The choice of antifungal drugs on the market is small, and there are limitations on which ones the NHS can prescribe. Many strains of fungus have evolved resistance to multiple drugs, and harsh side effects mean some patients cannot tolerate certain drugs, so there is a desperate need for new antifungals, ideally from new classes that are not yet affected by resistance.
How new drugs get approved
Getting a new drug approved is a long and expensive process that normally goes through the following stages:
|Basic research||Learning about the disease and looking for molecular targets for new drugs to be used against.|
|Drug discovery||Screening libraries of chemicals, or tweaking the structures of promising compounds.|
|Pre-clinical studies||Testing how well the potential new drug works in a test tube or animal model.|
|Application to begin human trials|
|Phase 0 and I||Testing the drug in healthy volunteers, to see what happens to the drug inside the body – how well is it absorbed into the bloodstream, distributed to the relevant tissues (e.g. lungs), metabolised and eliminated through the urine/faeces. This helps the researchers decide what range of dosages to use in the trials.|
|Phase II||Testing the drug in several hundred patients with the condition, to see which dosage is most effective and get an idea of any common side effects.|
|Phase III||Testing the drug in several hundred to several thousand patients with the condition, to accurately measure how well the drug treats the disease and how often it produces each side effect.|
|Application for drug approval||Applying to the EMA (Europe) or a country-specific medicines regulatory agency such as the FDA (U.S.) for permission to start selling the drug.|
|NICE assessment||Deciding whether the drug is beneficial enough to make it worth the cost to the NHS|
|Commissioning/funding||If NICE do not recommend a drug for routine use (which has been the case for many antifungals), a doctor can still prescribe it to a patient if their local CCG agrees to fund it. The NAC is a specialist CCG that has extra freedom to prescribe certain antifungals, and some transplant units may prescribe antifungal prophylaxis.|
|Phase IV||Also known as post-marketing. Checking that the drug performs as well as expected in a ‘real world’ setting.|
CCG = Clinical Commissioning Group
What new drugs are currently in trials for aspergillosis?
New drugs are usually approved for invasive aspergillosis before CPA/ABPA.
- Olorofim is a novel antifungal from a completely new class of drugs (the orotomides). It is being developed by F2G Ltd, which is a spin-off company whose advisors include Professor Denning. Olorofim has been through various Phase I trials, Phase II trials and has recently (March 2022) entered a Phase III trial to see how well it works in 225 patients with invasive fungal infections.
- Rezafungin is a type of echinocandin drug, these work by inhibiting a fungal cell wall components essential to homeostasis. It is being developed to retain the safety of other echinocandins whilst having stronger pharmokinetic properties. It is currently in phase III of trials.
- Ibrexafungerp is the first of a new class of antifungals called Triterpenoids. Ibrexafungerp works in a similar way to the echinocandins, but it has an entirely different structure, making it more stable and meaning it can be given orally. There are two ongoing phase 3 trials of ibrexafungerp. One being the FURI study involving 200 participants with invasive and/or severe fungal disease.
- Fosmanogepix is a first of its kind antifungal which blocks the production of an essential compound that is important for the construction of the cell wall and self-regulation. It has recently completed its phase II trial which involved 21 participants.
- 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. It is in phase 3 of development and currently under FDA consideration for approval to treat recurrent vulvovaginal candidiasis.
- Encochleated Amphotericin B is a type of Polyene which kill fungi by binding to ergosterol which acts to maintain cell membrane integrity. However, 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 and is currently in phases 1 & 2 of development.
- ATI-2307 is a type of Arylamidine which inhibits mitochondrial function in yeast therefore inhibiting growth. It has completed three phase I trials and is set to enter phase II trials in 2022.
How to look up information about aspergillosis trials
Clinical trials must be registered publicly for ethical reasons (because they involve human subjects). You can use clinicaltrials.gov to search for trials that you might be eligible to participate in, or to find the results of trials that have recently been completed.
If you aren’t comfortable with the risks involved in testing a new drug, you could volunteer for a registry or diagnostics/biomarker study instead. Many trials look at how we can use existing drugs in new dosages or new combinations, or in different groups of patients e.g. ATCF: Itraconazole/voriconazole for cystic fibrosis patients whose sputum is persistently positive for Aspergillus.