VT-1598 / 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

Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target. (PubMed, J Med Chem) - "The strongest inhibition was observed with voriconazole (1 h IC50 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of A. castellanii CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness."

Journal • CNS Disorders • Infectious Disease • Keratitis • Ocular Inflammation • Ophthalmology

Cryptococcosis and Cryptococcal Meningitis: A Narrative Review and the Up-to-Date Management Approach. (PubMed, Cureus) - "This narrative review provides an evidence-based summary of the current treatment modalities and future trial options, including newer ones, namely, 18B7, T-2307, VT-1598, AR12, manogepix, and miltefosine...The disease can easily evade diagnosis with subacute presentation. Despite the severity of the disease, treatment options for cryptococcosis remain limited, and more research is needed."

Journal • Review • CNS Disorders • Human Immunodeficiency Virus • Infectious Disease

Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-Human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598. (PubMed, Med Mycol) - "No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development."

Clinical • Journal • P1 data • PK/PD data

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

Safety and Pharmacokinetics of VT-1598 (clinicaltrials.gov) - P1 | N=48 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Completed

Trial completion • Respiratory Diseases

Novel antifungal agents in clinical trials. (PubMed, F1000Res) - "Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics.  The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics.  This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim.  We examine three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties."

Journal • Review • 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

Advances in anti-fungal therapies. (PubMed, Mycopathologia) - "These include VT-1161 and VT-1598, modified azoles with a tetrazole metal-binding group; the echinocandin rezafugin; the novel β-1,3-d-glucan synthase inhibitor ibrexafungerp; fosmanogepix, a novel anti-fungal targeting Gwt1; the arylamidine T-2307; the dihydroorotate inhibitor olorofim; and the cyclic hexapeptide ASP2397. The available data including spectrum of activity, toxicity and stage of clinical development will be discussed for each of these so clinicians are aware of promising anti-fungal agents with a strong likelihood of clinical availability in the next 5-7 years."

Journal • Review

Recent advances and future perspectives in the pharmacological treatment of Candida auris infections. (PubMed, Expert Rev Clin Pharmacol) - "auris activity. The research on antifungal agents active against C. auris has made important steps forward in recent years: (i) the development of drugs with novel mechanisms of action, such as ibrexafungerp and fosmanogepix, could provide a valid option against C. auris strains resistant to one or more older antifungals, including pan-resistant strains; (ii) rezafungin could allow once weekly administration of an active drug in the case of echinocandin-susceptible isolates, providing an effective outpatient treatment, while at the same time relieving selective pressure on novel classes; (iii) the development of oral formulations could allow step-down therapy and/or early discharge, or even to avoid hospitalization in mild or non-invasive diseases; (iv) according to available data, these novel agents show a good safety profile and a low potential for drug-drug interactions."

Journal • Infectious Disease

Safety and Pharmacokinetics of VT-1598 (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Trial completion date: Jul 2021 ➔ Oct 2021; Trial primary completion date: May 2021 ➔ Oct 2021

Clinical • Trial completion date • Trial primary completion date • Respiratory Diseases

Safety and Pharmacokinetics of VT-1598 (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Trial completion date: Dec 2020 ➔ May 2021; Trial primary completion date: Oct 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date • Respiratory Diseases

[VIRTUAL] PERSISTENT FUNGEMIA WITH CANDIDA AURIS IN A PATIENT WITH ENTEROCUTANEOUS FISTULA (CHEST 2020) - "She continued to have candidemia despite Micafungin...Work is ongoing on novel drugs like SCY-078 and VT-1598(2)... Prompt identification and institution of antifungals with ancillary measures including surgery remain key to successfully treating C auris."

Clinical • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders • Nephrology • Oncology • Pneumonia • Renal Disease • Respiratory Diseases

The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis. (PubMed, Med Mycol) - "Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection."

Journal • Preclinical • Neutropenia

Safety and Pharmacokinetics of VT-1598 (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

In vitro activities of the novel investigational tetrazoles VT-1161 and VT-1598 compared to the triazole antifungals against azole-resistant strains and clinical isolates of Candida albicans. (PubMed, Antimicrob Agents Chemother) - "To evaluate their in vitro activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68 C...VT-1161 MICs were elevated compared to the control strain SC5314 for hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R), but showed activity against hyperactive Mrr1 and Upc2 strains. While mutations affecting Erg3 activity appear to greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for four isolates could not be explained by known azole resistance mechanisms, suggesting the presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol demethylase inhibitors."

Journal

The Fungal Cyp51 Specific Inhibitor VT-1598 Demonstrates In vitro and In vivo Activity against Candida auris. (PubMed, Antimicrob Agents Chemother) - "Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris."

Journal • Preclinical

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."

Journal

Safety and Pharmacokinetics of VT-1598 (clinicaltrials.gov) - P1; N=48; Not yet recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Trial completion date: Feb 2020 ➔ Dec 2020; Trial primary completion date: Feb 2020 ➔ Aug 2020

Clinical • Trial completion date • Trial primary completion date