The exact implications of the paxalisib disappointment are still unclear, though it is highly likely that the candidate will be dropped from the GBM AGILE umbrella trial.
Australian biotech Kazia Therapeutics Ltd announced Monday that its lead glioblastoma candidate, paxalisib, failed to meet “pre-defined criteria” for moving to the second phase of a large, pivotal glioblastoma clinical trial.
Paxalisib is currently being assessed in the GBM AGILE study, a global adaptive umbrella trial designed to investigate several potential therapies for glioblastoma in parallel. Study sponsor, the Global Coalition for Adaptive Research, informed Kazia that the drug fell short of particular measures that would carry it through GBM AGILE’s second stage of enrollment.
Kazia remains blinded to the trial’s details, so it is currently unable to identify what these pre-defined criteria were. However, GBM AGILE is designed to advance treatments that it finds to be effective. Candidates are dropped if they prove to be unsafe or if further testing is deemed futile. GBM AGILE’s primary endpoint is overall survival.
Challenges May Lay Ahead
The exact implications of the paxalisib letdown are still unclear, though it is highly likely that the candidate will be dropped from the umbrella trial.
“Today’s news defines the remaining trajectory of the study, with modestly positive implications for both costs and timelines,” Dr. James Garner, chief executive officer of Kazia said in a statement. “It does not allow us to draw any meaningful inferences about the outcomes of the study, and indeed it is critical for regulatory purposes that we remain blinded to the evolving data.” Final results are expected next year.
Garner flagged potential regulatory hurdles that Kazia may face in China. Because enrollment has been closed, the trial is no longer opening paxalisib arms in Germany and China. This could lead to issues in the East Asian country, which requires local data before a drug can be approved. In March 2021, Chinese pharma firm Simcere Pharmaceutical licensed the rights to paxalisib in the Greater China area. Kazia and Simcere are working out a way forward for paxalisib in the region.
Kazia, formerly Novogen, earned the exclusive global license to paxalisib from Genentech in 2016. The candidate is a PI3K inhibitor, a well-validated class of anti-cancer drugs. Gilead’s Zydelig (idelalisib) and Secura Bio’s Copkitra (duvelisib), both approved for chronic lymphocytic leukemia, also work by targeting PI3K. Paxalisib sets itself apart from other PI3K inhibitors by being able to cross the near-impregnable blood-brain barrier. This has been a critical hurdle for other drugs that hope to target the brain.
Paxalisib’s proven mechanism of action, combined with its unique ability to enter the brain, has made it Kazia’s star asset thus far. In early June, the company presented final Phase II data at the American Society for Clinical Oncology’s Annual Meeting, showing that paxalisib led to better overall and progression-free survival in glioblastoma patients while also having an acceptable safety profile. Shortly after, poster presentations at the 20th International Symposium on Pediatric Neuro-Oncology underscored the value of paxalisib in rare brain cancers in kids.
Paxalisib also earned the U.S. Food and Drug Administration’s Rare Pediatric Disease Designation last month for the treatment of the rare and aggressive atypical rhabdoid/teratoid tumors in children.
These make its failure in the GBM AGILE trial surprising. But Kazia is determined to stand by paxalisib and is currently assessing its value in other indications.
“We are excited by some of the emerging data in diffuse intrinsic pontine glioma (DIPG) and brain metastases, which have become increasingly important areas of focus for the company and look forward to sharing more detail on those activities in due course,” Garner said.
