FDA panel tips in favour of high-risk neuroblastoma therapy
04 Oct 2023
ImmunotherapyAcquisitionClinical ResultClinical StudyDrug Approval
An FDA advisory panel voted 14 to 6 on Wednesday that US WorldMeds provided sufficient evidence to conclude that eflornithine improves event-free survival (EFS) in patients with high-risk neuroblastoma. The company is seeking US approval of the drug, also referred to as DFMO, to lower the risk of relapse in paediatric patients with high-risk neuroblastoma who have completed multiagent, multimodality therapy.
Eflornithine is an oral irreversible inhibitor of ornithine decarboxylase, the first and rate-limiting enzyme in the biosynthesis of polyamines and a transcriptional target of MYCN. In neuroblastoma, the drug was initially developed by an investigator sponsor through multiple interactions with the FDA. In a 2015 meeting, the US regulator had recommended that a randomised controlled trial (RCT) be conducted, but "despite efforts by the sponsor to assess the feasibility of a randomised trial in this setting, the sponsor elected to develop the drug in single-arm cohorts," FDA staff wrote in briefing documents released this week ahead of the AdCom.
Agency scientists noted that RCTs are the gold standard for evaluating time-to-event endpoints, but said results provided by US World Meds from a large, single-arm trial suggested "substantive improvement over a benchmark historic control." The company submitted results of a single externally controlled trial (ECT) and supportive data to bolster its application. The ECT was designed to compare data from an open-label, single-arm trial of eflornithine monotherapy for up to two years in paediatric patients in remission after immunotherapy, to an external control arm constructed from patients from another open-label, randomised trial of immunotherapy plus standard upfront therapy versus upfront therapy alone.
According to the FDA briefing document, the primary analysis resulted in a hazard ratio (HR) for EFS of 0.48 and 0.32 for overall survival, favouring the eflornithine arm. Agency staff wrote that "the use of an external…controlled trial to support a marketing application may be acceptable in the setting of a rare disease with a well-defined natural history and poor prognosis if the expected treatment effect is estimated to be large, particularly in a setting where conduct of an RCT may be infeasible."
Concerns over externally controlled trials
However, some AdCom members questioned that stance, including panelist Dan Spratt, who voted against eflornithine, asking why a randomised trial was not done given "this could be a very feasible small trial." Committee chair Christopher Lieu, who was a yes vote, highlighted "significant concerns about setting a precedent for using externally controlled trials."
Meanwhile, panel member Caleb Alexander admitted "this is one of the tougher advisory committees I've participated in, in terms of managing uncertainty," although he said he does believe "the product works to some degree." However, Alexander was "hedging" his response to some degree, saying "I'm not clear that the evidence we've reviewed meets statutory thresholds, and I also think FDA has to be careful what they wish for and the ways that any favourable decision here may have significant consequences on future drug development and be precedence-setting."
Committee member Shahab Asgharzadeh, who voted yes as well, noted that there are diseases where it is possible to run a randomised trial quickly, "but I felt in this setting, that the evidence shows that DFMO is effective. The preclinical studies are also compelling with the use of the TH-MYCN models."
In July, US WorldMeds acquired certain assets in Panbela Therapeutics' eflornithine paediatric neuroblastoma programme for a total of up to $9.5 million.
For more details,please visit the original website
The content of the article does not represent any opinions of Synapse and its affiliated companies. If there is any copyright infringement or error, please contact us, and we will deal with it within 24 hours.
Organizations
Indications
Hot reports
Get started for free today!
Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.
Start your data trial now!
Synapse data is also accessible to external entities via APIs or data packages. Leverages most recent intelligence information, enabling fullest potential.