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D. Das et al.
Aspergillus Therapeutics: Future Agents
15
YashikBansal , ReetuKundu , andNidhiSingla
Abstract
With the rising population of immunocompromised individuals in the population
owing to various factors, such as longer life span, use of immunosuppressant
drugs, newer interventions in cancer patients prolonging the life span, and spread
of HIV/AIDS, the incidence of invasive fungal infections has increased globally
with more than 1.5million estimated deaths every year. The emergence of drugresistant fungi such as azole-resistant Aspergillus fumigatus, Candida auris, and
echinocandin-resistant Candida glabrata, coupled with a lack of antifungal susceptibility data for many fungi and difculty in performing susceptibility testing
by broth dilution method, has further necessitated the need for development of
new drugs.
The development of newer antifungals has shown promise as many drugs
have entered phase-III clinical trials, while others are in various stages of clinical
trials, pre-clinical, or in-vitro studies. These drugs comprise of both novel classes
of antifungals as well as modications or existing drugs or repurposed drugs as
well. This chapter discusses these novel drugs under development that can be the
future of the treatment of infections caused by drug-resistant Aspergillus species.
Y. Bansal
Department of Microbiology, ESIC Medical College and Hospital, Alwar, Rajasthan, India
R. Kundu
Department of Cytology and Gynaecological Pathology, Post Graduate Institute of Medical
Education and Research, Chandigarh, India
N. Singla (*)
Department of Microbiology, Government Medical College and Hospital, Chandigarh, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
S. Hameed, P. Vijayaraghavan (eds.), Recent Advances in Human Fungal
Diseases, https://doi.org/10.1007/978-981-97-4909-6_15
365
366
Keywords
Y. Bansal et al.
Aspergillus · Novel antifungals · Drug resistance · Ibrexafungerp · Tetrazole
15.1 Introduction
The exact understanding of fungi and their role in health and disease in humans is
evolving. Fungi are ubiquitous in nature and are found in close association with
human, being involved in diseases that range from supercial infections to deep,
systemic, or invasive infections that are life threatening (Arastehfar etal. 2020). It
has been estimated that approximately 1.5 million deaths are caused by fungal
infections every year with more than one billion people suffering from supercial
infections every year (Brown etal. 2012). Fungi are organisms of comparatively
lower virulence in general and cause invasive fungal infections mainly in immunocompromised individuals, such as those suffering from HIV/AIDS, older age group,
cancer patients, and patients on immunosuppressive drugs (Banaji 2021). As the
population of immunocompromised individuals is rising in the population, the incidence of fungal infections has seen an upward trend (Bansal etal. 2019).
The use of broad spectrum antifungal agents has improved the survival of such
patients, but the lack of quality mycology services including accurate diagnosis of
the fungi, antifungal susceptibility (AFST) data, difculty in performing microbroth dilution method in routine diagnostic laboratory, and lack of epidemiological
cutoffs for determining minimum inhibitory concentration (MIC) for many fungal
agents (e.g., Fusarium spp.) (Bansal etal. 2016) has led to non-judicious use of
antifungals. The consequence of such misuse is the emergence of drug resistance to
many antifungals agents, notoriously in dermatophytes, along with emergence of
drug-resistant fungi, such as Candida auris (Ahmad and Alfouzan 2021),
echinocandin- resistant Candida glabrata (Kanafani and Perfect 2008), and azole-
resistant Aspergillus fumigatus (Buil etal. 2019).
Aspergillus fumigatus and Aspergillus avus are the two commonest species of
Aspergillus seen in clinical specimen. The emergence of azole-resistant strains in
these Aspergillus spp. is concerning as they are the most common etiological agents
in cases of invasive fungal infection. The outbreak of mucormycosis during the
COVID-19 pandemic has sensitized the masses regarding the impact of fungal
infections and antifungal therapy. Furthermore, antifungals are drugs that act on
eukaryotic organisms (fungi) compared to antibiotics that act on prokaryotic cells
(bacteria). Therefore, antifungal therapy is riddled with side effects and tolerancerelated issues (Girois et al. 2006). All these factors, coupled with the increasing
drug resistance in some fungi, have warranted the necessity to develop new antifungal agents that can be used in the future to tackle drug-resistant fungal infections.
There are ve classes of antifungals available for the management of fungal
infections in humans. The polyenes act by binding with the ergosterol present in the
cell membrane. The conventional formulations have signicant toxicities and can
only be administered through the intravenous route. Liposomal formulations
15 Aspergillus Therapeutics: Future Agents
367
overcame this issue but still have side effects and are expensive. Echinocandins are
another intravenous only antifungals that are useful for the treatment of Candida
spp. The azole group of antifungals act by blocking the formation of ergosterol from
lanosterol. These drugs can be given through the oral route but have potential drug–
drug interactions owing to their property of binding to the mammalian cytochrome
P450 enzyme. Azoles also suffer from high drug resistance in some agents, such as
Aspergillus fumigatus. Flucytosine is a pyrimidine analogue that is used as a combination therapy for treatment of fungal infections, while allylamines are antifungal
drugs that are given as prolonged therapy for the treatment of dermatophytoses.
To develop new antifungal agents, a host of approaches is currently being
explored by the researchers that include developing new classes of antifungal drugs
(Perfect 2017), discovering new drugs from existing class of antifungals (Gintjee
etal. 2020), modications to the existing drugs to improve their tolerance/reduce
their side effects, and drug repurposing of existing drugs that can exhibit antifungal
properties as well and/or immunotherapy.
15.2 New Antifungals inPipeline
Various new antifungals in development are discussed below and the current updates
are summarized in Tables 15.1 and 15.2, while the chemical structures are shown in
Fig.15.1. Most of these (except oteseconazole) are capable of acting upon drugresistant Aspergillus spp. as per preliminary data generated through pre-clinical and
early clinical trials. There are novel drugs that target the integrity of the cell wall
that include Fosmanogepix, Rezafungin, and Ibrexafungerp. New antifungal agents
that act on the cell membrane through a variety of mechanisms include the next
generation of azoles, i.e., VT-1129, VT-1161, and VT-1598. A modied version of
Amphotericin-B, known as encochleated amphotericin-B and aureobasidin A, are
other drugs that act on the cell membrane. Finally, there are drugs that act on various
intracellular enzymes, such as oloron, VL-2397, T-2307, MGCD290, and AR-12.
15.2.1 Fosmanogepix
Fosmanogepix is a prodrug in phase II trial that releases the active moiety, manogepix,
inside the body due to the action by the systemic phosphatases (Hoenigl etal. 2021). This
is an entirely new class of antifungal drug that inhibits the Gwt1 protein that is required
for the production of glycosylphosphatidylinositol, which in turn is required for the
anchoring of cell wall proteins with the plasma membrane (McCarty and Pappas 2021).
The drug was discovered in 2010 and in-vitro studies showed promising results
against a wide spectrum of fungi, ranging from yeasts, such as Candida spp. (except
Candida krusei against which the drug exhibited elevated MICs), Cryptococcus
spp., Malassezia, and Trichosporon spp. (McCarty and Pappas 2021). A notable
property was the drug’s activity against Candida auris, multidrug-resistant organism. In-vitro activity against molds was reported against Aspergillus, Fusarium, and
368
Y. Bansal et al.
Table 15.1 Mechanism of action and phase of development of novel antifungal drugs
Drug
Fosmanogepix/
manogepix
(APX001)
Ibrexafungerp Triterpenoid
Olorom
(F901318)
Antimicrobial class Mechanism of action
Glycosylphosphatidylinositol
Inhibition of fungal Gwt1
protein maturation
inhibitor
1,3-β--glucan synthase
(similar to
inhibitor
echinocandin in
action)
Orotomide Inhibition of dihydroorotate
dehydrogenase, thereby
Phase of trial
Phase II
Phase-IIIa (FDA
approved for
vaginal
candidiasis)
Phase-IIb
targeting pyrimidine synthesis
Opelconazole
(PC945)
Triazole Inhibits CYP51A1 enzyme,
thereby stopping ergosterol
Phase-III
synthesis resulting in
dysfunction of fungal cell
membrane
Rezafungin
(CD101)
MGCD-290 Histone deacetylase
VT-1598 Tetrazole Inhibitor of cell membrane
Echinocandin Echinocandin with prolonged
half-life
Inhibits fungal histone
inhibitors
deacetylase enzyme
Phase-III
Phase-II
Phase-I
formation/ ergosterol synthesis
by selectively blocking fungal
cytochrome P450 enzyme
VT-1129 Tetrazole Blocks fungal cytochrome P450
enzyme
Oteseconazole
(VT-1161)
VL-2397
(ASP-2397)
Tetrazole Blocks fungal cytochrome P450
enzyme
Siderophore Accumulates in the fungal cells
via iron siderophore transporter
T-2307/ATI-2307 Arylamidine Inhibits fungal mitochondrial
Pre-clinical
trials
Phase-III
b
Phase-II
Phase-II
function
Encochleated
amphotericin-B
SUBAitraconazole
Tacrolimus Calcineurin
Cyclosporin A Calcineurin
Polyene Binds to ergosterol, causing
leakage across cell membrane
Azole Blocks cytochrome P450
enzyme
inhibitors
Phase-II
FDA approved
In-vitro studies/
animal studies
In-vitro studies
inhibitors
Geldanamycin hsp90 inhibitor In-vitro studies
Trichostatin A HDAC inhibitors In-vitro studies
Auredosidin A Glycolipiod
inhibitors
a
The drug has received FDA approval for vaginal candidiasis
b
Phase-II clinical trials terminated
Blocks inositol
phosphorylceramide synthase
In-vitro studies
15 Aspergillus Therapeutics: Future Agents
Table 15.2 Route of administration and antifungal spectrum of novel antifungal drugs
Route of
Drug
Fosmanogepix/
manogepix (APX001)
Ibrexafungerp Oral Aspergillus spp., Candida spp. (including
Olorom (F901318) IV/ oral Aspergillus spp., dimorphic fungi causing
Opelconazole
(PC945)
Rezafungin (CD101) IV Aspergillus spp., Candida spp. (including
MGCD-290 Oral Aspergillus spp., Candida spp.
a
VT-1129
VT-1598 Oral Candida spp. (including Candida auris),
Oteseconazolea
(VT-1161)
VL-2397 (ASP-2397) IV Aspergillus spp., Mucorales
ATI-2307 Subcutaneous in
Encochleated
amphotericin-B
SUBA-itraconazole Oral Aspergillus spp., dimorphic fungi
IV intravenous, spp. species, SUBA super bioavailable
a
Indicates lack of studies regarding use against Aspergillosis at present
administration
IV/ oral Aspergillus spp., Candida spp. (including
Inhalational Aspergillus spp.
Oral Cryptococus spp., Candida spp.
Oral Candida spp., Rhizopus spp.
animal models
Oral Candida spp.
Antifungal spectrum in trial(s)
Candida auris), Cryptococcus spp., Fusarium
spp., Scedosporium spp.
Candida auris)
endemic mycoses
Candida auris), Pneumocystis spp.
Cryptococcus, Aspergillus spp.
Aspergillus spp., Candida spp.
369
Scedosporium spp., but low activity was observed against Mucorales. The pre-
clinical, phase I and II clinical trials also showed similar results and excellent pharmacokinetics and pharmacodynamics property.
The drug is scheduled to begin phase III trials (clinicaltrials ID: NCT05421858
2023a) in coming future after another phase III trial was terminated (clinicaltrials
ID: NCT04240886 2020a) and the US Food and Drug Administration (FDA) has
given this drug a fast track status owing to its novel mechanism of action and wide
spectrum of action that includes drug-resistant fungi. Phase I trials were conducted
in healthy volunteers (clinicaltrials ID: NCT02957929 2016a; NCT02956499
2016b; NCT03333005 2017a). Another open label, phase I trial is currently under-
way (clinicaltrials ID: NCT05582187 2022a) to better understand the processing of
the drug by individuals having a varying degree of hepatic impairment.
15.2.2 Ibrexafungerp
Ibrexafungerp (previously SCY-078) is an antifungal drug belonging to the class
triterpenoids, similar in action to echinocandins. It has demonstrated fungistatic
370
Fig. 15.1 Chemical structure of antifungal drugs in development
Y. Bansal et al.
action on Aspergillus spp. by inhibiting the 1,3-β--glucan synthase enzyme. This
blocks the production of 1,3-β--glucan in the fungal cell wall. It is notable that
there is minimal cross-resistance between echinocandins and ibrexafungerp despite
similar mechanism of action. This is attributable to the difference in binding site for
both the antifungal drugs. Ibrexafungerp is also an orally administered drug in contrast to the echinocandins that are exclusively IV drugs (Hoenigl etal. 2021) and,
therefore, suitable only for patients that are hospitalized.
These two properties provide an edge to ibrexafungerp in clinical application
where echinocandin resistance is observed, e.g., in case of infections with Candida
spp., such as Candida glabrata and Candida auris. In-vitro studies have shown
excellent activity against azole-resistant strains of Aspergillus, such as Aspergillus
fumigatus. The drug has just completed two phase III clinical trials, to study its
efcacy and safety in patients suffering from invasive fungal infections that are
refractory to presently available antifungal therapy (clinicaltrials ID: NCT03059992
2017b) and another study to evaluate the efcacy and safety of ibrexafungerp in
patients suffering from invasive Candida auris infections (clinicaltrials ID:
NCT03363841 2017c). An important milestone in the development of this drug is
the recent FDA approval for its use in vulvovaginal candidiasis patients (Phillips
et al. 2023). A phase II trial called SCYNERGIA trial (clinicaltrials ID:
NCT03672292 2019a) has recently been completed to assess the safety and efcacy
of combination therapy of voriconazole and ibrexafungerp in adult patients.
15 Aspergillus Therapeutics: Future Agents
371
15.2.3 Olorofim
Olorom is an antifungal belonging to the novel class of antifungals called orotomides. This antifungal drug acts through inhibition of dihydroorotate dehydrogenase, thereby targeting pyrimidine synthesis (Seyedmousavi etal. 2019). The action
on the dihydroorotate dehydrogenase is selectively exerted on the fungal enzyme,
sparing the human dihydroorotate dehydrogenase. This reduces the toxicity and
improves the safety prole of the drug (Rauseo etal. 2020). The drug can be administered both orally as well as through the intravenous route.
Early data during pre-clinical, in-vitro studies were encouraging and many hyalines and dematicious molds (including Aspergillus spp., Talaromyces marneffei,
and Scedosporium spp.) exhibited low MICs against olorom (Hope etal. 2017).
However, this drug has no action against yeasts due to a different dihydroorotate
dehydrogenase enzyme (Oliver etal. 2016). Reports of tissue distribution of this
water insoluble drug have shown good distribution in kidneys, liver, and lungs, but
comparatively lower levels were attained in the brain (Oliver etal. 2016). Olorom
also has anti-biolm activity and combined with its activity against pan-resistant
molds, and it is expected to play a signicant role in treatment of invasive fungal
infections in hospitalized patients (Kirchhoff etal. 2020).
Olorom underwent phase I clinical trials for both oral (clinicaltrials ID:
NCT03340597 2017d) as well as IV formulations (clinicaltrials ID: NCT02342574
2015; NCT02142153 2014). Studies were also conducted to ascertain the pharma-
cokinetics of olorom in study participants with hepatic (NCT04752540 2021a) and
renal (NCT05200286 2022b) impairment. The drug is presently undergoing phaseIIb clinical trials with an open-label study FORMULA-OLS, study 32, clinical trials
ID: NCT03583164 2018a. Another phase-III clinical trial (clinicaltrials ID:
NCT05101187 2022c) is underway to compare the efcacy and safety of olorom
as compared to amphotericin-B in patients with invasive aspergillosis.
15.2.4 Opelconazole
Opelconazole is the rst drug in its class, triazoles, in which the lipophilic properties are enhanced, while the size of the molecule is reduced, making it suitable to be
administered through inhalation via nebulization. The drug acts by inhibiting the
CYP51A1 enzyme that stops the conversion of lanosterol into ergosterol in the fungal cells. Cessation of ergosterol formation induces dysfunction of the cell membrane (Colley etal. 2017).
Due to the differences in its chemical and physical properties as compared to
other triazoles, the drug is highly localized in the lungs, coupled with a longer retention duration. The drug, therefore, acts mainly in the lungs with little systemic
absorption making it appropriate for the treatment of pulmonary fungal infections,
such as pulmonary aspergillosis. Studies have shown opelconazole to be active
against a wide spectrum of fungi, such as Candida spp. (including Candida auris),
Cryptococcus spp., Aspergillus spp., and Rhizopus spp.
372
Y. Bansal et al.
In-vitro studies have shown synergistic activity between opelconazole and
posaconazole or voriconazole co-administration as inhaled (opelconazole) and systemic (posaconazole or voriconazole) drug (Colley etal. 2019). A phase I randomized control trial was conducted in 2018 (clinicaltrials ID: NCT02715570 2017e) to
assess the safety prole of the drug followed by a few, phase II clinical trials that
were terminated early in 2020 due to the COVID-19 outbreak. These include a
double-blind randomized control trial of inhaled opelconazole against invasive
aspergillosis (clinicaltrials ID: NCT03745196 2018b) and two therapeutic, openlabel trials of inhaled opelconazole against invasive aspergillosis (clinicaltrials ID:
NCT03870841 2019b; NCT03905447 2019c). A phase II open-label randomized
control trial called OPERA S Study (clinicaltrials ID: NCT05037851 2021b or PC_
ASP_007) has recently concluded to assess the efcacy of opelconazole prophylaxis or pre-emptive therapy against invasive aspergillosis in lung transplant patients.
A phase-III trial called the OPERA-T study (clinicaltrials ID: NCT05238116
2022d) has started recruitment of participants to assess the efcacy of inhaled opel-
conazole when given in combination with the standard antifungal therapy for refractory invasive aspergillosis.
15.2.5 Rezafungin
Rezafungin is a drug belonging to the existing class of antifungals, i.e.,
Echinocandins. It is a second generation echinocandin with optimized pharmacokinetics. It is similar to anidulafungin in chemical structure where a choline aminal
ether replaces the C5 ornithine hemiaminal present in the cyclic core of anidulafungin (James etal. 2017). This reduces the hepatotoxicity considerably while simultaneously improving the drug’s half-life to around 80h after dose and 150 h after
subsequent doses. This allows for a weekly dose of the antifungal.
The drug acts by inhibition of the enzyme 1,3-β--glucan synthase, causing cell
wall disruption. It displays high activity with very low MICs against most Candida
spp. (Pfaller etal. 2017; Arendrup et al. 2018; Toth etal. 2019), Aspergillus spp.
(including Aspergillus fumigatus) (Wiederhold etal. 2018), dermatophytes but has
no activity against other molds, and Cryptococcus (Pfaller etal. 2017). A study
(NCT02733432 2016c, RADIANT study for vulvovaginal candidiasis) investigating oral formulation reported unfavorable outcome in patients, and thus, the drug is
now given only through the intravenous route. The safety and tolerance of the drug
in pediatric population are being evaluated by a phase-I clinical trial (clinicaltrials
ID: NCT05534529 2023b). Another phase-III trial is present underway to assess the
efcacy of rezafungin in preventing invasive fungal infections in patients undergoing allogeneic blood and bone-marrow transplant (clinicaltrials ID:
NCT04368559 2020b).