Isavuconazole: the latest addition to the antifungal armamentarium
Isavuconazole (Cresemba®), a triazole antifungal, authorised in the EU since October 2015, demonstrated clinical effectiveness in pivotal trials of invasive aspergillosis and mucormycosis, and a favourable side-effect profile. In addition, it has a number of beneficial pharmacological properties, which differentiate if from existing antifungals.1-3
Invasive fungal infections such as aspergillosis and mucormycosis occur predominantly among immune- deficient patients and are associated with high morbidity and mortality, as reported by Prof. Cornelia Lass-Flörl (Innsbruck, Austria).4,5 The incidence of these infections has increased over the last few years.4 A possible explanation may be an increasing number of high-risk patients who receive better treatment for their underlying disease, and thus may survive longer. This includes in particular patients with haematopoietic stem cell or organ transplants or with malignant haematological diseases, who are typically under immunosuppression. In addition, an increasingly ageing population is likewise at increased risk. The clinically most significant examples of pathogens among opportunistic invasive fungal infections are Aspergillus species (spp.), Candida spp. and rarer fungal species such as Mucorales. Many are ubiquitous in the environment but display limited virulence and only reveal their pathogenic potential where there is decreased immunocompetence. An increase in rare fungal species such as mucormycetes has been observed.4 At the same time, due to success in treating antifungal-sensitive species, there is increased selection of the less responsive fungi, as explained by Lass-Flörl.
Early diagnosis and treatment is often life-saving
Appropriate treatment with a specifically- effective antifungal is key. The prerequisite of clinical success however is identification of the fungus responsible – according to Lass-Flörl, this represents a significant challenge from the clinical point of view. A central problem is the lack of specific clinical symptoms Among immunosuppressed patients with invasive, progressive disease and organ infection in particular, the clinical symptoms do not indicate whether the pathogen is a fungus or bacterium. In addition, the microbiologist remarked that diagnostic methods are often insufficient, so culture and identification of the fungal pathogen are not always successful. Treatment can be problematic, as Prof. Helmut Ostermann (Munich, Germany) emphasised. It is made more difficult due to increasing antifungal resistance, particularly in the case of Aspergillus spp. Success rates are unsatisfactory and antifungal therapies can carry significant side effects. There is thus room for improvement in the treatment of invasive mycoses.
A triazole with broad spectrum of activity and favourable pharmacokinetics
Isavuconazole (Cresemba®) has been approved since October 2015 for the treatment of adult patients with invasive aspergillosis, and for adult patients with mucormycosis for whom treatment with amphotericin B is not appropriate.1 Against the background described above, the introduction of isavuconazole, the latest azole antifungal, represents an important broadening of the therapeutic spectrum for these serious, life-threatening infections. As Ostermann outlined, isavuconazole displays a broad spectrum of activity.2,3 It is the only azole approved for both the treatment of invasive aspergilloses and mucormycoses.2 In addition to its good efficacy and favourable side-effect profile, isavuconazole possesses a range of advantageous pharmacological properties when compared with older antifungals used for the treatment of invasive fungal infections (Tab. 1).1,2,3 These include indicators of penetration into the CNS, arising from cases in which isavuconazole has been used to treat cerebral fungal infections.6
Compelling clinical effectiveness
Ostermann reported that the safety and efficacy of isavuconazole among patients with invasive aspergillosis were examined in two clinical phase III trials. In the randomised, double-blind SECURE study, isavuconazole was compared with voriconazole among 516 patients with invasive aspergillosis. Here, isavuconazole proved to be non-inferior to voriconazole with respect to the primary efficacy endpoint of all-cause mortality at day 42 in the intentionto- treat (ITT) population (19% vs. 20%). The all-cause mortality in the other pre-defined populations (ITT, modified ITT [mITT] and mycological ITT [myITT]) after 42 and 84 days were also consistent. Comparable results (35% isavuconazole vs. 36% voriconazole) were also observed with respect to clinical response rates at the end of treatment.7 The safety and efficacy profile of isavuconazole among patients with mucormycosis was established with data from the VITAL study.8 This open label, non-comparative study comprised a subgroup of 37 patients with proven or probable mucormycosis, of whom 21 received isavuconazole for primary treatment. Isavuconazole proved effective against mucormycetes with respect to mortality, and the clinical response was determined by an independent data review committee. The 42-day all-cause mortality was 38%. Results from a matched case control analysis for indirect comparison with patient data from the FungiScope Registry* indicate that isavuconazole exhibits comparable efficacy to the standard treatment (amphotericin B). For instance, the all-cause mortality after 42 days was 33% with isavuconazole (n=21) and 39% with amphotericin B (n=33).8
Favourable side effects profile
In the SECURE study, isavuconazole showed a favourable tolerability profile. While rates of adverse events were similar for both treatment arms, patients receiving isavuconazole exhibited fewer treatment-related adverse events (TEAEs) compared with voriconazole (42% vs. 60%, p<0.001). Furthermore, isavuconazole-treated patients had a lower frequency of hepatobiliary (9% vs. 16%; p=0.016), skin (33% vs. 42%; p=0.037) and eye disorders (15% vs. 27%; p=0.002). Rates of treatment discontinuation due to TEAEs or drug-related adverse events were also numerically lower for isavuconazole than for voriconazole (14% vs. 23%; p<0.05, and 8% vs. 14%; NS.).7 Finally, the proportion of patients with raised levels of transaminase and bilirubin at the end of treatment with isavuconazole was lower than that observed with voriconazole (Fig. 1).7,9
Low drug interaction potential
Among patients receiving immunosuppressants, who are therefore at greater risk of invasive mycoses, the relatively low potential for drug interactions with isavuconazole is notable. In general, all azoles inhibit the CYP3A4/5 system. Simultaneous administration of CYP3A4/ 5 substrates including immunosuppressants such as cyclosporine, sirolimus or tacrolimus may markedly increase the concentration of these substances and thus require caution. In some cases, combinations are contraindicated. Clinical pharmacological studies indicate ability to use isavuconazole in tandem with these kinds of immunosuppressants since its effect on the pharmacokinetics of CYP3A4 substrates is less pronounced than that of posaconazole and voriconazole.1,10
Basilea Symposium, Press Talk, and Clinical Forum on the occasion of the annual meeting of the German, Austrian, and Swiss Society of Hematology and Medical Oncology (Deutsche, Österreichische und Schweizerische Gesellschaften für Hämatologie und Medizinische Onkologie), Oct 16 2016 in Leipzig, Germany
1. Cresemba® Summary of Product Characteristics; http://www.ema.europa.eu
2. Chitasombat MN et al. The ‘cephalosporin era’ of triazole therapy: isavuconazole, a welcomed newcomer for the treatment of invasive fungal infections. Exp Opin Pharmacother 2015; 6 (10): 1543-1558.
3. Miceli MH, Kauffman CA. Isavuconazole: A new broad-spectrum triazole antifungal agent. Clin Infect Dis 2015; 61 (19): 1558-1565.
4. Bitar D et al. Population-Based Analysis of Invasive Fungal Infections, France, 2001–2010 Emerg Infect Dis 2014; 20: 1149-1155
5. Slavin M et al. Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality. Clin Microbiol Infect 2015; 21 (5): 490.e1-490.e10
6. Ananda-Rajah MR, Kontoyiannis D. Isavuconazole: a new extended spectrum triazole for invasive mold diseases. Future Microbiol 2015; 10 (5): 693-708
7. Maertens JA et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomisedcontrolled, non-inferiority trial. Lancet 2016; 387: 760-769
8. Marty FM et al. Isavuconazole treatment for mucormycosis: a single-arm openlabel trial and case-control analysis. Lancet Infect Dis 2016; 16 (7): 828-37
9. Ullmann AF et al. A comparison of the safety profiles of isavuconazole vs voriconazole n the Phase 3 SECURE study in patient with invasive mould infections. European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2015, Poster EP018.
10. Townsend R et al. Drug interaction profiles of isavuconazole, voriconazole and posaconazole with immunosuppressants metabolized by CYP450 3A4. 7th Congress on Trends in Medical Mycology (TIMM) 2015; Lissabon, Portugal, Poster P464