The FDA has accepted for filing the resubmission of the new drug application for a unique formulation of sodium thiosulfate, for the prevention of ototoxicity that is induced by cisplatin chemotherapy in patients between the ages of 1 month and 18 years who have localized, nonmetastatic, solid tumors.
The FDA has accepted for filing the resubmission of the new drug application for a unique formulation of sodium thiosulfate (Pedmark), for the prevention of ototoxicity that is induced by cisplatin chemotherapy in patients between the ages of 1 month and 18 years who have localized, nonmetastatic, solid tumors.1
The application was resubmitted to the regulatory agency in June 2021. Previously, in August 2020, the FDA had issued a complete response letter to Fennec Pharmaceuticals, Inc., the drug developer.2
The regulatory agency had completed a pre-approval inspection of the manufacturing facility for the product and detected deficiencies, which led to the issuance of a Form 483, which lists conditions or practices that need to be addressed prior to approval. Notably, however, no clinical safety or efficacy issues were noted, and no further clinical data were requested by the FDA.
The regulatory agency is slated to decide on the application for the water-soluble thiol compound by November 27, 2021, in accordance with the Prescription Drug User Fee Act.
“We are pleased that the FDA has accepted our Pedmark resubmission,” Rosty Raykov, chief executive office of Fennec Pharmaceuticals, Inc., stated in a press release. “We look forward to working closely with the FDA through the review process. We are committed to bringing this treatment to children receiving cisplatin chemotherapy, an area of high unmet medical need. If approved, Pedmark stands to be the first FDA-approved therapy to reduce the risk of cisplatin-induced ototoxicity in pediatric patients.”
The agent has been examined in the following phase 3 trials: The Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.
The COG Study ACCL0431 trial enrolled patients who had received a prior diagnosis of childhood cancer. Investigators set out to examine how effective sodium thiosulfate was in preventing hearing loss in children who were receiving cisplatin chemotherapy.
Investigators hypothesized that the agent would lead to a relative reduction in hearing loss of 50% in these patients.3 Moreover, the change in mean hearing thresholds was also evaluated in this research, along with the incidence of other grade 3 or 4 toxicities. Regarding efficacy, event-free survival (EFS) and overall survival (OS) would also be monitored in the trial.
In total, 125 patients were enrolled to the trial; of these patients, 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other cancers that had not been specifically defined. Additionally, 104 of these patients were found to be evaluable for the primary end point analysis. Most of the participants were male (64%) and 29 patients were under the age of 5 years.
Participants were randomized to either intravenous (IV) administration of sodium thiosulfate at a dose of 16 mg/m2 over a duration of 15 minutes, 6 hours following each dose of cisplatin, or placebo. Investigators measured hearing by utilizing the standard audiometry for age; these data were centrally reviewed in accordance with the American Speech-Language-Hearing Association criteria.
Results indicated that less patients experienced hearing loss in the investigative arm vs the control arm, at 28.6% vs 56.4%, respectively (P = .004). In the patient subset who were under the age of 5 years (n = 29), 21.4% of patients who received sodium thiosulfate experienced hearing loss vs 73.3% of those who received placebo (P = .005); this translates to more than a three-fold reduction in the subset.
The SIOPEL 6 trial, which was conducted by the International Childhood Liver Tumour Strategy Group, also examined the safety and efficacy of sodium thiosulfate to reduce cisplatin-induced hearing loss in patients with newly diagnosed, standard-risk hepatoblastoma. Investigators also monitored the impact of the agent on response to cisplatin and survival. The key objective in this research was focused on absolute hearing threshold of 3.5 years of age or older per central review and the use of pure tone audiometry, which was graded by Brock criteria.
On this study, participants were given 4 courses of chemotherapy on a biweekly basis before surgery. Then, 2 courses of chemotherapy were administered after the procedure. In total, 109 patients were randomized to cisplatin followed by sodium thiosulfate (n = 57) or cisplatin alone (n = 52).
Patients received cisplatin at an IV dose of 10 mg/m2 over a duration of 6 hours. Patients were given sodium thiosulfate via IV administration every 6 hours after cisplatin was stopped; the investigative agent was given at a dose of 20 mg/m2 over the course of 15 minutes.
Results from this trial revealed that at 52 months of follow-up, the 3-year EFS rate achieved with sodium thiosulfate was 82.1% vs 78.8% with cisplatin alone. At this time point, the OS rates in the investigative and control arms were 98.2% and 92.3%, respectively.
Treatment failure was defined as experiencing disease progression at 4 cycles of treatment; rates of this were reported to be equivalent between the 2 arms. Among the 101 evaluable patients, the rate of hearing loss was almost halved with sodium thiosulfate compared with cisplatin alone, at 32% vs 63%, respectively; this translated to a relative risk of 0.56 (P = .002). Sodium thiosulfate was also determined to have favorable tolerability in this population.
Previously in March 2018, sodium thiosulfate was granted both a fast track designation and a breakthrough therapy designation from the FDA.4,5