FDA Guidance Raises Concerns about Y-mAbs’ Neuroblastoma Treatment before Adcomm

 FDA scientists raised questions about the efficacy of Y-mAbs Therapeutics’ experimental neuroblastoma treatment, omburtamab, two days before the regulator’s Oncologic Drugs Advisory Committee meets to examine data supporting the BLA.

The adcomm released briefing documents that question the potential of omburtamab as a treatment for pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma.

The FDA honed in on three key issues with the submitted data that could become a stumbling block for potential approval.

First, the FDA stated the external control population is not fit-for-purpose as a comparator. The regulatory team said this is primarily due to substantive differences between the study and control populations that limit the ability to attribute survival differences to the effect of omburtamab.

The FDA stated that patients who participated in the Y-mAbs study “received multimodality treatment for CNS/LM relapse” prior to receiving omburtamab.

The agency highlighted potential sources of bias in the treatment population that could have skewed trial results, and conducted its own analyses to determine if this was a factor. Its findings showed the results in survival “cannot be reliably attributed to omburtamab,” the FDA said in its briefing documents.

Lastly, the regulator noted that Y-mAbs' BLA does not include reliable response rate data supporting omburtamab’s efficacy. The FDA’s scientists said no patient in the Y-mAbs study demonstrated a response that can be “unequivocally attributed” to omburtamab.

Based on these concerns, the FDA staff said it cannot establish a substantive risk-benefit relationship for the use of omburtamab in patients with CNS/LM relapsed neuroblastoma.

“There is no reliable information on tumor response rate, leading to significant questions as to whether the submitted study can be considered an adequate and well-controlled trial necessary to establish effectiveness,” the FDA wrote.

CNS/LM is a rare and usually fatal complication of neuroblastoma in which the disease spreads to the membranes, or meninges, surrounding the brain and spinal cord in the central nervous system.

Omburtamab targets an immune checkpoint molecule called B7-H3.

In May, the FDA accepted the BLA under priority review. It was supported by data from two Phase II studies, 101 and 03-133. The data from these clinical trials has not yet been published. The company anticipates publishing the data later this year.

Y-mAbs’ shares have fallen more than 10% in Wednesday trading. BioSpace has reached out to the company but had not heard back as of press time. 

This isn’t the first time Y-mAbs has faced difficulty getting omburtamab across the finish line. Two years ago, the FDA handed the company a Refusal to File letter. The letter raised concerns about Chemistry, Manufacturing and Control module and also said the Clinical module of the BLA required further detail.

Earlier this month, Y-mAbs announced interim results from 32 patients who participated in a separate study of omburtamab radiolabeled with Iodine-131. One-year overall survival was 73.5%, with a median follow-up of 25 months, the company revealed.

Additionally, interim results from this study showed an objective response rate of 31.3% in patients with measurable disease. This was after central review based on criteria from both the Response Assessment in Neuro-Oncology and the European Association of Neuro-Oncology/European Society for Medical Oncology. A total of 75% of the patient population with measurable disease achieved disease control.

A little more than 40% of patients experienced a serious adverse event. Y-mAbs reported the SAEs were primarily related to myelosuppression.

This study is expected to bolster the clinical data submitted with the BLA, the company said.

The FDA has set a PDUFA date for Nov. 30.

https://www.biospace.com/article/fda-briefing-docs-raise-concerns-before-adcomm-for-y-mabs-neuroblastoma-treatment/