Olorofim (orotomide) / F2G, Shionogi - LARVOL DELTA

A Stroke Mimicker: Primary CNS Scedosporium (ISHLT 2025) - "We present a case of primary CNS Scedosporium apiospermum in a patient with no known prior pulmonary involvement.Case Report A 69-year-old female, 227 days post-bilateral lung transplantation and on tacrolimus, mycophenolate, and prednisone, presented with four days of right-sided weakness and vision loss...She was treated empirically with linezolid and meropenem...She was loaded with voriconazole and showed improvement in neurologic deficits, later a therapeutic trough of 3.4 mcg/mL was obtained...Terbinafine was added, and expanded access to olorofim was pursued...Prognosis is poor even when susceptibility testing reveals low MICs to antifungals. New antifungals with novel mechanisms of action such as olorofim are an exciting potential treatment necessitating future study."

Cardiovascular • Infectious Disease • Ischemic stroke • Pain • Respiratory Diseases

Olorofim for the Treatment of Invasive Fungal Infections (IFI) in Thoracic Transplant Recipients Lacking Suitable Options, Sub-Analysis of an Open-Label, Single-Arm, Phase 2b Trial (nct03583164; S32) (ISHLT 2025) - P2 | "When needed for difficult or slow-to-respond IFI, ET for > 1 year was well tolerated. Future studies should assess the earlier use of Olorofim in the treatment of IFI."

Clinical • P2b data • Hepatology • Infectious Disease • Liver Failure • Respiratory Diseases • Transplantation

Trends of Azole-Resistant Aspergillus Fumigatus Susceptibility Over 12 Years from a German ECMM Excellence Center. (PubMed, Mycopathologia) - "We assessed ARAf susceptibility trends towards five antifungal agents (amphotericin B (AMB), itraconazole (ITR), voriconazole (VCZ), olorofim (OLO) and manogepix (MGX)) over twelve years in a German Excellence Center for Medical Mycology (ECMM). Before 2016, the azole resistance underlying mutations were mainly TR34/L98H, but the portion of isolates with TR46/Y121F/T289A and other Cyp51A mutated isolates increased afterwards. We showed almost stable MICs for ITR and VCZ over twelve years in ARAf isolates from West Germany while occurring azole resistance underlying mutations varied with an increase in the proportion of TR46/Y121F/T289A and other Cyp51A mutations after 2016."

Journal • Infectious Disease

CLINICAL AND MICROBIOLOGICAL FEATURES OF FUSARIUM INFECTIONS IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (EBMT 2025) - "All patients received combined antifungal therapy with liposomal amphotericin B (n=5) plus either isavuconazole (n=1), voriconazole (n=3) or fluconazole (n=1) plus caspofungin (n=1); anidulafungin (n=2) or terbinafine (n=1). One patient received olorofim within a compassionate use program after failing triplet therapy, the same patient also received intravitreal voriconazole and amphotericin B for endophthalmitis... Despite combination of broad antifungal therapy, outcome in this cohort of patients with IF after alloSCT is dismal, even in patients without previous intensive therapy. There is an immense medical need to improve therapeutic options for IF."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Neutropenia • Ocular Infections • Ocular Inflammation • Oncology • Ophthalmology • Respiratory Diseases • Transplantation

CLINICAL AND MICROBIOLOGICAL FEATURES OF FUSARIUM INFECTIONS IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (EBMT 2025) - "All patients received combined antifungal therapy with liposomal amphotericin B (n=5) plus either isavuconazole (n=1), voriconazole (n=3) or fluconazole (n=1) plus caspofungin (n=1); anidulafungin (n=2) or terbinafine (n=1). One patient received olorofim within a compassionate use program after failing triplet therapy, the same patient also received intravitreal voriconazole and amphotericin B for endophthalmitis... Despite combination of broad antifungal therapy, outcome in this cohort of patients with IF after alloSCT is dismal, even in patients without previous intensive therapy. There is an immense medical need to improve therapeutic options for IF."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Neutropenia • Ocular Infections • Ocular Inflammation • Oncology • Ophthalmology • Respiratory Diseases • Transplantation

In vitro antagonism between voriconazole and olorofim against 30 clinical strains of Aspergillus fumigatus (ESCMID Global 2025) - No abstract available

Preclinical

In vitro olorofim activity against Aspergillus spp clinical isolates collected as part as two national surveys on azole resistance conducted in Spain (ASPEIN II and III) (ESCMID Global 2025) - No abstract available

Preclinical

Clinical significance and antifungal susceptibility profile of 103 clinical isolates of Scedosporium species complex and Lomentospora prolificans obtained from NIH patients. (PubMed, J Clin Microbiol) - "and L. prolificans, followed by micafungin...Itraconazole, isavuconazole, and terbinafine had higher MIC values against Scedosporium spp...Clinical data were retrospectively reviewed for 90 isolates, of which nine patients (28 isolates) had active disease/infection and received antifungal treatment that included voriconazole or posaconazole...The novel investigational antifungal olorofim may be a promising therapy...Our study showed that species-specific and inter-species differences exist in the distribution of antifungal susceptibility patterns between Scedosporium and L. prolificans. Our clinical data also highlight that host status, along with effective antifungal therapy, plays a crucial role in determining treatment outcomes."

Journal • Immunology • Infectious Disease • Primary Immunodeficiency • Transplantation

Antifungal pipeline: New tools for the treatment of mycoses. (PubMed, Rev Iberoam Micol) - "New antifungal agents, such as ibrexafungerp, rezafungin, oteseconazole, and miltefosine, offer novel mechanisms of action along with reduced toxicity...This review provides a comprehensive overview of these new agents and their mechanisms, and explores the challenges and roles of antifungal drugs in LMICs, where the burden of fungal infections is high. Continued research and development are essential to address the rising incidence and resistance of fungal infections globally."

Journal • Dermatology • Infectious Disease

An update on newer antifungals. (PubMed, Expert Rev Anti Infect Ther) - "New antifungal agents hold promising future for difficult-to-treat fungal infections, providing for improved bioavailability, pharmacokinetic properties, adverse events and drug interactions, as well as, spectrum of activity. However, further data is needed before incorporating these agents in everyday clinical practice for the management of invasive fungal infections."

Journal • Review • Candidiasis • Infectious Disease • Pulmonary Disease • Respiratory Diseases

40 Years of Preventing Fungal Infections in Hematological Malignancies - Lessons Learned from Clinical Trials with 20,753 Patients (ASH 2024) - "Out of these, 7,586 received fluconazole (FLU), 4,080 were included in trials with posaconazole (POS) or voriconazole (VOR), 1,717 received itraconazole (ITRA), 1,895 echinocandins and 1,594 amphotericin B (AmB)(AmB deoxycholate, liposomal AmB or inhalational AmB), respectively...No prospective studies for AFP with isavuconazole and new antifungal agents like rezafungin or olorofim are available...In those receiving venetoclax/HMA, AFP practices were heterogeneous and IFI incidence ranged from 5% to 16.1% (overall probable/proven IFI : n=102 (10.6%), possible IFI not reported in all studies). In pts treated with midostaurin, 2 studies (n= 218 pts) reported 29 probable/proven IFI (13.3%). In pts treated with gilteritinib, 2 studies reported 55 pts with an IFI rate of 27.2% (including possible IFI)...Despite numerous trials for prevention of IFI, only posaconazole and fluconazole proved reduction in OM rates. There is a need for prospective clinical trials addressing..."

Clinical • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology

Olorofim demonstrates in vitro activity against Coccidioides species, including isolates against which fluconazole has reduced activity. (PubMed, Antimicrob Agents Chemother) - "Olorofim demonstrated potent in vitro activity against all isolates tested with a minimum inhibitory concentration (MIC) range ≤0.008-0.06 µg/mL and geometric mean MIC of 0.010 µg/mL. This activity was also maintained against isolates with elevated fluconazole MICs (≥16 µg/mL), including strains with MICs ≥32 µg/mL (olorofim MIC range ≤0.008-0.06 µg/mL and geometric mean MICs of ≤0.009 and ≤0.013 µg/mL, respectively)."

Journal • Preclinical

Review of the novel antifungal drug olorofim (F901318). (PubMed, BMC Infect Dis) - "It is only orally available and shows very promising results in ongoing clinical trials. In this review we will describe the mechanism of action of olorofim, the spectrum of activity in vitro and in vivo, pharmacokinetics, pharmacodynamics, drug-drug interactions, resistance, and clinical outcomes."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases

A Phase 1 Study to Assess the Pharmacokinetics and Safety of a Single Oral Dose of Olorofim in Healthy Chinese Participants (ChiCTR) - P1 | N=12 | Completed | Sponsor: Nanfang Hospital of Southern Medical University; Shionogi & Co., Ltd.

New P1 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases

Intrinsic Natural Resistance of Various Plant Pathogens to Ipflufenoquin, a New DHODH (Dihydroorotate Dehydrogenase)-inhibiting Fungicide, in Relation to Unaltered Amino Acid Sequence of the Target Site. (PubMed, Plant Dis) - "The risk for dual use of DHODH inhibitors in agriculture and medicine has also become a great concern because a new antifungal olorofim is under development against human pathogens now and cross-resistance has recently been reported between ipflufenoquin and olorofim in Aspergillus fumigatus...To understand the mechanism of natural resistance, we analyzed the partial sequence of pyrE genes, which encode the DHODH enzyme, but did not find any differences in the deduced amino acids that were thought to be associated with resistance. Thus, mechanisms other than target-site mutations might be involved in the intrinsic resistance."

Journal

A difficult-to-treat septic arthritis by Scedosporium apiospermum successfully treated with olorofim. (PubMed, J Antimicrob Chemother) - No abstract available

Journal • Immunology • Rheumatology

Shining a light on the impact of antifungals on Aspergillus fumigatus subcellular dynamics through fluorescence imaging. (PubMed, Antimicrob Agents Chemother) - "Using this strain, we describe and compare the dynamic responses of organelles to stresses induced by voriconazole, amphotericin B, and the novel antifungal drugs olorofim and manogepix. The expansion to the fluorescent genetic toolbox will overcome boundaries in research applications that involve fluorescence imaging in filamentous fungi."

Journal • Infectious Disease

Systemic Exposure of Olorofim in Children with Invasive Fungal Infections (IDWeek 2024) - No abstract available

Clinical • Infectious Disease

Assessment of Body Weight upon PK of Olorofim in Patients with Invasive Mould Infections (IDWeek 2024) - No abstract available

Clinical • Infectious Disease

Clinical outcomes in four patients with refractory Coccidioidal meningitis treated with olorofim (IDWeek 2024) - No abstract available

Clinical • Clinical data • Infectious Disease

Assessment of Body Weight upon PK of Olorofim in Patients with Invasive Mould Infections (IDWeek 2024) - No abstract available

Clinical • Infectious Disease

Novel Antifungal Olorofim Use in Intractable CNS and Non-CNS Disseminated Coccidioidomycosis (IDWeek 2024) - No abstract available

Infectious Disease

Usage of Antifungal Agents in Pediatric Patients Versus Adults: Knowledge and Gaps. (PubMed, Mycopathologia) - "The oral formulations of ibrexafungerp, fosmanogepix and olorofim along with the extended dosing intervals of rezafungin show promising features for effective antifungal treatment in pediatrics. Despite the promising potential of novel antifungal drugs, their performance in heavily immunosuppressed patients remains unstudied. Until then, dedicated antifungal stewardship programs for high-risk patients are essential to optimize therapeutic outcomes, improve patient care, and limit the emergence of resistance."

Journal • Review • Infectious Disease • Pediatrics

Two cases of fungemia due to Lomentospora prolificans in haematological patients with different outcome. (PubMed, Diagn Microbiol Infect Dis) - "The current treatment is still based on a combination of conventional antifungal drugs, although in much cases this strategy is not sufficient. The introduction of new promising antifungal agents such as fosmanogepix® and olorofim® may open new perspectives in the treatment of invasive infections caused by L. prolificans, as in our patient."

Journal • Hematological Disorders • Hematological Malignancies • Infectious Disease • Neutropenia • Oncology

In vitro activity of olorofim against 507 filamentous fungi including antifungal drug-resistant strains at a tertiary laboratory in Australia: 2020-2023. (PubMed, J Antimicrob Chemother) - "Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus, L. prolificans, Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava."

Journal • Preclinical