FDA Rejects NDA for Avasopasem in RT-Induced Severe Oral Mucositis

• Data supporting the new drug application (NDA) for avasopasem manganese are sifficent to support approval, according to the FDA.

• Galera Therapeutics is planning a Type A meeting with the FDA to discuss how to get the agent approved for the propsed indication in the future.

• This news comes after prior fast track, breakthrough therapy, and priority review designation granted for the agent by the FDA.

The FDA has issued a complete response letter regarding the new drug application (NDA) for avasopasem manganese (GC4419) for the treatment of radiotherapy-induced severe oral mucositis (SOM) in patients with head and neck cancer who are receiving standard-of-care treatment.¹

The FDA previously granted a priority review to the NDA, based on the results of the phase 2b GT-201 (NCT02508389) and phase 3 ROMAN (NCT03689712) trials, which led to a significant reduction in the median duration of SOM at 1.5 days compared with placebo at 19 days (P =.024) in the phase 2 trial and lowered the incidence rate in the phase 3 study to 54% vs 64% (relative risk, 0.84; P =.045), respectively.² However, the CRL stated that data from these trials were not substantial enough to prove avasopasem’s efficacy and safety in reducing SOM in patients. The FDA wrote that another clinical trial will be needed for resubmission of the NDA.¹

In a press release, developer of avasopasem, Galera Therapeutics, announced an upcoming Type A meeting with the FDA to discuss a path forward for the drug. The company also plans to sign into partnership with other companies to continue the development of development of avasopasem and another drug, rucosopasem manganese (GC4711).

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“Oral mucositis is a common painful and debilitating side effect from head and neck radiation therapy. Avasopasem will decrease the incidence, and more importantly, the duration of severe oral mucositis. This drug has the potential to significantly decrease patient suffering from treatment side effects,” Carryn Anderson, MD, clinical associate professor of cancer and radiation oncology at University of Iowa Hospitals & Clinics told Targeted Oncology^TM.

The selective small molecule dismutase mimetic is an agent designed to protect normal cells from radiation therapy by converting radiation-induced superoxide into hydrogen peroxide. In the phase 2 study, the results confirmed that this method protected patients from radiotherapy-induced SOM without negating treatment benefits for patients with head and neck cancer.

The GT-201 study enrolled 223 patients with locally advanced head and neck cancer and had been given at least 7 weeks of standard-of-care radiotherapy plus cisplatin.² After randomizing patients with either 30 mg of avasopasem, 90 mg of avasopasem, or placebo they found the 90 mg of the agent to be the optimal dose. This led to the ROMAN trial which enrolled 455 patients and randomized patients 3:2 to avasopasem or placebo. However, the primary endpoint of the ROMAN study was cumulative incidence of SOM from the first intensity-modulated radiation therapy (IMRT) fraction until the end of the study treatment periods.³

The results of the ROMAN study showed that by givingavasopasem at prior to IMRT patients had a 56% reduction in the median duration of their SOM compared with placebo at 8 vs 18 days, respectively (P  =.002).³ Moreover, they had a 27% reduction in the incidence of grade 4 SOM (P =.052) and a 34% reduction in the mean number of days of grade 4 SOM incidence at 7.2 vs 5.5 days (P =.143).

Safety signals with avasopasem were consistent with previous reporting and no new safety signals were found.

“This response from the FDA is deeply disappointing for Galera and for patients who suffer from severe oral mucositis,” said Mel Sorensen, MD, president and chief executive officer of Galera Therapeutics, in the press release.¹ “We continue to believe in avasopasem’s potential to bring a meaningful benefit to these patients, who currently have no FDA-approved drugs for this debilitating condition.”

Despite the FDA decision, some are hopeful that the drug will be available for use in the future.

"I am looking forward to incorporating it into my clinical practice," said Anderson.

_Reference:

_{1. Galera receives complete response letter from U.S. FDA for avasopasem manganese. News release. Galera Therapeutics. August 9, 2023. Accessed August 9, 2023. https://tinyurl.com/4xzyjp3w}

_{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 CMm Lee C<, Kelley J, 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(16):6005-6005. doi:10.1200/JCO.2022.40.16_suppl.6005}