Antifungal Drug Pipeline
Many of our patients already know of the increasing need for new antifungal drugs; treatments for fungal diseases like aspergillosis have significant limitations. Toxicities, drug-drug interactions, resistance, and dosing are all issues that can complicate therapy; therefore, the more treatment options we have, the more likely we are to find an optimal therapeutic option for patients.
Developing antifungal drugs is difficult because of the biological similarities between people and fungi; we share many of the same biological pathways as fungi, creating issues in developing safe antifungals. To develop new antifungal drugs, researchers must look at how they can exploit some of the differences we do have.
Below is a layman’s breakdown of a recently published review that looked at seven antifungal drugs currently in various stages of development. The majority of new antifungals have been new versions of old drugs, but the ones discussed in this review have new mechanisms of action and different dosing regimens, so, if approved, these drugs could provide a ray of hope in the not so distant future in terms of treatment.
Rezafungin is currently in phase 3 of development. It is a member of the echinocandin class of drugs, including micafungin and caspofungin; Echinocandins work by inhibiting a fungal cell wall component essential to homeostasis.
Rezafungin has been developed to retain the safety benefits of its echinocandin predecessors; while enhancing its pharmacokinetic and pharmacodynamic properties to create a unique, longer-acting, more stable treatment that allows for weekly intravenous rather than daily administration, potentially expanding treatment options in the setting of echinocandin resistance.
Fosmanogepix is known as a first-in-class drug (so first of its kind antifungal) that blocks the production of an essential compound that is important for the construction of the cell wall and self-regulation. Blocking the production of this compound weakens the cell’s wall enough that the cell can no longer infect other cells or evade the immune system. It is currently in Phase 2 clinical trials and is showing promising results in the oral and intravenous treatment of multiple invasive fungal infections, demonstrating efficacy in multi-drug resistant and other difficult-to-treat infections.
Olorifim falls under an entirely new class of antifungal drugs called orotomides. The orotomides have a distinct mechanism of action, selectively targeting a key enzyme in pyrimidine biosynthesis. Pyrimidine is an essential molecule in DNA, RNA, cell wall and phospholipid synthesis, cell regulation, and protein production, so when Olorofim targets this enzyme, it profoundly affects the fungi. Unfortunately, Olorifim isn’t broad spectrum, and it only kills a few fungi – pertinently, Aspergillus, and the fungus that causes valley fever (which affects the brain), Coccidioides. Since its discovery, it has progressed through pre-clinical studies and phase 1 human trials and is currently an ongoing phase 2 clinical trial testing its use orally and intravenously.
Ibrexafungerp is the first of a new class of antifungals called Triterpenoids. Ibrexafungerp targets the same essential component of the fungal cell wall that the echinocandins do, but it has an entirely different structure, making it stabler and meaning it can be given orally; differentiating Ibrexafungerp from the three currently available echinocandins (caspofungin, micafungin, andulafungin), which can only be given intravenously limiting their use to hospitalised patients and those with indwelling venous access.
There are two ongoing phase 3 trials of ibrexafungerp. The most extensive enrolling study to date is the FURI study, which evaluates the efficacy and safety of Ibrexafungerp among patients with severe fungal infection and who are unresponsive or intolerant of standard antifungal agents. The oral formulation was recently approved by the USA’s Food and Drug Administration (FDA) for the treatment of vulvovaginal candidiasis (VVC).
Oteseconazole is the first of several tetrazole agents designed with the goal of greater selectivity, fewer side effects, and improved efficacy compared to currently available azoles. Oteseconazole has been designed to tightly bind to an enzyme called cytochrome P450. When we discussed earlier fungi and humans being similar, cytochrome P450 is one of those similarities. Human cells contain various species of cytochrome P450, which are responsible for many important metabolic functions. Therefore, if azole antifungal agents inhibit the human cytochrome P450, the result can be adverse reactions. But, unlike other azole antifungals, Oteseconazole only inhibits the fungal cytochrome p450- not the human one because of its affinity for the target enzyme (cytochrome P450) is greater. This should mean fewer drug-drug interactions and less direct toxicity.
Oteseconazole is in phase 3 of development and is currently under FDA consideration for approval to treat recurrent vulvovaginal candidiasis.
Encochleated Amphotericin B
Many of our patients will already be aware of Amphotericin B, which has been around since the 1950s. Amphotericin B falls under the class of drugs called Polyenes- the oldest class of antifungal drugs available. They kill fungi by binding to ergosterol which acts to maintain cell membrane integrity. The drug works by stripping away the ergosterol, causing holes in the cell membrane, making it leaky enough to fail. But, polyenes also interact with cholesterol in human cell membranes, meaning they have significant toxicities. Encochleated Amphotericin B has been developed to avoid these significant toxicities – its novel lipid nanocrystal design allows for drug delivery directly to the infected tissues, shielding the body from unnecessary exposure – and it can be given orally, potentially reducing hospital stays.
Encochleated Amphotericin B is currently in phases 1 & 2 of development, so a little way off. Still, it promises the potential of an oral drug with little, if any, of the typical toxicities of amphotericin B.
ATI-2307 is in the very early stages of development and is a new antifungal drug with a unique mechanism of action. ATI-2307 inhibits mitochondrial function (mitochondria are structures within cells that convert food to energy), decreasing the production of ATP (adenosine triphosphate), which is the molecule that carries energy, leading to growth inhibition.
As mentioned earlier, ATI-2307 is still in the early stages. Still, researchers have completed three Phase 1 clinical studies that demonstrated it was well tolerated in humans at anticipated therapeutic dose levels. Thus, the clinical role for ATI–2307 is unclear; however, its broad in vitro activity against a host of important fungal pathogens, including multi-drug resistant organisms, could translate into a critical role for this compound, especially for fungal infections due to drug-resistant organisms such as azole-resistant Aspergillus species.