avasopasem (GC4419) / Galera Therap - LARVOL DELTA

Managing strategies of chemotherapy and radiotherapy-induced oral mucositis. (PubMed, Cancer Treat Rev) - "For example, clinical trials assessing established drugs such as melatonin, clonidine, and pentoxifylline indicate promising potential for managing OM. Besides, Verbascoside, Palifermin, Amifostine, and Avasopasem manganese can be suggested for OM management, while the side effects should be monitored. The accessibility and cost/effectiveness of specific managing strategies of OM should be considered when selecting appropriate options."

Clinical • Journal • Review • Head and Neck Cancer • Mucositis • Oncology • Solid Tumor • Stomatitis

Galera Therapeutics completes acquisition of Nova Pharmaceuticals (GlobeNewswire) - "Galera’s new lead program is the Investigator-sponsored Phase 1/2 trial of a pan-NOS Inhibitor on top of standard-of-care nab-paclitaxel and alpelisib in metaplastic breast cancer. The Company’s cash balance at closing is anticipated to fund operations into 2026 and through data readout from its lead program in metaplastic breast cancer. A second trial is planned for this agent in TNBC in collaboration with the I-SPY 2 consortium. The Company intends to support a third trial of Avasopasem, one of its small molecule dismutase mimetics, in patients with hormone-receptor positive (HR+) advanced breast cancer who have become resistant to conventional therapy. This trial is expected to commence enrollment in the first half of 2025."

M&A • New trial • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer

Benefit of Avasopasem Manganese on Severe Oral Mucositis in Head and Neck Cancer in the ROMAN Trial: Unplanned Secondary Analysis. (PubMed, Adv Radiat Oncol) - "Oral mucositis (OM) is a debilitating side effect of cisplatin and intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. All outcomes contributed to NTB, reflecting improvements in SOM incidence, onset and duration, and in grade 4 OM incidence seen in the original ROMAN analysis. This GPC analysis shows compelling evidence from the ROMAN trial of AVA's clinical benefit across key parameters of SOM burden."

Journal • Head and Neck Cancer • Mucositis • Oncology • Solid Tumor • Stomatitis

Galera Announces Final Results from Pancreatic Cancer Trial Showing Improvements on all Efficacy Parameters (GlobeNewswire) - P1/2, N=42; NCT03340974; Sponsor: Galera Therapeutics; "Galera Therapeutics...announced final results from its Phase 1/2 pilot trial of its dismutase mimetic, GC4419, versus placebo, in patients with unresectable or borderline resectable locally advanced pancreatic cancer (LAPC), who are undergoing stereotactic body radiation therapy (SBRT). The results include a minimum of one year of follow up on all 42 patients enrolled in the trial....In this proof-of-concept trial, improvements were observed in overall survival (HR=0.48; 95% CI: 0.20-1.14; p=0.090), progression-free survival (HR=0.46; 95% CI: 0.22-0.98; p=0.040), local tumor control (HR=0.30; 95% CI: 0.08-1.10; p=0.055) and time to distant metastases (HR=0.39; 95% CI: 0.16-0.93; p=0.028)."

P2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Exploring the Role of Reactive Oxygen Species in the Pathogenesis and Pathophysiology of Alzheimer's and Parkinson's Disease and the Efficacy of Antioxidant Treatment. (PubMed, Antioxidants (Basel)) - "Taken together, antioxidant treatment is a promising avenue in neurodegenerative disease therapy and subsequent clinical trials are needed to provide a definitive answer on the protective effects of antioxidants. No current treatment strategies have significant impact in treating advanced AD and PD, but new mimetics of endogenous mitochondrial antioxidant enzymes (Avasopasem Manganese, GC4419 AVA) may be a promising innovative option for decelerating neurodegenerative progress in the future at the mitochondrial level of OS."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CAT

Long-Term Tumor Outcomes in Patients with Head and Neck Cancer Treated with Avasopasem Manganese to Mitigate Severe Oral Mucositis: A Single Institution Retrospective Analysis (ASTRO 2024) - "Our study showed that among patients undergoing CRT for locoregionally advanced head and neck cancer, those who received AVA had similar long-term tumor outcomes compared to patients who received placebo. Regardless of treatment arm, patients with oral cavity primaries had worse outcomes compared to those with oropharyngeal primaries."

Retrospective data • Head and Neck Cancer • Mucositis • Oncology • Solid Tumor • Stomatitis

Analysis of Avasopasem Manganese on Swallowing Outcomes for Oropharynx and Oral Cavity Patients Following Chemoradiation - A Single Institution Report (ASTRO 2024) - "Radiation dose to pharyngeal constrictors differed by primary site and treatment arm in our study, which may impact assessment of AVA vs PBO on dysphagia outcomes. We had too few patients to statistically analyze the impact of AVA vs PBO on dysphagia but EAT-10 scores at approximately 1-month post-RT trended towards improvement with AVA. Later assessments with OPMS and PAS (3+ months) trended similar or worse in AVA group."

Clinical • Gastrointestinal Disorder • Head and Neck Cancer • Mucositis • Oncology • Solid Tumor • Stomatitis

Characterizing Radiation Induced Subclonal Kinetics in Pancreatic Ductal Adenocarcinoma (ASTRO 2024) - "Materials/ Tumor biopsies were acquired before and after SBRT as part of a phase I/II dose escalation clinical trial of SBRT (50-60Gy in 5 fx) with a radiomodulating agent, avasopasem manganese... Through longitudinal tumor biopsies, we were able to observe significant selection pressures on tumor subclones in PDAC following SBRT. This allowed us to identify molecular processes related to response to SBRT as well as TME modifications induced during adaptive pressures. Ultimately, identification of resistant and responsive populations may allow for characterization of novel targets for combinatory therapeutic intervention such as inhibition of KRAS related signaling."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • TNFA

Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing. (PubMed, Antioxidants (Basel)) - "Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs."

Journal • Fibrosarcoma • Fibrosis • Immunology • Leiomyosarcoma • Liposarcoma • Mucositis • Oncology • Respiratory Diseases • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Stomatitis • CAT • GPX1

Galera Reports First Quarter 2024 Financial Results and Recent Corporate Updates (GlobeNewswire) - "Research and development expenses were $1.5 million in the first quarter of 2024, compared to $7.3 million for the same period in 2023. The decrease was primarily attributable to a decrease in avasopasem and rucosopasem development costs. The Company has ceased all clinical trial activity and suspended the clinical development of its product candidates as it explores potential strategic alternatives."

Commercial • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Comparisons of successful and failed Phase III trials of drugs and biologicals tested for mitigation of oral mucositis in patients being treated with radiotherapy with or without concomitant chemotherapy for cancers of the head and neck. (PubMed, Drug Dev Res) - "Of the three successful Phase III trials, one investigated avasopasem manganese (Galera Therapeutics) and two examined palifermin (Amgen). The three failed trials included those evaluating dusquetide (Soligenix), iseganan hydrochloride (IntraBiotics Pharmaceuticals), and clonidine (Monopar Therapeutics). We found that differences in the level of sponsor funding, patient inclusion criteria including radiation source and concomitant chemotherapy regimen, and concordance of primary efficacy outcomes between Phase II and Phase III trials influenced outcomes. To properly design clinical trials for OM in HNC patients, it is important that researchers and sponsors take note of specific study characteristics associated with success or failure, particularly with Phase III trials where the risks and costs are the highest."

Clinical • Journal • P3 data • Head and Neck Cancer • Mucositis • Oncology • Oral Cancer • Solid Tumor • Stomatitis

Subgroup analysis of the benefit of avasopasem manganese on the incidence, severity, duration and onset of severe oral mucositis in ROMAN Phase 3 Trial (MHNCS 2024) - "Purpose/Objective(s): IMRT plus cisplatin is established treatment for LAHNC, but ~70% of patients develop severe oral mucositis (SOM; WHO grade 3 or 4), limiting their ability to eat solids (gr 3) or liquids (gr 4), and often requiring feeding tube nutrition. In this phase 3 randomized placebo-controlled trial, AVA markedly reduced SOM incidence, severity and duration, and delayed its onset, in patients treated definitively, but not postoperatively. Cisplatin schedule, HPV status and primary tumor type did not influence AVA benefit. Future trials of novel mucosal radioprotectant agents should consider that postoperative patients may experience SOM differently than definitive chemoradiation patients."

P3 data • Mucositis • Oncology • Stomatitis

Two-year intention-to-treat analysis for tumor outcome in patients treated with avasopasem for oral cavity and oral pharynx primaries (MHNCS 2024) - "Purpose/Objective(s): IMRT plus cisplatin (CRT) is established treatment for LAHNC, but ~70% of patients develop severe oral mucositis (SOM), often requiring feeding tube nutrition. Based on 2-year ITT analysis, AVA does not seem to have oncologic detriment in both low and high-risk patients compared to PBO. Both arms performed better than previously published data for a mixed OC/OP, HPV+/HPV- population."

Clinical • Mucositis • Oncology • Stomatitis

Generalized Pairwise Comparisons Method to Assess Total Severe Oral Mucositis Burden and Interventional Benefit in HNC (MHNCS 2024) - P2, P3 | "Two placebo (PBO)-controlled trials (phase 2b and phase 3 ROMAN) showed avasopasem manganese 90mg (AVA) significantly decreased individual endpoints of SOM incidence and duration, with nominal decrease in severity (WHO Gr 4 incidence) and delay in SOM onset. GPC method allows holistic analysis of SOM burden in HNC patients receiving concurrent cisplatin and IMRT. Phase 2b and ROMAN individual GPC analyses and integrated GPC meta-analysis show compelling evidence of AVA clinical benefit as a therapeutic for SOM."

Head and Neck Cancer • Mucositis • Stomatitis

The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury. (PubMed, Redox Biol) - P2, P3 | "Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation."

Clinical • Journal • Acute Kidney Injury • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease • ICAM1 • NOX4 • TNFA • VCAM1

Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants. (PubMed, Brain Commun) - "Antioxidant therapy is considered for age-related neurodegenerative diseases, and a new mimetic of a manganese superoxide dismutase, avasopasem manganese, is described and suggested as a putative treatment to reduce the oxidative stress that causes neurodegenerative disease. The aim of this narrative review is to explore the evidence that oxidative stress causes neurodegenerative damage and the role of antioxidant genes in inhibiting reactive oxygen species damage. Can the neuronal environment of oxidative stress, causing neuroinflammation and neurodegeneration, be reduced or reversed?"

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Toward Ablative SBRT for Nonmetastatic PDAC. (PubMed, Cancer Discov) - "Combining a superoxide dismutase mimetic, avasopasem manganese, with stereotactic body radiation therapy may enable safe delivery of higher than standard radiation doses for patients with nonmetastatic, inoperable pancreatic adenocarcinoma. The phase Ib/II findings also suggest improved outcomes with avasopasem's addition, although the trial wasn't designed to compare arms and a larger study is needed."

Journal • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial. (PubMed, Lancet Oncol) - P1/2, P2b | "SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results."

Journal • P1/2 data • P2 data • Acute Kidney Injury • Atrial Fibrillation • Cardiovascular • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immunology • Infectious Disease • Nephrology • Oncology • Pain • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pneumonia • Renal Disease • Respiratory Diseases • Septic Shock • Solid Tumor

Effects of Avasopasem Manganese on Cisplatin-Induced AKI and CKD (KIDNEY WEEK 2023) - "In patients with HNC receiving radiation plus high-dose cisplatin, AVA, a superoxide dismutase mimetic, was significantly associated with decreased incidence and severity of CKD, with a trend towards decreased incidence of grade 3+ acute renal AEs. AE profile was otherwise consistent with expectations for CRT."

Acute Kidney Injury • Chronic Kidney Disease • Head and Neck Cancer • Mucositis • Nephrology • Oncology • Renal Disease • Solid Tumor • Stomatitis

Galera Announces Receipt of Type A Meeting Minutes and Strategic Update (GlobeNewswire) - "Galera Therapeutics, Inc...announced that it has received official meeting minutes from the Type A meeting with the United States Food and Drug Administration (FDA) held September 28, 2023 in which the FDA reiterated the need for an additional Phase 3 trial of avasopasem manganese (avasopasem) for radiotherapy-induced SOM. The Company also decided to halt the Phase 2b GRECO-2 trial of rucosopasem manganese (rucosopasem) in patients with locally advanced pancreatic cancer (LAPC) and the Phase 1/2 GRECO-1 trial of rucosopasem in patients with non-small cell lung cancer (NCSLC), following a futility analysis of the GRECO-2 trial....In the Type A Meeting minutes, the FDA reiterated that results from an additional Phase 3 trial will be required to support resubmission of the Company’s New Drug Application (NDA) for avasopasem in radiotherapy-induced SOM."

FDA event • Trial termination • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Meta-analysis of two placebo-controlled trials of avasopasem manganese (AVA) in patients with locally advanced, head & neck cancer (LAHNC) (ESMO 2023) - P2, P3 | "Clinical trial identification GTI-4419-301, 13 July 2020 (NCT03689712). Conclusions AVA produced statistically significant, clinically meaningful improvement of SOM vs PBO that was consistent across multiple measures of SOM, with an adverse event profile consistent with expectations for IMRT/cisplatin. At 1-year follow-up, AVA appears to reduce cisplatin-related CKD in the study population."

Metastases • Retrospective data • Head and Neck Cancer • Oncology • Solid Tumor

ROMAN: Phase 3 Trial Investigating the Effects of GC4419 on Radiation Induced Oral Mucositis in Head/Neck Cancer Patients (clinicaltrials.gov) - P3 | N=455 | Completed | Sponsor: Galera Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Aug 2023

Metastases • Trial completion • Trial completion date • Head and Neck Cancer • Mucositis • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Stomatitis

Enhanced Peroxide Fluxes and Radiosensitization in Colorectal Tumors but Not Normal Enterocytes from the Combination of Superoxide Dismutase Mimetics and Pharmacological Ascorbate. (PubMed, Int J Radiat Oncol Biol Phys) - "Co-treatment with DMs and P-AscH selectively enhanced tumor radiosensitization by increasing oxygen consumption and H0 fluxes even in tumor models which are known to be resistant to oxidative stressors (HT29). In contrast, each agent conferred a radioprotective effect in the rectum. Combination therapy with DMs and P-AscH may represent a novel, potent approach to target dysregulated redox metabolism in colorectal tumors."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CAT

Enhanced Peroxide Fluxes and Radiosensitization in Colorectal Tumors but Not Normal Enterocytes from the Combination of Superoxide Disumutase Mimetics and Pharmacological Ascorbate (ASTRO 2023) - "Purpose/Objective(s): Selective superoxide dismutase mimetics (DMs), including GC4419 and GC4711, are radiation (RT) modulators which induce opposite effects in tumors and normal tissues and may be ideally suited for locally advanced rectal cancer. Co-treatment with DMs and P-AscH selectively enhanced tumor radiosensitization by increasing oxygen consumption and H 2 0 2 fluxes even in tumor models which are known to be resistant to oxidative stressors (HT29). In contrast, each agent conferred a radioprotective effect in the rectum. Combination therapy with DMs and P-AscH may represent a novel, potent approach to target dysregulated redox metabolism in colorectal tumors."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CAT

Galera Schedules Type A Meeting with FDA to Discuss Next Steps for Avasopasem (GlobeNewswire) - "Galera Therapeutics, Inc...announced that a Type A Meeting has been scheduled for September 28, 2023 with the U.S. Food and Drug Administration (FDA) regarding the Complete Response Letter (CRL) received for the Company’s New Drug Application (NDA) for avasopasem manganese (avasopasem). The FDA is expected to issue written meeting minutes approximately 30 days following the meeting....The Company intends to gain an understanding from the FDA of its evaluation of avasopasem for radiotherapy-induced severe oral mucositis (SOM) in patients with head and neck cancer undergoing standard-of-care treatment and next steps to support an NDA resubmission."

FDA event • Head and Neck Cancer • Mucositis • Oncology • Solid Tumor