An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *
FDA Accepts Supplemental New Drug Application for Advanced Neuroendocrine Tumor Treatment
On August 3, Exelixis announced that its supplemental New Drug Application (sNDA) for cabozantinib (CABOMETYX®) has been accepted by U.S. Food and Drug Administration (FDA) for to treat patients with advanced neuroendocrine tumors.
Specifically, the drug was approved for: 1) the treatment of adults with previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated pancreatic neuroendocrine tumors (pNET), and 2) the treatment of adults with previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated extra-pancreatic NET (epNET).
The U.S. Food and Drug Administration (FDA) also granted orphan drug designation to cabozantinib for the treatment of pNET. The FDA assigned a standard review with a Prescription Drug User Fee Act target action date of April 3, 2025.
“The FDA’s acceptance of this application marks another important milestone in our commitment to bringing cabozantinib to patients living with difficult-to-treat cancers and who have limited treatment options,” said Amy Peterson, MD, executive vice president, Product Development & Medical Affairs, and chief medical officer, Exelixis. “We appreciate the opportunity to work with the FDA in the coming months as they review our application, with the goal to bring this new, effective treatment option to patients with advanced neuroendocrine tumors as quickly as possible.”
The sNDA is based on the final results of the phase 3 CABINET pivotal trial evaluating cabozantinib compared with placebo in two cohorts of patients with previously treated NET: advanced pNET and advanced epNET. As previously announced, CABINET was stopped early for compelling activity; all patients were unblinded and those on placebo were given the option to cross over to active treatment with cabozantinib. This early stopping was due to a dramatic improvement in progression-free survival (PFS) observed at an interim analysis in both cohorts. The study demonstrated a statistically significant and clinically meaningful improvement in PFS with cabozantinib versus placebo, based on results of both local review and available independent blinded central radiology review. Initial results were presented at the 2023 European Society of Medical Oncology (ESMO) Congress; final results will be presented at the 2024 ESMO Congress on September 16th in Barcelona, Spain.
About CABINET (Alliance A021602)
CABINET (Randomized, Double-Blinded Phase III Study of CABozantinib versus Placebo In Patients with Advanced NEuroendocrine Tumors After Progression on Prior Therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program.
CABINET is a multicenter, randomized, double-blinded, placebo-controlled phase 3 pivotal trial that had enrolled a total of 290 patients in the U.S. at the time of the interim analysis. Patients were randomized 2:1 to cabozantinib or placebo in two separate cohorts (pNET, n=93; epNET, n=197). The epNET cohort included patients with the following primary tumor sites: gastrointestinal (GI) tract, lung and other. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. FDA-approved line of prior therapy other than somatostatin analogs. The primary endpoint in each cohort was PFS per RECIST 1.1 by retrospective blinded independent central review. Upon disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with cabozantinib. Secondary endpoints included overall survival, radiographic response rate and safety. More information about this trial is available at ClinicalTrials.gov.
Amylyx Pharmaceuticals Receives Orphan Drug Designation From the European Commission for AMX0035 to Treat Wolfram Syndrome
On August 2, Amylyx Pharmaceuticals, Inc., announced the European Commission (EC), based on a positive opinion issued by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA), has granted Orphan Drug Designation for AMX0035, Amylyx’ proprietary, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine outside of the U.S.) for the treatment of Wolfram syndrome.
Wolfram syndrome is a prototypical disease of endoplasmic reticulum (ER) stress that is rare, progressive, and monogenic and is characterized by childhood-onset diabetes mellitus, optic nerve atrophy, deafness, diabetes insipidus, and neurodegeneration. There are currently no drugs approved for Wolfram syndrome, and many people with the disease die prematurely with severe neurological disabilities.
The FDA previously granted AMX0035 Orphan Drug Designation for the treatment of Wolfram syndrome in 2020. The EMA grants Orphan Drug Designation status for products intended for the treatment, prevention, or diagnosis of rare, life-threatening, or chronically debilitating conditions where the product may represent a significant benefit over existing treatments.
“Wolfram syndrome is considered a prototypical endoplasmic reticulum (ER) stress disorder because of the clear link between WFS1 mutations and ER stress. AMX0035 is believed to target ER stress and mitochondrial dysfunction.”
Amylyx recently presented positive data from an interim analysis of its Phase 2 HELIOS study, including eight participants with Wolfram syndrome assessed at Week 24, which demonstrated that AMX0035 improved pancreatic function and glycemic control, as measured by C-peptide, HbA1c, and other markers of glucose metabolism. All eight participants met prespecified responder criteria showing either improvement or stabilization of disease according to both the Patient Reported Global Impression of Change (PGIC) and the Clinical Reported Global Impression of Change (CGIC) scales. The majority of participants reported some improvement in vision. In Wolfram syndrome, progressive decline and worsening of outcomes would have been expected on all measures, so disease improvement or stabilization alone is clinically meaningful. AMX0035 was generally well tolerated in all participants. The Company anticipates reporting topline data from all 12 participants at Week 24 this fall.
“Wolfram syndrome is a disease where there are well-defined measurable biomarkers, rigorous supporting preclinical data, and clear rationale for our potential therapy based on its mechanism of action. Specifically, Wolfram syndrome is considered a prototypical endoplasmic reticulum (ER) stress disorder because of the clear link between WFS1 mutations and ER stress. AMX0035 is believed to target ER stress and mitochondrial dysfunction,” said Endocrine Society member Camille L. Bedrosian, MD, chief medical officer at Amylyx. “The interim data from HELIOS showed stabilization or even improvement across key outcomes at Week 24. HELIOS follows strong preclinical research with data showing clear effects in cellular and animal models. We look forward to reporting topline data from all participants at Week 24 this fall. We aim to address an urgent unmet medical need, given there are no approved treatment options for Wolfram syndrome.”
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