Driving Value from Lead to Clinic

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Elke Lipka, PhD, MBAPresident

elipka@tsrlinc.com

Drew Hertig, MBABusiness Development

ahertig@tsrlinc.com

Modified Dosage Forms for Water-Insoluble DrugsA Patented Approach for Extended or Delayed Release Delivery

Contents

• Team

• Strategy

• Intellectual Property

• Proof-of concept

• PK/PD Rationale

• Commercial Rationale

• TSRL Proposal

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TSRL Management Team

Gordon Amidon, PhD, Chairman and CSOProfessor of Pharmacy, University of Michigan, Internationally recognized expert in the field of solubility, transport phenomena, prodrugs, and drug absorption with more than 40 year of research experience

Elke Lipka, PhD, MBA, PresidentDirector Strategic Operations & Assoc. Research Fellow (Parke-Davis, Pfizer, Esperion); 20 years of drug development experience and management of business operations and strategic partnerships

Dawn Reyna, Senior Director Laboratory Services17 years experience in quality assurance, toxicology study conduct, and pharmaceutical research management (MPI Research, Pfizer)

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TSRL Formulation Strategy

• Unique Formulation for Modified Release• Solubility; Bioavailability

• Match Region of Interest & Release Rate

• Allow for Reduced Dose(s)

• Minimize Toxicity

• Improve Compliance

• Patented Formulation

• 505(b)(2)Submission• Reduced Cost

• Reduced Time

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Technology Highlights

• Pharmaceutical Composition

• Hydrophilic Solubility Technology

• Aqueous-based coating system

• Controlled release excipient

• Delayed release coating

• Method of Making such Composition

• Flexible formulation platform for designing optimized drug product release rates

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Extended Delivery Addressing Common Disease States:

Cholesterol Synthesis

Cardiovascular Disease

Asthma Bronchial

Peptic Ulcer Disease

Gastric Secretion

Metabolic syndrome, and consequently obesity, Type 2 diabetes and dyslipidemia

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Pain

Renal

Antiparasitics

Antibacterials

Antifungals

Immunosuppressants

Inflammation

IP: US 8,535,716

• Broad coverage: Any API and combinations of active ingredients (platform patent)

• There are nine layers of claims on how it is formulated (heightens barrier to entry)

• Patent valid through Sept 2033

• Initial FTO: no issues found regarding similar valid patents

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Methods and Composition of Delayed and Extended Delivery of Water Insoluble Drugs

• Initial freedom to operate opinion– no issues found regarding similar issued or valid patents

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Supported IP Cont’d

Our family of drug delivery IP:

Supported IP for this proposal

Clinical Proof-of-concept

Goal – To demonstrate scale up of HST formulations and proof-of-concept for example drug in normal healthy volunteers

• BA/BE study conducted at the University of Mainz, Germany

• Simvastatin was chosen as the example drug/API

• Dosage forms prepared – HST-immediate release, HST-delayed release

• 7 normal healthy volunteers (6 male, 1 female)

• Study design – randomized, open, three phase, single dose study

• Reference agent - Zocor®

• Bioanalysis – Validated LC/MS/MS method

• PK analysis - WinNonlin

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Results – Simvastatin and acid metabolite

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Tubic-Grozdanis et al., Pharm. Res., 25(7), 2007, page 1591-1600

Results – Summary

• Simvastatin is a substrate for CYP3A in the intestine and liver; a major reason for low oral bioavailability

• HST-delayed release increases exposure of Simvastatin by ~3-fold compared to Zocor® or HST-immediate release

• HST-delayed release increases half-life of Simvastatin compared to Zocor®

• Exposure of metabolite (acid) was similar although half-life was longer in HST-delayed release compared to Zocor® or HST-immediate release

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Tubic-Grozdanis et al., Pharm. Res., 25(7), 2007, page 1591-1600

• Drugs and disease state mechanisms that follow circadian pattern and underserved by marketed immediate release formulations can be more effectively delivered using HST-delayed or extended release

• HST technology can provide for extended or delayed release formulations to achieve better therapeutic efficacy at lower doses by modulating plasma or target organ delivery of drug or metabolite(s)

• For approved drugs that result in poor compliance due to high peak concentration or exposure, HST formulations can modulate PK profile to retain efficacy and concomitantly reduce systemic toxicity.

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PK/PD Rationale for choice of APIs

Examples of possible APIs

Market Size >5 billion: Cyclosporin, griseofulvin, digoxin, nifedipine, itraconazole, carbamazepine, piroxicam, fluconazole, finasteride, diflunisal, lovastatin, simvastatin and glipizide

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0 200 400 600 800 1000 1200 1400 1600 1800

MILLIONS USD

2013 WW Sales of Select Generics

Simvastatin

Nifedipine

Cyclosporin

Commercial Feasibility & Testing

• Process inexpensive to test and scale up

• No harmful solvents used

• Modified pharmaceutical ingredients can be manufactured with standard mixing/coating/freeze drying equipment

• Preparation of 5-8 batches of API/polymer systems and assessment of their dissolution characteristics per USP dissolution under $10k

• Cost does not include API & excipients

TSRL will provide:• Relevant data regarding technology• Suggestions for excipients covered under IP

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Expectations

• Low-cost option to test technology

• Upfront payment upon transfer

• Development & commercial milestones

• Royalties on net revenues

• Flexibility on licensing terms (field of use, scope)

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Summary

Match Region of Interest & Release Rate

Allow for Reduced Dose & Minimize Toxicity

Simple Manufacturing Steps, Non-Toxic Solvents

Opportunity for Data Exclusivity & Unique Label Claims

Potential for 505(b)(2) Submission

Issued Patent Protection Until 2033

Flexible Terms

Covers Formulations with Significant Market Potential

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