FDA Issues Complete Response Letter Regarding NDA for Pedmark in Cisplatin-Induced Ototoxicity

The FDA issued a complete response letter (CRL) to Fennec Pharmaceuticals Inc, developer of a sodium thiosulfate formulation, Pedmark, which is intended for the treatment of patients aged 18 years or younger with localized, non-metastatic solid tumors, as prevention of cisplatin-induced ototoxicity, Fennec Pharmaceutical announced in a press release.¹

The CRL noted deficiencies noticed during the pre-approval inspection of the manufacturing facility resulting in a Form 483. As a result, Fennec Pharmaceuticals plans to request a Type A meeting with the FDA to discuss the steps required to resubmit the New Drug Application (NDA) for approval of Pedmark. The CRL did not mention any efficacy or safety concerns with the drug.

“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,” said Rosty Raykov, CEO of Fennec Pharmaceuticals, in the 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.”

The NDA was submitted based on 2 phase 3 clinical trials, ACCL0431 (NCT00716976) and SIOPEL 6 (NCT00652132).

ACCL0431 was a randomized, open-label phase 3 study of 125 patients with various newly diagnosed solid tumors. The primary end point of the study was the incidence of hearing loss 4 weeks after the final dose of cisplatin.²

A total of 104 patients were evaluable for the primary end points. It was determined that 14 patients (28.6%; 95% CI, 16.6%-43.4%) had hearing loss after treatment with cisplatin in the sodium thiosulfate arm, compared with 31 patients (56.4%; 95% CI, 42.3%-69.7%) in the control arm (P = .00022). Investigators led by David R. Freyer, DO, found that the patients who received sodium thiosulfate rather than observation were overall less likely to have hearing loss following cisplatin (odds ratio [OR], 0.31; 95% CI, 0.13-0.73; P = .0036).

Sixty-seven of the 104 evaluable patients were also evaluable at 1 year in the post-hoc analysis. The analysis showed that 28% of patients had hearing loss in the sodium thiosulfate group versus 54% in the control group (P = .0015).

Toxicities did not appear to be different between the 2 study arms. Specifically, hematologic toxicity occurred in 77% of participant cycles in the sodium thiosulfate arm compared with 77% in the control arm (P = .95). The most common grade 3/4 hematological adverse event (AEs) in the experimental versus the control arm was neutropenia (66% vs 65%). The most common non-hematological AE was hypokalemia, which occurred in 17% of patients who received sodium thiosulfate versus 12% of those who received observation alone.

Based on the data from ACCL0431, Freyer et al determined that sodium thiosulfate prevents cisplatin-induced hearing loss without serious toxicity in patients with various solid tumors.

SIOPEL 6 was a multicenter, open-label, randomized phase 3 trial, which evaluated the efficacy of cisplatin plus sodium thiosulfate compared with cisplatin alone in 109 children. The primary end point was the absolute hearing loss threshold. The secondary end points included response to preoperative chemotherapy, complete resection, complete remission, event-free survival (EFS), overall survival (OS), safety, long-term renal clearance or glomerular filtration rate, and the feasibility of central audiologic review.³

In the study, cisplatin was dosed at 80 mg/m2 of the body-surface area and administered over a 6-hour period. Sodium thiosulfate was dosed at 20 g/m2 and administered intravenously over a 15-minute period, 6 hours following the discontinuation of cisplatin treatment.

The results showed that grade 1 or higher hearing loss occurred in 33% of patients in the cisplatin plus sodium thiosulfate group compared with 63% in the cisplatin-only group. This finding was indicative of a 48% lower risk of developing hearing loss in the cisplatin plus sodium thiosulfate arm (relative risk, 0.52, 95% CI, 0.33-0.81; P = .002).

At a median follow-up of 52 months, the 3-year OS rate was 98% (95% CI, 88%-100%) in the cisplatin plus sodium thiosulfate arm compared with 92% (95% CI, 81%-97%) in the cisplatin only arm. The 3-year EFS rates in the cisplatin plus sodium thiosulfate arm was 82% (95% CI, 69%-90%) versus 79% (95% CI, 65%-88%) with cisplatin alone.

In terms of safety, 57 patients who received cisplatin plus sodium thiosulfate and 52 who received cisplatin alone experienced AEs. The most common were grade 3 infection, occurring in 31% of the chemotherapy arm versus 23% of the cisplatin plus sodium thiosulfate arm, and grade 3 febrile neutropenia, which occurred in 19% versus 14%, respectively.

Investigators led by Peppy Brock, MD, concluded that administering sodium thiosulfate 6 hours after cisplatin-based chemotherapy can decrease the indicine of hearing loss in children with standard-risk hepatoblastoma.

Prior to being FDA approved, Pedmark was granted Orphan Drug Designation by the FDA for this indication and also received Breakthrough Therapy and Fast Track designation from the FDA in March of 2018. When the NDA was submitted for Pedmark, the FDA granted the application a priority review.

_References:

_{1. Pennec 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 Inc. August 11, 2020. Accessed August 11, 2020. https://bit.ly/3kALCN6}

_{2. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74. doi:10.1016/ S1470-2045(16)30625-8}

_{3. Brock PR, Maibahc R, Childs M, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med. 2018;378(25):2376-2385. doi:10.1056/NEJMoa1801109}