OLYMPIC THERAPEUTICS

Warren Wheeler Olympic was formed to develop and achieve MBA, Principal, [email protected] regulatory approval for a new class Richard C. Honour of Drugs for the treatment of PhD, Principal, [email protected] Resistant, Invasive, Opportunistic or other www.olympictherapeutics.com Life-Threatening Fungal . Fungal Sepsis

Sepsis: Immune Response (Immune over-response) to that causes injury to tissues and organs: • $24 billion added costs/yr • 40% of patients with severe sepsis do not survive • 50% of survivors suffer post-sepsis syndrome

The most costly and life-threatening Fungemic condition.

Fungemia: The presence of fungi in the blood: • 70% incited by C albicans • 10% incited by C glabrata • C auris is an emerging multidrug-resistant that causes invasive and fungemic infections associated with high mortality • Incited also by Saccharomyces, and Cryptococcus spp Diagnosis and management of invasive in the ICU: an updated approach

• Invasive fungal infections in critically ill patients are associated with high morbidity and mortality • Candida and Aspergillus Spp are most frequent causes of healthcare- associated fungal infections • Candida species account for 70 - 90% of invasive fungal infections • Candida infections are the most frequent fungal infections in the ICU • About 30 - 35% of all episodes of Candidemia occur in ICU patients • Rates of Candidemia in ICUs are increasing • is a highly lethal infection with mortality rates of 40 - 60% • Most common species are C albicans, C glabrata, C tropicalis, C parapsilosis and C krusei • Invasive is associated with yet higher morbidity and mortality Globally, Fungal Pathogens Incite More Than:

• 1.0 Billion cutaneous fungal infections/yr • 12.0 Million life-threatening infections/yr • 1.6 Million deaths/yr

Greatest Challenges to Clinical Success:

• Echinocandin resistance in Candida spp • Azole resistance in Candida and Aspergillus spp • Multidrug resistance in and C auris • Few new antimycotic drugs in development; No new classes

Olympic is targeting resistant, invasive, opportunistic, life-threatening mycoses in immunocompromised persons, such as persons with weakened immunity, including AIDS, cancer and transplant patients, plus persons with inherited diseases that affect immunity. US Department of Health & Human Services Centers for Disease Control and Prevention

• Candida is the most common cause of healthcare-associated bloodstream infections in the US • Candida bloodstream infections add 3 - 13 days of hospitalization and $6,000 - $29,000 to healthcare costs per patient • Candida spp are increasingly resistant to first-line and second-line (fluconazole and echinocandins [anidulafungin, caspofungin and micafungin]) • About 7% of Candida glabrata bloodstream isolates are resistant to fluconazole • Echinocandin resistance appears to be on the rise, especially in Candida glabrata • Up to 8% of Candida glabrata isolates in 2014 are resistant echinocandins, with the rate doubling from 4% in 2008 • Echinocandins are the mainstay of treatment for fluconazole- resistant Candida glabrata Limitations of Antifungal Drugs:

• Fungistatic, not fungicidal • High Resistance to single drugs • Broad Multidrug Resistance • Highly toxic (Except for Echinocandins) • IV administration is required • High cost of drugs and administration

Immune Dysregulation is a Primary Risk Factor for Fungal Infections:

• Among immunocompetent hosts, keratitis and are most common (May include sinusitis, pneumonia, thrombophlebitis, peritonitis, fungemia, endophtalmitis, septic arthritis, vulvovaginitis and osteomyelitis) • In immunocompromised hosts, any in the environment may be pathogenic • Aspergillus and Candida spp. are most frequent in immunocompromised patients • Other fungal aetiologic agents of immunocompromised hosts may include: • Cryptococcus spp. • spp. • Zygomycetes () • Dematiaceous fungi • Opportunistic yeast-like fungi Invasive Fungal Opportunistic Infections: Fungal Infections:

• Greater than 50% mortality • Cryptococcal meningitis • Most result from impaired immunity ( or C • Most caused by Candida, Aspergillus, gattii) Cryptococcus or Pneumocystis • • Many caused by dimorphic fungi that (, formerly P incite: carinii) • ( • Histoplasmosis () capsulatum) • (Coccidioides • infection immitis or C posadasii) • Emerging mycoses, such as: • • Emmonsiosis (Emmonsia (Paracoccidioides brasiliensis) pasteuriana) • Pythiosis (Pythium insidiosum [an Oomycete]) Antimycotic (Antifungal) Resistance:

• Fungi intrinsically resistant to conventional antifungal drugs include Aspergillus tares (), Candida krusei (Fluconazole) Cryptococcus spp. (Echinocandins) • Biofilms confer all or partial resistance to most drug classes • The occurrence of drug-resistant Cryptic Species is increasing • Emerging species resistant to all antifungal drug classes (C auris) are increasing • Echinocandins are critical for treatment of resistant, invasive, opportunistic candidiasis Antifungal Markets

Forecasted Market Growth for Antifungal Therapeutics:

Global: $13.9 billion (2018) - $17.4 billion (2025) US: $4.9 billion (2013) - $5.5 billion (2018) Europe: $3.9 billion (2013) - $4.4 billion (2018)

Antifungal Market Segmentation:

Drug Type: Azoles, Echinocandins, Polyenes, “Other” Indication: Aspergillosis, , Candidiasis, “Other” Application: Topical vs Oral Geography: North America, Asia-Pacific, Europe, Rest of World Antifungal Market Makers Pharmaceutical Antifungal Manufacturers

Prescription Drug Manufacturers OTC Drug Manufacturers

Abbott Laboratories Kramer Laboratories Alva-Amco Pharmacal Arbor Pharmaceuticals Merck & Co Blaine Labs Astellas Pharma Novartis International AG Dartmouth Baxter Pfizer Pharmaceuticals Bayer HealthCare Sanofi-Aventis McNeil Consumer Healthcare Enzon Pharmaceuticals Taro Pharmaceutical Ind PEDiNOL Pharmacal Galderma Pharma SA Teva Pharmaceutical Ind Perrigo Company Gilead Sciences Valeant Pharmaceuticals Stiefel Laboratories GlaxoSmithKline Vertex Pharmaceuticals Tarmac Products Johnson & Johnson Classes of Azoles (Five-membered heterocyclic compounds): • Ketoconazole (Original) Antifungal • Triazoles (Original) - Fluconazole, Itraconazole Drugs: • Triazoles (New) - Voriconazole, Posaconazole, Ravuconazole (Azole-resistant: Candida glabrata, C haemulonii complex, C auris, C tropicalis and C krusei (Resistant to Fluconazole, Voriconazole and Posaconazole), and, Aspergillus lentulus, A fumigatiaffinis, A viridinutans, A pseudofischeri, A flavus, A niger, A terreus (Resistant to Itraconazole, Voriconazole and Posaconazole))

Echinocandins (Derived from Papulacandins from Papularia [Arthrinium] sphaerosperma): • Anidulafungin • Caspofungin • Micafungin (Echinocandin-resistance: , C. glabrata, C. lusitaniae, C. tropicalis, and C. parapsilosis)

Polyenes (Macrolides derived from Streptomyces spp): • Amphotericin B • Nystatin • Natamycin (Pimaricin) (Amphotericin B was primary therapy for Invasive Fungal Infections (IFIs), including invasive aspergillosis, , , candidaemia, coccidioidomycosis, histoplasmosis, and ; however, renal toxicity relegated it to a second-line therapy) (Amphotericin B-resistant species include Scedosporium spp, Fusarium spp, spp, , Aspergillus nidulans, A terreus, A flavus, A calidoustus, and A lentulus, Candida albicans, C krusei, C glabrata, C rugosa, C lusitaniae, C neoformans, C auris, C tropicalis, and the (Mucorales are resistant mostly to Itraconazole and Voriconazole, leaving Posaconazole as the only azole with activity) Azole Products:

Sporanox-PulsePak (Itraconazole-tablets), meningitis-immunocompetent-host, Noxafil (Posaconazole-delayed-release-tablets), Cryptococcosis, Cutaneous-fungal-infection, Diflucan (Fluconazole-injection-solution), Dermatophytosis, Esophageal-candidiasis, Nizoral (Ketoconazole-systemic), Mycelex Troche , Febrile-neutropenia, Fungal- (Clotrimazole-oral), Cresemba (Isavuconazonium- infection-prophylaxis, Fungal-infection- sulfate-capsules), Onmel (Itraconazole-tablets), disseminated, Fungal-meningitis, Fungal- Oravig (Miconazole-oral), Vfend (Voriconazole- peritonitis, Fungal-pneumonia, Fusariosis, injection) Histoplasmosis, , Mucormycosis, Fungal-infection, Onychomycosis-fingernail, Azole Indications: Aspergillosis-, Onychomycosis-toenail, Oral-thrush, Aspergillosis-invasive, Blastomycosis, Bone- Paracoccidioidomycosis, Pseudoallescheriosis, marrow-transplantation, Candida-urinary-tract- , Systemic-candidiasis, Systemic- infection, Candidemia, Chromomycosis, Chronic- fungal-infection, Tinea-capitis, Tinea-corporis, mucocutaneous-candidiasis, Coccidioidomycosis, Tinea-Cruris, Tinea-versicolor, Vaginal-candidiasis Coccidioidomycosis-meningitis, Cryptococcal-

Echinocandin Products:

Cancidas (Caspofungin), Eraxis (Anidulafungin), Mycamine (Micafungin)

Echinocandin Indications: Aspergillosis-Invasive, Candidemia, Esophageal-Candidiasis, Febrile- Neutropenia, Fungal-Infection-Prophylaxis Polyene Products:

Nilstat (Nystatin-tablets-and-capsules), Abelcet Coccidioidomycosis, Coccidioidomycosis- (Amphotericin-b-lipid-complex), AmBisome meningitis, Cryptococcal-meningitis- (Amphotericin-b-liposomal), Amphocin immunocompetent-host, Cryptococcal- (Amphotericin-b-conventional), Amphotec meningitis-immunosuppressed-host, (Amphotericin-b-cholesteryl-sulfate-complex), Cryptococcosis, Esophageal-candidiasis, Bio-Statin (Nystatin-tablets-and-capsules), Febrile-neutropenia, Fungal-endocarditis, Fungizone (Amphotericin-b-conventional), Fungal-infection-prophylaxis, Intestinal- Mycostatin (Nystatin-tablets-and-capsules) candidiasis, Histoplasmosis, Histoplasmosis- immunocompetent-host, Histoplasmosis- Polyene Indications: Aspergillosis-aspergilloma, meningitis, Leishmaniasis, Oral-thrush, Aspergillosis-invasive, Blastomycosis, Paracoccidioidomycosis, Sporotrichosis Candida-urinary-tract-infection, Candidemia, “Other” Antifungal Agent

Grifulvin+V (Griseofulvin-microsize-tablets), meningitis-immunocompetent-host, Lamisil (Terbinafine-tablets), Gris-PEG Cryptococcal-meningitis-immunosuppressed- (Griseofulvin-microsize-tablets), Ancobon host, Cryptococcosis, Cutaneous-candidiasis, (Flucytosine), Fulvicin+P (Fulvicin-p-g), Terbinex Dermatophytosis, Fungal-endocarditis, (Terbinafine-tablets Terbinafine/Terbinex) Onychomycosis, Onychomycosis-fingernail, Onychomycosis-toenail, Systemic-fungal- “Other” Indications: Candida-urinary- infection, Tinea-barbae, Tinea-capitis, Tinea- tract-infection, Candidemia, Cryptococcal- corporis, Tinea-cruris, Tinea-pedis Product/Market Objective:

• Olympic has access to a chemistry with known antimycotic activity in multiple derivatives, analogues and formulations • Olympic has access to an immune-modulating chemistry with known favorable activity as an adjuvant for use with antimicrobial drugs • Olympic is capturing core Intellectual Property surrounding novel combinations of the antimycotic chemistry and the immune-modulating adjuvant, providing a new class of antimycotic drug intended to address substantial global markets • Olympic will synthesize the core Antimycotic Drug(s) and the Immune-Modulating Drug(s) with the intent to formulate and test novel Antimycotic Product Candidates • Olympic will screen the resulting Antimycotic Product Candidates against an array of fungal infectious agents for antimycotic activity and for the emergence of resistance • Olympic will engage a Manufacturing Contract Research Organization (Manufacturing CRO) to produce Near Current Good Manufacturing Practices (Near cGMP) lots of the resulting Antimycotic Product Candidate Active Ingredient and the Immune-Modulating Adjuvant Active Ingredient for use in formulations, screening and preclinical studies under Current Good Laboratory Practices (cGLP) guidelines • Elucidation of the Mechanism of Action and subsequent Reduction to Practice will generate a stream of new Intellectual Property intended to validate the New Class of Antimycotic Drugs Intellectual Property (IP) Strategy

• Olympic is developing a new class Antimycotic Drugs that will employ a unique Active Ingredient (AI), combined with an Immune-Modulating Adjuvant (IMA). • The IMA signals the Innate Immune System through toll-like receptor 7 (TLR7), which is involved in pathogen recognition. The IMA activates Langerhans cells, which migrate to local lymph nodes to activate the Adaptive Immune System. Other cell types activated by the IMA and TLR-7 secrete cytokines, such as interferon-α (IFN-α), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The IMA also incites activation of Natural Killer Cells, Macrophages and B-Lymphocytes. The IMA acts synergistically with the antifungal activity of the AI. • Olympic is capturing core Intellectual Property surrounding novel combinations of the Antimycotic AI and the IMA, offering a new class of Antimycotic Drug Products intended to address substantial global markets. • Olympic will screen the Antimycotic Product Candidates against an array of fungal infectious agents for antimycotic activity and for the emergence of resistance. • Olympic will engage a Manufacturing Contract Research Organization (Manufacturing CRO) to produce Near Current Good Manufacturing Practices (Near cGMP) lots of the Antimycotic Product Candidate AI, the IMA and the resulting formulated Product Candidate for use in screening and preclinical studies under Current Good Laboratory Practices (cGLP) guidelines. • Elucidation of the Mechanism of Action and subsequent Reduction to Practice will generate a stream of new Intellectual Property intended to validate the New Class of Antimycotic Drugs. Product/Market Objective:

Develop new Antimycotic Drug Products formulated for the treatment of: Aspergillus, Candida and Cryptococcus spp intended to replace: Amphotericin B, Fluconazole and Echinocandins

Product Candidates will be screened for activity against: • Aspergillus lentulus, A nidulans, A terreus, A flavus, A calidoustus, A fumigatiaffinis, A viridinutans, A pseudofischeri, A niger, A terreus • Candida albicans, C krusei, C glabrata, C rugosa, C lusitaniae, C neoformans, C auris, C tropicalis glabrata, C haemulonii complex, C tropicalis, C. parapsilosis • Cryptococcus neoformans, Cryptococcus gattii Pharmaceutical Development: Key Performance Milestones Antifungal Drug Product #1: Aspergillus, Candida, Cryptococcus (Estimated Timelines)

Scale-Up Manufacturing Development

Drug Substance Screening Preclinical Testing

Clinical Supplies Manufacturing

Phase I Clinical Trial

Phase II Clinical Trials (Series)

Phase I & II Report Generation

0 mo 6 mo 12 mo 18 mo 24 mo 30 mo Timeline (months) Estimated Use of Proceeds

Expenditure Line Items (Categories) ($)

Year 1 Year 2 Year 3 Product Development 1,262,013 1,615,863 1,665,215 Chemical Synthesis & Analysis 150,000 50,000 105,000 Manufacturing Development/Formulations 2,400,000 1,600,000 1,850,000 Product Activity Screening/Clinical Isolates 550,000 400,000 475,000 Preclinical Safety/Toxicology/Resistance 1,500,000 1,000,000 1,250,000 Regulatory Affairs/Documentation/QA.QC 1,048,593 1,294,482 1,289,441 Clinical Development 100,000 1,000,000 2,574,984 General & Administrative 583,829 618,050 630,411 Facility Development/Leasehold 50,004 - - Capital Expenditures 64,675 10,800 10,800 Total 7,709,060 7,589,195 9,850,851 Opportunities for Liquidity • Acquisition, License Agreement, Co-Development (36 – 40 Partnership: Months) • Pharmaceutical Company • Biotechnology Company • Institutional Investor • Secondary Offering

Note: Corporate Opportunities include License Fees and Staged Payments: • Licensing of an individual product for a specific market • Licensing of a line of Human Therapeutic products • Licensing Core Technology and Emerging Products for Specialty Markets • Acquisition of the Company to benefit from the Intellectual Property Base, Core Technology and Products in Development Project Summary

• ‘Emerging Infectious Diseases’ is a key growth sector for Big Pharma • ‘Resistant,’ ‘Invasive’ and ‘Opportunistic’ Fungal Infections represents a • Substantial new opportunity, not addressed currently by industry or academia • Alternatives to conventional antimycotics are sought by Big Pharma • Technology and product in-licensing is an active strategy of Big Pharma • Next-Generation Antimycotic Products are needed as resistance increases • A new class of Antimycotic Products, combined with an Immune-Modulating • Adjuvant, represents discrimination and innovation in global markets • Antimycotic markets show strong growth, despite continuing drug resistance • Developing a novel class of antimycotic drug products, based on a strong • Intellectual Property base, with expedited entry into first human clinical trials, • Enables addressing substantial financial markets of 2018 and beyond Glossary:

Antifungal Drug: An antifungal (antimycotic) intended to prevent or treat fungal infections Antimycotic (Antifungal) Resistance: Intrinsic or acquired resistance to an antimycotic drug Biofilm: An aggregated self-protective layer of microbial cells, within a matrix of self-produced extracellular polymeric material, that adheres to surfaces and confers resistance to penetration by antimicrobial drugs : a fatal fungal infection, it is emerging globally and is now resistant to all classes of antifungal (antimycotic) medications; C auris bloodstream infections have a 50% fatality rate; Multidrug-resistant strains of C auris cannot be treated by any of the three classes of antifungal drugs Common moulds may become invasive pathogens Cryptic Species: Closely related species, generally within a ‘complex’ of species, that are difficult to discriminate, other than by DNA analysis Dimorphic fungi: may grow either as filamentous fungi or as yeast-like single cells Drug-Resistant Candida albicans: listed as one of the 18 most serious drug-resistant infectious agents by the US Centers for Disease Control and Prevention (CDC) Immunocompromised Person: A person who is immunodeficient by any of several mechanisms, wherein the immune system is unable to respond effectively to an infectious disease or cancer Invasive Fungal Infection: A fungal infection that invades tissues and organs, commonly by Candida, Aspergillus, Cryptococcus or Pneumocystis spp, or by fungi not considered previously as being pathogens Keratitis: fungal infection of the cornea Omycetes: non-fungal, fungus-like eukaryotic microorganisms Onychomycosis: fungal infection of toenails or fingernails Opportunistic Fungal Infection: A fungal infection in an Immunocompromised person, commonly by Cryptococcus, Pneumocystis, Histoplasma or Talaromyces spp Resistant Fungal Infection: A fungal infection that is resistant to the antifungal activity of an antifungal medication, typically in response to prior or current exposure to the same antifungal medication Bibliography:

Burghi G., et al., Outcomes of mechanically ventilated hematology patients with invasive pulmonary aspergillosis, Intensive Care Med., 37:1605–12, 2011.

Calandra T., et al., Critical Care, 2016, 20:125, https://doi.org/10.1186/s13054- 016-1313-6

Colombo A.L., et al., Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter studies sequentially conducted over a 9-year period, Intensive Care Med., 40:1489–98, 2014.

Montagna M.T., et al., Epidemiology of invasive fungal infections in the intensive care unit: results of a multicenter Italian survey (AURORA Project), Infection, 41:645–53, 2013.

Vincent J.L., et al., International study of the prevalence and outcomes of infection in intensive care units, JAMA, 302:2323–9, 2009. Disclaimer. This document is offered as an overview and a starting point only - it should not be used as a single, sole authoritative guide. You should not consider this as legal guidance. Where matters of legal compliance are concerned you should always take independent advice from appropriately qualified individuals or firms. Copyright. This material is proprietary to Olympic Terapeutics and has been furnished on a confidential and restricted basis. Olympic Terapeutics hereby expressly reserves all rights, without waiver, election or other limitation to the full extent permitted by law, in and to this material and the information contained therein. Any reproduction, use or display or other disclosure or dissemination, by any method now known or later developed, of this material or the information contained herein, in whole or in part, without the prior written consent of Olympic Terapeutics is strictly prohibited. www.olympictherapeutics.com