New (& Nearly New) Antifungal Drugs for Coccidioidomycosis

Transcription

1 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

2 Presenter Disclosures Thomas F Patterson MD The following relationships with commercial interests related to this presentation existed during the past 24 months: Company Name: Grant support Consultant Speakers' bureau Major Stock holder Other material support Nature of Relationship: Consultant, Speakers Bureau, Sponsored Research, Other None Astellas, Basilea, Gilead, Merck, Scynexis,Toyama None None NIH/NIAID (Amplyx, Cidara, F2G, Matinas, Mirati, Scynexis, Toyama, Viamet, Vical, Valley Fever Solutions)

3 Current and (selected!) new agents for invasive fungal infections Polyenes AmB deoxycholate lipid AmB formulations AmB nanoparticles AmB cochleates Others flucytosine terbinafine miltefosine nikkomycin Z (VFS-1) arylamides (T-2307) enfumafungin (SCY-078) GPI inhibitors (APX001) Immunotherapy (C-403) Azoles fluconazole itraconazole voriconazole posaconazole isavuconazole itra nanoparticles Echinocandins caspofungin micafungin anidulafungin aminocandin biafungin (CD101) histone deacetylase inhibitors (MGCD290) novel CYP inhibitors (VT1129/1161/1598) calcineurin inhibitors/combinations other essential enzymes/targets (BDM-I; F901318, ASP2397, AR-12, others) repurposed drugs: sertraline, auranofin etc., etc. Note: AmB=amphotericin B; GPI=glycosylphosphatidylinositol Blue text, earlier development

4 The Antifungal Pipeline: A Reality Check Perfect JR. Nat Rev 2017;12 May.

5 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 F 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)

6 Urgent need for efficient diagnostic tests Safe and effective new drugs and vaccines Sci Trans Med 19 Dec 2012; 4,165rv13

7 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.

8 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 Broad spectrum: yeasts, moulds including Mucorales, endemics (cocci) Clinical studies Phase III clinical trials Invasive aspergillosis (NCT ) Rare fungi (NCT ) including mucormycosis, endemics: cocci Candidemia (NCT ) Isavuconazonium (BAL-8557) Warn PA et al, JAC 2006;58: ; 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: ; Thompson GR, et al. Clin Infect Dis 2016; 63:356-62; Maertens J, et al. Lancet Feb 20;387(10020):760-9 Isavuconazole (BAL-4815)

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 Well tolerated Serum Levels: D7: 3.20 μg/ml ( ) D14: 3.86 μg/ml( ) D28: 4.01 μg/ml( ) Steady state: 4.05 μg/ml ( ) Thompson GR, et al. Clin Infect Dis 2016; 63:

10 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: Unpublished data (UT Health Science Center San Antonio Fungus Testing Laboratory) Thanks! Nathan

11 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 Adelaide, Australia. Poster 68; Australian Approved LOZANOC 50mg Capsules Product Information dated 16 April 2014.

12 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: ; Hector RF, et al. Antimicrob Agents Chemother 1990;34:587-93; Najvar LK, et al. ICAAC,

13 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 (more so than the azoles) K d against fungal Cyp51 39 nm Failed to inhibit human CYP450 at 50 μm VT-1161 Hoekstra WJ et al. Bioorg Med Chem Lett 2014;24: Warrilow AG et al. Antimicrob Agents Chemother 2014:58:

14 VT-1129 & VT-1161 In vitro Potency Potent in vitro activity against Cryptococcus & Candida species Antifungal VT-1129 VT-1161 FLU CAS Cryptococcus neoformans MIC NT MIC NT GM MIC NT Cryptococcus gattii MIC NT MIC NT GM MIC NT Candida albicans MIC MIC GM MIC Fothergill AW et al. ICAAC 2010.

15 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 Wiederhold et al. ECCMID 2011.

16 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.

17 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 dogs Mean entrance score: 13.3 Mean exit score: 5.0 Mean plasma concentration: 36 ±14 µg/ml* 9/12 dogs (75%) experienced 75%-100% reduction in clinical signs; 1 dog removed for progressive lung consolidation on day 35 66% of dogs had at least one dilution reduction in titer and 66% had reduction or resolution of CBC/serum chemistry abnormalities Radiographic improvement was mixed, ranging from no change to 90% improvement Low Dose (10/1.6 mg/kg) 10 dogs Mean entrance score: 14.4 Mean exit score: 4.7 Mean plasma concentration: 19 ± 8 µg/ml* All 10 dogs experienced clinical improvement though 1 had radiographic progression and increased titer 60% of dogs had at least 1 dilution reduction in titer and 80% had reduction or resolution of CBC/serum chemistry abnormalities Radiographic improvement mixed, ranging from no change to 85% 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. 60 th CSG. Thanks! Lisa!

18 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 Proportion of Mice Surviving mpk mpk mpk mpk 1161 Placebo Days Survived VT-1161 s prolonged survival benefit is tied to its very long half-life (6-8 days) Half-life of VT-1598 ~1d in mouse; survival wanes due to fungistatic mechanism of drug By comparison with prior 1161/flu study (left graph), VT-1598 appears to improve survival at least as well as fluconazole (25 mg/kg BID) even at lowest tested dose (3.2 mg/kg/day) Shubitz LF, et al. 60 th CSG; Shubitz LF, et al. Antimicrob Agents Chemother 2015;59:

19 Murine Coccidioidomycosis Brain Fungal Burden and Dissemination 7 Log 10 CFU/g Brain Controls died on days 6-9; drug-tx d survived Both doses of 1598 significantly reduced brain fungal burden compared to 1161 (P<0.001) With 20 mg/kg VT-1598, 4/10 animals had undetectable brain CFUs (range 0-18 CFU/g) Both doses of VT-1598 prevented dissemination mpk mpk mpk Placebo Conclusion: VT-1598 yielded greater fungal burden reduction at 1/5 the dose of VT- 1161; therefore ~10-fold more potent in vivo Shubitz L, et al. 60 th CSG.

20 In vitro activity of VT-1598, Posaconazole, & Fluconazole against C. immitis & C. posadasii Species Coccidioides immitis (n = 17) Coccidioides posadasii (n = 23) Antifungal VT-1598 Posaconazole Fluconazole VT-1598 Posaconazole Fluconazole MIC range MIC MIC GM MIC Wiederhold NP, et al. Microbe

21 VT-1598 in Murine CNS Coccidioidomycosis: Survival at Day 30 Group Control VT mg/kg VT mg/kg VT mg/kg Fluconazole 25 mg/kg Median Survival (days) 9 days >30 days *p< >30 days *p< **p= >30 days *p< **p= days *p< Percent Survival (days) 0% 70% *p= % *p< **p= % *p< **p= % *p= *p-value vs. Control; **p-value vs. Fluconazole Wiederhold NP, et al. Poster presentation; 7 th Int l CSG 2017

22 VT-1598 in Murine CNS Coccidioidomycosis: Tissue Fungal Burden Tissue burden in fungal burden arm (day 9: A); and survival arm after 14 days of treatment wash-out (B). Lower Limit of Detection = 10 CFU/g. Wiederhold NP, et al. Poster presentation; 7 th Int l CSG 2017

23 Orotomide: F (F2G) Mechanism of Action, Spectrum F is a potent inhibitor of A. fumigatus DHODH DHODH (Dihydroorotate dehydrogenase) is a key enzyme involved in pyrimidine biosynthesis Mechanism was identified using genetic studies in Aspergillus nidulans Confirmed by in vitro enzyme assays Humans also have this enzyme But, > 2000-fold difference in IC 50 between human and fungal enzymes Spectrum of activity: highly active against moulds/endemics F structure

24 In vitro activity is consistent across all major Aspergillus spp., including A. terreus Intrinsic resistance to ampho B A. fumigatus n = 80 A. terreus n =45 F Itraconazole Posaconazole Voriconazole Amphotericin B Geo mean Range Geo mean Range A. flavus n = 50 Geo mean Range A. niger n=46 Geo mean Range MICs in mg/l, Isolates from UK and Austria

25 Other moulds Activity against S. (Lomentospora) prolificans and other Scedosporium species has been confirmed in a larger study. Variable activity vs. Fusarium spp. Not active vs. Candida, Cryptococcus, or Mucorales n MIC Range (mg/l) Scedosporium (L.) prolificans 3 <0.06 Scedosporium apiospermum 2 <0.06 Aspergillus lentulus 4 <0.06 Paecilomyces variotii 3 <0.06 Sporothrix schenckii 5 <0.06 Acremonium sp. 5 < Scopulariopsis brevicaulis 5 <0.06 Penicillium chrysogenum 5 <0.06 Penicillium marneffii 5 <0.06 Coccidioides immitis 5 <0.06 Blastomyces dermatitidis 5 <0.06 Histoplasma capsulatum 5 <

26 F in vitro activity against Coccidioides spp. Coccidioides MICs (20 isolates) Range: Geometric mean: Animal models in progress Species Isolate No. F Coccidioides sp. Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Cocci Data courtesy Nathan Wiederhold, UTHSA Fungus Testing Laboratory & Mike Birch, F2G

27 GPI Biosynthesis Inhibition APX001 (Amplyx) Fungal adhesion ligands derived from GPI-anchored proteins Candida albicans possess ~115 GPI-anchored proteins Als protein family members GWT1 gene encodes Gwt1p an inositol acyltransferase in early GPI biosynthesis pathway 1-(4-butylbenzyl)isoquinoline (BIQ) APX001 [E1210] (3-(3-{4[(pyridin-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-amine Selectively inhibits fungal inositol acyltransferase Reduces expression of Als1p on C. albicans cell surface Umemura et al. J Biol Chem 2003; 278: Watanabe et al. Antimicrob Agents Chemother 2012: 56:

28 APX001[E1210] In vitro Activity Organism Range MIC50 MIC90 C. albicans (52) < < < C. glabrata (44) < C. tropicalis (23) < C. parapsilosis (26) < < A. fumigatus (20) A. terreus (23) F. solani (23) F. oxysporum (15) S. prolificans (28) S. apiospermum (28) *50% inhibition of growth for Candida; MEC endpoint for moulds (static activity) **Inactive against C. krusei and members of the Order Mucorales Active against fluconazole-resistant Candida (MIC μg/ml) Miyazaki et al. Antimicrob Agents Chemother 2011; 55: Castanhelra et al. Antimicrob Agents Chemother 2012; 56: Pfaller et al. Antimicrob Agents Chemother 2011; 55: Wiederhold NP, et al. Antimicrob Agents Chemother 2015;59:690-2.

29 APX001[E1210] In vivo Efficacy In vivo efficacy demonstrated in murine models of invasive fungal infections Invasive Candidiasis (C. albicans) Invasive Pulmonary Aspergillosis (A. flavus) Disseminated Fusariosis (F. solani) PK parameter Tmax Bioavailability Half-life 1 mg/kg PO X1 0.5 hours 57.5% 2.2 hours Efficacy also demonstrated in vitro and in vivo against echinocandin-resistant Candida albicans Hata et al. Antimicrob Agents Chemother 2011; 55: ; Wiederhold NP, et al. Antimicrob Agents Chemother 2015;59:690-2.

30 Efficacy of APX001-A in vitro and in vivo against Coccidioides In vitro testing using agar dilution: MICs (2): C. immitis 0.019, C. posadasii 0.16 Murine pulmonary coccidioidomycosis 50 mg/kg bid starting d 4 and continuing for 14d 3-log reduction in lung CFU treated vs untreated controls No dissemination to spleen (0/10) vs controls (8/10); GM fungal burden 3.7 log10 Fierer J et al. Poster presentation, 60 th CSG, 2016

31 AmB Cochleates (MAT2203) (Matinas) Cochleate targeted nanoparticle delivery Reduced toxicity Targeted delivery Oral delivery MAT2203 Animal studies Human Phase I tolerability

32 CD101 (Biafungin) A novel echinocandin antifungal (Cidara) N + O H 3 C HO H 3 C N + O O O - O N N H O HN OH O H N O OH Structural modification yields chemical stability & enhanced biological properties Permanent charge and highly stable ring structure Prolongs PK: once weekly dosing Eliminates toxic degradation products: improved safety & dose range Allows high exposures: treats less susceptible pathogens Enables multiple formulations: systemic and topical HO HO O HO NH H N OH O O N CH 3 OH Biafungin (CD101 Acetate) O ICAAC 2015: multiple posters

33 CD101 IV dosing designed to optimize outcome CD101 IV 200 mg IV Q7D; AUC = 700 µg.hr/ml per dose Concentration in Plasma (µg/ml) 10 For Echinocandins exposure improves outcomes 5 0 CD101 MIC 90 range for echinocandin resistant Candida Days Above graphic is a model

34 CD101 IV vs. echinocandin-resistant strains Heterozygous FKS Mutant (S645P) in Mice 48h post infection; MIC (µg/ml) Micafungin & CD101 = 0.5 Vehicle 32,040,000 CD mg/kg 5,212 P <0.01* CD mg/kg 4,698 P <0.01* CD mg/kg 3,294 P <0.01* Micafungin 5 mg/kg 97,740 * P value compared with Micafungin 5 mg/kg 1.E+00 1.E+03 1.E+06 1.E+09 Log 10 (CFU/g) in kidney Y. Zhao, D.S. Perlin, et al. Efficacy of CD101 to Treat Echinocandin-resistant Candida albicans in a Murine Model of Invasive Candidiasis (F-748),ICAAC 2015

35 Glucan Synthase Inhibitors: Enfumafungins SCY-078 (Scynexis) Semi-synthetic derivative of natural product New molecular class Potent β 1,3 glucan synthesis inhibitor (GSI) Same target as echinocandin antifungals (marketed) Blocks synthesis of essential component of cell wall of pathogenic fungi Unique target not in mammalian cells Excellent in vitro & in vivo activity against Candida and Aspergillus Active in vitro against azole & echinocandin resistant strains Orally bioavailable current marketed GSIs are IV only; IV under development Extensive tissue distribution: kidney, lungs Phase I/II - generally well tolerated with good pharmacokinetics (QD) ICAAC 2015 posters: F-745, A-468, F-744

36 In vitro Activity of MK-3113 [SCY-078] against Candida species 31 strains with fks mutations: SCY-078 MIC <2 100%; <1 in 71% Pfaller MA, et al. JAC 2013;68:658-63

37 Histone Deacetylase Inhibitors Azoles deacetylate promotors of transcription resulting in downregulation of repression (upregulate resistance genes) Histone deacetylase inhibitors may enhance susceptibility of fungi to azoles Reduction in azole-dependent upregulation of efflux pumps (CDR1 & CDR2) Reduction in transcription of genes encoding ergosterol biosynthesis pathway (ERG1 & ERG11) Reduced transcription (50%) when fluconazole or terbinafine combined with trichostatin A (TSA) Non-specific histone deacetylase inhibitor Smith, Edlind. Antimicrob Agents Chemother 2002; 46: 3532.

38 MGCD290 (Mirati [MethylGene]) Synergistic with azoles against yeast & moulds MGCD290 Combined with Percent Synergy Percent Antagonism Fluconazole 60% (50/91 isolates) 1.1% (1/91 isolates) Posaconazole 51% (46/91 isolates) 1.1% (1/91 isolates) Voriconazole 53% (48/91 isolates) 3.3% (3/91 isolates) Synergy when combined with fluconazole 87% Candida isolates (all that were fluconazole resistant [>64 μg/ml] became susceptible [<8 μg/ml]) All 5 C. krusei isolates 60% (6/10) Aspergillus isolates Pfaller MA et al. J Clin Microbiol 2009;47:

39 Sertraline Serotonin-reuptake inhibitor Activity against other fungi (Cryptococcus) In vitro activity again C. immitis vs fluconazole and in combination Simon P et al. Poster presentation, 60 th CSG, 2016

40 C-403: Cloudbreak Antifungal Immunotherapy (Cidara) Microbe TM EM Immune Component TARGETING MOIETY EFFECTOR MOIETY Antibacterials Neutrophil recruiter Antifungals Macrophage recruiter Antivirals NK/T cell engagers* ADCC/CDC IgM/IgG engager

41 C-403 Dual Mechanism Fungal pathogen 1 2 Direct kill: novel TM tightly binds conserved target to kill fungi Immunomodulatory: EM recruits and initiates an innate immune system response Efficacy in vitro, ex vivo and in animal models

42 New Antifungals for Cocci: What Do We Need? Significant unmet medical needs: resistance, toxicity, drug interactions, oral bioavailability Many new potential targets and compounds under early stages of investigation New methods of delivery for old drugs New uses for existing compounds New agents in currently used classes New compounds with novel mechanisms of action!

43 Acknowledgments IAAM/AMoID Investigators UTHSCSA Nathan Wiederhold Laura Najvar Gabriel Catano William R. Kirkpatrick Brian Wickes David Kadosh Annette Fothergill Fungus Testing Lab Harbor-UCLA Scott Filler Ashraf Ibrahim Jack Edwards McGill Don Sheppard Manchester Peter Warn David Denning Cincinnati Melanie Cushion UTSA Chiungyu Hung NIAID Dennis Dixon Rory Duncan Maliha Ilias Erin Zeituni Dona Love NCATS Liz Ottinger $ NIAID Contracts IAAM: N01-AI (IAAM) AMoID: HHSN I HHSN (A13) HHSN (A05) HHSN (A93) HHSN (A98) HHSN (A107) HHSN I/ HHSN (A21) HHSN (A28) NCI/NCATS-TRND: SAIC-F 12XS348

44 Thank you! Special Thanks! Drs. Nathan Wiederhold, GR Thompson, Lisa Shubitz, Ken Bartizal, Kevin Forrest, Mike Birch, Paula Fenwick, Ed Garvey, Doug Kling