VL-2397 / Astellas, Fresh Tracks Therap - LARVOL DELTA

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

GR-2397: Review of the Novel Siderophore-like Antifungal Agent for the Treatment of Invasive Aspergillosis. (PubMed, J Fungi (Basel)) - "GR-2397 (previously VL-2397, ASP2397) is a first-in-class antifungal agent for the treatment of invasive aspergillosis...The favorable safety, tolerability and drug-drug interaction profile, along with good tissue distribution, support further development of GR-2397 as a new treatment option for patients with invasive aspergillosis. This systematic review summarizes the published findings of GR-2397."

Journal • Review • Pulmonary Disease • Respiratory Diseases

Invasive candidiasis: Investigational drugs in the clinical development pipeline and mechanisms of action. (PubMed, Expert Opin Investig Drugs) - "Insights are offered on the potential future roles of the investigational agents MAT-2203, oteseconazole, ATI-2307, VL-2397, NP-339, and the repurposed drug miltefosine. Ibrexafungerp and fosmanogepix have novel mechanisms of action and will provide effective options for the treatment of Candida infections (including those caused by multiresistant Candida spp). Rezafungin, an echinocandin with an extended half-life allowing for once weekly administration, will be particularly valuable for outpatient treatment and prophylaxis. Despite this, there is an urgent need to garner clinical data on investigational drugs, especially in the current rise of azole-resistant and multi-drug resistant Candida spp."

Journal • Candidiasis • Infectious Disease

Differential Biosynthesis and Roles of Two Ferrichrome-Type Siderophores, ASP2397/AS2488053 and Ferricrocin, in Acremonium persicinum. (PubMed, ACS Chem Biol) - "Notably, the phylogenetic analyses suggest the different evolutionary origin of AS2488059 from that of conventional ferrichrome-type siderophores. Harnessing two ferrichrome-type siderophores with distinct biological properties may give A. persicinum a competitive advantage for surviving the natural environment."

Journal

"Are you interested in writing a follow-up article with the information on MAT2203 and VL-2397?" (@HTSchlamm)

"Agree! Btw has somebody else taken up VL2397 development or is it still dead on the scene since Vical has stopped developing it further?" (@martinhoenigl)

The Siderophore Transporters Sit1 and Sit2 Are Essential for Utilization of Ferrichrome-, Ferrioxamine- and Coprogen-Type Siderophores in Aspergillus fumigatus. (PubMed, J Fungi (Basel)) - "Siderophore-mediated acquisition of iron has been shown to be indispensable for the virulence of several fungal pathogens, the siderophore transporter Sit1 was found to mediate uptake of the novel antifungal drug VL-2397, and siderophores were shown to be useful as biomarkers as well as for imaging of fungal infections...Moreover, both Sit1 and Sit2 mediated use of the coprogen-type siderophores coprogen and coprogen B, while only Sit1 transported the bacterial ferrioxamine-type xenosiderophores ferrioxamines B, G, and E. Neither Sit1 nor Sit2 were important for the utilization of the endogenous siderophores fusarinine C and triacetylfusarinine C. Furthermore, A. fumigatus was found to lack utilization of the xenosiderophores schizokinen, basidiochrome, rhizoferrin, ornibactin, rhodotorulic acid, and enterobactin. Taken together, this study characterized siderophore use by A. fumigatus and substrate characteristics of Sit1 and Sit2."

Journal • CNS Disorders • Infectious Disease • Psychiatry • Schizophrenia

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

A First-in-Human Phase 1 Study to Assess Safety, Tolerability and Pharmacokinetics of a Novel Antifungal Drug VL-2397 in Healthy Adults. (PubMed, Antimicrob Agents Chemother) - "Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis."

Clinical • Journal • P1 data • PK/PD data

ASP2397, a novel natural compound that exhibits rapid and potent fungicidal activity against Aspergillus species through a specific transporter. (PubMed, Antimicrob Agents Chemother) - "In addition, ASP2397 inhibited hyphal elongation from germinated conidia of A. fumigatus, A. terreus, and A. flavus more rapidly than voriconazole. Under conditions of delayed treatment initiation in an IPA mouse model, ASP2397 had efficacy superior to that of posaconazole, with 100% survival and over 1 log CFU/g reduction in lung fungal burden...The mutant had a point mutation in the siderophore transporter gene sit1, which is absent in mammalian cells. These findings suggest that ASP2397 may improve clinical treatment options for IPA."

Journal

The siderophore transporter Sit1 determines susceptibility to the antifungal VL-2397. (PubMed, Antimicrob Agents Chemother) - "In contrast to A. fumigatus and Candida glabrata, Saccharomyces cerevisiae displays intrinsic resistance to VL-2397 antifungal activity. However, expression of sit1 from A. fumigatus, or its homologue from C.glabrata, resulted in susceptibility to VL-2397, which suggests that the intrinsic resistance of S. cerevisiae is based on lack of uptake and that A. fumigatus, C. glabrata, and S. cerevisiae may share a common intracellular target for VL-2397."

Journal

"Vical's antifungal agent VL-2397 found to be safe and well tolerated in phase I trial. Live from #ASMicrobe"

P1 data • Biosimilar

ASP2397: a novel antifungal agent produced by Acremonium persicinum MF-347833. (PubMed) - J Antibiot (Tokyo) - "However, ASP2397 differs structurally from licensed antifungal agents such as amphotericin B, triazoles and echinocandins. To understand the relationship between chemical structure and biological function, we isolated certain ASP2397 derivatives from the culture broth, and we further chemically converted the metal-free form to other derivatives.The Journal of Antibiotics advance online publication, 7 September 2016; doi:10.1038/ja.2016.107."

Journal • Biosimilar

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

Population Pharmacokinetic Modeling of VL-2397, A Novel Systemic Antifungal Agent: Analysis of a Single and Multiple Ascending Dose Study in Healthy Subjects. (PubMed, Antimicrob Agents Chemother) - "Protein binding is the likely primary source of the non-linearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets."

Clinical • Journal • PK/PD data

Hope on the Horizon: Novel Fungal Treatments in Development. (PubMed, Open Forum Infect Dis) - "Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. In addition, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis. With a field full of novel treatments for fungal infections, the future looks promising."

Journal • Review

Multiresistant Fusarium Pathogens on Plants and Humans: Solutions in (from) the Antifungal Pipeline? (PubMed, Infect Drug Resist) - "ESCMID and ECMM joint guidelines, following the majority of published studies, suggest early therapy with amphotericin B and voriconazole, in conjunction with surgical debridement and reversal of immunosuppression...Recent studies present novel compounds that are effective against some pathogenic fungi including Fusarium. We discuss the robust and dynamic antifungal pipeline, including results from clinical trials as well as preclinical data that might appear beneficial for patients with invasive fusariosis."

Journal • Review

VL-2397 Compared to Standard First-Line Treatment for Invasive Aspergillosis (IA) in Adults (clinicaltrials.gov) - P2; N=4; Terminated; Sponsor: Vical; N=200 ➔ 4; Trial completion date: Dec 2019 ➔ Jan 2019; Recruiting ➔ Terminated; Trial primary completion date: Dec 2019 ➔ Jan 2019; Business decision

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination