Fungal infections can pose similar problems to those of drug-resistant bacterial infections, such as MRSA and C. difficile, and invasive aspergillosis and mucormycosis can be life threatening. A new antifungal agent, isavuconazole, is being developed by Astellas, under licence from Basilea.1 It has been granted fast-track status by the FDA, as well as being designated a qualified infectious disease product, and an orphan drug for invasive aspergillosis and mucormycosis.
The drug is a triazole, and a water-soluble prodrug of Basilea’s earlier investigational agent, BAL4815, that is active against a broad spectrum of opportunistic and pathogenic fungi. These include strains that are resistant to other azole drugs. The lack of water solubility of BAL4815 led to the company going down the soluble prodrug route to enable successful oral dosing.
The pharmacokinetics of prodrug and dosed orally and intravenously were compared in two Phase I trials in healthy volunteers. In one trial,2 subjects were given single ascending oral doses of isavuconazole equivalent to 100, 200 or 400mg of BAL4815, or single ascending intravenous infusions equivalent to 50, 100 or 200mg, or placebo. Maximum plasma concentrations were achieved 1.5 to 3 hours after oral administration, or at the end of the infusion. Urinary recovery was less than 0.4% of the infused dose, implying high bioavailability.
In the other study,3 multiple doses were given for 21 days orally or 14 days intravenously. Adverse events were mild or moderate, and there was a steadily increasing accumulation of active drug in plasma, reflecting its long elimination half-life.
Results of a Phase III trial comparing its efficacy with voriconazole have recently been presented.4 A total of 527 patients with invasive fungal disease caused by aspergillus or other filamentous fungi were randomised to receive 200mg intravenous isavuconazole three times a day for two days, followed by daily doses of 200mg, either intravenously or orally, or voriconazole in a largely similar dosing schedule. The primary endpoint of all-cause mortality after six weeks was 18.6% in the isavuconazole group, and 20.2% for voriconazole. Importantly, adverse events were statistically lower in the isavuconazole group, at 42% compared with 60%. The most common adverse events were nausea, vomiting, pyrexia and diarrhoea. Further Phase III trials are under way.
A couple of single-patient last-ditch treatment results have also been published. In one, a patient with relapsed acute myelogenous leukaemia developed disseminated mucormycosis.5 After failing posaconazole and being intolerant to amphotericin, he was successfully treated with isavoconazole for more than six months alongside his ongoing leukaemia treatment.
And a patient with rhinocerebral mucormycosis that was refractory to amphotericin and posaconazole was given isavuconazole salvage therapy.6 It was well tolerated, and the patient has remained disease free for 24 months after treatment.
References
1. G.R. Thompson III and N.P. Weiderhold, Mycopathologia 2010, 170, 291
2. A. Schmitt-Hoffman et al. Antimicrob. Ag. Chemother. 2006, 50, 279
3. A. Schmitt-Hoffman et al. Antimicrob. Ag. Chemother. 2006, 50, 286
4. J. Maertens et al. Eur. Soc. Clin. Microbiol. Inf. Dis. 2014 (Barcelona, 10–13 May), Antibodies. O230a
5. D. Peixoto et al. J. Clin. Microbiol 2014, 52, 1016
6. J. Ervens et al. Infection 2014, 42, 429