The new drug application (NDA) for iobenguane I-131, a novel iodine-131 metaiodobenzylguanidine (MIBG), was based on findings from a phase IIb clinical trial that was conducted under the FDA's special protocol assessment. In the trial, the radiopharmaceutical elicited a ≥50% reduction in antihypertensive medication use for ≥6 months, which was the primary endpoint of the trial, for 25% of patients with PPGL (95% CI, 16%-37%). In those receiving at least 2 therapeutic doses, the primary endpoint was achieved for 32% of patients (95% CI, 21%-46%).
Prior to submission of the NDA, iobenguane I-131 was granted a breakthrough therapy designation for the treatment of PPGL, along with orphan drug and fast track designations. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by April 30, 2018.
“With no FDA-approved therapies for these rare tumors, Azedra has the potential to address the high unmet need of patients with malignant pheochromocytoma and paraganglioma,” Mark R. Baker, chief executive officer of Progenics, said in a statement. “We are pleased that the FDA has accepted our NDA with priority review, and look forward to working with the Agency during the review process. At the same time, we will continue to lay the groundwork for our commercial plan and prepare to launch quickly following a potential approval.”
The novel version of iobenguane I-131 is made using a system known as UltraTrace, which results in less non-radioactive MIBG during enrichment leading to greater delivery of radiation to the tumor. The UltraTrace technology was developed by Molecular Insight Pharmaceuticals, which was acquired by Progenics in early 2013.
The pivotal, open-label clinical trial enrolled 68 patients with MIBG-avid PPGL who were ineligible for curative surgery, failed prior therapy, or were not candidates for chemotherapy. Iobenguane I-131 was given at an initial dosimetric dose of 111 to 222 MBq at the time of enrollment, which was followed by a therapeutic dose of 296 MBq/kg. Three months after the first dose, a second therapeutic dose of 18.5 GBq was administered. In total, 50 patients received both therapeutic doses per protocol.
The primary endpoint of reduction in antihypertensive medication was selected since PPGL leads to higher levels of catecholamines and subsequently hypertension and other cardiovascular issues. All patients in the trial were receiving antihypertensive therapy for at least 30 days prior to entry in the study. The key secondary endpoint of the study focused on the objective response rate (ORR) by RECIST criteria.
Prior to enrollment, 71% of patients had received ≥2 prior lines of therapy. Most patients had a diagnosis of pheochromocytoma (71.6%), with the remainder having paraganglioma (28.4%). Prior treatment included surgery for 89.2% of patients. Additionally, 29.7% of those enrolled in the trial had received traditional I-131 MIBG therapy and 37.6% of patients had received chemotherapy.
The ORR, which consisted entirely of partial responses, was 23.4% with iobenguane I-131 for all patients enrolled in the trial. Additionally, stable disease (SD) was achieved for 68.8% of patients, for a disease control rate (ORR + SD) of 92.2%. In the per protocol group, the ORR was 30% and 68% of patients had stable disease. The disease control rate was 98%.
In addition to those meeting the primary endpoint, 31.4% of patients had a ≥50% reduction in antihypertensive medication use; however, this did not last ≥6 months. For those achieving the primary endpoint, the median duration of clinical benefit was 13.3 months (range, 8.0-60.2).
The median time from enrollment to death was 36.7 months (95% CI, 29.9-49.1). Survival did not differ based on the site of metastatic disease. Those with lung metastases had a median survival of 42.6 months and those with liver metastases had a median survival of 41.1 months.
There were no unexpected adverse events (AEs) in the trial. The most common treatment-emergent AEs, which occurred in ≥50% of patients, included nausea, myelosuppression, and fatigue. There were no acute drug-related hypertensive crises reported in the trial nor were there any new cases of severe acute hypertension.
An expanded access program for iobenguane I-131 is currently available for patients with MIBG-avid malignant and/or recurrent PPGL. Outside of providing access to the medication, the program also plans to further assess safety (NCT02961491).