NDA Resubmitted to FDA for Pedmark in Prevention of Cisplatin-Induced Ototoxicity in Solid Tumors


The new drug application seeking the approval of a unique formulation of sodium thiosulfate for the prevention of ototoxicity induced by cisplatin chemotherapy in patients aged 1 month to less than 18 years of age with localized, nonmetastatic solid tumors has been resubmitted to the FDA.



The new drug application seeking the approval of a unique formulation of sodium thiosulfate (Pedmark) for the prevention of ototoxicity induced by cisplatin chemotherapy in patients aged 1 month to less than 18 years of age with localized, nonmetastatic solid tumors has been resubmitted to the FDA.1

The decision follows the receipt of final minutes from a Type A meeting with the regulatory agency. Previously, in August 2020, the FDA issued a complete response letter after a pre-approval inspection of the manufacturing facility for the product had been completed and deficiencies were detected.2 This led to the issuance of a Form 483, which is a list of conditions or practices that need to be addressed before the agent can obtain approval.

Notably, no clinical safety or efficacy issues had been identified, and no further clinical data were 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 through the review process,” Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, Inc., stated in a press release. “We remain committed to reducing the risk of lifelong hearing loss for children receiving cisplatin chemotherapy. If approved, Pedmark stands to 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 trials: The Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.

In the COG Study ACCL0431, investigators enrolled patients who had previously been diagnosed with a childhood cancer. The goal of the trial was to evaluate the efficacy of sodium thiosulfate in the prevention of hearing loss in children undergoing cisplatin chemotherapy. The hypothesis was that treatment with the product would result in a 50% relative reduction in hearing loss in this population.3

Another objective of the trial was to compare the change in mean hearing thresholds and the incidence of other grade 3 or 4 adverse effects. Investigators 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 trial; 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other cancers that were not specifically defined. Moreover, 104 of these patients were determined to be evaluable for the primary end point analysis of the trial. Sixty-four of these patients were male, and 29 were younger than 5 years of age.

Study participants were randomized to either intravenous sodium thiosulfate at 16 g/m2 over the course of 15 minutes, 6 hours after each dose of cisplatin, or placebo. Hearing was measured using standard audiometry for age and these findings underwent central review in accordance with the American Speech-Language-Hearing Association criteria.

Results revealed that 28.6% of those who received sodium thiosulfate experienced hearing loss compared with 56.4% of those given the placebo (P = .004). In a subgroup comprised of 29 patients under 5 years of age, rates of hearing loss were 21.4% and 73.3% in the investigative and control arms, respectively (P = .005).

Additionally, the SIOPEL 6 trial, which was done by the International Childhood Liver Tumour Strategy Group, evaluated the efficacy of sodium thiosulfate in reducing cisplatin-induced hearing loss. Investigators also monitored the potential impact of the agent on response to cisplatin and survival. The primary objective of the trial was absolute hearing threshold of 3.5 years of age or older per central review and the use of pure tone audiometry graded by Brock criteria.

The trial included patients with newly diagnosed, standard-risk hepatoblastoma. Participants received 4 courses of chemotherapy on a biweekly basis prior to surgery and then 2 chemotherapy courses following surgery.

A total of 109 patients were randomized to cisplatin followed by sodium thiosulfate (n = 57) or cisplatin alone (n = 52). Cisplatin was delivered at a dose of 10 mg/m2 intravenously over the course of 6 hours. Sodium thiosulfate was given intravenously every 6 hours after cisplatin was stopped; the investigative agent was administered at a dose of 20 g/m2 over the course of 15 minutes.

Data from the trial showed that at 52 months of follow-up, the 3-year EFS rate was 82.1% in the investigative arm vs 78.8% in the control arm; the OS rates at this timepoint were 98.2% and 92.3%, respectively.

Treatment failure, which was defined as progressive disease at 4 cycles of treatment, proved to be equivalent in both treatment arms. Of 101 evaluable patients, 63% and 32% of those on the control and investigative arms, respectively, experienced hearing loss; this translated to a relative risk of 0.56 (P = .002). The sodium thiosulfate combination was also found to be well tolerated.


  1. Fennec Pharmaceuticals resubmits new drug application to US Food and Drug Administration for Pedmark. News release. Fennec Pharmaceuticals, Inc. May 28, 2021. Accessed June 1, 2021. https://bit.ly/3pj91FO
  2. Fennec Pharmaceuticals receives complete response letter from the FDA for its new drug application for Pedmark to prevent ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic, solid tumors. News release. Fennec Pharmaceuticals. August 11, 2020. Accessed June 1, 2021. https://bit.ly/30LptDZ
  3. Clinical trials. Fennec Pharmaceuticals Inc website. Accessed June 1, 2021. https://bit.ly/30FpoSp
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