Interim data from Opera-T showed a numerically lower Day 84 favorable response rate and a numerically higher mortality rate in the opelconazole arm versus control among patients with refractory invasive pulmonary aspergillosis.
Pulmocide has terminated the Phase 3 Opera-T study of inhaled opelconazole following an interim analysis conducted at roughly 50% randomization with adequate follow-up to Day 84. The trial targeted a severely immunocompromised population, predominantly patients with life‑threatening hematologic malignancies or transplant recipients, and the majority had failed at least two prior antifungal regimens before enrollment. While investigators did not attribute any deaths at the time of analysis to the blinded study drug, the unfavorable efficacy and mortality trends prompted the company to halt the program and move to a full unblinded review to determine next steps.
Strategically, this is a setback for the inhaled-antifungal thesis in invasive disease, particularly in the salvage/refractory setting where efficacy hurdles are high and background therapy is complex. The study’s adaptive design and interim recalculation trigger suggest a preplanned path to detect futility early; the decision to stop indicates a low probability that additional enrollment would reverse the observed trends. The result pressures a development narrative that emphasized high local pulmonary exposure with low systemic toxicity. In angioinvasive infections among profoundly immunosuppressed patients, localized delivery may not overcome the disease biology or the need for robust systemic coverage. It also underscores the difficulty of demonstrating additive clinical benefit on top of optimized standard regimens in late-line IPA.
Operationally, the termination immediately affects hematology-oncology and transplant centers that were recruiting this hard-to-enroll population, many of which had built workflows around device management and inhalation training. Sites and CROs will pivot to wind-down: final safety follow-up, device reconciliation, drug accountability, and accelerated data cleaning as the database transitions to unblinding. Contract amendments and budget true-ups will follow, with potential staffing ripple effects at high-volume transplant programs that had dedicated coordinators to the study. For sponsors across antifungal development, the signal raises the bar for inhaled or lung-targeted approaches in invasive disease and may shift interest toward prophylaxis, earlier-line adjunctive use, or chronic pulmonary aspergillosis where localized drug delivery may align more directly with disease compartmentalization and tolerability goals.
Competitively, the outcome could modestly advantage systemic agents in late-stage development for aspergillosis that aim to demonstrate clear survival or response benefits in salvage settings, while also reminding the field that refractory IPA trials are attrition-heavy, expensive, and statistically unforgiving. Regulators will scrutinize any forthcoming subgroup analyses to understand whether certain cohorts, timing of initiation, or concomitant antifungal backbones fared differently. Vendors supporting inhalation delivery should anticipate tighter evidentiary expectations for invasive indications and potentially more emphasis on PK/PD bridging to clinically meaningful endpoints.
The next proof points to watch are Pulmocide’s unblinded analyses: exposure–response data in the sickest subsets, transplant versus hematologic malignancy stratification, interactions with concurrent antifungals, and any signals that support repositioning as add-on or in less refractory populations. If the mortality imbalance persists across subgroups, an invasive-disease pivot will be hard to justify, pushing the program toward chronic or preventive settings if the safety and local exposure profiles remain favorable. More broadly, expect upcoming IPA studies to bias toward combination designs, earlier lines of therapy, and adaptive frameworks with stringent futility controls, as sponsors recalibrate risk around one of the toughest infectious disease populations to study.
