Investigational Antifungal Agents for Invasive Mycoses: A Clinical Perspective Free

Abstract

Treatment of invasive fungal infections (IFIs) remains challenging, because of the limitations of the current antifungal agents (ie, mode of administration, toxicity, and drug-drug interactions) and the emergence of resistant fungal pathogens. Therefore, there is an urgent need to expand our antifungal armamentarium. Several compounds are reaching the stage of phase II or III clinical assessment. These include new drugs within the existing antifungal classes or displaying similar mechanism of activity with improved pharmacologic properties (rezafungin and ibrexafungerp) or first-in-class drugs with novel mechanisms of action (olorofim and fosmanogepix). Although critical information regarding the performance of these agents in heavily immunosuppressed patients is pending, they may provide useful additions to current therapies in some clinical scenarios, including IFIs caused by azole-resistant Aspergillus or multiresistant fungal pathogens (eg, Candida auris, Lomentospora prolificans). However, their limited activity against Mucorales and some other opportunistic molds (eg, some Fusarium spp.) persists as a major unmet need.

Despite advances in diagnostic methods and management strategies, mortality rates due to invasive fungal infections (IFIs) remain high. Among the reasons for suboptimal outcomes are the limitations of the current antifungal agents, along with the emergence of new and/or more resistant fungal pathogens [1]. The restricted antifungal armamentarium reflects the difficulty in developing fungus-specific targets as biosynthetic pathways are evolutionary conserved between mammalian and fungal cells. Therefore, existing antifungal drugs target the components of the fungal cell wall (eg, echinocandins) or fungal membrane (eg, azoles and polyenes), or pyrimidine biosynthesis (eg, fluorocytosine). Furthermore, current antifungal treatment options are frequently limited by (1) adverse events or drug interactions leading to treatment interruption (eg, azoles and amphotericin B), (2) lack of oral formulations (eg, echinocandins and amphotericin B) for infections that typically require prolonged treatment, and even more importantly and (3) the rise of resistance among Candida (eg, Candida auris and Candida glabrata) and Aspergillus (azole-resistant Aspergillus fumigatus and cryptic Aspergillus species), non-Aspergillus molds, and non-Candida resistant yeasts [2–5].

During the last 2 decades, there has been an acceleration in antifungal drug discovery, with the development of new compounds with either novel mechanisms of action or improved potency and pharmacokinetic characteristics within existing classes. These novel antifungal drugs have been extensively discussed in several excellent reviews [6–8]. Here, we seek to give a more clinical perspective on the advantages and limitations of these compounds and attempt to predict their future place in therapeutic management across the spectrum of IFIs. Specifically, we will focus on novel antifungals for which data from phase II or III clinical trials have been reported for IFI treatment, such as rezafungin, ibrexafungerp, olorofim, and fosmanogepix. All these drugs have received qualified infectious diseases product and various orphan drug designations from the Food and Drug Administration. In addition, olorofim has received breakthrough therapy drug designation.

REZAFUNGIN

Pharmacologic Properties

Rezafungin (CD101) is an intravenous next-generation echinocandin (ie, β-glucan synthase inhibitor), with a chemical structure similar to anidulafungin. This novel molecule is characterized by enhanced stability and solubility and a slow rate of elimination (half-life >130 hours), which results in prolonged activity and a convenient mode of administration of only once weekly (compared with the once-daily dosing of other echinocandins) [9] (Table 1). It has a wide tissue distribution, except in the central nervous system (CNS), eye, and urine (similar to other echinocandins). The pharmacokinetics are dose dependent and linear, with little intrapatient and interpatient variability [9].

Preclinical Data

The in vitro activity of rezafungin against Candida spp., including C. auris, is comparable to that of currently licensed echinocandins (Figure 1), with similar minimal inhibitory concentration (MIC) values and cross-resistance to Candida isolates harboring FKS mutations [10–12]. Its activity against Cryptococcus spp. is marginal [11]. Rezafungin demonstrates in vitro fungistatic activity against Aspergillus spp., which was comparable to that of other echinocandins (Figure 1) [13]. In murine models, rezafungin displayed efficacy for prophylaxis and treatment of invasive candidiasis (IC) and invasive aspergillosis (IA) [14–16] (Figure 1). Its microbiologic efficacy was superior to that of micafungin in a murine model of disseminated C. auris infection [17]. Rezafungin also displayed enhanced penetration (superior to micafungin) into abdominal abscesses in a murine model of intra-abdominal candidiasis [18]. Rezafungin was also tested as prophylaxis against Pneumocystis pneumonia in mice and demonstrated efficacy comparable to that of trimethoprim-sulfamethoxazole [14, 19].

Clinical Studies

Rezafungin was well tolerated in phase I human studies [20]. One phase II double-blind randomized controlled “proof of concept” trial (STRIVE) that enrolled 207 patients showed similar efficacy for once-weekly rezafungin and once-daily caspofungin regimens for the treatment of candidemia and other ICs [21] (Table 2). Two phase III trials are ongoing, one for the treatment of IC (ReSTORE) and one for the prophylaxis of IFIs caused by Aspergillus spp., Candida spp., or Pneumocystis jirovecii in allogeneic stem cell transplant recipients (ReSPECT) (Table 2).

Perspectives

Rezafungin displays an antifungal spectrum and activity similar to those of conventional echinocandins, with the main advantage of once-weekly intravenous administration and excellent penetration at sites of infection, which is of particular interest for early discharge or prolonged therapy of complicated IC, particularly intra-abdominal IC, when an azole is not an alternative because of resistance (eg, with C. auris, C. glabrata, or Candida krusei), toxicity, or inability to take oral medications. Whether the enhanced tissue penetration of rezafungin results in sufficient pharmacokinetic-pharmacodynamic attainment to overcome the high MICs of FKS mutant isolates (as suggested by pharmacokinetic-pharmacodynamic modeling and 1 case report) requires further confirmation [22, 23]. Rezafungin may also represent an option as second-line or maintenance therapy following first-line amphotericin B treatment of IA due to azole-resistant A. fumigatus. However, more data are needed regarding the pharmacokinetic behavior of rezafungin for chronic infections in the bone, eye, kidney, or brain where echinocandin exposure might be suboptimal. The drug has no role in the treatment of non-Aspergillus molds, Cryptococcus spp., endemic fungi, or rare non-Candida opportunistic yeasts (eg, Trichosporon spp., Rhodotorula spp., and Saprochaete spp.).

The role of rezafungin as antifungal prophylaxis will be clarified by an ongoing phase III trial; it could be an appealing option to prevent Candida, Aspergillus, and Pneumocystis infections in both high-risk hematology inpatients and outpatients, provided that the local epidemiology does not suggest an issue with non-Aspergillus mold infections, such as Mucorales. Another potential advantage of rezafungin consists of its reduced risk of toxic effect and drug interactions that are common with triazoles and trimethoprim-sulfamethoxazole, especially in transplant recipients. Caution is warranted in using rezafungin as a single agent for treating IA, especially in neutropenic patients with hematologic cancer, considering the general suboptimal efficacy of echinocandins in this subset of patients [24, 25].

IBREXAFUNGERP

Pharmacologic Properties

Ibrexafungerp (SCY-078 or MK-3118) is a triterpenoid antifungal derived from the natural product enfumafungin. It is structurally distinct from echinocandins but shares the same mechanism of action by inhibiting the 1,3-β-d-glucan synthase [26]. Because the binding site of ibrexafungerp and echinocandins overlap only partially, hot-spot mutations of resistance are distinct, with resulting limited cross-resistance between ibrexafungerp and conventional echinocandins [26]. A major advantage of ibrexafungerp over current echinocandins is the availability of an oral formulation, which has been the focus of clinical studies to date. Of note, a liposomal intravenous formulation has also been developed and is currently in earlier stages of clinical development. The drug has linear pharmacokinetics and a half-life of 20–30 hours [27] (Table 1). The estimated bioavailability of ibrexafungerp tablets is 35%–50% [28]. However, low gastric pH and food are required for optimal absorption. The drug has large volume of distribution despite high protein binding (>99%) with excellent penetration in most deep tissues, except the CNS [26]. Elimination is mainly biliary with very low concentrations in urine. Unlike echinocandins, ibrexafungerp is metabolized by CYP3A4 and is an inhibitor of CYP2C8, even though results of phase I studies in healthy volunteers have suggested a low risk for drug interactions [29, 30].

Preclinical Data

Ibrexafungerp has an antifungal spectrum similar to that of echinocandins, but it may overcome echinocandin resistance in some cases (Figure 1). Importantly, ibrexafungerp displays potent fungicidal activity against most pathogenic Candida spp., including C. parapsilosis, C. auris, and echinocandin-resistant C. albicans/C. glabrata harboring FKS mutations [31–33], which was established in murine models of IC [34, 35]. In mice, ibrexafungerp also demonstrated excellent penetration in liver abscesses (ie, concentrations 100-fold higher than those in serum) and efficacy in decreasing liver fungal burden, which was superior to that of micafungin [36]. In contrast to echinocandins, ibrexafungerp displays good tissue concentrations in bone (exceeding those in plasma) in animal models [37]. However, its brain penetration is similarly low [37].

The in vitro activity of ibrexafungerp against Aspergillus spp. (including cryptic species and azole-resistant isolates) is comparable to that of echinocandins, with a fungistatic effect and synergistic interactions with triazoles and amphotericin B [38–40], and this activity was confirmed in a murine model of IA [41]. Similar to echinocandins, ibrexafungerp is not active in vitro against Mucorales and Fusarium spp., and it displays marginal fungistatic activity against some Scedosporium spp. and Lomentospora prolificans isolates [42]. Ibrexafungerp was as effective as trimethoprim-sulfamethoxazole in preventing and treating murine Pneumocystis pneumonia [43, 44].

Clinical Studies

Oral ibrexafungerp was well tolerated in phase I studies with mainly mild gastrointestinal side effects [26]. It has now been approved by the Food and Drug Administration for the treatment of vulvovaginal candidiasis following results of recent phase III studies [45, 46]. Its assessment for the treatment of IFI is currently ongoing. One small open-labeled phase II study (including 27 patients) assessed the safety and efficacy of ibrexafungerp as step-down therapy of IC, which was similar to the standard of care [47] (Table 2). One phase III open-label study (CARES) evaluating the safety and efficacy of ibrexafungerp for C. auris infection is ongoing (Table 2). Studies assessing the safety and efficacy of combined ibrexafungerp and voriconazole therapy for IA (SCYNERGIA) and ibrexafungerp monotherapy for refractory IFI (FURI) are also ongoing (Table 2).

Perspectives

Its oral bioavailability places ibrexafungerp as an alternative to intravenous echinocandins in scenarios where early discharge or prolonged administration of echinocandins is warranted. However, additional data will be required to elucidate the absorption characteristics in patients with altered gastrointestinal function associated with chemotherapy or mucositis, poor appetite, acid suppression therapy, or severe diarrhea. The high degree of ibrexafungerp tissue distribution, including in deep tissue abscesses in animal models [36], suggests that the drug may be a good candidate for second-line oral treatment of intra-abdominal IC in case of azole resistance or intolerance. However, similarly to echinocandins, ibrexafungerp has no role or a limited role for CNS or urinary tract infections because of poor penetration at these sites.

The conserved activity of ibrexafungerp against echinocandin-resistant FKS C. albicans/C. glabrata or emerging multiresistant C. auris can have important clinical implications. In addition, for the treatment of IA, ibrexafungerp could be considered for a switch to oral treatment after initial amphotericin B treatment of azole-resistant A. fumigatus infections or in combined therapy with triazoles for azole-sensitive IA. However, as with echinocandins, more data are needed regarding the efficacy of ibrexafungerp as single agents against IA in neutropenic patients. The drug has no role in the treatment of non-Aspergillus molds, Cryptococcus spp., endemic fungi or rare non-Candida opportunistic yeasts. Data about the role of ibrexafungerp in antifungal prophylaxis are lacking, but it could theoretically represent an interesting option for preventing IC, IA, and Pneumocystis pneumonia in high-risk patients in centers where local epidemiology does not suggest an issue with non-Aspergillus mold infections.

OLOROFIM

Pharmacologic Properties

Olorofim (F901318) is the first compound from the novel orotomide class of antifungals, which makes it distinct from the currently available antifungal agents. Olorofim selectively inhibits fungal dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, with much lower affinity (2200-fold less) for human dihydroorotate dehydrogenase, thus reducing the potential for toxicity [48]. Its action results in loss of essential substrates for different cellular processes including cell wall integrity and DNA replication [48, 49]. Olorofim can be administered both intravenously and orally. It is almost completely absorbed when given by mouth (<1% is found in feces), may be dosed with or without food, and has oral bioavailability of 45%–82% [48] (Table 1). Its pharmacokinetics are characterized by a high level of plasma protein binding (>99%) and a large volume of distribution. Therapeutic concentrations are achieved in all targeted organs and tissues, including lung, brain, liver, and kidney [50]. Olorofim is metabolized by several cytochrome P450 isoenzymes, but drug-drug interactions may be less clinically relevant than those observed with mold-active triazoles [51].

Preclinical Data

Olorofim has a broad spectrum of activity against molds, with the exception of Mucorales (Figure 1). Notably, it is not active against yeasts, including Candida and Cryptococcus spp. The effect of olorofim against Aspergillus spp. is characterized by prompt inhibition of germination and hyphal elongation at low concentrations and a time-dependent fungicidal effect resulting from cell swelling and lysis after prolonged exposure [52]. Olorofim is highly active, with uniformally low MICs (≤0.25 µg/mL) against all pathogenic Aspergillus spp., including cryptic species and azole-resistant A. fumigatus [53–55]. This efficacy was also confirmed in murine models of IA [56–58]. Olorofim also demonstrated potent in vitro activity (MIC, ≤0.5 µg/mL) against Scedosporium apiospermum complex and L. prolificans [59–61]. However, the effect of olorofim against Fusarium spp. seems to be species specific, with better effect against Fusarium oxysporum complex than against Fusarium solani complex, and significant intraspecies and isolate-specific variations [54, 62]. Regarding dimorphic fungi, olorofim demonstrated potent in vitro activity against both Coccidioides immitis and Coccidioides posadasii; it was effective in a murine model of C. immitis cerebral coccidioidomycosis [63]. High in vitro activity against Talaromyces marneffei has also been reported [64].

Clinical Studies

Phase I studies in healthy volunteers demonstrated good tolerability [48]. One phase II open-label single-arm study (FORMULA-OLS) is ongoing, considering the treatment of probable pulmonary IA or proven mold infections in patients with limited treatment options (Table 2). Case reports from that study show some promising clinical data for the treatment of L. prolificans infections and coccidioidomycosis [48].

Perspectives

Olorofim may represent a promising antifungal option against azole-resistant Aspergillus spp. or uncommon fungi—for which therapeutic options are very limited (eg, L. prolificans), provided that more efficacy data are obtained, especially in highly immunocompromised patients. Preclinical studies and case reports suggest that olorofim could represent an important therapy for coccidiodomycosis, including infections with CNS involvement. The notable gaps in coverage against yeasts and Mucorales suggest that the drug will be most useful for documented refractory infections where clinical efficacy of the drug is recognized. In contrast, olorofim monotherapy should not be appropriate as preemptive therapy in presumed fungal pneumonias, especially in centers where local epidemiology suggests an issue with non-Aspergillus mold infections. Finally, more human data are needed on the pharmacokinetic behavior of the drug in anatomically privileged sites, such as the CNS. A possible role for therapeutic drug monitoring should be further evaluated in real-life clinical practice.

FOSMANOGEPIX

Pharmacologic Properties

Fosmanogepix (APX001, E1211) is a prodrug, which is converted by systemic phosphatases to the active moiety manogepix (APX001A, E1210). This first-in-class antifungal agent inhibits Gwt1, an enzyme in the glycosylphosphatidylinositol biosynthesis pathway [65]. The resulting loss of anchoring of mannoproteins compromises cell wall integrity, and impairs fungal adhesion and its evasion from the host immune system [65]. Manogepix displays potent fungistatic activity with a prolonged postantifungal effect [65, 66]. The drug can be administered by both intravenous and oral routes, with oral bioavailability of >90% in a phase I study [65] (Table 1). It distributes well to many difficult-to-treat body sites, including the brain, eyes, and intra-abdominal abscesses, with documented efficacy in animal models [67, 68]. Although manogepix interacts with some cytochrome P450 isoenzymes, preliminary results of phase I studies suggest a favorable drug-drug interaction profile [65].

Preclinical Data

Manogepix activity is expressed as MIC (ie, 50% growth reduction) for yeasts and minimal effective concentrations (MECs; ie, production of small rounded hyphae, comparable to the effect of echinocandins) for molds [65, 66]. Manogepix has broad-spectrum antifungal activity (Figure 1). It is highly active against most pathogenic Candida spp., including C. auris (90% MIC [MIC₉₀], ≤0.12 µg/mL), with the exception of C. krusei and Candida kefyr, which display MICs about 10-fold higher [65, 69, 70]. In vitro experiments in Candida spp. have shown that decreased susceptibility to manogepix can be induced by drug preexposure, and results from a mutation in the target gene (Gwt1) or from efflux pumps activity [71, 72]. However, cross-resistance was rarely observed with azoles or other antifungal classes [71]. In general, manogepix displayed similar good in vitro activity against the majority of echinocandin and azole-resistant Candida spp., although some correlation between manogepix and azoles MIC was observed, notably in C. auris [73, 74]. Manogepix is also active against Cryptococcus neoformans [75].

Regarding molds, manogepix displays potent antifungal activity against Aspergillus spp. (90% MEC [MEC₉₀], ≤0.06 µg/mL) including azole-resistant A. fumigatus and cryptic species (eg, Aspergillus lentulus, Aspergillus calidoustus) [65, 70, 76, 77]. It is also active against most Fusarium spp., in particular F. solani and F. oxysporum complexes, despite some reduced susceptibility reported among F. verticilloides [62, 77, 78]. Manogepix was also highly active against most Scedosporium spp. and L. prolificans isolates, albeit a wider MEC range has been observed for S. apiospermum in 1 study [65, 77, 78]. In contrast, the in vitro antifungal activity of manogepix against most Mucorales is limited (MEC₉₀, 4–16 µg/mL), although some isolates with low MEC (ie, <1 µg/mL) have been observed [65, 66, 77].

The efficacy of manogepix/fosmanogepix has been demonstrated in various murine models of IC, IA, disseminated fusariosis, and scedosporiosis [65, 79, 80]. For IC and IA, its efficacy was similar to that of other antifungal classes. Of interest, despite its limited in vitro activity, fosmanogepix was comparable to isavuconazole in a murine model of Rhizopus arrhizus mucormycosis when tested against infecting strains with both low (0.25 µg/mL) and elevated (4 µg/mL) MECs [81].

Clinical Studies

In phase I studies, fosmanogepix in oral or intravenous administration was well tolerated, with a linear dose-plasma concentration relationship and low intersubject variability [65]. One phase II study, which enrolled 21 nonneutropenic patients with candidemia, showed an 80% success rate without reporting serious adverse events [65] (Table 2). Two other phase II studies are ongoing, addressing the efficacy of fosmanogepix for the treatment of C. auris IC (APEX) and invasive mold infections caused by Aspergillus spp. and other molds (AEGIS) [65] (Table 2).

Perspectives

Fosmanogepix has several attractive features, such as its novel mechanism of action, a very broad-spectrum antifungal spectrum, its availability for both oral and parenteral administration, and its excellent tolerability. The fact that the drug influences fungal morphogenesis and cell wall remodeling may represent a potential for additional immunomodulatory effect [82], but more studies are needed. These pleomorphic effects could also make it a candidate for studies about combination antifungal therapies.

Fosmanogepix has the potential to become an important addition for the treatment of notoriously difficult-to-treat invasive mold infections, such as disseminated fusariosis or scedosporiosis/lomentosporiosis, or IA and IC caused by multiresistant species. Its potential for the treatment of mucormycosis should be further investigated despite limited in vitro activity, as the drug demonstrated some efficacy in a murine model. More data are needed in terms of potential of cross-resistance with azoles, where efflux is the predominant mechanism of action, and for induction of resistance. Finally, as for all new drugs, its efficacy in highly immunosuppressed patients, especially persistently neutropenic patients, and the potential of escape mutations and resistance associated with prolonged use remains to be seen.

OTHER UPCOMING ANTIFUNGALS

In addition to these compounds being at the stage of phase II/III clinical trials for IFI, other promising molecules are contemplated for a future clinical application (Table 3). These include novel molecules within known antifungal drug classes with modified molecular structures and improved pharmacologic properties (notably less toxicity and/or fewer drug-drug interactions), such as the tetrazoles (VT-1161, VT-1129, and VT-1598) [85], the inhaled triazole PC945 [86], and encochleated amphotericin B [87]. These compounds may offer better tolerability or bioavailability but do not expand the antifungal spectrum, except possibly for tetrazoles against C. auris or other azole-resistant Candida spp. [88, 89] and PC945 for preventing invasive pulmonary aspergillosis due to azole-resistant Aspergillus spp. [86]. While tetrazoles and encochleated amphotericin B have been tested in phase II trials of mucocutaneous candidiasis [90–92], clinical data for IFI treatment are still lacking. A phase II trial of preemptive PC945 treatment in lung transplant recipients with A. fumigatus lung colonization has been prematurely interrupted owing to the coronavirus disease 2019 (COVID-19) pandemic (NCT 03905447).

Novel first-in-class antifungal compounds under investigation include MGCD290 (an inhibitor of histone deacetylase) and ATI-2307 (an inhibitor of the mitochondrial respiratory chain). ATI-2307 could be considered for the treatment of cryptococcal meningitis or echinocandin-resistant IC, including C. auris, according to previous in vitro and in vivo results [93]. The interest of MGCD290 seems limited to combined therapy for its synergistic interaction with existing antifungals (ie, azoles and echinocandins) [94, 95]. Some of these novel antifungals are expected to enter phase II or III clinical trials in the near future.

FUTURE DIRECTIONS AND CONCLUSIONS

While our armamentarium against IFI has been limited to only 3 drug classes for decades, recent advances in antifungal drug development, with the drugs discussed in this review along with others undergoing preclinical testing or entering phase I trials for IFIs, signal the beginning of a new era of antifungal therapy. First, known and time-honored antifungal drug classes, in particular the azoles and echinocandins, are being repurposed and their impact has been expanded based on their improved pharmacologic properties. Second, novel classes of compounds targeting other fungal-specific pathways are expected to find a niche for the treatment of IFIs that are difficult to treat because of intrinsic or acquired antifungal resistance, as illustrated in Figure 2.

While these new compounds have demonstrated promising results in vitro and in murine models, none of them seems to represent a promising therapeutic option for the treatment of mucormycosis, which remains a major challenge in medical mycology because of rising frequency, suboptimal diagnosis and high mortality rates, as shown by the “tsunami” of mucormycosis cases complicating COVID-19 in India [96, 97]. Table 4 shows some of the questions of the future research agenda with these new antifungal compounds.

In conclusion, the current novel antifungal drug candidates may provide a measured optimism about new options for the treatment of emerging resistant Candida and Aspergillus spp., as well as some notoriously refractory invasive mold infections (eg, disseminated fusariosis and scedosporiosis/lomentosporiosis). However, they do not seem to represent an alternative for the treatment of mucormycosis, and the limited available therapeutic options against this devastating disease remain a major issue. Importantly, more validation is needed about long-term safety, propensity of resistance development, pharmacokinetics in difficult to treat infection sites, and performance in debilitated, frail, and heavily immunosuppressed patients. The commercial viability of these “niche” compounds depend on their true antifungal effect in real life and their thoughtful integration into the existing antifungal armamentarium [98].

Notes

Acknowledgments. D. P. K. acknowledges the Robert C Hickey Chair endowment. The authors thank Taylor Sandison (Cidara Therapeutics), John Rex (F2G), David Angulo (Scynexis) Michael R. Hodges (formerly Amplyx Pharmaceuticals, now a Pfizer subsidiary) for sharing information and useful comments.

References

Author notes