ effects on exercise training in humans. The Journal of Physiology 591: 5251–5252. PMID: 24130323

• Agarwal B, Campen MJ, Channell MM, Wherry SJ, Varamini B, Davis JG, Baur JA, and Smoliga JM (2013) Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int J Cardiol 166, 246-248 PMID: 23098852

• Smoliga JM, Vang O, and Baur JA. (2012) Challenges of translating basic research into therapeutics: resveratrol as an example. J Gerontol A Biol Sci Med Sci 67, 158-167 PMID: 21746739

Otis Blanchard (founder and patent holder)B.S. Biology; B.B.A. Management, University of Texas at San Antonio. Graduate studies

at University of Texas – Austin: Cell & Molecular Biology.

• Recognized expert in Resveratrol translational Pharmacology and dosage design. – Four publications on subject from 2013

• Protections for buccal delivery of resveratrol. – U.S.S.N. 14/691,320 :Method patent issued Q3 2015– U.S.S.N. 12/955,810 :Expected issuance of composition of matter patent in 4Q

2015

Publications: Otis Blanchard• Blanchard OL & Smoliga JM (2015) Translating dosages from animal models to human clinical trials - revisiting body

surface area scaling, Federation of American Societies for Experimental Biology (FASEB) Journal pii: fj.14-269043. PMID: 25657112

• Smoliga JM & Blanchard OL (2014) Enhancing the Delivery of Resveratrol in Humans: If Low Bioavailability is the Problem, What is The Solution? Molecules 19(11):17154-17172 PMID: 25347459

• Blanchard OL, Friesenhahn G, Javors MA, Smoliga JM. (2014) Development of a Lozenge for Oral Transmucosal Delivery of Trans-Resveratrol in Humans: Proof of Concept PLoS ONE 9(2): e90131. PMID: 24587240

• Smoliga JM & Blanchard OL (2013) Recent data do not provide evidence that resveratrol causes 'mainly negative' or 'adverse' effects on exercise training in humans. J Physiol. 2013 Oct 15;591(Pt 20):5251-2. PMID: 24130323

• Grey et al. (2009) The planar cell polarity effector Fuz is essential for targeted membrane trafficking, ciliogenesis and mouse embryonic development. Nat Cell Biol. 2009 Oct;11(10):1225-32. PMID: 19767740