The decision follows receipt of the final minutes of a Type A meeting with the regulator. Earlier, in August 2020, FDA has issued a full response letter after a pre-approval inspection for the product was completed and deficiencies were discovered.2 This led to the issuance of a Form 483, which is a list of conditions or practices that must be addressed before the agent can obtain approval.
Notably, no clinical safety or efficacy concerns were identified and no further clinical data was requested, according to Fennec Pharmaceuticals, Inc., the drug developer.
“We are pleased to have resubmitted the NDA for Pedmark and look forward to working with the FDA during the review process,” said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, Inc. in a press release. “We remain committed to reducing the risk of lifelong hearing loss for children receiving chemotherapy with cisplatin. If approved, Pedmark will be the first FDA-approved therapy to reduce the risk of cisplatin-induced ototoxicity in pediatric patients.”
A water-soluble thiol compound, sodium thiosulfate, also acts as a chemical reducing agent. The product was evaluated in 2 Phase 3 studies: The Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.
In the COG study ACCL0431, researchers enrolled patients who had previously been diagnosed with childhood cancer. The aim of the study was to evaluate the efficacy of sodium thiosulfate in the prevention of hearing loss in children undergoing chemotherapy with cisplatin. It was hypothesized that treatment with the product would result in a 50% relative reduction in hearing loss in this population
Another aim of the study was to compare the change in mean hearing thresholds and the incidence of other grade 3 or 4 adverse events. Researchers also sought to monitor event-free survival (EFS) and overall survival (OS) in both patient groups.
A total of 125 patients were determined to be eligible for the study; 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other cancers not specifically defined. In addition, 104 of these patients were determined to be evaluable for the analysis of the study’s primary endpoint. Sixty-four of these patients were male and 29 were under 5 years of age.
Study participants were randomized to receive either intravenous sodium thiosulfate at 16 g/m2 over 15 minutes, 6 hours after each dose of cisplatin, or placebo. Hearing was measured using standard age audiometry and these findings were assessed centrally in accordance with American Speech-Language-Hearing Association criteria.
The results showed that 28.6% of those who received sodium thiosulfate had hearing loss, compared to 56.4% of those who received the placebo (P = .004). In a subgroup consisting of 29 patients less than 5 years of age, the hearing loss rates were 21.4% and 73.3% in the study and control arms, respectively (P = 0.005).
In addition, the SIOPEL 6 study, conducted by the International Childhood Liver Tumor Strategy Group, evaluated the efficacy of sodium thiosulfate in reducing cisplatin-induced hearing loss. Researchers also monitored the drug’s potential impact on cisplatin response and survival. The primary goal of the study was an absolute hearing threshold of 3.5 years or older per central assessment and the use of pure tone audiometry according to Brock criteria.
The study included patients with newly diagnosed standard-risk hepatoblastoma. The participants received four courses of chemotherapy every two weeks before surgery and then two courses of chemotherapy after surgery.
A total of 109 patients were randomized to cisplatin followed by sodium thiosulfate (n = 57) or cisplatin alone (n = 52). Cisplatin was administered intravenously at a dose of 10 mg/m 2 over 6 hours. Sodium thiosulfate was administered intravenously every 6 hours after cisplatin was discontinued; the tracer was administered at a dose of 20 g/m 2 over 15 minutes.
Data from the study showed that at 52 months of follow-up, the 3-year EFS rate was 82.1% in the study arm versus 78.8% in the control arm; the OS rates at this time point were 98.2% and 92.3%, respectively.
Treatment failure, which was defined as progressive disease after 4 treatment cycles, was found to be equivalent in both treatment arms. Of the 101 evaluable patients, 63% and 32% of those in the control and study arm, respectively, experienced hearing loss; this translated into a relative risk of 0.56 (P = .002). The sodium thiosulfate combination was also found to be well tolerated.
Fennec Pharmaceuticals is again filing a new drug application with the US Food and Drug Administration for Pedmark. news item. Fennec Pharmaceuticals, Inc. May 28, 2021. Accessed June 1, 2021. https://bit.ly/3pj91FOFennec Pharmaceuticals receives full response letter from FDA for its new drug application for Pedmark to prevent ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic, solid tumors. news item. Fennec Pharmaceuticals. August 11, 2020. Access until June 1, 2021. https://bit.ly/30LptDZKlinischetrials. Fennec Pharmaceuticals Inc website. Accessible on June 1, 2021. https://bit.ly/30FpoSp