New (& Nearly New) Antifungal Drugs for Coccidioidomycosis Thomas F. Patterson, MD, FACP, FIDSA Professor of Medicine Vice-Chair for Faculty Development Chief, Division of Infectious Diseases Director, San Antonio Center for Medical Mycology UT Health San Antonio, Texas Presenter Disclosures Thomas F Patterson MD The following relationships with commercial interests related to this presentation existed during the past 24 months: Company Nature of Relationship: Consultant, Speakers Name: Bureau, Sponsored Research, Other Grant support None Consultant Astellas, Basilea, Gilead, Merck, Scynexis,Toyama Speakers' None bureau Major Stock None holder Other material NIH/NIAID (Amplyx, Cidara, F2G, Matinas, Mirati, support Scynexis, Toyama, Viamet, Vical, Valley Fever Solutions) Current and (selected!) new agents for invasive fungal infections Polyenes Azoles Echinocandins • AmB deoxycholate • fluconazole • caspofungin • lipid AmB formulations • itraconazole • micafungin • AmB nanoparticles • voriconazole • anidulafungin • AmB cochleates • posaconazole • aminocandin • isavuconazole • biafungin (CD101) • itra nanoparticles Others • flucytosine • histone deacetylase inhibitors • terbinafine (MGCD290) • miltefosine • novel CYP inhibitors (VT1129/1161/1598) • nikkomycin Z (VFS-1) • calcineurin inhibitors/combinations • arylamides (T-2307) • other essential enzymes/targets (BDM-I; • enfumafungin (SCY-078) F901318, ASP2397, AR-12, others) • GPI inhibitors (APX001) • repurposed drugs: sertraline, auranofin • Immunotherapy (C-403) • etc., etc. Note: AmB=amphotericin B; GPI=glycosylphosphatidylinositol Blue text, earlier development The Antifungal Pipeline: A Reality Check Perfect JR. Nat Rev 2017;12 May. The Antifungal Armamentarum: Key Questions for Coccidioidomycosis • Unmet need: burden of infection; impact of resistance • Clinical agents with activity in cocci . Isavuconazole . Posaconazole tablets/IV . SUBA-itraconazole • Drugs with in vitro / in vivo activity in coccidioidomycosis . Nikkomycin Z (VFS-1) . VT 1161/1598 . F901318 . AXP001 • Other drugs in the pipeline: unknown cocci activity . AmB cochleates . Glucan synthase inhibitors (CD101, SCY-078) . Others: histone deacytelase inhibitors (MGCD290), sertraline, immunotherapy (C-403) • Urgent need for efficient diagnostic tests • Safe and effective new drugs and vaccines Sci Trans Med 19 Dec 2012; 4,165rv13 Large-scale Susceptibility Testing of Coccidioides Isolates • Coccidioides isolates (n = 581) • Elevated MIC values: . Flu: ≥16 μg/ml, 37.3%; ≥32 μg/ml, 7.9% . Itra: ≥2 μg/ml, 1.0% . Posa: ≥1 μg/ml, 1.0% . Vori: ≥2 μg/ml, 1.2% Mould-active azoles low MICs for majority of isolates Clinical correlation with outcomes needed Thompson GR, et al. Antimicrob Agents Chemother 2017;17 April. New Agents of Available Classes • Isavuconazole (Basilea, Astellas) – Broad-spectrum triazole – Oral & IV formulations • Prodrug (BAL-8557) cleaved to active component (BAL-4815) by plasma esterases – Long t1/2 Isavuconazonium (BAL-8557) – Broad spectrum: yeasts, moulds including Mucorales, endemics (cocci) • Clinical studies Isavuconazole (BAL-4815) – Phase III clinical trials • Invasive aspergillosis (NCT 00412893) • Rare fungi (NCT 00644049) including mucormycosis, endemics: cocci • Candidemia (NCT 00413218) Warn PA et al, JAC 2006;58:1198-1207; Thompson GR et al, AAC 2009;53:309-11; Verweij PA, J Chemother 2009;21:272-81; Thompson GR, JAC. 2009;64:79-83; Thomspon GR, Wiederhold NP. Mycopathologia 2010;170:291-313; Thompson GR, et al. Clin Infect Dis 2016; 63:356-62; Maertens J, et al. Lancet. 2016 Feb 20;387(10020):760-9 Isavuconazole (ISAV) for Endemic Fungi & Cryptococcosis • Coccioidomycosis: primary therapy . Pulmonary • ISA: 200mg tid X 2 days then 200 mg/d • Median duration: 180d • DRC Clinical Response: 9/9 • MICs 0.06-0.12 • Well tolerated • Serum Levels: . D7: 3.20 μg/ml (0.6-5.08) . D14: 3.86 μg/ml(0.88-5.98) . D28: 4.01 μg/ml(0.78-7.80) . Steady state: 4.05 μg/ml (1.09-8.96) Thompson GR, et al. Clin Infect Dis 2016; 63:356-62. Posaconazole With New Formulations UT Health Science Center Experience Prior to December 2013 Since December 2013 • Shift in posaconazole concentrations to higher levels – Higher percentage of patients with concentrations ≥1 μg/ml – Fewer patients with concentrations <0.5 μg/ml – ~10% with posaconazole concentrations >3.5 μg/ml • Clinical relevance of high levels unknown • Limited clinical data with new formulation • Further clinical trials in development Wiederhold NP et al. Antimicrob Agents Chemother 2014;58:424-31. Unpublished data (UT Health Science Center San Antonio Fungus Testing Laboratory) Thanks! Nathan SUBA-itraconazole (Mayne Pharmaceuticals) • ‘SUBA’ technology: proprietary ‘SUperBioAvailable formulation of itraconazole: spray drying technology to create nano-particles (<40µm) of itraconazole in a polymer matrix=increased solubility . Better bioavailability (55% vs ~100%) . Lower inter- and intra-patient variability . Less food effectustralian approved bioequivalence dosing at 50mg vs 100mg conventional itraconazole Clinical US trials in development with MSG Mudge S, et al. Poster presented at the Annual Scientific Meeting of the Australian Society of Infectious Disease 2014. Adelaide, Australia. Poster 68; Australian Approved LOZANOC 50mg Capsules Product Information dated 16 April 2014. Nikkomycin Z (VFS1) (Valley Fever Solutions) • Nikkomycin Z (NikZ) is first in a new class of antifungal, chitin synthase inhibition . Novel mechanism of action, significant unmet medical need . Activity against Coccidioides, Blastomyces, Histoplasma, Aspergillus, others . Selective to fungal cells - thus far no safety concerns in mammals - Efficacy in murine models - Efficacy in naturally occurring pulmonary coccioidomycosis in dogs . May enhance other anti-fungal treatments in combination with other drugs . In 2014, GAIN Act QIDP designation—providing 7 and 5 years sequential market exclusivity after marketing approval. Scaled up trial material in process, Phase IIa trials in clinical infection, Summer 2017 Shubitz LF, et al. J Infect Dis 2014;209:1949-54; Hector RF, et al. Antimicrob Agents Chemother 1990;34:587-93; Najvar LK, et al. ICAAC, 2015 http://valleyfeversolutions.com/ Novel Cyp51 Inhibitors VT-1129/1161/1598 (Viamet Pharmaceuticals, Inc.) • Investigational fungal Cyp51 inhibitors • MOA similar to azoles • Highly selective for fungal Cyp51 enzyme vs human Cyp450 enzymes VT-1161 (more so than the azoles) – Kd against fungal Cyp51 ≤39 nM – Failed to inhibit human CYP450 at 50 μM Hoekstra WJ et al. Bioorg Med Chem Lett 2014;24:3455-8. Warrilow AG et al. Antimicrob Agents Chemother 2014:58:7121-7. VT-1129 & VT-1161 In vitro Potency Potent in vitro activity against Cryptococcus & Candida species Antifungal VT-1129 VT-1161 FLU CAS Cryptococcus neoformans MIC50 0.015 0.03 2 NT MIC90 0.06 0.125 8 NT GM MIC 0.03 0.04 2.32 NT Cryptococcus gattii MIC50 0.06 0.06 2 NT MIC90 0.125 0.25 4 NT GM MIC 0.05 0.08 2.28 NT Candida albicans MIC50 0.03 0.03 0.125 0.125 MIC90 0.03 0.03 0.25 0.125 GM MIC 0.03 0.03 0.15 0.1 Fothergill AW et al. ICAAC 2010. Cryptococcal Meningitis - VT-1129 Monotherapy Combined with single dose AMBd • Effective as monotherapy & in combination with amphotericin B against cryptococcal meningitis – Murine model with intracranial inoculation – Improvements in survival & significant reductions in fungal burden (>4 log reduction CFU/g when combined with AMB) – Rapid fungicidal activity and tissue sterilization—not seen with other antifungal agents or combinations Wiederhold et al. ICAAC 2010. Wiederhold et al. ECCMID 2011. Invasive Candidiasis – VT-1161 • Echinocandin and azole resistant Candida albicans – Improved survival and reductions in kidney fungal burden vs. caspofungin and fluconazole Najvar LK, et al. ISHAM 2012. VT-1161 in Naturally Infected Dogs with Coccidioidomycosis Enrolled respiratory cases based on clinical signs, radiographs, serology, clinical pathology 60 days of medication: 14 days loading dose, followed by 46 days maintenance at ~5-fold lower dose High dose – (29/6 mg/kg) – 12 Low Dose (10/1.6 mg/kg) – 10 dogs dogs Mean entrance score: 13.3 Mean entrance score: 14.4 Mean exit score: 5.0 Mean exit score: 4.7 Mean plasma concentration: 36 ±14 µg/ml* Mean plasma concentration: 19 ± 8 µg/ml* 9/12 dogs (75%) experienced 75%-100% All 10 dogs experienced clinical improvement reduction in clinical signs; 1 dog removed for progressive lung consolidation on day 35 though 1 had radiographic progression and increased titer 66% of dogs had at least one dilution reduction in titer and 66% had reduction or 60% of dogs had at least 1 dilution reduction in resolution of CBC/serum chemistry titer and 80% had reduction or resolution of abnormalities CBC/serum chemistry abnormalities Radiographic improvement was mixed, Radiographic improvement mixed, ranging ranging from no change to 90% from no change to 85% improvement improvement *In vitro MIC90 and MIC range of 2 and 1-4 µg/ml for 52 clinical isolates of Coccidioides Shubitz LF, Antimicrob Agents Chemother 2017;Apr 24;6(5). Shubitz L, et al. 60th CSG. Thanks! Lisa! VT-1161 & VT-1598 in Murine CNS Coccidioidomycosis Survival from Coccidioidal Meningitis after Treatment with VT-1161 or VT-1598 Swiss-Webster mice, 65 spores intracerebrally 1.0 0.8 3.2 mpk 1598 0.6 8 mpk 1598 20 mpk 1598 20 mpk 1161 Placebo 0.4 0.2 Proportion of Mice Surviving Mice of Proportion 0.0 0 10 20 30 40 50 Days Survived VT-1161’s prolonged survival benefit is tied to its very long half-life (6-8 days)