Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections
Abstract
:1. Introduction
2. Literature Review
3. Discovery of Manogepix
4. Mechanism of Action
5. Effects on Virulence Factors and Biofilms
6. Time Kill and Post Antifungal Effects
7. MGX In Vitro Activity against Yeasts
8. MGX In Vitro Activity against Molds
9. Resistance
10. Activity against Echinocandin-, Azole- and AMB-Resistant Candida spp.
11. Activity against Azole- and AMB-Resistant Aspergillus spp.
12. Pharmacokinetics/Pharmacodynamics
13. In Vivo Efficacy
14. Tissue Distribution
15. Phase 1 Clinical Trials
16. Phase 2 Clinical Trials
17. Regulatory Submissions
18. Discussion
Author Contributions
Funding
Conflicts of Interest
References
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Organism (of Strains) | Method | MIC90 | Reference | |||||||
---|---|---|---|---|---|---|---|---|---|---|
MGX | FLC | VRC | POS | ITC | CAS | AFG | AMB | |||
C. albicans (21) | CLSI | 0.06 | 64 | 0.5 | 0.5 | nt | 4 | nt | nt | [32] |
C. albicans (402) | EUCAST | 0.016 | 0.25 | 0.008 | nt | nt | nt | 0.008 | 0.25 | [34] |
C. albicans (414) | CLSI | 0.008 | 0.25 | 0.015 | 0.06 | nt | nt | 0.03 | 1 | [30] |
C. albicans (29) | CLSI | ≤0.03 | >64 | nt | nt | nt | 2 | nt | nt | [40] |
C. auris (16) | CLSI | 0.03 | >64 | 1 | 1 | 1 | 1 | 0.25 | 4 | [33] |
C. auris (122) | CLSI | 0.03 | 512 | 4 | 0.12 | 0.25 | nt | 0.5 | 1 | [37] |
C. auris (200) | CLSI | 0.03 | 256 | 2 | 0.5 | 1 | 0.25 | 1 | 2 | [35] |
C. auris (100) | CLSI | 0.008 | nt | nt | nt | nt | nt | nt | nt | [41] |
C. dubliniensis (48) | EUCAST | 0.008 | 0.5 | 0.016 | nt | nt | nt | 0.016 | 0.06 | [34] |
C. dubliniensis (49) | CLSI | 0.008 | 0.25 | 0.015 | 0.06 | nt | nt | 0.12 | 0.06 | [30] |
C. glabrata (321) | CLSI | 0.12 | 32 | 1 | 1 | nt | nt | 0.12 | 1 | [30] |
C. glabrata (20) | CLSI | 0.06 | 32 | 1 | 1 | nt | 2 | nt | nt | [32] |
C. glabrata (188) | EUCAST | 0.125 | 32 | 0.5 | nt | nt | nt | 0.03 | 0.5 | [34] |
C. kefyr (12) | EUCAST | 0.5 | 0.5 | 0.016 | nt | nt | nt | 0.03 | 0.5 | [34] |
C. kefyr (13) | CLSI | 0.5 | 0.25 | ≤0.008 | 0.12 | nt | nt | 0.12 | 1 | [30] |
C. krusei (43) | CLSI | >2 | 32 | 0.5 | 0.5 | nt | nt | 0.12 | 1 | [30] |
C. krusei (54) | EUCAST | >0.5 | 64 | 0.5 | nt | nt | nt | 0.06 | 1 | [34] |
C. lusitaniae (39) | CLSI | 0.12 | 2 | 0.015 | 0.12 | nt | nt | 0.5 | 1 | [30] |
C. lusitaniae (12) | EUCAST | 0.016 | 0.5 | 0.016 | nt | nt | nt | 0.06 | 0.25 | [34] |
C. parapsilosis (270) | CLSI | 0.015 | 2 | 0.06 | 0.12 | nt | nt | 1 | 1 | [30] |
C. parapsilosis (25) | CLSI | 0.06 | 16 | 0.25 | 0.12 | nt | 4 | nt | nt | [32] |
C. parapsilosis (39) | EUCAST | 0.03 | 2 | 0.03 | nt | nt | nt | 2 | 0.5 | [34] |
C. tropicalis (24) | CLSI | 0.06 | 64 | 2 | 0.5 | nt | 4 | nt | nt | [32] |
C. tropicalis (151) | CLSI | 0.03 | 0.5 | 0.06 | 0.5 | nt | nt | 0.06 | 1 | [30] |
C. tropicalis (41) | EUCAST | 0.016 | 1 | 0.03 | nt | nt | nt | 0.03 | 0.5 | [34] |
C. neoformans (30) | CLSI | 0.5 | 4 | 0.06 | 0.25 | nt | nt | >4 | 1 | [30] |
Strain Source | Strains | MIC50 (µg/mL) | MIC90 (µg/mL) | MIC Range (µg/mL) | Reference |
---|---|---|---|---|---|
Worldwide | 100 | 0.004 | 0.008 | <0.0005–0.015 | [41] |
India, Japan, Korea, Germany | 16 | 0.004 | 0.03 | 0.002–0.015 | [33] |
Worldwide | 13 | 0.03 | 0.03 | ≤0.002–0.03 | [43] |
USA | 1 | -- | -- | 0.06 | [30] |
USA | 5 | 0.03 | -- | 0.03–0.06 | [28] |
Panama | 6 | 0.004 | -- | ≤0.002–0.015 | [28] |
India | 122 | 0.008 | 0.03 | 0.001–0.25 | [37] |
NY/NJ, USA | 200 | 0.016 | 0.03 | 0.008 -0.03 | [35] |
Organism (of Strains) | Method | MIC90/MEC90 | Reference | ||||||
---|---|---|---|---|---|---|---|---|---|
MGX | VRC | POS | ITC | CAS | AFG | AMB | |||
Alternaria alternata (10) | CLSI | 4 | nt | 16 | nt | nt | nt | 4 | [31] |
A. alliaceus (10) | CLSI | 0.03 | nt | 0.12 | nt | nt | nt | 32 | [31] |
A. calidoustus (10) | CLSI | 0.03 | nt | 16 | nt | nt | nt | 1 | [31] |
A. flavus (20) | CLSI | 0.03 | 1 | 1 | 1 | 0.12 | ≤0.008 | nt | [44] |
A. flavus (18) | CLSI | 0.015 | 1 | 0.5 | 1 | nt | 0.03 | 2 | [30] |
A. fumigatiaffinis (10) | CLSI | 0.03 | nt | 0.5 | nt | nt | nt | 4 | [31] |
A. fumigatus (182) | CLSI | 0.03 | 0.5 | 0.5 | 1 | nt | 0.03 | 2 | [30] |
A. fumigatus (22) | CLSI | 0.06 | 2 | 1 | >8 | 0.12 | 0.015 | nt | [44] |
A. fumigatus (121) | EUCAST | 0.06 | 0.5 | 0.12 | 0.25 | nt | nt | 0.5 | [29] |
A. lentulus (10) | CLSI | 0.03 | nt | 1 | nt | nt | nt | 1 | [31] |
A. niger (18) | EUCAST | 0.03 | 2 | 0.25 | 1 | nt | nt | 0.25 | [29] |
A. niger (13) | CLSI | 0.015 | 2 | 1 | 4 | 0.12 | ≤0.008 | nt | [44] |
A. niger (23) | CLSI | 0.015 | 2 | 1 | 4 | nt | 0.015 | 1 | [30] |
A. terreus (23) | CLSI | 0.06 | 1 | 0.5 | 1 | 0.12 | 0.015 | nt | [44] |
A. terreus (10) | CLSI | 0.03 | 0.5 | 0.25 | 0.5 | nt | 0.015 | 2 | [30] |
A. thermomutatus (10) | CLSI | 0.25 | nt | 1 | nt | nt | nt | 2 | [31] |
A. udagawae (10) | CLSI | 0.06 | nt | 0.5 | nt | nt | nt | 1 | [31] |
Cunninghamella bertholletiae (10) | CLSI | 16 | nt | 2 | nt | nt | nt | 4 | [31] |
F. solani (15) | CLSI | 0.06 | >8 | >8 | >8 | >8 | >8 | 2 | [36] |
F. oxysporum (15) | CLSI | 0.25 | 4 | 2 | >8 | >8 | >8 | 4 | [36] |
F. oxysporum (10) | CLSI | 16 | nt | 16 | nt | nt | nt | 1 | [31] |
F. verticilloides (10) | CLSI | 16 | nt | 16 | nt | nt | nt | 32 | [31] |
Gibberella fujikuroi (30) | CLSI | 0.12 | 8 | >8 | >8 | >8 | >8 | 4 | [36] |
Lichtheimia corymbifera (10) | CLSI | 16 | nt | 2 | nt | nt | nt | 0.12 | [31] |
Lichtheimia ramosa (10) | CLSI | 16 | nt | 0.5 | nt | nt | nt | 0.06 | [31] |
Lomentospora prolificans (10) | CLSI | 0.06 | nt | 16 | nt | nt | nt | 8 | [31] |
M. circinelloides (10) | CLSI | 8 | nt | 1 | nt | nt | nt | 0.03 | [31] |
Rhizomucor pusillus (10) | CLSI | 16 | nt | 2 | nt | nt | nt | 0.06 | [31] |
R. arrhizus (10) | CLSI | 16 | nt | 0.5 | nt | nt | nt | 0.12 | [31] |
R. microsporus (10) | CLSI | 16 | nt | 2 | nt | nt | nt | 0.12 | [31] |
S. apiospermum (28) | CLSI | 0.12 | 1 | 2 | 4 | >8 | 4 | >4 | [36] |
S. apiospermum (10) | CLSI | 16 | nt | 8 | nt | nt | nt | 32 | [31] |
S. aurantiacum (10) | CLSI | 0.03 | nt | 16 | nt | nt | nt | 16 | [31] |
S. boydii (10) | CLSI | 0.12 | nt | 2 | nt | nt | nt | 2 | [31] |
S. prolificans (28) | CLSI | 0.12 | >8 | >8 | >8 | >8 | 4 | >4 | [36] |
Pathogen | Infection Type | Efficacy Endpoint (Special Study) | Reference |
---|---|---|---|
Manogepix | |||
C. albicans | oropharyngeal | Oral CFU | [53] |
C. albicans | disseminated | Survival | [53] |
C. albicans | disseminated | Survival, kidney CFU | [40] |
C. tropicalis | disseminated | Survival | [53] |
A. fumigatus | pulmonary | Survival | [53] |
A. flavus | pulmonary | Survival | [53] |
F. solani | disseminated | Survival | [53] |
Fosmanogepix | |||
C. albicans | oropharyngeal | Oral CFU | [16] |
C. albicans | disseminated | Survival | [16] |
C. albicans | disseminated | Kidney CFU | [51] |
C. albicans | disseminated | Kidney CFU (PK/PD) | [54] |
C. albicans1 | disseminated | Brain, eye CFU | [55] |
C. auris | disseminated | Survival; kidney, lung, brain CFU | [33] |
C. auris | disseminated | Survival; kidney, lung, brain CFU | [43] |
C. auris | disseminated | Kidney CFU (PK/PD) | [54] |
C. glabrata | disseminated | Kidney CFU (PK/PD) | [54] |
C. glabrata | disseminated | Kidney CFU | [51] |
C. immitis | pulmonary | Survival; lung, spleen CFU | [47] |
C. neoformans | disseminated | Brain, lung CFU | [56] |
A. flavus | pulmonary | Survival | [16] |
A. flavus | pulmonary | Survival (combination MFG, AFG) | [57] |
A. fumigatus | pulmonary | Survival | [16] |
A. fumigatus | pulmonary | Lung CFU (PK/PD) | [58] |
A. fumigatus | pulmonary | Lung CFU, survival, histology | [59] |
A. fumigatus | pulmonary | Lung CFU; serum, BAL GM (GM biomarker) | [60] |
F. solani | disseminated | Survival | [16] |
F. solani | disseminated | Survival; kidney, brain CFU; histology | [61] |
R. arrhizus var. arrhizus | pulmonary | Survival; lung, brain CFU | [62] |
R. arrhizus var. delemar | pulmonary | Survival; lung, brain CFU | [62] |
S. apiospermum | pulmonary | Survival; kidney, lung, brain CFU; histology | [61] |
S. prolificans | pulmonary | Survival | [16] |
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Shaw, K.J.; Ibrahim, A.S. Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections. J. Fungi 2020, 6, 239. https://doi.org/10.3390/jof6040239
Shaw KJ, Ibrahim AS. Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections. Journal of Fungi. 2020; 6(4):239. https://doi.org/10.3390/jof6040239
Chicago/Turabian StyleShaw, Karen Joy, and Ashraf S. Ibrahim. 2020. "Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections" Journal of Fungi 6, no. 4: 239. https://doi.org/10.3390/jof6040239