Hope on the Horizon: Novel Fungal Treatments in Development

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Abstract

The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug resistance. This review focuses on novel therapies in clinical development, including drugs and a device.

Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. In addition, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis.

THE NOVEL THERAPEUTICS

AGENTS TARGETING CELL WALL INTEGRITY

Rezafungin (CD101)

Mechanism of action and potential role.

Rezafungin is used for treating infections caused by Candida, Aspergillus, and Pneumocystis spp in bone marrow transplant patients. The US Food and Drug Administration (FDA) has designated intravenous (IV) rezafungin as a Qualified Infectious Disease Product (QIDP) with fast track status for its development program. The antifungal compounds currently in development have several novel mechanisms of action or new formulations to improve efficacy or reduce toxicity and target different sites in the cell wall, cell membrane, and also intracellular targets(Figure 1).

Pharmacokinetics/Pharmacodynamics

Pharmacologically, rezafungin has a much longer half-life (approximately 80 hours after the first dose and 150 hours after the second or third dose) than any currently available echinocandin, allowing for extended-interval IV dosing, such as weekly regimens.

Theoretically, this would increase pathogen killing and reduce spontaneous mutations by maximizing the drug effect early in the course of therapy when the burden of the pathogen is greatest.

However, the risk of development of resistance in the long “tail” of the pharmacokinetics (PK) has yet to be fully evaluated.

Activity

Rezafungin exhibits a broad in vitro potency against fungal pathogens comparable to that of other echinocandins (Figure 2). Rezafungin is being developed as a subcutaneous and IV medication. By both Clinical and Laboratory Standards Institute (CLSI) and EUCAST broth microdilution methods, the minimum inhibitory concentrations (MICs) for rezafungin were determined to range between ≤0.008 and 2 mg/L against Candida species.

Activity against Aspergillus spp was comparable to other echinocandins with minimal effective concentrations (MECs) that ranged from ≤0.008 to 0.03 mg/L in one study and ≤0.015–2 mg/L for all Aspergillus isolates.

Stage of Development and Ongoing Clinical Studies

A phase 1 study showed low toxicity and a favorable safety profile in humans with no serious or severe adverse events (AEs) or withdrawals from the study due to an AE, with the majority of AEs being mild and all with complete resolution.

In a phase 2 multicenter, randomized, double-blinded trial, patients with candidemia and/or invasive candidiasis receiving rezafungin were compared with patients receiving a regimen of daily caspofungin with fluconazole stepdown once clinically stable. Rezafungin was well tolerated and provided clearance of blood cultures and other sterile sites, meeting all primary safety and efficacy end points.

Novel antifungals with spectrum of activity. New antifungal compounds show extensive spectrum of activity to overcome resistant fungi; however, several gaps still remain. *MGCD290: Potent activity in combination with azoles and/or echinocandins. ABA, aureobasidin A; CAMB, encochleated amphotericin B; FOSMANO, fosmanogepix; GSI, glucan synthase inhibitor; IBREXA, ibrexafungerp; NIKZ, nikkomycin Z; REZA, rezafungin.

Future plans include a second phase 3 trial (ReSPECT study) using rezafungin in a 90-day prophylactic regimen for Candida, Aspergillus, and Pneumocystis infections in allogeneic bone marrow transplant patients, with results expected in 2020 (Figure 3).

Ibrexafungerp (SCY-078)

Mechanism of Action and Potential Role

Ibrexafungerp is a first-in-class oral glucan synthase inhibitor, semisynthetic derivative of enfumafungin and represents the first compound of the triterpenoid antifungals to reach clinical development for the treatment of invasive candidiasis. Ibrexafungerp has been designated as a QIDP for oral and IV use by the FDA, for the indications of invasive candidiasis and invasive aspergillosis.

Pharmacokinetics/Pharmacodynamics

Ibrexafungerp is being developed for both oral and IV dosing, but only the oral dosing is currently in clinical trials. It is characterized by high-volume distribution and extensive tissue penetration. It met efficacy end points across multiple murine models of invasive candidiasis at concentrations that have been safely achieved after oral administration in humans, but it does not achieve central nervous system (CNS) penetration. 

In vitro studies indicate that ibrexafungerp is a modest inhibitor of CYP450 (CYP2C8) with markedly lower effect over other CYP450 isozymes; however, substrates were not affected to a clinically meaningful extent in the presence of therapeutically relevant ibrexafungerp concentrations, suggesting low risk for significant CYP450 drug-drug interactions.

Activity

In vitro and in vivo studies have demonstrated potency against the most common Candida spp, as well as resistant isolates. In addition, it demonstrates excellent in vitro activity against wild-type and azole-resistant strains of Aspergillus spp, Paecilomyces variotii, and some activity against L prolificans, but poor activity was observed against Mucor and Fusarium spp.

Stage of clinical development of the novel antifungals. New antifungal compounds are currently in several stages of development. Most have advanced to phase 2 or 3, but a few still remain in phase 1 or preclinical development. VL-2397 had early termination of phase 2 trial, and there are currently no ongoing trials. AR-12 and MGCD290 have no ongoing trials.

Stage of Development and Ongoing Clinical Studies

Ibrexafungerp met primary end points in 2 phase 2 clinical trials (NCT02679456, NCT02244606) in VVC and invasive candidiasis, respectively. In VVC, oral ibrexafungerp was superior compared with oral fluconazole.

A recently completed phase 2 trial, the DOVE study (NCT03253094), explored 5 dosing regimens of oral ibrexafungerp versus fluconazole in patients with acute VVC to identify an optimal dose for a phase 3 trial. Results have not been published.

Currently, there are multiple ongoing phase 3 trials in the United States and India assessing ibrexafungerp for the treatment of C auris infections.Initial results of 20 patients who completed therapy were favorable.

Fosmanogepix (APX001)

Mechanism of Action and Potential Role

Fosmanogepix, a first-in-class antifungal, is a prodrug of Manogepix (E1210), and it displays highly selective antifungal activity by inhibiting fungal enzyme Gwt1 and subsequently inactivating posttranslational modification of glycosylphosphatidylinositol (GPI) anchor proteins, also known as mannoproteins.

The action of fosmanogepix appears to be specific to fungi, because it does not inhibit human inositol acylation, resulting in a wide therapeutic index (Figure 1 and Table 1). Fosmanogepix received QIDP and fast track designations as well as orphan drug status for 4 indications: invasive candidiasis, invasive aspergillosis, coccidioidomycosis, and rare molds, including Scedosporium and Fusarium.

Activity

Fosmanogepix has in vitro activity against a broad spectrum of fungi, including yeast such as Candida spp, Cryptococcus neoformans, Coccidioides immitis, and C auris , but it lacks activity against C krusei.

Stage of Development and Ongoing Clinical Studies

Phase 1 clinical studies have demonstrated >90% bioavailability for fosmanogepix, in both oral and IV formulations. These trials have determined the safety, tolerability, and PK of fosmanogepix in healthy volunteers and patients with acute myelogenous leukemia, who are at increased risk of IFIs.

The clinical pharmacological profile, including drug-drug interactions and drug distribution, was also studied. Currently, phase 2 proof-of-concept studies are being conducted in patients with invasive candidiasis/candidemia and invasive aspergillosis (Figure 3).

Nikkomycin Z

Mechanism of Action and Potential Role

Nikkomycin Z is a first-in-class antifungal derived from Streptomyces tendae, with a novel mechanism of action through inhibition of chitin synthases, an essential component of the fungal cell wall (Figure 1 and Table 1). The target enzyme is absent in mammalian hosts, making NikZ selective to fungal cells with little to no toxicity in humans. This agent is under development as an orphan product for the treatment of coccidioidomycosis, and in 2014 it gained the QIDP designation.

Activity

Nikkomycin Z has potent in vitro and in vivo activity against dimorphic fungi with high quantities of chitin, including C immitis and Blastomyces dermatitidis. This agent has demonstrated activity in murine models of coccidioidomycosis, blastomycosis, and histoplasmosis.

Its fungicidal effect exceeded that of azoles and AmB, by sterilizing the lungs of most mice in murine models of pulmonary coccidioidomycosis and blastomycosis; however, moderate efficacy was seen for histoplasmosis.

Pharmacokinetics/Pharmacodynamics

Pharmacologic studies in mice showed that NikZ administered through IV infusion was rapidly eliminated; however, oral administration resulted in slow absorption, allowing inhibitory levels to persist for hours. Experimental murine studies suggest that twice-daily dosing of 250–500 mg could achieve optimal plasma concentrations in humans.

Stage of Development and Ongoing Clinical Studies

Nikkomycin Z has completed phase 1 clinical development and showed excellent safety in healthy humans, without AEs observed. A phase 2 trial to determine a safe dose in patients with pulmonary coccidioidomycosis was terminated early due to recruitment challenges and lack of funding, but a phase 2a trial is planned for 2020 (Figure 3).

AGENTS TARGETING CELL MEMBRANE

VT-1129, VT-1161, and VT-1598

Mechanism of Action and Potential Role

VT-1129, VT-1161 (or Oteseconazole), and VT-1598 are next-generation azoles, termed tetrazoles, attempting to remedy this limitation through improved binding discrimination between fungal and mammalian CYP450 enzymes. By replacing the triazole metal-binding group with a tetrazole, this group achieves greater selectivity for fungal lanosterol 14α demethylase (CYP51), which will hopefully result in fewer safety issues and lower MICs.

The FDA has granted QIDP, fast track, and orphan drug designation to VT-1598 for the treatment of coccidioidomycosis, and VT-1161 received QIDP and fast track status for recurrent VVC.

Activity

Each of these agents has potent activity against various yeast isolates, including C albicans and non-C albicans species, and Cryptococcus spp, as well as significant mold activity (Figure 2).

Potent in vitro activity has been reported for VT-1161 against Candida spp. VT-1129, which is structurally very similar to VT-1161, was mainly designed to treat cryptococcal meningitis (CM).

Of these 3 investigational agents, VT-1598 has the broadest spectrum and most potent activity against molds, including various Aspergillus spp and R.arrhizus, as well as endemic fungi, including Coccidioides with elevated fluconazole MICs, Blastomyces and Histoplasma isolates.

Stage of Development and Ongoing Clinical Studies

Preclinical results of VT-1129, VT-1161, and VT-1598 have been reported in the literature, and VT-1161 is currently in clinical development (Figure 3). Phase 2 clinical trials have evaluated the efficacy and safety of VT-1161 for the treatment of tinea pedis, onychomycosis, and acute and recurrent. Two phase 3 trials in recruitment will evaluate the effectiveness and safety of VT-1161 versus fluconazole and a placebo for the treatment of VVC.

Encochleated Amphotericin B (MAT2203)

Mechanism of Action and Potential Role

MAT2203 is a novel encochleated amphotericin B (CAmB) formulation for oral administration. Recent investigations have shown the safety and efficacy of the lipid-based cochleates formulation as a delivery system for AmB for use in Candida infections.

Cochleates result in a stable, nontoxic, highly efficacious AmB lipid particle, enabling its potential oral formulation. There is direct interaction between CAmB and the fungus cell membrane, but the precise mechanism by which cochleates fuse with cell membranes is not yet fully understood.

Encochleated AmB received QIDP designation as well as fast track status from the FDA in 2015 for the treatment of invasive candidiasis, aspergillosis, and the prevention of IFIs in patients on immunosuppressive therapy.

Pharmacokinetics/Pharmacodynamics

In vivo safety studies in murine models have shown 100% survival after 30 days when administering escalating daily doses of intraperitoneal CAmB, and equivalent safety of high oral CAmB doses, suggesting that CAmB could be administered in more aggressive doses (as high as 25 mg/kg) than currently available formulas.

Encochleated AmB produced no hemolysis at concentrations as high as 500 µg/mL AmB, whereas DAmB was highly hemolytic at 10 µg/mL, possibly due to a low interaction of CAmB with red blood cells, in contrast to DAmB.

Stage of Development and Ongoing Clinical Studies

Preliminary results from a phase 1 study demonstrated that single doses of 200 and 400 mg were well tolerated without serious AEs, opening the way for phase 2 trials. MAT2203 was well tolerated, with AEs mostly related to mild gastrointestinal symptoms, and showed a favorable safety profile without the renal and hepatic toxicities seen with IV AmB.

Enrollment is currently underway for a phase 2a clinical trial assessing orally administered MAT2203 (200–800 mg) in refractory mucocutaneous candidiasis. Preliminary results are promising, with MAT2203 being well tolerated and effective.

A phase 2 study was being planned to investigate MAT2203 for the prevention of IFIs, but the trial was recently withdrawn due to protocol redundancy.

Aureobasidin A

Mechanism of Action and Potential Role

Aureobasidin A exhibits antifungal activity through inhibition of inositol phosphorylceramide synthase, an important enzyme expressed from the AUR1 gene involved in sphingolipid synthesis, exclusively found in the fungal cell membrane (Figure 1). The absence of this enzyme in mammalian cells decreases the risk of toxicity. Resistance to AbA can be seen due to mutation of the AUR1 gene in fungi.

Activity

In vitro studies have shown activity against Saccharomyces cerevisiae, Candida spp, Cryptococcus spp, Schizosaccharomyces pombe, and some Aspergillus spp (Figure 2). An in vivo murine model of candidiasis showed fungicidal activity of AbA with low toxicity and prolonged survival.

Stage of Development and Clinical Studies

This drug remains in the preclinical developmental, but it has a favorable profile to advance for clinical use (Figure 3).

AGENTS WITH INTRACELLULAR TARGETS

Olorofim (F901318)

Mechanism of Action and Potential Role

Olorofim is a novel antifungal drug in a novel class of orotomides. Its mechanism of action involves the inhibition of fungal dihydroorotate dehydrogenase (DHODH), an important enzyme in pyrimidine biosynthesis essential for deoxyribonucleic acid synthesis. Olorofim has no activity against human DHODH, resulting in limited toxicity and a favorable safety profile.

Pharmacokinetics/Pharmacodynamics

Olorofim is relatively insoluble in water and highly protein bound, but it has good distribution to tissues, including kidney, liver, lung, and, although at lower levels, has been detected in the brain. Olorofim demonstrates time-dependent killing effect and shows a typical pharmacokinetic profile when dosed by IV and oral routes (bioavailability >45%).

Activity

In vitro studies have shown broad-spectrum activity against filamentous and dimorphic fungi including Aspergillus spp, Histoplasma capsulatum, B dermatitidis, C immitis, Talaromyces (formerly Penicillium) marneffei, and Fusarium spp, as well as organisms pan-resistant to clinically available antifungal agents such as Scedosporium apiospermum, L prolificans and Scopulariopsis spp (including Scopulariopsis brumptii).

Olorofim therapy demonstrated robust antifungal activity, leading to prolonged survival and a concentration-dependent decline in circulating galactomannan levels in an immunosuppressed murine model.

Stage of Development and Ongoing Clinical Studies

Both oral and IV formulations are being developed, but the exact dosing regimen for both formulations is still being studied.

An oral immediate release tablet evaluated in a phase 1 study showed that olorofim was well tolerated and effective. Two phase 2 trialsfor use as fungal prophylaxis were recently withdrawn, because they were no longer required.

The drug is now in phase 2b clinical development with a global open-label study (FORMULA-OLS, NCT03583164) to evaluate olorofim for difficult-to-treat IFIs, including azole-resistant aspergillosis, scedosporiosis, lomentosporiosis, and other rare molds, in patients lacking suitable alternative treatment options.

VL-2397

Mechanism of Action and Potential Role

VL-2397 potentially represents a new class of antifungal agents. It is a cyclic hexapeptide isolated from the fermentation broth of Acremonium persicinum. However, it is known that it triggers a potent and rapid antifungal effect after transport into fungal cells, specifically A fumigatus, via siderophore iron transporter 1 (Sit1), which is absent in mammalian cells. Live cell imaging suggests that VL-2397 causes arrest of hyphal elongation. 

The FDA has granted QIDP, Orphan Drug, and fast track designations to VL-2397 for the treatment of invasive aspergillosis.

Activity

VL-2397 is active against different fungi (Figure 2). It demonstrates rapid onset of inhibition (within the first 2 to 4 hours) and potent in vitro fungicidal activity against hyphal elongation compared with existing drugs.

It has proven activity against Aspergillus spp (including wild-type as well as azole-resistant strains), some Candida spp (only C glabrata and C kefyr), C neoformans, and Trichosporon asahii.

There is evidence of in vivo efficacy in a neutropenic murine model of invasive candidiasis caused by both wild-type and azole- and echinocandin-resistant C glabrata isolates.

Stage of Development and Ongoing Clinical Studies

A phase 1 study showed that this agent was well tolerated in healthy volunteers who received escalating single and multiple IV doses per day. It was well tolerated up to 1200 mg, and no accumulation was observed for 21 days. There were no reported serious AEs related to the drug.

A phase 2 trial for the treatment of invasive aspergillosis in acute leukemia patients and recipients of bone marrow transplants was underway, but this was terminated early due to a business decision.

T-2307

Mechanism of Action and Potential Role

T-2307 is an investigational arylamidine, structurally similar to a class of aromatic diamidines that includes pentamidine. Its mechanism of action remains unknown; however, it appears to cause the collapse of fungal mitochondrial membrane potential in yeasts (Figure 1).

T-2307 inhibits the respiratory chain complexes in whole yeast cells and isolated yeast mitochondria, which is key for selective disruption of yeast mitochondrial function and antifungal activity.

Activity

T-2307 has potent in vitro and in vivo activity against Candida species, including azole- and echinocandin-resistant Candida spp, C neoformans, C gattii, Malassezia furfur, and F solani. The in vitro activity of T-2307 was far superior to the activities of fluconazole, voriconazole, micafungin, and AmB.

T-2307 was active against Aspergillus spp, and in vitro activity against these species was shown to be comparable to the activities of micafungin and voriconazole (Figure 2).

AR-12

Mechanism of Action and Potential Role

AR-12 is a novel molecule, antitumor celecoxib-derivative that has progressed as an anticancer agent and has activity against a number of infectious agents including fungi, bacteria, and viruses.

It is interesting to note that AR-12 has also shown activity against bacteria, including Salmonella and Francisella, and hemorrhagic fever viruses. The European Commission has designated AR-12 as an orphan drug for use in combination with other drugs for treatment of cryptococcosis and tularemia.

Activity

AR-12 has broad-spectrum antifungal activity against yeasts, molds, and dimorphic fungi (Figure 2). This includes Candida spp, including C glabrata and C krusei, and isolates of C neoformans with elevated fluconazole MICs. It has also shown activity against dimorphic fungi including Blastomyces, Histoplasma, and Coccidioides.

Stage of Development and Ongoing Clinical Studies

Target serum concentrations providing antifungal activity were safely achieved during phase 1 clinical trials as an anticancer agent (NCT00978523), indicating that AR-12 is promising candidate for repurposing as an antifungal agent. However, Arno Therapeutics declared bankruptcy in 2017 leaving the future of the medication in limbo (Figure 3).

MGCD290

Mechanism of Action and Potential Role

MGCD290 is a novel antifungal that inhibits fungal histone deacetylase 2. It has shown a synergistic effect with other antifungals such as azoles or echinocandins. In cases of mutant-resistant isolates, MGCD290 produces a favorable influence on the MICs, restoring sensitivity.

Activity

MGCD290 only has modest activity against Candida spp. However, it has demonstrated in vitro synergy with azoles and echinocandins against many azole- and echinocandin-resistant isolates including Candida spp, Aspergillus spp, Mucor, and Fusarium (Figure 2).

This drug is currently in clinical development, and a phase 2 trial was completed that evaluated the cure rate with combination treatment of MGCD290 and fluconazole compared with fluconazole alone for patients with moderate to severe VVC.

DEVICE

Neurapheresis

Mechanism of Action and Potential Role

The neurapheresis therapy system is a closed-loop system designed to filter fungal pathogens from human cerebrospinal fluid (CSF). It operates by extracting CSF from the subarachnoid space, removing pathogens through a filtration system, and then redepositing the CSF through the same catheter. It is currently considered as a potential novel adjunctive therapy for CM.

Stage of Development and Ongoing Clinical Studies

The neurapheresis system is expected to (1) allow physicians to modulate the high ICP typical of CM patients more directly and (2) also serve as a favorable alternative to other drainage procedures, minimizing the need for repeated lumbar punctures and/or placement of shunts.

Ongoing studies include a clinical trial evaluating the safety and feasibility of this system in patients with subarachnoid hemorrhages. Upcoming studies will explore the ability of the neurapheresis system to (1) filter smaller mediators such as cytokines and chemokines to control the neuroinflammatory response seen in CM and (2) avoid dangerous levels of inflammation or even immune reconstitution inflammatory syndrome (IRIS) within the CNS.

DISCUSSION

These new antifungals have many potential roles and advantages over current drugs. New drugs, including olorofim, fosmanogepix, and ibrexafungerp, are now available options for the treatment of previously pan-resistant organisms. This is incredibly important because these drugs offer options for physicians where there were previously no treatment avenues available.

Still, chemical classes for IFI treatment are so few that emergence of resistance to even 1 drug class tragically limits therapy options.

Many of the described therapies have improved safety profiles with reduced toxicity and fewer adverse effects and drug-drug interactions while preserving efficacy. The burden of administration requirements is reduced with the oral formulation of ibrexafungerp, olorofim, and CAmB decreasing barriers of IV administration, and rezafungin has a longer half-life allowing weekly dosing.

Complex dosing schedules and IV administration requirements are known to negatively impact medication adherence, and, for patients receiving antifungal treatment for extended periods, these oral formulations and reduced dosing intervals have the potential to decrease hospital and clinic visits and ultimately increase patient adherence during treatment.

CONCLUSIONS

These promising features begin to address the urgent need for improvement in available therapies, but there is work still to be done. It is unfortunate that the potential toxicities and disadvantages of these therapies have not been fully evaluated, because most of them have not reached advanced clinical development in stage 3 or 4 studies.

Even with all of the drugs in development, not every compound with antifungal activity will result in an approved drug for the market. Translating the results of early studies into clinical candidates can be difficult due to efficacy and financial reasons, and only approximately 20% of the potential antifungal targets published in the literature were further developed. However, given the number of new promising compounds in development, the future is brighter than it has ever been.

Source: Adriana M Rauseo, Ariella Coler-Reilly, Lindsey Larson, Andrej Spec, Hope on the Horizon: Novel Fungal Treatments in Development, Open Forum Infectious Diseases, Volume 7, Issue 2, February 2020, ofaa016, https://doi.org/10.1093/ofid/ofaa016