avasopasem (GC4419) / Galera Therap, Biossil - LARVOL DELTA

GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer. (ASCO 2022) - P2b | "In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT...Materials/ GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet...Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial is now enrolling."

Clinical • Combination therapy • P2 data • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CA 19-9

Randomized, Double-Blinded, Placebo-controlled Multicenter Adaptive Phase 1-2 Trial of GC 4419, a Dismutase Mimetic, in Combination with High Dose Stereotactic Body Radiation Therapy (SBRT) in Locally Advanced Pancreatic Cancer (PC). (PubMed, Int J Radiat Oncol Biol Phys) - No abstract available

Clinical • Combination therapy • Journal • P1/2 data • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

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). (ASCO 2022) - P3 | "Funded by: Pharmaceutical/Biotech Company. AVA produced statistically significant, clinically meaningful improvement of SOM vs PBO that was consistent across multiple measures of SOM, and was well tolerated, with an adverse event profile consistent with expectations for IMRT/cisplatin in LAHNC."

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

Tumor Outcomes for ROMAN: Phase 3 Trial of Avasopasem Manganese (GC4419) for Severe Oral Mucositis (SOM) in Patients Receiving Chemoradiotherapy (CRT) for Locally Advanced Head and Neck Cancer (LAHNC) (ASTRO 2022) - P3 | "Screens: N/A/3Purpose/Objective(s): Intensity-modulated radiotherapy (IMRT) plus cisplatin is an established treatment for LAHNC, but ~70% of patients develop SOM (WHO grade [gr] 3 or 4), limiting their ability to eat solids (gr 3) or liquids (gr 4), and often requiring feeding tube nutrition. 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. Tumor outcomes will be reported"

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

Single cell transcriptomic sequencing of pancreatic ductal adenocarcinoma reveals an enrichment of immunosuppressive pathways in patients at high risk for early local progression following stereotactic body radiation therapy (AACR 2023) - "In order to identify these potential nodes of therapeutic actionability, we leveraged a phase I/II dose escalation clinical trial of SBRT with a radiomodulating agent, GC4419, undertaken in patients with locally advanced PDAC...This has revealed an interplay between members of the tumor microenvironment whereby immunosuppressive pathways appear to prevail over immunostimulatory signals in nonresponders. Understanding which pathways are enriched in those patients at highest risk for local recurrence may provide insight into novel therapeutic strategies that can be implemented concurrently with radiation therapy."

Clinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • CD4

Breaking the Vicious Cycle: Avasopasem Manganese Disrupts ER Stress-Oxidative Damage Crosstalk in Ischemic Cardiac Injury in Type 1 Diabetic Mice. (PubMed, Eur J Pharmacol) - "In the diabetic and ischemic mice, mRNA expression of ERS-related proteins (GRP78, PERK, IRE1, ATF4, XBP1, and Nrf2) was elevated but significantly reduced after AVA administration. AVA treatment improved cardiac outcomes by reducing OS and inflammation and downregulating ERS-related protein expression in diabetic and ischemic mice."

Journal • Preclinical • Diabetes • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus • ATF4 • CASP1 • CASP12 • CAT • ERN1 • HSPA5 • MPO • XBP1

Clinical Trial of Avasopasem in Patients With Metastatic Hormone Receptor Positive Breast Cancer With Progression on a CDK 4/6 Inhibitor and Hormonal Therapy (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Not yet recruiting ➔ Recruiting | Trial completion date: Jul 2028 ➔ Oct 2028 | Trial primary completion date: Jul 2027 ➔ Oct 2027

Enrollment open • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Avasopasem manganese treatment for severe oral mucositis from chemoradiotherapy for locally advanced head and neck cancer: phase 3 randomized controlled trial (ROMAN). (PubMed, EClinicalMedicine) - P3 | "Of patients who receive standard concomitant chemoradiation (CRT; intensity-modulated radiation therapy [IMRT] plus cisplatin) for locally advanced head and neck cancer (HNC), approximately two-thirds will develop severe oral mucositis (SOM), limiting their ability to eat solids (WHO grade 3) or drink liquids (WHO grade 4). A confirmatory phase 3 trial was requested. Provided by Galera Therapeutics, Inc."

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

Galera has entered into an Asset Purchase Agreement with Toronto-based Biossil for Galera’s dismutase mimetics portfolio, including all avasopasem and rucosopasem formulations and indications. (The Manila Times) - "The agreement includes 1) an upfront payment of $3.5 million, 2) potential future regulatory milestones, commercial milestones, and contingent value rights of up to $105 million."

Commercial • Pancreatic Cancer

Avasopasem Manganese Shows Potential to Reduce High-Risk Carotid Plaque in Patients With Head and Neck Cancer Undergoing Chemoradiation Therapy: A Post Hoc Analysis of 2 Randomized Trials. (PubMed, J Am Heart Assoc) - No abstract available

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Head and Neck Cancer • Oncology • Solid Tumor

Clinical Trial of Avasopasem in Patients With Metastatic Hormone Receptor Positive Breast Cancer With Progression on a CDK 4/6 Inhibitor and Hormonal Therapy (clinicaltrials.gov) - P1 | N=35 | Not yet recruiting | Sponsor: The University of Texas Health Science Center at San Antonio

New P1 trial • Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Protective effects of avasopasem manganese (GC4419) against sepsis-induced acute lung injury: A comprehensive experimental study. (PubMed, Eur J Clin Invest) - "AVA demonstrated a significant protective effect against sepsis-induced lung injury through its antioxidant and anti-inflammatory properties. The most effective dose was determined to be 10 mg/kg. These findings suggest the potential use of AVA as an adjunctive agent in sepsis treatment."

Journal • Acute Lung Injury • Infectious Disease • Oncology • Respiratory Diseases • Septic Shock • CAT • IL1B • IL6 • TNFA

Addressing Pain in Oral Mucositis: Narrative Review of Current Practices and Emerging Treatments. (PubMed, J Pain Res) - "Given the debilitating nature of OM in cancer patients and the critical need for effective pain control, this review aims to examine pharmacological advancements targeting the complex nature of OM-related pain, including agents such as lidocaine, doxepin, benzydamine, methylene blue, opioids, gabapentin, palifermin, caphosol, and ketamine...This review highlights the clinical applicability of emerging therapies, such as avasopasem manganese, which has demonstrated efficacy in mitigating OM progression...Addressing the multifaceted nature of OM-associated pain is essential for enhancing quality of life and optimizing cancer treatment outcomes. Further research is needed to establish robust, evidence-based guidelines for OM pain management."

Journal • Review • Bone Marrow Transplantation • Head and Neck Cancer • Infectious Disease • Mucositis • Oncology • Oral Cancer • Pain • Solid Tumor • Stomatitis • Transplantation

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