quilseconazole (VT-1129) / Mycovia Pharma - LARVOL DELTA

Assessment of the potential risk of oteseconazole and two other tetrazole antifungals to inhibit adrenal steroidogenesis and peripheral metabolism of corticosteroids. (PubMed, Front Pharmacol) - "The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism...This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2...Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia."

Journal • Cardiovascular • Endocrine Disorders • Hypertension • Nephrology • Renal Disease • CYP17A1

Analysis of the inhibition of adrenal synthesis and peripheral metabolism of corticosteroids by oteseconazole and two preclinical tetrazole antifungals (ENDO 2024) - "The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia by blocking adrenal cortisol synthesis and its peripheral inactivation [1]...Steroidomic footprint analyses of H295R cell supernatants using untargeted LC-HRMS with steroid annotation indicated common features of the oteseconazole and VT-1129 patterns with that of the triazole itraconazole, and similarities between VT-1598 and the triazole isavuconazole...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO."

Preclinical • Cardiovascular • Endocrine Disorders • Hypertension • Nephrology • Renal Disease • CYP11B1 • CYP17A1

Recent Antifungal Pipeline Developments against Candida auris: A Systematic Review. (PubMed, J Fungi (Basel)) - "These included new additions to existing antifungal classes (rezafungin and opelconazole), first-in-class drugs such as ibrexafungerp, manogepix/fosmanogepix, olorofim and tetrazoles (quilseconazole, oteseconazole and VT-1598), as well as other innovative agents like ATI-2307, MGCD290 and VL-2397. All these compounds demonstrated significant improvements in survival and reduction in tissue fungal burden on neutropenic animal models of candidemia due to C. auris. Continual efforts towards the discovery of new treatments against this multidrug-resistant fungus are essential."

Journal • Review • Infectious Disease

Characterisation of Candida parapsilosis CYP51 as a Drug Target Using Saccharomyces cerevisiae as Host. (PubMed, J Fungi (Basel)) - "Constitutive expression of CpCYP51 Y132F conferred a 10- to 12-fold resistance to fluconazole and voriconazole, reduced to ~6-fold resistance for the tetrazoles VT-1161 and VT-1129, but did not confer resistance to the long-tailed triazoles. We report the X-ray crystal structure of ScCYP51 in complex with VT-1129 obtained at a resolution of 2.1 Å. Structural analysis of azole-enzyme interactions and functional studies of recombinant CYP51 from C. parapsilosis have improved understanding of their susceptibility to azole drugs and will help advance structure-directed antifungal discovery."

Journal • Candidiasis • Infectious Disease

Investigational antifungal agents for invasive mycoses: a clinical perspective. (PubMed, Clin Infect Dis) - "These include new drugs within the existing antifungal classes or displaying similar mechanism of activity with improved pharmacologic properties (rezafungin, ibrexafungerp) or first-in-class drugs with novel mechanisms of action (olorofim, fosmanogepix). Although critical information regarding the performance of these agents in heavily immunosuppressed patients is pending, they may provide useful additions to current therapies in some clinical scenarios, including IFI caused by azole-resistant Aspergillus or multi-resistant fungal pathogens (e.g. Candida auris, Lomentospora prolificans). However, their limited activity against Mucorales and some other opportunistic molds (e.g. some Fusarium spp.) persists as a major unmet need."

Clinical • Journal • Dermatology • Infectious Disease

Systemic Antifungal Agents: Current Status and Projected Future Developments. (PubMed) - Methods Mol Biol - "This chapter focuses on the currently available classes and representatives of systemic antifungal drugs in clinical use. We further discuss the unmet clinical needs in the antifungal research field; efforts in reformulation of available drugs such as Amphotericin B nanoparticles for oral drug delivery; development of new agents of known antifungal drug classes, such as albaconazole, SCY-078, and biafungin; and new drugs with novel targets for treatment of invasive fungal infections, including nikkomycin Z, sordarin derivatives, VT-1161 and VT-1129, F901318, VL-2397, and T-2307."

Journal • Biosimilar • Immunology

The Investigational Drug VT-1129 is a Highly Potent Inhibitor of Cryptococcus species CYP51 but only Weakly Inhibits the Human Enzyme. (PubMed) - "Furthermore, VT-1129 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4 suggesting a low drug-drug interaction potential. Finally, the cellular mode of action for VT-1129 was confirmed to be CYP51 inhibition resulting in the depletion of ergosterol and ergosta-7-enol and the accumulation of eburicol, obtusifolione and lanosterol/obtusifoliol in the cell membranes."

Journal • Biosimilar • Gene Therapies

New and Promising Chemotherapeutics for Emerging Infections Involving Drug-Resistant Non-albicans Candida Species. (PubMed, Curr Top Med Chem) - "Among these are the tetrazoles VT-1129, VT-1161, and VT-1598, the echinocandin CD101, and the glucan synthase inhibitor SCY-078. In addition to possibly overcoming the limitations of currently available antifungals, new investigational chemical agents that can enhance classic antifungal activity, thereby reversing previously resistant phenotypes, were also highlighted. While novel and increasingly MDR non-albicans Candida species continue to emerge worldwide, novel strategies for rapid identification and treatment are needed to combat these life-threatening opportunistic fungal infections."

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Distribution and Diversity of Cytochrome P450 Monooxygenases in the Fungal Class Tremellomycetes. (PubMed, Int J Mol Sci) - "Moreover, the novel drug, VT-1129, that is in the pipeline is reported to exert its effect by binding and inhibiting CYP51...Pathogenic cryptococcal species have 50% fewer CYP genes than non-pathogenic species. The results of this study will serve as reference for future annotation and characterization of CYPs in species of Tremellomycetes."

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In Vivo Efficacy of VT-1129 against Experimental Cryptococcal Meningitis with the Use of a Loading Dose-Maintenance Dose Administration Strategy. (PubMed, Antimicrob Agents Chemother) - "With the highest LD-MD dose, fungal burden was undetectable in half of the mice in the fungal burden arm, and in a quarter of the mice in the survival arm, 20 days after final dose. These data support an LD-MD strategy for quickly reaching highly efficacious VT-1129 concentrations in treating cryptococcal meningitis."

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The Fungal Cyp-51 Inhibitor VT-1129 is Efficacious in an Experimental Model of Cryptococcal Meningitis. (PubMed, Antimicrob Agents Chemother) - "These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis."

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