FDA Approval Sought for Avasopasem for Radiotherapy-Induced Severe Oral Mucositis in Head and Neck Cancer

Galera Therapeutics, Inc. has submitted a new drug application (NDA) to the FDA that is seeking the approval ofavasopasem manganese (GC4419) for radiotherapy-induced severe oral mucositis (SOM) in patients with head and neck cancer who are undergoing standard treatment.¹

The application is supported by data from a total of 678 patients enrolled to the phase 2b GT-201 (NCT02508389) and the phase 3 ROMAN (NCT03689712) trials.

Findings from the phase 2b trial showed a significant reduction in SOM duration with 90 mg of avasopasem vs placebo, at a median of 1.5 days vs 19 days (P = .024).² SOM incidence was also improved with avasopasem vs placebo, at 43% vs 65%, respectively (P = .009); this was true for SOM severity, with grade 4 incidences of 16% and 30%, respectively (P = .045). Investigators sought to confirm these data in ROMAN.

Data from ROMAN, presented during the 2022 ASCO Annual Meeting, demonstrated a significant reduction in the incidence of SOM.³ Specifically, through the course of intensity-modulated radiation therapy (IMRT), the incidence rate of SOM was 54% in those who received avasopasem (n = 241) vs 64% in those who were given placebo (n = 166; relative risk [RR], 0.84; P = .045), meeting the primary end point of the trial.

When avasopasem was given before IMRT, patients experienced a 56% reduction in median days of SOM (18 days vs 8 days, respectively; P = .002). These patients also had a 27% reduction in grade 4 incidence of SOM (33% vs 24%; P = .052) and a 24% reduction in the mean number of days of grade 4 incidence (7.2 days vs 5.5 days; P = .143).

“With submission of this NDA, we achieved an important milestone toward our goal of transforming radiotherapy, potentially bringing patients with head and neck cancer the first approved drug for SOM and relief from its tremendous burden,” Mel Sorensen, MD, president and chief executive office of Galera Therapeutics, stated in a press release.

Avasopasem manganese is a selective small molecule dismutase mimetic that is designed to protect normal cells from radiation but not cancer cells; the agent does this by converting radiation-induced superoxide, which initiates the tissue damage and inflammatory cascade that results in oral mucositis, into hydrogen peroxide.

ROMAN enrolled patients with squamous cell carcinoma of the head and neck who were at least 18 years of age and had a plan to receive IMRT in single daily fractions of 2.0 to 2.2 Gy with a cumulative radiation dose of 60 to 62 Gy in combination with standard cisplatin treatment. Patients were required to have an ECOG performance status of 0 to 2 and acceptable hematologic, renal, and liver function.

Study participants were randomly assigned 3:2 to receive avasopasem at 90 mg or placebo as a 60-minute infusion, Monday to Friday, for 7 weeks, before radiation. Stratification factors included surgery status (post-operative vs definitive) and cisplatin schedule (every 3 weeks vs weekly).

The primary end point of the trial was incidence of SOM through IMRT, and secondary end points included total number of days of SOM and incidence and total number of days of grade 4 SOM. Additional end points of interest comprised safety and tolerability, as well as tumor outcomes at 1 to 2 years.

In the avasopasem arm, 80% had oropharyngeal disease, 16% had disease in the oral cavity, and 4% had it in an unknown place; these rates were 85%, 13%, and 2%, respectively, in the placebo arm. Most patients across the investigative and control arms had human papillomavirus (80% vs 81%, respectively). Eighty-one percent of patients in both arms had definitive surgery; 19% of those in both arms had post-operative treatment. Cisplatin was given every 3 weeks in 42% and 45% of patients, respectively, and weekly in 58% and 55% of patients, respectively.

Additional data from the trial showed that full courses of avasopasem showcased greater SOM incidence reduction.

When avasopasem was administered at a dose of 90 mg, it was noted to be generally well tolerated, with findings consistent with what had previously been reported in the phase 2b trial. The most common toxicities included lymphopenia, nausea, fatigue, oropharyngeal pain, constipation, dysgeusia, dry mouth, radiation skin injury, vomiting, decreased weight, leukopenia, dysphagia, dehydration, reduced appetite, neutropenia, headache, tinnitus, and oral candidiasis.

The most common grade 3 or higher adverse effects were lymphopenia, leukopenia, and neutropenia.

“Our 2 rigorous, placebo-controlled trials which enrolled nearly 700 patients give us confidence that avasopasem has the potential to provide meaningful clinical benefit for patients by reducing SOM incidence, days, and severity while also delaying its onset,” Sorensen added in the press release. “We look forward to working closely with the FDA during the review process.”

References

1. Galera submits new drug application for avasopasem for severe oral mucositis. News release. Galera Therapeutics. December 12, 2022. Accessed December 12, 2022. https://bit.ly/3FLxgpR
2. Anderson CCM, Lee CM, Saunders DP, et al. Phase IIb, randomized, double-blind trial of GC4419 versus placebo to reduce severe oral mucositis due to concurrent radiotherapy and cisplatin for head and neck cancer. J Clin Oncol. 2019;37(34):3256-3265. doi:10.1200/JCO.19.01507
3. Anderson CM, Lee CM, Kelley Jr, et al. ROMAN: phase 3 trial of avasopasem manganese (GC4419) for severe oral mucositis (SOM) in patients receiving chemoradiotherapy (CRT) for locally advanced, nonmetastatic head and neck cancer (LAHNC). J Clin Oncol.2022;40 (suppl 16):abstr 6005. doi:10.1200/JCO.2022.40.16_suppl.6005