Krystal Biotech has suspended enrollment in its Phase I/II OPAL-1 study of KB707, an investigational intratumoral viral immunotherapy for melanoma, following regulatory uncertainty created by the FDA's recent rejection of a similar treatment. The Pennsylvania-based company cited "heightened uncertainty regarding potential accelerated approval pathways" as the primary factor behind the decision to halt the melanoma program.
The move comes after the FDA delivered a surprise rejection last month to Replimune's RP1, which operates through a similar mechanism to KB707. Both therapies are immunotherapies that use modified herpes simplex virus type 1 vectors to trigger an immune response against tumors, specifically targeting melanoma.
Controversial FDA Decision Impacts Entire Drug Class
The FDA's rejection of RP1 has generated significant controversy within the oncology community. According to reports from Endpoints News and STAT, Richard Pazdur, director of the FDA's Oncology Center of Excellence and acting director of the Office on Oncology Diseases, overruled agency reviewers and pushed for the candidate's rejection.
The decision prompted an unprecedented response from the scientific community. More than 20 melanoma and cancer experts signed an open letter urging the FDA to re-review the application, directly addressing concerns raised in the agency's complete response letter. The experts argued that one key FDA concern—the heterogeneity of the Phase III IGNYTE trial's patient population—actually provided a more accurate representation of real-world treatment scenarios than a more uniform population would have.
"Melanoma treatment guidelines currently in place show multiple treatment pathways in both the adjuvant and advanced disease setting funneling to the point of IGNYTE eligibility," the experts wrote in their letter.
Krystal Shifts Focus to Lung Cancer Program
While continuing to monitor patients already dosed in the OPAL-1 study for safety and efficacy, Krystal announced it may adjust development plans for intratumoral KB707 based on trial findings. However, the company is now prioritizing an inhaled version of KB707 for non-small cell lung cancer (NSCLC).
The inhaled formulation has shown promising early results, with a June readout demonstrating a 36% objective response rate in heavily pretreated NSCLC patients. Notably, median duration of response and progression-free survival were not reached in the study, and there were no grade 4 or 5 adverse events reported.
Regulatory Path Forward
Krystal has secured an End of Phase II meeting with the FDA scheduled for October, following what the company described as "promising early evidence of efficacy" of inhaled KB707. This regulatory meeting will help determine potential pathways for advancing the inhaled formulation through the approval process.
Stéphane Paquette, Krystal's vice president for corporate development, confirmed to STAT News that the regulatory uncertainty surrounding the accelerated approval pathway for viral immunotherapies following RP1's rejection was a significant factor in the company's decision to suspend the melanoma study.
The development highlights the broader challenges facing companies developing viral immunotherapies, as regulatory precedents can significantly impact the entire therapeutic class and influence strategic decisions across multiple development programs.
