avasopasem (GC4419) / Biossil, Obsidian - LARVOL DELTA

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

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

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

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

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

APPROVED AND EMERGING OPTIONS FOR ONCOLOGY TREATMENT-RELATED TOXICITIES: A TARGETED LITERATURE REVIEW OF THE LANDSCAPE AND REMAINING UNMET NEEDS (ISPOR 2026) - "Agents were cataloged by intended use: (a) rescue therapies for acute overdose or early severe toxicity (e.g., glucarpidase, uridine triacetate, leucovorin rescue); (b) prophylactic organ-protective agents (e.g., mesna, amifostine, dexrazoxane, sodium thiosulfate, palifermin, trilaciclib); (c) countermeasures for immune-mediated toxicities (e.g., tocilizumab for cytokine release syndrome); and (d) radiation normal-tissue protectants in development (e.g., superoxide dismutase mimetics, avasopasem [GC-4419]). Across drug classes, agents demonstrated substantial clinical benefit in narrow, time-sensitive indications (e.g., rescue for high-dose methotrexate or fluoropyrimidine toxicity; cardioprotection with dexrazoxane; otoprotection with sodium thiosulfate in pediatric cisplatin-treated patients; and reduced mucositis with palifermin in select HSCT regimens)... Timely rescue administration can improve outcomes for patients experiencing severe treatment-related toxicities...."

Review • Bone Marrow Transplantation • Cardiovascular • Inflammation • Mucositis

Obsidian Therapeutics and Galera Therapeutics Announce Merger Agreement and $350 Million Concurrent Private Placement (Businesswire) - "In support of the transaction, Galera and Obsidian have secured commitments for an oversubscribed private placement financing that is expected to result in total gross proceeds of $350 million..The combined company’s cash and cash equivalents balance at closing, including the funds from the private placement financing, is anticipated to fund the combined company’s operations into the second half of 2028 and provides runway through key clinical milestones for Obsidian’s lead product candidate, OBX-115. These include Phase 1 data from the ongoing NSCLC trial expected in the first half of 2027, and by year-end 2027, topline data from their melanoma registration-enabling trial. The combined company will also continue to support Galera’s pipeline."

M&A • P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Melanoma • Non Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer

Avasopasem manganese acts as both a radioprotector and a radiomitigator of radiation-induced acute or late effects. (PubMed, Front Oncol) - "However, AVA's effect on fibrosis decreased as the time between irradiation and post-irradiation AVA application increased. These studies confirm the efficacy of AVA as a radioprotector and mitigator of both radiation-induced acute and late effects after high dose per fraction exposures while not protecting tumor cells to radiation exposure."

Journal • Fibrosis • Gastrointestinal Disorder • Immunology • Lung Cancer • Mucositis • Oncology • Respiratory Diseases • Solid Tumor • Stomatitis

Clinical evidence for managing radiotherapy-induced oral mucositis and xerostomia in head and neck cancer patients: a review of Phase III-IV trials. (PubMed, Int J Oral Maxillofac Surg) - "For oral mucositis, effective pharmacological agents included palifermin, avasopasem manganese, doxepin, morphine mouthwash, and gabapentin, while non-pharmacological options such as low-level laser therapy, honey, and Aloe vera showed additional benefit in reducing severity and improving healing. In managing radiotherapy-induced xerostomia, pilocarpine, amifostine, and cevimeline significantly enhanced salivary function, with adaptive radiotherapy techniques offering protective effects on the salivary glands...Although several interventions demonstrated promising clinical efficacy, the heterogeneity in study design, outcome measures, and follow-up duration limits definitive conclusions. Therefore, customized, evidence-driven approaches informed by existing recommendations and developed data are crucial for enhancing outcomes and reducing the burden of therapy-induced toxicities in head and neck cancer patients."

Journal • P3 data • Review • Dental Disorders • Head and Neck Cancer • Mucositis • Oncology • Oral Cancer • Solid Tumor • Stomatitis • Xerostomia

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