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Overview Olympic Therapeutics 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 Antifungal Drugs for the treatment of PhD, Principal, [email protected] Resistant, Invasive, Opportunistic or other www.olympictherapeutics.com Life-Threatening Fungal Infections. Fungal Sepsis Sepsis: Immune Response (Immune over-response) to infection 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 yeast that causes invasive and fungemic infections associated with high mortality • Incited also by Saccharomyces, Aspergillus and Cryptococcus spp Diagnosis and management of invasive candidiasis 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 • Invasive Candidiasis 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 Aspergillosis 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 Candida glabrata 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 medications (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 onychomycosis are most common (May include sinusitis, pneumonia, thrombophlebitis, peritonitis, fungemia, endophtalmitis, septic arthritis, vulvovaginitis and osteomyelitis) • In immunocompromised hosts, any fungus 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. • Fusarium spp. • Zygomycetes (Zygomycota) • Dematiaceous fungi • Opportunistic yeast-like fungi Invasive Fungal Opportunistic Infections: Fungal Infections: • Greater than 50% mortality • Cryptococcal meningitis • Most result from impaired immunity (Cryptococcus neoformans or C • Most caused by Candida, Aspergillus, gattii) Cryptococcus or Pneumocystis • Pneumocystis pneumonia • Many caused by dimorphic fungi that (Pneumocystis jirovecii, formerly P incite: carinii) • Histoplasmosis (Histoplasma • Histoplasmosis (Histoplasma capsulatum) capsulatum) • Coccidioidomycosis (Coccidioides • Talaromyces marneffei infection immitis or C posadasii) • Emerging mycoses, such as: • Paracoccidioidomycosis • Emmonsiosis (Emmonsia (Paracoccidioides brasiliensis) pasteuriana) • Pythiosis (Pythium insidiosum [an Oomycete]) Antimycotic (Antifungal) Resistance: • Fungi intrinsically resistant to conventional antifungal drugs include Aspergillus tares (Amphotericin B), 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, Dermatophytosis, 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: Candida albicans, 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, cryptococcosis, blastomycosis, candidaemia, coccidioidomycosis, histoplasmosis, and mucormycosis; however, renal toxicity relegated it to a second-line therapy) (Amphotericin B-resistant species include Scedosporium spp, Fusarium spp, Trichosporon spp, Sporothrix schenckii, 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 (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 Eumycetoma, 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, Microsporidiosis, Mucormycosis, Fungal-infection, Onychomycosis-fingernail, Azole Indications: Aspergillosis-aspergilloma, Onychomycosis-toenail, Oral-thrush, Aspergillosis-invasive, Blastomycosis, Bone- Paracoccidioidomycosis, Pseudoallescheriosis, marrow-transplantation, Candida-urinary-tract- Sporotrichosis, 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-
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