FDA Accepts NDA Resubmission for Pedmark in Prevention of Platinum-Induced Ototoxicity in Solid Tumors

US FDA

The FDA has accepted for filing the new drug application (NDA) resubmission for a unique formulation of sodium thiosulfate (Pedmark) for the prevention of platinum-induced ototoxicity in patients between the ages of 1 month and 18 years who have localized, nonmetastatic, solid tumors.¹

The first NDA submission for the agent received a priority review designation from the regulatory agency in August 2020.² However, a few days later, the FDA issued a complete response letter to Fennec Pharmaceuticals, the drug developer, after a pre-approval inspection of the manufacturing facility for sodium thiosulfate revealed deficiencies that resulted in a Form 483, which detailed conditions or practices that needed to be addressed before the agent could receive approval.³

After receipt of the final minutes from a Type A meeting with the FDA, the NDA for Pedmark was resubmitted to the FDA in June 2021.4 The application was accepted by the agency later that month for filing.5 However, in November 2021, a second CRL was issued to the company after manufacturing deficiencies were still identified.⁶

The target action date for the current NDA is September 23, 2022, under the Prescription Drug User Fee Act.

“We are pleased that the FDA has accepted our resubmission and we look forward to working with the Agency to facilitate their review of our NDA,” Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, stated in a press release. “If approved, Pedmark has the potential to become a transformative treatment for pediatric patients at risk of cisplatin induced ototoxicity.”

There are currently no approved therapies for platinum-induced hearing loss in the United States.

Sodium thiosulfate was investigated in the phase 3 Clinical Oncology Group (COG) Protocol ACCL0431 (NCT00716976) and SIOPEL 6 (NCT00652132) trials in pediatric patients as an option that can be used in the prevention of hearing loss associated with cisplatin-based chemotherapy.

The multicenter, open-label, phase 3 COG ACCL0431 trial enrolled patients with newly diagnosed hepatoblastoma, germ cell tumor, medulloblastoma or central nervous system primitive neuroectodermal tumor, neuroblastoma, osteosarcoma, or other cancers treated with cisplatin.⁷

To be eligible for enrollment, patients needed to be between the ages of 1 year and 18 years, have a Karnofsky performance score of 50% or higher, and acceptable hematologic, renal, and hepatic function. All patients needed to have normal hearing prior to trial enrollment. They could not have previously received cisplatin or carboplatin treatment, nor could they have known thiol hypersensitivity.

On this study, patients received either a cisplatin-containing treatment regimen alone (n = 64) or 16 g/m2 of intravenous (IV) sodium thiosulfate over 15 minutes, beginning 6 hours after each dose of cisplatin (n = 61). Standard audiometry for age was used to measure hearing, and data were centrally reviewed in accordance with the American Speech-Language-Hearing Association criteria.

Baseline characteristics were comparable between the treatment arms, and disease-specific characteristics with respect to age and extent of disease were well balanced. Most patients in both arms were male, White, non-Hispanic, and had localized disease.

Results showed that 28.6% (95% CI, 16.6%-43.3%) of patients in the sodium thiosulfate arm experienced hearing loss compared with 56.4% (95% CI, 42.3%-69.7%) of those in the placebo arm (P = .00022). When adjusted for stratification variables, the likelihood of hearing loss was noted to be significantly lower with the investigative treatment vs the control (odds ratio, 0.31; 95% CI, 0.13-0.73; P = .0036).

Moreover, among the subset of patients who were younger than 5 years of age, incidence of hearing loss was found to be substantially lower in the sodium thiosulfate arm vs the control arm, at 21.4% (95% CI, 4.7%-50.8%) and 73.3% (95% CI, 44.9%-92.2%), respectively. However, among the subset of patients who were older, the difference in incidence between the arms was not as large, at 31.4% (95% CI, 16.9%-49.3%) and 50.0% (95% CI, 33.8%-66.2%), respectively.

After cisplatin infusion of 2 to 6 hours, the incidence of hearing loss was found to be lower in those randomized to the investigative arm vs those in the control arm, at 41.7% (95% CI, 22.1%-63.4%) and 70.0% (95% CI, 50.6%-85.2%), respectively. This was also true after a cisplatin infusion of less than 2 hours, at 16.0% (95% CI, 4.5%-36.1%) and 40.0% (95% CI, 21.1%-61.3%), respectively.

The international, cooperative, prospective SIOPEL 6 trial enrolled patients with standard-risk hepatoblastoma who were younger than 18 years of age and who had not previously received treatment.⁸

Overall, 109 patients were randomized to cisplatin followed by sodium thiosulfate (n = 57) or cisplatin alone (n = 52). Patients received 4 courses of biweekly neoadjuvant chemotherapy, followed by 2 courses of adjuvant chemotherapy. Cisplatin was administered intravenously at 10 mg/m2 over 6 hours. In the investigative arm, 20 mg/m2 of IV sodium thiosulfate was given 6 hours after the completion of cisplatin treatment.

The primary end point of the trial was the absolute hearing threshold at a minimum age of 3.5 years, as measured by pure-tone audiometry. Key secondary end points comprised response to preoperative chemotherapy, complete resection, complete remission, event-free survival (EFS), overall survival (OS), toxicity, and long-term renal clearance or glomerular filtration rate.

Patient characteristics were noted to be well balanced between the 2 treatment arms.

At a median of 52 months of follow-up, the addition of sodium thiosulfate resulted in a 3-year EFS rate of 82% (95% CI, 69%-90%) vs 79% (95% CI, 65%-88%) with cisplatin alone. The 3-year OS rates in the sodium thiosulfate and control arms were 98% (95% CI, 88%-100%) and 92% (95% CI, 81%-97%), respectively.

Treatment failure was defined as experiencing disease progression at 4 cycles of treatment; rates of this were reported to be equivalent between the 2 arms. Among the 101 evaluable patients, the rate of grade 1 or higher hearing loss was almost halved with sodium thiosulfate vs cisplatin alone, at 33% (95% CI, 21%-47%) and 63% (95% CI, 48%-77%; P = .002). The relative risk of any hearing loss with cisplatin and sodium thiosulfate was 0.52 (95% CI, 0.33-0.81), which translates to a 48% risk reduction with the investigative treatment.

In March 2018, Pedmark received breakthrough therapy⁹ and fast track¹⁰ designations from the FDA.

References

1. Fennec Pharmaceuticals announces FDA acceptance for filing of new drug application resubmission for Pedmark. News release. Fennec Pharmaceuticals. April 27, 2022. Accessed April 27, 2022. https://bit.ly/37TCwJM
2. Fennec Pharmaceuticals announces FDA filing acceptance and priority review of new drug application for Pedmark. News release. Fennec Pharmaceuticals. April 13, 2020. Accessed April 27, 2022. https://bit.ly/2Du9Urm
3. 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 April 27, 2022. https://bit.ly/30LptDZ
4. Fennec Pharmaceuticals resubmits new drug application to US Food and Drug Administration for Pedmark. News release. Fennec Pharmaceuticals, Inc. May 28, 2021. Accessed April 27, 2022. https://bit.ly/3pj91FO
5. Fennec Pharmaceuticals announces FDA acceptance of new drug application resubmission for Pedmark. News release. Fennec Pharmaceuticals, Inc. June 22, 2021. Accessed April 27, 2022. https://bit.ly/3j4WsMX
6. 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. November 30, 2021. Accessed March 24, 2022. https://bit.ly/3izYcwq
7. 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
8. Brock PR, Maibach 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
9. Fennec Pharmaceuticals receives breakthrough therapy designation by FDA for Pedmark. News release. Fennec Pharmaceuticals, Inc. March 27, 2018. Accessed April 27, 2022. https://bit.ly/3vmg2dx
10. Fennec Pharmaceuticals receives fast track designation by FDA for Pedmark. News release. Fennec Pharmaceuticals Inc. March 21, 2018. Accessed April 27, 2022. https://bit.ly/3j9oO9b