opelconazole (PC945) / Pulmocide - LARVOL DELTA

Emerging antifungal agents in human medicine: Mechanisms, clinical progress, and future perspectives. (PubMed, Eur J Med Chem) - "This narrative review summarizes the current landscape of emerging antifungal therapies, focusing on ibrexafungerp 1, rezafungin 2, fosmanogepix 3, olorofim 4, opelconazole 5, and oteseconazole 6. However, important challenges remain, including limited activity against Mucorales for several agents, the potential emergence of future resistance, and the need for additional comparative clinical data and real-world experience. Overall, the expanding antifungal pipeline represents a major advancement toward more targeted and individualized antifungal therapy and may significantly reshape the future management of invasive and refractory fungal infections."

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

Multicenter surveillance of antifungal susceptibility of clinical Aspergillus isolates to conventional and novel antifungal agents in Taiwan, 2021-2023. (PubMed, Microbiol Spectr) - "Members of the Aspergillus niger clade exhibited reduced susceptibility to itraconazole and isavuconazole. Anidulafungin, along with novel antifungals including orolofim, manogepix, and rezafungin, demonstrated broad activity across Aspergillus species, including those with intrinsic or acquired azole resistance...Novel antifungals, including orolofim, manogepix, rezafungin, and ibrexafungerp, demonstrated broad activity across Aspergillus species, including resistant isolates. Nevertheless, the inhaled agent opelconazole exhibited limited activity against A. flavus regardless of voriconazole susceptibility and against other species showing reduced susceptibility to itraconazole. These findings highlight the importance of species-level identification, susceptibility testing, and continued surveillance and support the use of novel antifungals for aspergillosis."

Clinical • Journal • Pulmonary Disease • Respiratory Diseases

New antifungals for the treatment of invasive mold disease. (PubMed, Clin Microbiol Infect) - "Development of new antifungal agents is challenging due to limited target sites, emergence of resistance, and adverse toxicity profiles. However, clinical data from fosmanogepix, olorofim, and encochleated amphotericin B are promising in both clinical efficacy and safety for the treatment of invasive mold infections. These new agents offer alternative options for difficult to treat infections, while providing promising efficacy and improved safety outcomes."

Journal • Review • Infectious Disease

Emerging Applications of Triazole Antifungal Drugs. (PubMed, Int J Mol Sci) - "The clinical utility of key antifungal agents, namely, posaconazole, isavuconazole, and voriconazole, is critically evaluated. We also examine the potential role of emerging agents such as opelconazole, which enables targeted pulmonary delivery and prolonged epithelial retention, representing a promising approach to IFI prevention. Drug-specific considerations, including pharmacokinetics, drug-drug interactions, toxicity profiles, and cost-effectiveness, are analyzed in the context of clinical decision-making. Finally, we emphasize the importance of tailoring antifungal strategies based on leukemia subtype, immunosuppressive status, and individual patient factors to optimize outcomes and support antifungal stewardship in hematologic malignancies."

Journal • Review • Acute Myelogenous Leukemia • Chemotherapy-Induced Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology

DrugBank mining with machine learning reveals novel candidates for BCL-2 inhibition. (PubMed, Sci Rep) - "This strategy identified two candidate compounds, Opelconazole and Zongertinib, from the curated DrugBank All dataset, which covered all categories. These results demonstrate the potential of machine learning-based drug repositioning for the discovery of effective BCL-2 inhibitors, which could contribute to the development of targeted antiapoptotic therapeutics."

Journal • Oncology

Safety and Efficacy of PC945 (Opelconazole) in Combination With Other Antifungal Therapy for the Treatment of Refractory Invasive Pulmonary Aspergillosis (OPERA-T Study) (clinicaltrials.gov) - P3 | N=85 | Terminated | Sponsor: Pulmocide Ltd | N=123 ➔ 85 | Trial completion date: Apr 2026 ➔ Dec 2025 | Recruiting ➔ Terminated | Trial primary completion date: Mar 2026 ➔ Dec 2025; Sponsor Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Pulmonary Disease • Respiratory Diseases

In vitro and clinical data demonstrate negligible risk of drug-drug interactions with opelconazole, a novel inhaled antifungal agent. (PubMed, J Antimicrob Chemother) - "Systemic steady-state concentrations achieved after clinical dosing of inhaled opelconazole are unlikely to be associated with CYP-mediated DDIs or transporter-mediated DDIs."

Clinical data • Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • CYP1A2 • CYP3A4

Novel antifungal opelconazole showed no evidence of inducing a proinflammatory response following inhalation delivery for 12 weeks (ERS 2025) - P2 | "Despite high lung concentrations, OPL did not show a higher proinflammatory profile compared with SOC, providing supportive evidence of its potential to be a generally well-tolerated inhaled antifungal agent."

Inflammation • Respiratory Diseases • CHI3L1 • CX3CL1 • CXCL8 • IFNG • IL33 • IL6 • TNFA

Can Inhaled Antifungals Provide a Viable Solution for Treatment-Refractory Pulmonary Fungal Infections? (PubMed, Expert Rev Anti Infect Ther) - No abstract available

Journal • Infectious Disease

Successful treatment of an allergic bronchopulmonary aspergillosis patient with inhaled antifungal opelconazole. (PubMed, J Allergy Clin Immunol Pract) - No abstract available

Journal • Allergic Bronchopulmonary Aspergillosis • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

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

Safety and Efficacy of PC945 (Opelconazole) in Combination With Other Antifungal Therapy for the Treatment of Refractory Invasive Pulmonary Aspergillosis (OPERA-T Study) (clinicaltrials.gov) - P3 | N=123 | Recruiting | Sponsor: Pulmocide Ltd | Trial completion date: Dec 2025 ➔ Apr 2026 | Trial primary completion date: Nov 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Pulmonary Disease • Respiratory Diseases

Safety and Efficacy of PC945 (Opelconazole) in Combination With Other Antifungal Therapy for the Treatment of Refractory Invasive Pulmonary Aspergillosis (OPERA-T Study) (clinicaltrials.gov) - P3 | N=123 | Recruiting | Sponsor: Pulmocide Ltd | Trial completion date: Apr 2025 ➔ Dec 2025 | Trial primary completion date: Mar 2025 ➔ Nov 2025

Combination therapy • Trial completion date • Trial primary completion date • Pulmonary Disease • Respiratory Diseases

New and emerging roles for inhalational and direct antifungal drug delivery approaches for treatment of invasive fungal infections. (PubMed, Expert Rev Anti Infect Ther) - "Novel compounds (e.g. opelconazole) and existing antifungals with innovative drug delivery systems currently undergoing clinical trials and/or used off-label in the clinical setting are discussed. For both inhalational agents and direct delivery approaches, there are similar challenges that include the absence of: approved formulations for specific administration routes, delivery vehicles that are simple and safe to use whilst maintaining potency and efficiency of delivery, animal models suitable for investigating pharmacokinetic/pharmacodynamic profiles of inhaled antifungals, and consensus on the composite endpoints and intervals for of follow-up in clinical trials. To meet these challenges, cooperation of all stakeholders in drug development and regulation is required."

Journal • Review • Infectious Disease

Pipeline of Novel Antifungals for Invasive Fungal Disease in Transplant Recipients: A Pediatric Perspective. (PubMed, J Pediatric Infect Dis Soc) - "The overarching goal of this review is to discuss the mechanisms of action, spectrum of activity, stage of development, and pediatric-specific data for the following agents: encochleated amphotericin B deoxycholate, fosmanogepix, ibrexafungerp, isavuconazole, olorofim, opelconazole, oteseconazole, and rezafungin. Additionally, key drug attributes of these novel agents and their potential future therapeutic roles in pediatric transplant recipients are discussed."

Journal • Infectious Disease • Pediatrics • Transplantation

New treatment options for critically important WHO fungal priority pathogens. (PubMed, Clin Microbiol Infect) - "While the limited number of targets and the emergence of resistance have posed challenges to antifungal treatment, new drugs such as ibrexafungerp, rezafungin, fosmanogepix, or olorofim have shown promising clinical efficacy. These drugs not only provide alternative options for invasive fungal infections but also alleviate treatment in outpatient settings. More clinical data, implementation of stewardship programs, and surveillance, including utilization of drugs in agriculture are necessary to prevent resistance development and ensure the safety and efficacy of these new agents."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Antifungal Therapies for Aspergillus spp.: Present and Future. (PubMed, Semin Respir Crit Care Med) - "Rezafungin (a once-weekly dosed echinocandin) and ibrexafungerp (oral agent with same mechanism of action as echinocandins) will likely be reserved for combination therapy or refractory/intolerance scenarios with no other options. Inhaled opelconazole is an attractive option for combination therapy and prophylaxis of pulmonary aspergillosis...Finally, olorofim and fosmanogepix, two agents with novel mechanisms of action and oral formulations, hold significant potential to challenge the triazole antifungals place as preferred therapies. However, many questions remain regarding these novel agents, and at the time of this writing, none of these agents have been robustly studied in Phase III studies of aspergillosis, and so their promise remains investigational."

Journal • Pulmonary Disease • Respiratory Diseases

Safety and Efficacy of PC945 (Opelconazole) in Combination With Other Antifungal Therapy for the Treatment of Refractory Invasive Pulmonary Aspergillosis (clinicaltrials.gov) - P3 | N=123 | Recruiting | Sponsor: Pulmocide Ltd | Trial completion date: Nov 2023 ➔ Apr 2025 | Trial primary completion date: Oct 2023 ➔ Mar 2025

Combination therapy • Trial completion date • Trial primary completion date • Pulmonary Disease • Respiratory Diseases

A Safety Study of PC945 (Opelconazole) Prophylaxis or Pre-emptive Therapy Against Pulmonary Aspergillosis in Lung Transplant Recipients (clinicaltrials.gov) - P2 | N=102 | Completed | Sponsor: Pulmocide Ltd | Active, not recruiting ➔ Completed

Trial completion • Pulmonary Disease • Respiratory Diseases • Transplantation

PC945 (OPELCONAZOLE) NEBULIZER SUSPENSION - a new inhaled antifungal in development for pulmonary aspergillosis (IDWeek 2023) - No abstract available

Infectious Disease

Anti-infective treatment of fungal infections by Candida and Aspergillus (PubMed, Med Klin Intensivmed Notfmed) - "Knowledge about risk factors and the correct treatment management is crucial for the survival of patients with invasive fungal infections."

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

Emerging Diagnostics and Therapeutics for Invasive Fungal Infections. (PubMed, Infect Dis Clin North Am) - "Compared with traditional fungal diagnostics, molecular assays promise improved sensitivity and specificity, the ability to test a range of samples (including noninvasive samples, ie, blood), the detection of genetic mutations associated with antifungal resistance, and the potential for a faster turnaround time. Antifungals in late-stage clinical development include agents with novel mechanisms of action (olorofim and fosmanogepix) and new members of existing classes with distinct advantages over existing antifungals in toxicity, drug-drug interactions, and dosing convenience (oteseconazole, opelconazole, rezafungin, ibrexafungerp, encochleated amphotericin B)."

Journal • Review • Infectious Disease • Transplantation

PC945 Prophylaxis or Pre-emptive Therapy Against Pulmonary Aspergillosis in Lung Transplant Recipients (clinicaltrials.gov) - P2 | N=100 | Active, not recruiting | Sponsor: Pulmocide Ltd | Recruiting ➔ Active, not recruiting

Enrollment closed • Pulmonary Disease • Respiratory Diseases • Transplantation

Discovery of PC945, a novel antifungal agent for inhaled administration (ACS-Fall 2023) - "In temporarily neutropenic, immunocompromised mice infected with A. fumigatus, half of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse.In addition, clinical data under a special needs program will be presented using PC945 as part of a combination treatment for a refractory fungal bronchial anastomotic infection and tracheobronchitis. In this setting, PC945 showed excellent tolerability profile and had promising efficacy in controlling the active infection."

Hepatology • Infectious Disease • Liver Failure • Pulmonary Disease • Respiratory Diseases • Solid Organ Transplantation • Transplantation