An Insight Into the Antifungal Pipeline: Selected New Molecules and Beyond
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REVIEWS An insight into the antifungal pipeline: selected new molecules and beyond Luis Ostrosky-Zeichner*, Arturo Casadevall‡, John N. Galgiani§, Frank C. Odds|| and John H. Rex*¶ Abstract | Invasive fungal infections are increasing in incidence and are associated with substantial mortality. Improved diagnostics and the availability of new antifungals have revolutionized the field of medical mycology in the past decades. This Review focuses on recent developments in the antifungal pipeline, concentrating on promising candidates such as new azoles, polyenes and echinocandins, as well as agents such as nikkomycin Z and the sordarins. Developments in vaccines and antibody-based immunotherapy are also discussed. Few therapeutic products are currently in active development, and progression of therapeutic agents with fungus-specific mechanisms of action is of key importance. Invasive fungal infections have transitioned from a rare newest class of antifungals. They are characterized by curiosity to an everyday problem for the practising their inhibition of the synthesis of (1,3)-β-d-glucan (a physician. Invasive candidiasis is the third to fourth most key component of many fungal cell walls) and are there- common bloodstream infection in surveys in the United fore the first class of antifungal agents that act against States. Similar trends have been reported in several a specific component of the fungal organisms and not regions throughout the world, although the incidence mammalian cells11–13. Their safety profile is remarkable, by country can vary dramatically1–4. Rates of invasive setting the bar for new antifungals that are under devel- aspergillosis and mucormycosis continue to increase in opment. The mechanism of action of these agents, along *Division of Infectious parallel with the growth of immunocompromised patient with that of other antifungals currently in development, Diseases, University of Texas populations5–9. Invasive fungal infections are associated is illustrated in FIG. 2. Medical School at Houston, with substantial morbidity and mortality, despite optimal Antifungal research and development is challenging. 6431 Fannin, MSB 2.112, Houston, Texas 77030, USA. antifungal therapy, and carry a high financial burden. Apart from the fungal cell wall, fungi are metabolically ‡Department of Microbiology Improved diagnostics, new epidemiological studies and similar to mammalian cells and therefore offer few path- and Immunology, and the the availability of new antifungals have revolutionized ogen-specific targets. Clinical development is hampered Department of Medicine, the field of medical mycology in the past few decades. by challenges in timely and definitive diagnosis of the Albert Einstein College of Medicine, 1300 Morris Park Although systemic antifungals have been available less common or more resistant fungi. Despite these issues, Avenue, Bronx, New York since the 1950s, the early antifungal pipeline was char- some novel products are progressing in development. 10461, USA. acterized by compounds with limited efficacy owing to This Review focuses on the most recent developments §Valley Fever Center for toxicity, such as nystatin and amphotericin B10, and by in the antifungal pipeline, concentrating on the most Excellence, University of the lack of substantial developments for decades. The promising candidates that are nearing or currently in Arizona College of Medicine, Tucson, Arizona 85724, USA. 1980s saw the development of the triazoles, which revo- clinical development. ||Aberdeen Fungal Group, lutionized medical mycology as these compounds were Institute of Medical Sciences, available both in intravenous and oral formulations, New and small molecules Aberdeen, AB25 2ZD, UK. and were effective against fungal pathogens that were Azoles. The imidazole and triazole antifungal class has ¶AstraZeneca (FIG. 1) Pharmaceuticals, Alderley refractory to the polyenes . The 1990s were char- been the most successful in terms of numbers of different Park, Macclesfield, Cheshire, acterized by further triazole development and by the agents that have entered clinical use. However, most of SK10 4TF, UK. reformulation of amphotericin B with lipid compounds. the antifungal imidazoles are formulated only for topical Correspondence to L.O.-Z. These lipid-based preparations were considerably less use, usually because of toxicity or bioavailability prob- e-mail: Luis.Ostrosky- toxic and allowed the true efficacy of amphotericin B to lems that limit their potential as systemic agents. Agents [email protected] doi:10.1038/nrd3074 be explored, expanding the pharmacokinetic and phar- that are licensed for clinical use in invasive fungal disease 10 Published online macodynamic limits of the agents . The new millennium are all triazoles: fluconazole, itraconazole, posaconazole 20 August 2010 brought the echinocandins to the market, which are the and voriconazole. NATURE REVIEWS | DRUG DISCOVERY VOLUME 9 | SEPTEMBER 2010 | 719 © 2010 Macmillan Publishers Limited. All rights reserved REVIEWS 14 undergoing development in the form of the orally active, Anidulafungin water-soluble prodrug BAL-8557, which is amenable to 12 Caspofungin L-AmB intravenous formulation18. Isavuconazole is currently in Micafungin s Voriconazole ABCD Phase III clinical trials. 10 Posaconazole ABLC Many new antifungal triazole molecules are disclosed Terbinafine in primary research papers and patents, but only the 8 Itraconazole compounds listed above meet the definition of the anti- Fluconazole fungal pipeline used in this article — namely, promising ailable antifungal candidates that are nearing or currently in clinical 6 Ketoconazole Miconazole development. It is too early to know whether any of the triazoles mentioned will show genuine improvements 4 5-FC over existing, licensed triazoles. New triazoles could Number of av Griseofulvin offer advantages by extending the spectrum of activity 2 Amphotericin B to include rare but difficult-to-treat invasive mycoses Nystatin (infections caused by Fusarium spp., Scedosporium spp. 0 or the Zygomycota) or by improving the drug–drug 1950 1960 1970 1980 1990 2000 interaction profile. In addition, new triazoles might Figure 1 | Timeline of systemic antifungals. The graph have a pharmacokinetic profile that would substantially shows the name, number andNa rateture of Re developmentviews | Drug Disc ofov ery available systemic antifungal agents from the 1950s to the reduce dosing frequency and/or a more favourable 2000s. ABCD, amphotericin B colloidal dispersion; ABLC, adverse effects profile. However, none of the triazoles amphotericin B lipid complex; 5-FC, flucytosine; L-AmB, in the pipeline has yet clearly shown such advantages, liposomal amphotericin B. mainly because of the paucity of clinical data. Polyenes. The broad-spectrum polyene antibiotic ampho- tericin B became the early mainstay for the treatment of Posaconazole and voriconazole represent specific many types of invasive fungal infection. Amphotericin B advances in the understanding of structure–activity binds strongly to ergosterol, the principal sterol in fungal relationships for antifungal azoles, as evidenced by their membranes. Aggregates of amphotericin B–ergosterol progression over the past 30 years (FIG. 3). A triazole- complexes form membrane pores, leading to leakage based pharmacophore has replaced the earlier imidazole of intracellular constituents19. The differential binding pharmacophore in systemically active azoles because affinity of amphotericin B for ergosterol over cholesterol, the triazole group enhances the specificity for fungal the mammalian membrane sterol, accounts for its selec- cytochrome P450 (Erg11) targets and slows metabo- tive toxicity. However, amphotericin B can affect mam- lism of the agents in vivo14. In a fluconazole-based malian cells, and nephrotoxicity is a common sequela structural type, the extra methyl group at carbon atom of clinical usage20. The introduction of lipid-complexed number 3 enhances hydrophobic interactions at the amphotericin B formulations considerably reduced the Erg11 active site and extends the antifungal spectrum15. incidence of renal toxicity from amphotericin B. Two A 2,4-di fluorophenyl substituent rather than a dichloro- lipid products — a liposomal formulation and a lipid phenyl at carbon atom number 2 has become standard for complex — are now commonly used to treat a wide triazole agents. Replacement of the 1,3-dioxolane moiety range of life-threatening mycoses. in ketoconazole and itraconazole with a furan ring, as in Although numerous new polyenes, modifications of posaconazole, alters and enhances activity, as extensively existing polyenes and novel polyene formulations have demonstrated in mouse models of fungal disease16. been reported, only two meet the criteria for inclusion Triazole agents in the development pipeline benefit in this Review. A cochleate formulation of amphotericin from these optimized structural features. Albaconazole B has shown efficacy in experimental models of can- (UR-9825) (FIG. 3) is currently under development didiasis and aspergillosis21–23. This formulation entraps by Stiefel under licence from its discoverers, Uriach. the amphotericin B molecules in a large, stable, spirally The orally active agent has shown efficacy in animal rolled lipid bilayer. The formulation promises oral models of infections caused by Aspergillus, Candida, bioavailability of amphotericin B, but to date the only Cryptococcus and Scedosporium spp.17. However, its most pharmacokinetic