FDA Reviewing Ofranergene Obadenovec CMC, Recruitment in OVAL Paused


The FDA has paused the clearance of new ofranergene obadenovec batches while it reviews chemistry, manufacturing, and controls at various source locations.

Dror Harats, MD, CEO of VBL Therapeutics

Dror Harats, MD

The FDA has paused the clearance of new ofranergene obadenovec (VB-111) batches entering the United States while it reviews chemistry, manufacturing, and controls (CMC) at various source locations, according to a statement from VBL Therapeutics, the company developing the gene therapy.

The company anticipates a temporary shortage of ofranergene obadenovec resulting from the technical review and will be temporarily pausing new patient enrollment in the United States for the pivotal phase 3 OVAL study exploring the therapy for women with recurrent ovarian cancer. At the time of the pause, the study, which passed an interim safety analysis in February 2021, has recruited approximately 300 out of 400 patients (75%). All enrolled patients will continue to be treated according to the protocol while supplies of the medication are available.

“Our team is working to provide the requested information to the FDA as quickly as possible,” Dror Harats, MD, CEO of VBL Therapeutics, said in a statement. “Since receipt of the notification, we have submitted some of the requested information, and are preparing the remaining documentation, which we believe can be completed and submitted to the agency in the next 2 to 3 months."

Ofranergene obadenovec is manufactured using a replication deficient adenovirus 5 to have a dual mechanism of action. The first mechanism is a partially artificial angiogenesis promoter labeled PPR-1-3X, which targets endothelial cells within angiogenic blood vessels. Once the endothelial cells are targeted, they are killed by a TNF/FAS chimera death receptor transgene, cutting off the blood supply to the tumor. In addition to the release of neoantigens from tumor necrosis, the utilization of a viral vector further draws the immune system to the tumor, resulting in further anti-tumor response, VBL theorizes.

OVAL is a phase 3 randomized study investigating paclitaxel in combination with either ofranergene obadenovec or placebo for women with recurrent, platinum-resistant ovarian cancer. The trial was recently amended following meetings with the FDA to include a second primary end point of progression-free survival, which joined the existing end point of overall survival (OS). Secondary measures include objective response rate and response by CA-125 levels.

Early results from the first 60 patients enrolled in the study were released in March 2020, showing promising signs of activity. In this assessment, data were not released specifically for each treatment arm; however, across all patients, 53.3% experienced a CA-125 response. At this analysis, an independent data monitoring board concluded that treatment with ofranergene obadenovec was at least 10% superior to placebo arm and the study was allowed to continue.

In these interim data, if randomization was even between groups, the CA-125 response rate with ofranergene obadenovec would be 58%, the company hypothesized. Moreover, in patients who experienced a post-dosing fever, which is an indication of an immune response, the CA-125 response rate was 69%. There were early signs that a response was associated with improved survival, although these data are early (P = .067).

VBL anticipates completing enrollment by the end of 2021 or in early 2022. The study began in 2017 and the estimated primary completion date is December 2022 (NCT03398655), which VBL does not expect to be altered by the pause.

"We do not expect a material change to our data readout timelines," said Harats. "We are in regular contact with the FDA and taking the steps necessary to minimize disruption to the trial in the United States.”

In addition to ovarian cancer, ofranergene obadenovec has also received orphan designation in both the United States and Europe as a treatment for patients with recurrent glioblastoma multiforme (rGBM). Additionally, the agent was given a fast track designation from the FDA for rGBM. The phase 3 GLOBE study assessed the gene therapy in combination with bevacizumab versus bevacizumab alone. However, in findings from this study, the combination failed to show an improvement in outcomes.

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