1258 - Activity of a Series of Investigational Compounds Tested Against Invasive Fungal Isolates

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Co-Author(s)

PR

Paul R. Rhomberg

Drug Development Manager
JMI Laboratories
North Liberty, Iowa
Disclosure: Cidara Therapeutics (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Merck (Research Grant or Support)
SM

Shawn A. Messer

Dr.
Microbiologist III
North Liberty, Iowa
Disclosure: Amplyx Pharmaceuticals (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)
RS

Richard W. Scott

Vice President, Research
Fox Chase Chemical Diversity Center, Inc.
Doylestown, Pennsylvania
Disclosure: Fox Chase Chemical Diversity Center (Employee)
SB

Simon DP Baugh

Dr
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: Fox Chase Chemical Diversity Center (Employee)
MP

Michael A. Pfaller

Director
JMI Laboratories
North Liberty, Iowa
Disclosure: Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)
Mariana Castanheira

Chief Scientific Officer
JMI Laboratories
North Liberty, Iowa
Disclosure: 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support)

Presenting Author(s)

Cecilia G. Carvalhaes

Associate Director for Clinical Microbiology
JMI Laboratories
North Liberty, IA
Disclosure: A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)

Background: Fox Chase Chemical Diversity Center (FCC) is developing non-peptide analogs of host defense proteins for the treatment of invasive fungal infections mainly caused by Candida (CAN) and Aspergillus (ASP). We evaluated the activity of 6 novel compounds and 2 comparators against 150 isolates from 15 fungal groups.

Methods: Susceptibility testing was performed per CLSI broth microdilution methods for investigational compounds and comparators against 70 CAN and 40 ASP isolates in addition to 10 Cryptococcus spp. (CRYP), 10 Fusarium spp. (FUS), 10 Mucorales, and 10 Scedosporium spp. (SCED) isolates from recent (2017-2019) clinical infections. MIC results were determined as ≥ 50% reduction at 24 and 72 hours for CAN and CRYP respectively, and 100% reduction at 24, 72, and 48 hours for Mucorales, SCED, and other moulds, respectively. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied for comparators.

Results: Compounds FC10790, FC11083, FC11212, and FC11275 had MIC₅₀results at ≤ 0.015 mg/L and MIC₉₀ results at ≤ 0.015 to 0.12 mg/L against CRYP, ASP, and FUS isolates. Compounds FC5096 and FC11022 were 2- to 4-fold less active while demonstrating MIC₅₀ and MIC₉₀ results of 0.03 to 0.5 mg/L against CAN, CRYP, ASP, and FUS isolates. The Mucorales isolate set showed the widest range of MIC results for FC compounds. FC10790 exhibited the greatest potency with a MIC_50/90at 0.5/2 mg/L. FC compounds showed potent activity against SCED with MIC₉₀ results of 0.03 to 0.25 mg/L. Fluconazole showed a wide range of MIC results, from 0.06 to >64 mg/L, but the highest results observed were for Candida auris (MIC_50/90, 64/ > 64 mg/L) and Candida krusei (MIC_50/90; 16/32 mg/L). Itraconazole was active against all ASP (MIC_50/90, 1/1 mg/L), but showed poor activity against FUS (MIC_50/90, > 8/ > 8 mg/L). Amphotericin B showed a narrow range of MIC results (0.5 to 2 mg/L) for all isolates except 1 ASP and most SCED.

Conclusion: Novel FCC compounds showed equal or greater activity than comparators against most CAN, ASP, SCED, and FUS. FC10790, FC11212, and FC11275 showed the greatest activity against all tested fungal isolates. development of this series of compounds for clinical studies.Table 1