EV-086 for Invasive Fungal Infections

About Invasive Fungal Infections

The human body is naturally exposed to various species of fungi. The immune system of the healthy individual efficiently protects the body from these microorganisms. In individuals with a weakened immune system, however, IFIs can occur. Fungi are disseminated in the blood stream and invade different organs. Mortality rates of IFIs are generally very high.

Conditions that compromise the function of the immune system are diverse. They include organ transplantations where the immune system has to be weakened artificially to prevent organ rejection, and cancer therapies, which not only target the hematologic malignancies but also the immune system. Age is also a predisposing condition for IFIs. The immune system is often weakened in newborns, especially low-birth-weight babies, and elderly people. Further people at risk are patients at the intensive care unit, general surgical patients, those with a central venous catheter or AIDS.

One of the most common IFI caused conditions is Candidaemia (a bloodstream infection with fungi of the Candida family), which is the fourth most common bloodstream infection in hospitalised patients in the USA. The second most common condition is Aspergillosis (a bloodstream infection with fungi of the Aspergillus family).

Current Treatments

Three main classes of drugs are currently used to treat IFIs:

• Azoles: the most widely used class. Whilst of reasonable efficacy, most of these drugs have a risk of causing liver damage, and inhibit metabolizing enzymes causing problematic drug-drug interactions. Resistance to this class of drugs is also increasing. The top selling Azole drug is Voriconazole (Vfend™, Pfizer), which had 2008 sales of $743mn. Other approved Azoles include Posaconazole (NoxafilTM, Merck) and Fluconazole (DiflucanTM, Pfizer).
• Echinocandins: primarily used for candida infections. They can only be administered via intravenous infusion. There has been recent development of resistance to drugs of this class. The top selling Echinocandin is Caspofungin (Cancidas™) from Merck, which had 2008 sales of $597mn. Other approved Echinocandins include Micafungin (Mycamine™, Astellas Pharma) and Anidulafungin (Eraxis™/Ecalta™, Pfizer).
• Amphotericin: a relatively old drug that still has an important role because of its broad spectrum of activity and the rarity of resistance. The use of conventional amphotericin B is however limited by its toxicity to the kidneys. Its lipid derivatives, particularly liposomal amphotericin B (Ambisome, $290mn, Gilead) are less nephrotoxic while maintaining the broad antifungal spectrum.

Compounds in late stage clinical development include a Phase III azole (Isavuconazole) from Basilea and a reformulation of Amphotericin (iCo-009) from iCo Therapeutics. A few companies, including F2G, Novexel and MethylGene, have products in late pre-clinical/early clinical development.

How EV-086 May Benefit Patients

EV-086 can potentially reduce the high levels of mortality associated with IFIs, which currently range from 30–80%. In-vitro, EV-086 can kill fungal strains that are resistant to existing antifungals, thus it can potentially benefit patients infected with these strains. Studies have shown that EV-086 in-vitro can be synergistic with certain existing antifungals and hence administration of EV-086 on top of standard treatment may offer higher efficacy with reduced toxicity. Its lack of P-450 interactions may simplify treatment since it would entail fewer drug-drug interactions.

Current Development Status

EV-086 is in late preclinical development. Good laboratory practice (“GLP”) toxicity studies on an oral formulation were completed in 2009. Evolva is currently conducting GLP infusion toxicity studies, after which a clinical trial application with the UK Medicines and Healthcare products Regulatory Agency for the first-in-man study (which will be a Phase I SAD study) with an intravenous infusion formulation will be submitted. The Phase I SAD study is planned for 2010. The Phase I SAD study will be a double-blind, placebo-controlled study with several cohorts of eight volunteers each (six on EV-086, two on a placebo). One cohort will use female post-menopausal subjects, whereas the other cohorts will use healthy male subjects. The intravenous infusion time will likely be three hours.