The recent FDA approval of Fennec Pharmaceuticals’ drug PEDMARK (sodium thiosulfate injection) marks a significant advance for cancer treatment-associated hearing loss therapies, amidst a bid to improve quality of life for cancer patients.
On 21 September, the FDA approved Pedmark for reducing the risk of ototoxicity associated with cisplatin therapy in paediatric patients with localized nonmetastatic solid tumours. Pedmark is the first drug to be approved for this indication. The therapy is a chemoprotective sodium thiosulphate drug that inactivates the metabolic byproducts from cisplatin that are responsible for hearing loss.
Following the approval, the company’s shares rose by 11.9% when the market closed on 20 September, compared to the previous day. More than double the volume of Fennec’s shares were traded on the day of the approval news in comparison to 19 September.
The current standard of care for many cancers is cisplatin chemotherapy or platinum therapy. Cisplatin has multiple side effects including loss of appetite, nausea, and ototoxicity (hearing loss). Currently, ototoxicity is the major dose-limiting factor which often causes patients to discontinue cisplatin therapy and move on to other chemotherapeutic agents. Cisplatin-associated ototoxicity usually manifests as an irreversible, progressive, bilateral, high sensorineural hearing loss with tinnitus.
The World Health Organization reports that annually an estimated 400,000 children and adolescents under the age of 19 years develop cancer. Younger patients are at a higher risk of developing hearing loss with cisplatin treatment compared to older patients. Additionally, loss of hearing at a young age is associated with impaired communication, cognitive impairment, poorer mental health and quality of life. Despite the primary focus in cancer treatment being overall survival, there is a burgeoning interest in treating secondary effects, such as ototoxicity, which majorly affects the quality of life.
In 2018, the FDA had granted Pedmark a breakthrough orphan drug designation. Breakthrough therapy designations are granted to drugs that treat serious conditions with preliminary clinical evidence, indicating a substantial improvement on one or more clinically significant endpoints over available therapies.
The US agency had previously rejected Fennec’s approval bid twice due to issues related to the drug’s manufacturing facility. As per the 21 September press release, Fennec’s CEO Rosty Raykov aims to immediately capitalise on this FDA approval, stating, “Fennec anticipates Pedmark to have broad and favourable payer coverage across commercial and government payers, and across in-patient and out-patient settings.”
Pedmark clinical trials
Fennec Pharmaceuticals assessed Pedmark in the two multicentre clinical trials SIOPEL 6 (NCT00652132) and COG ACCL0431 (NCT00716976). These open-label, randomized clinical trials were done in patients under 18 years of age. In the most recent Phase III ACCL0431 trial, 125 participants were given Pedmark or put on observation. Of the 104 assessable patients, hearing loss was identified in 26.8% of the participant group compared to 56.4% of the control group. Furthermore, the likelihood of hearing loss was much lower in the Pedmark group compared with the control group.
Fennec’s other Phase III trial SIOPEL 6, enrolled 116 participants with stage I, II and III childhood liver cancer to test Pedmark’s effects on the incidence of hearing loss and to investigate whether it would jeopardise the survival rates associated with cisplatin therapy. This trial assigned patients with either cisplatin alone or a cisplatin and Pedmark combination over a 15-month period. Out of the 109 evaluable patients, hearing loss occurred in 33% of patients in the Pedmark combination-treated group compared to an incidence of 63% in the cisplatin-alone group. Furthermore, after a 52 month-follow up, the three-year rates of event-free survival were 82% in the cisplatin-Pedmark group compared to 79% in the cisplatin-alone group.
The therapeutic landscape
Different therapies are being investigated for the treatment of cisplatin induced ototoxicity. The National Institute on Deafness and Other Communication Disorders (NIDCD) is currently recruiting patients for a Phase III trial (NCT04915183) investigating the effects of atorvastatin within the indication. The study aims to recruit 414 participants and who have head and neck cancer. This study will investigate the effects of the drug in participants who are 18 years or older.
The French company Sensorion is developing its own otoprotective agent for use with cisplatin therapy, indicated for paediatric patients. Sensorion’s SENS-401 (Arazasetron) exhibits vestibuloprotective activity—or protective of the vestibular system responsible for coordinating head and eye movements. A Phase II trial for patients with a severe or profound sensorineural hearing loss with the same drug failed at the beginning of the year. Currently, the company is seeking an amendment approval to assess the drug in a proof of concept clinical trial for cisplatin-induced ototoxicity with a decision expected by year’s end.
Following the approval, Raykov said,“The FDA approval of Pedmark represents an important breakthrough for paediatric patients with localized, non-metastatic solid tumours at risk for cisplatin-induced hearing loss.”
Furthermore, Fennec is looking to expand the drug’s scope with sodium thiosulfate currently under evaluation by the European Medicines Agency (EMA) under the tradename PEDMARQSI. The company also plans to initiate regulatory filings in select countries in the near future and plans to study Pedmark in more types of paediatric tumours.