A new drug application has been resubmitted to the FDA for Pedmark, a sodium thiosulfate formulation, for the prevention of ototoxicity induced by cisplatin-based chemotherapy in patients under the age of 18 years old with localized, non-metastatic solid tumors.
A new drug application (NDA) has been resubmitted to the FDA for Pedmark, a sodium thiosulfate formulation, for the prevention of ototoxicity induced by cisplatin-based chemotherapy in patients under the age of 18 years old with localized, non-metastatic solid tumors, according to a press release issued by Fennec Pharmaceuticals.1
The initial application for approval led to a complete response letter from the FDA due to the discovery of deficiencies during the pre-approval inspection of the manufacturing facility, which resulted in a Form 483. At the time, the FDA requested that the NDA be resubmitted.2
“We are pleased to have resubmitted the NDA for Pedmark™ and look forward to working with the FDA through the review process,” said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, Inc, in a statement. “We remain committed to reducing the risk of life-long 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.”
Results from the phase 3 ACCL 0431 trial (NCT00716976) and phase 3 SIOPEL 6 trial (NCT00652132) support the NDA.
ACCL0431 was a randomized, open-label study that included 125 patients with 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.3
Of the patients enrolled, 104 patients were evaluable for the primary end point. Fourteen patients (28.6%; 95% CI, 16.6%-43.4%) were found to have 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). Further, those 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).
A post hoc analysis for which 67 patients were evaluable for the primary end point showed that 28% of patients had hearing loss in the sodium thiosulfate group versus 54% in the control group (P = .0015).
In terms of safety, hematologic toxicity was observed in 77% of patients 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%, respectively). The most common non-hematological AE was hypokalemia, which was observed in 17% of patients who received sodium thiosulfate versus 12% of those who received observation alone.
In the multicenter, open-label, randomized SIOPEL 6 study, which evaluated the efficacy of cisplatin plus sodium thiosulfate compared with cisplatin alone in 109 children, investigators looked at the primary end point of 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.4
Patients in the study who received cisplatin were dosed at 80 mg/m2 of the body-surface area administered over a 6-hour period. Sodium thiosulfate was dosed at 20 mg/m2 and administered intravenously over a 15-minute period, about 6 hours after the end of cisplatin treatment.
Grade 1 or higher hearing loss was observed in 33% of patients in the cisplatin plus sodium thiosulfate arm compared with 63% in the cisplatin-only arm. 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%) with the combination of cisplatin and 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%) in the cisplatin-only arm.
Safety results from the SOPHA 6 trial showed that AEs occurred in 57 patients in the combination arm versus 52 in the monotherapy arm. The most common AEs observed 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.
Pedmark previously received orphan drug designation from the FDA for the prevention of ototoxicity induced by cisplatin-based chemotherapy in patients under the age of 18 years old with localized, non-metastatic solid tumors and breakthrough therapy and fast track designation from the FDA in March of 2018.1
1. Fennec Pharmaceuticals resubmits new drug application to U.S. food and drug administration for Pedmark™. News release. Fennec Pharmaceuticals. May 28, 2021. Accessed June 1, 2021. https://bit.ly/34zZlgq
2. 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 June 1, 2021. https://bit.ly/3kALCN6
3. 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
4. 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