FDA Issues Complete Response Letter for Sodium Thiosulfate

The FDA has issued a complete response letter (CRL) to Fennec Pharmaceuticals regarding its new drug application (NDA) for a unique formulation of sodium thiosulfate (Pedmark) for intravenous (IV) administration for the prevention of ototoxicity associated with cisplatin chemotherapy in pediatric patients at least 1 month of age to 18 years of age with localized, non-metastatic, solid tumors.¹

Following the recent completion of a pre-approval inspection of the agent’s manufacturing facility, the FDA noted in the CRL that they identified deficiencies resulting in a Form 483. According to Fennec, this is a list of conditions or practices that are required to be resolved prior to the approval of sodium thiosulfate.

To address the concerns and other matters described in the CRL applying to the steps required for the resubmission of the NDA for sodium thiosulfate, Fennec suggested plans to request a Type A meeting. Importantly though, there were no clinical safety or efficacy issues identified during the review and there was no request for further clinical data.

“We are steadfast in our commitment to reducing the risk of life-long hearing loss for children receiving cisplatin chemotherapy who currently have no approved therapies for this devastating condition,” Rosty Raykov, chief executive officer of Fennec, said in a press release. “We will work closely with our manufacturer and the FDA to fully address the issues raised in the letter as expeditiously as possible.”

Sodium thiosulfate has been studied by cooperative groups in 2 phase 3 clinical studies of survival and reduction of ototoxicity, including The Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6; both studies have already been completed.²

The COG ACCL0431 protocol enrolled patients with 1 of 5 childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease. In total, 125 eligible patients were enrolled, including 32 with germ cell tumor, 29 with osteosarcoma, 26 with neuroblastoma, 26 with medulloblastoma, 7 with hepatoblastoma, and 5 with other childhood cancers.

Of this cohort, 104 were evaluable for the primary end point evaluating the efficacy of sodium thiosulfate for prevention of hearing loss in children receiving cisplatin chemotherapy. At 4 weeks after the final cisplatin dose, the proportion of subjects with hearing loss with sodium thiosulfate was 28.6% (14/49) compared with 56.4% (31/55) with control (P = .004). Further, in a predefined subgroup of patients less than 5 years old which included 29 participants, hearing loss with sodium thiosulfate was 21.4% and 73.3% with control (P = .005).

SIOPEL 6 only enrolled patients with hepatoblastoma with localized tumors. Overall, 57 patients randomized to cisplatin plus sodium thiosulfate and 52 patients randomized to cisplatin only were evaluable. The primary end point was centrally reviewed absolute hearing threshold at the age of 3.5 years or older by pure tone audiometry, graded by Brock criteria.

With a follow up of 52 months, 3-year event-free survival (EFS) was 78.8% for the cisplatin group and 82.1% for those in the cisplatin plus sodium thiosulfate group. Moreover, the 3-year overall survival (OS) was 92.3% for cisplatin and 98.2% for cisplatin plus sodium thiosulfate. Of note, hearing loss occurred in 63% of patients in the cisplatin group and 32% in the cisplatin plus sodium thiosulfate group, corresponding to a relative risk of 0.56 (P = 0.002).

The FDA granted sodium thiosulfate breakthrough therapy and fast track designation in March 2018. Currently, a marketing authorization application (MAA) for sodium thiosulfate (Pedmarqsi) is under evaluation by the European Medicines Agency (EMA).

References:

1. 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]. Research Triangle Park, NC. Published August 11, 2020. Accessed August 11, 2020. https://www.globenewswire.com/news-release/2020/08/11/2076200/0/en/Fennec-Pharmaceuticals-Receives-Complete-Response-Letter-from-the-FDA-for-its-New-Drug-Application-for-PEDMARK-to-Prevent-Ototoxicity-Associated-with-Cisplatin-in-Pediatric-Patient.html

2. Fennec Pharma. Clinical Trials. Fennec Pharmaceuticals website. Published 2020. Accessed August 11, 2020. https://fennecpharma.com/product-candidates/pedmark/clinical-trials/