Y-mAbs Faces Delay In Pediatric Neuroblastoma With Refuse-To-File Letter
Executive Summary
Omburtamab, for CNS metastases resulting from neuroblastoma, needs more clinical and CMC data for its rolling BLA to be reviewed. The company says timelines for lead candidate naxitamab should not be affected.
With two neuroblastoma therapies under review at the US Food and Drug Administration, Y-mAbs Therapeutics Inc. is nearing some significant inflection points, including a 30 November user fee date for its lead candidate naxitamab. But the biotech hit a snag on 5 October when the FDA issued a refuse-to-file letter for the biologics license application (BLA) for its other neuroblastoma candidate, omburtamab.
Both of the monoclonal antibody candidates were in-licensed by Y-mAbs from Memorial Sloan Kettering Cancer Center in 2015 – omburtamab is radiolabeled with Iodine-131 and targets B7-H3 and is being developed to treat central nervous system/leptomeningeal metastases from neuroblastoma in pediatric patients. (Also see "Venture Funding Deals: From ADC To Y-mAbs, Capital Flows For New Platforms, Novel Approaches" - Scrip, 10 Nov, 2017.) The New York-based firm began a rolling BLA submission in June and submitted it for agency review in August.
Y-mAbs is seeking accelerated approval for the therapy, to be known as Omblastys, based on the Phase II Study 101 and Phase I Study 03-133, according to a July 2020 investor presentation. (Also see "Keeping Track: Veklury NDA Arrives At US FDA; Olinvyk Sees Approval; MAb Filings By Regneron, Y-mAbs" - Pink Sheet, 10 Aug, 2020.) In the 107-patient study 03-133, 131I-omburtamab demonstrated a median survival of 50.8 months, including an estimated five-year overall survival of about 44%. The historical median, Y-mAbs said, is approximately six to nine months.
During a 6 October investor call, Y-mAbs CEO Claus Moller said the FDA decided not to accept the filing for review because both its chemistry, manufacturing and controls (CMC) and clinical data modules needed additional detail. But the agency is not requesting any additional studies, he added, and so the company hopes to re-file the BLA before the end of 2020, which would put the therapy on track for potential approval in the third quarter of 2021.
Y-mAbs will seek a type A meeting with the agency in the next few weeks, Moller said. “I was very surprised and, of course, disappointed [by the letter],” he told the call. “And the FDA also expressed in the cover letter that they understood that we, of course, were disappointed, but they also reiterated their willingness to continue working with us to swiftly get this rectified.”
The additional CMC data, which the exec said should be available soon, was intended to be submitted as the rolling BLA was being reviewed. The clinical data, which the company believes it has on hand, will require a few weeks of work to document formally for inclusion in the BLA, he added.
RANO Tumor-Response Data Needed For Review
One of the FDA’s requests, Moller explained, is tumor-response data for the first 24 patients in the Phase II 101 trial, one of two backing the BLA, along with the Phase I 133 trial. These data were to be evaluated independently using the RANO (response assessment in neuro-oncology) criteria published in 2010, he said. Like the RECIST criteria for evaluating solid tumors, the RANO criteria give sponsors a standardized way to evaluate CNS tumors, the exec said.
“When we did the protocol for Study 101, in agreement with the FDA, we included tumor-response evaluations where we are looking at the tumor before the first dose of omburtamab, and we are following the response of the patients up to week 26,” Moller explained. “The FDA wants to see tumor responses for those patients among the first 24 patients in Study 101 that have measurable disease. And they want to have that included in the package because … they believe that that can give them the necessary confidence that this is sufficient to establish that there is a direct antitumor effect of omburtamab.”
The CEO also said he does not think there is any potential overlap from issues in reviewing the omburtamab filing with the BLA review for naxitamab. “We consider that as being completely on track for approval within the next very short period of time,” Moller noted.
In a 6 October note, WedBush analyst David Nierengarten said the timing outlined by Y-mAbs suggests approval by the third quarter of next year is possible and that a planned submission of omburtamab to the European Medicines Agency in February remains on track. He maintained an “outperform” rating for Y-mAbs’ shares, noting omburtamab’s lead indication is not a meaningful value-driver for the company. The firm’s main inflection point is the 30 November action date for naxitamab – a humanized 3F8 antibody targeting GD2 for neuroendocrine tumors, Nierengarten said.
WedBush projects naxitamab will bring in $472m in sales in 2028 across three cancer indications, while omburtamab is predicted to yield $168m that year, with $39m of that derived from use in CNS/leptomeningeal metastases. Y-mAbs is also developing omburtamab for diffuse intrinsic pontine glioma and desmoplastic small round cell tumors, both in pediatric patients.