At IDWeek 2024 [the annual meeting of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, the Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists] held from 16 to 19 October 2024 in Los Angeles, California, the findings from a study examining the efficacy of Scynexis’s SCY-247 on three different murine [mice] models were discussed.
SCY-247, a second-generation fungerp [class of antifungals], is a triterpenoid antifungal in the preclinical stage of development. The drug has broad-spectrum activity against a wide variety of fungi including yeasts, moulds, pneumocystis, dimorphic fungi and azole and echinocandin-resistant strains. SCY-247 inhibits glucan synthase, an enzyme involved in the formation of 1,3-beta-D-glucan, an essential component of the fungal cell wall, and scanning electron microscopy has shown that the drug significantly alters cell wall morphology. The drug recently demonstrated positive results in in vivo murine models of invasive candidiasis (IC) and pulmonary mucormycosis, and the response correlated with dose and exposure.
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The study assessed three different murine models; one displaying IC caused by Candida (C) albicans, another IC model caused by C glabrata, and a model of pulmonary mucormycosis caused by Rhizopus (R) delemar. SCY-247 was administered twice daily for seven days, with doses ranging from 16 to 48mg/kg. Endpoints measured included changes in tissue fungal burden on day eight and survival through to day 21 in the latter model.
Few treatments currently exist for invasive broad-spectrum fungal infection
In the IC model caused by C albicans, a significant (p< 0.005) difference in kidney fungal burden was detected between the treatment group and the vehicle control, and the effects were visible from the lowest treatment dose. In the IC model caused by C glabrata, SCY-247 showed a significant reduction in kidney fungal burden at all doses, and this was also seen with established antifungal caspofungin, but not fluconazole. Significant reductions in lung fungal burden were also observed with medium (32mg/kg) and high (48mg/kg) doses of SCY-247, but not with caspofungin or fluconazole. Lastly, in the pulmonary mucormycosis model, SCY-247 (medium and high doses) had a significant effect on survival compared to the vehicle control, and this was also observed when administering Liposomal Amphotericin B (LAmB). However, combination therapy (SCY-247 + LAmB) was most effective at improving survival compared to either monotherapy. The same findings applied to decreasing fungal burden, where combined SCY-247 and LAmB had the best outcome, although both the medium and high dose SCY-247 groups were able to significantly reduce fungal burden in lung and brain tissue too.
There are currently few treatment options for invasive fungal infections with broad-spectrum activity and thus these results are promising. Furthermore, whilst SCY-247 is similar to other echinocandins, it has the added benefit that it can be administered both orally and intravenously and can target infections with FKS [a membrane-integrated synthase] mutation (as it has a different enzyme binding site). The drug also has a low propensity for drug-drug interactions and extensive tissue penetration, and hence has a favourable pharmacokinetic profile. A first-in-human trial is expected to begin in December 2024.
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