TRANSFORMING RADIATION THERAPY

Our small-molecule dismutase mimetics are designed to accelerate the conversion of superoxide to hydrogen peroxide, which may be key to reducing treatment-related side effects and increasing the anti-cancer efficacy of these treatments.

The metabolic processing of superoxide is a critical cellular function and part of the broader oxygen metabolic pathways that keep cells functioning. While oxygen metabolic pathways are involved in a host of diseases, Galera is focused on transforming radiation therapy in patients with cancer to both reduce the side effects of radiation therapy and enhance the therapeutic effect.


 

DISMUTASE MIMETICS

Learn more about our pipeline, including GC4419, an investigational drug candidate for the reduction of the incidence, duration, and severity of radiation and chemotherapy-induced oral mucositis (OM).

Superoxide, a highly reactive molecule, is produced by every cell as a part of normal metabolism, but left uncontrolled it is highly toxic, leading to cell damage or cell death. To prevent this, the body produces superoxide dismutase enzymes, or SODs, which convert superoxide to hydrogen peroxide. Hydrogen peroxide is much less toxic than superoxide to normal tissue, but more toxic to cancer cells. Radiotherapy induces a large burst of superoxide in the irradiated tissues, which can overwhelm these SODs, damaging normal cells. Such damage to the oral mucosa, located in the mouth, is referred to as oral mucositis, or OM.

Drugs that mimic native SODs could address the inability of SODs to keep up with the superoxide bursts produced by radiotherapy. The challenge has been finding small molecule dismutase mimetics with similarly fast catalytic rates and high selectivity for superoxide that are also stable, and suitable for manufacturing. We have designed, and are developing, our dismutase mimetics to have these essential features.


Radiotherapy-induced OM

Oral mucositis occurs when radiotherapy induces the production of superoxide, which attacks and breaks down the epithelial cells lining the mouth. Severe oral mucositis, or SOM, is commonly defined as occurring when patients have ulcers and are unable to swallow solid food, or in the most severe form, oral alimentation (solid or liquid) is not possible.

SOM can lead to devastating complications, including:

  • Dehydration and malnutrition. Approximately 70% of patients with head and neck cancer, or HNC, receiving radiotherapy become unable to eat, drink, or both.
  • Treatment interruption. SOM can require a reduction or delay in radiotherapy, potentially leading to poorer clinical outcomes.
  • Increased economic burden. Based on an analysis of medical insurance claims, HNC patients treated with radiotherapy who developed OM incurred, on average, approximately $32,000 in additional medical expenses in the first six months from the start of radiotherapy compared to patients who did not develop OM.1

It is estimated that approximately 70% of locally advanced HNC patients being treated with the standard of care radiotherapy will develop SOM and between 20% to 30% will develop the most severe type, limiting the patient’s ability to eat or drink. 

Disarming OM

Superoxide plays key role in oral mucositis (OM)

Radiotherapy causes direct damage to the oral mucosa, at least in part via superoxide generated directly by radiation and by activation of superoxide-producing enzymes shortly thereafter. This damage then activates pathways—which may also involve excessive superoxide—all of which combine to result in mucositis.

As this damage accumulates with successive radiation doses, OM can progress until it becomes severe. If severe OM occurs early enough during the course of radiotherapy, or if it is prolonged or becomes even more severe, aggressive management is required including potentially interrupting or even ending radiotherapy.

Conversion of superoxide to hydrogen peroxide

Our dismutase mimetics are designed to convert the bursts of superoxide induced by radiotherapy to hydrogen peroxide, which is then converted to oxygen and water. In pre-clinical studies, they significantly reduced the immediate and long-term radiation damage to normal tissue in a variety of organs.2,3

Based on these results and the central role of superoxide in the process of OM, we are currently studying our dismutase mimetics in clinical trials to investigate their potential to reduce SOM in patients with Head and Neck Cancer.


 

AIMING TO INCREASE EFFICACY OF RADIATION THERAPY

Harnessing the Anticancer Power of Hydrogen Peroxide

As cancer cells are more susceptible than normal cells to increased levels of hydrogen peroxide, we believe the conversion of radiation-generated superoxide to hydrogen peroxide by our selective dismutase mimetics can improve outcomes for patients who receive radiation therapy.


In preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), our selective dismutase mimetics increased anticancer activity of high daily doses of radiation therapy similar to those used in SBRT for patients with cancer.

PANC-1 PDAC Xenografts - Slide 1
PANC-1 PDAC Xenografts - Slide 2 showing Control line
PANC-1 PDAC Xenografts - Slide 3 showing DM line
PANC-1 PDAC Xenografts - Slide 4 showing RT line
PANC-1 PDAC Xenografts - Slide 5 showing DM + RT line

H1299 NSCLC Xenografts - Slide 1
H1299 NSCLC Xenografts - Slide 2 showing Control line
H1299 NSCLC Xenografts - Slide 3 showing DM line
H1299 NSCLC Xenografts - Slide 4 showing RT line
H1299 NSCLC Xenografts - Slide 5 showing DM + RT line

 

Activity of radiation therapy is significantly enhanced by selective dismutase mimetics in cancer preclinical models.

 

Preclinical studies of mechanism show that our selective dismutase mimetics synergize with SBRT by generating hydrogen peroxide. For example, when tumors are genetically engineered to make catalase, which removes hydrogen peroxide, the boost in SBRT efficacy is no longer seen.

H12299Cat NSCLC Mouse Model - Slide 1
H12299Cat NSCLC Mouse Model - Slide 2 showing vehicle line growth
H12299Cat NSCLC Mouse Model - Slide 3 showing DM line growth
H12299Cat NSCLC Mouse Model - Slide 4 showing Gy x 1 RT line growth
H12299Cat NSCLC Mouse Model - Slide 5 showing RT + catalase line growth
H12299Cat NSCLC Mouse Model - Slide 6 showing DM + RT + catalase line growth
H12299Cat NSCLC Mouse Model - Slide 7 showing DM + RT line growth
H12299Cat NSCLC Mouse Model - Slide 8 highlighting difference between DM + RT and DM + RT + catalase

 

Aiming to Transform Outcomes for Patients With Locally Advanced Pancreatic Cancer

Pancreatic cancer incidence is rising, and this tumor is expected to become the second leading cause of cancer-related death in the United States by 2030.5 Over 60,000 people in the United States are estimated to be diagnosed with pancreatic cancer in 2021, and only 1 in 10 patients is expected to survive 5 years after diagnosis.6 Novel therapies to improve survival for patients with pancreatic cancer are needed.

Stereotactic body radiation therapy (SBRT) is increasingly used for locally advanced pancreatic cancer, which is less responsive to small daily doses of radiation therapy. SBRT is typically given in 3 to 5 large fractions.  Even with the use of SBRT, the opportunity for improvement in treatment outcomes is substantial.7

In a pilot Phase 1/2 trial, patients with locally advanced pancreatic cancer were randomized to receive SBRT plus either placebo or a rucosopasem analogue. This trial appears to demonstrate acceptable safety in combination with SBRT (10-11 Gy x 5), as well as suggesting improvements in overall survival, progression-free survival, locoregional control, and time to distant metastases. These data support the hypothesis currently being tested in the GRECO-2 trial, that rucosopasem may improve overall survival in combination with SBRT compared to SBRT alone.8

Group Chart - Slide 1 - OS / PFS / Locoregional Control / Distant Metastases Control
Group Chart - Slide 2 - showing line for Placebo + RT in all 4 charts
Group Chart - Slide 3 - showing line for DM + RT in all 4 charts

Click to enlarge.

Minimum 12-month follow-up on all patients. DMC and LRC defined as distant metastasis or local regional progression, not censored for treatment post SBRT.

Rucosopasem combined with SBRT is being studied as it may improve survival in patients with locally advanced pancreatic cancer.

 


 

SELECT PUBLICATIONS

Sishc, et al., Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide Science Translational Medicine 12 May 2021:Vol. 13, Issue 593


Steinbach, et al., Effects of GC4419 (avasopasem manganese) on chronic kidney disease in head and neck cancer patients treated with radiation and cisplatin. J Clin Oncol 2020;38(suppl; abstr 12071); doi: 10.1200/JCO.2020.38.15_suppl.12071, ACSO, May 29, 2020.


C. M. Anderson, C. M. Lee, D. Saunders, et al., “Tumor Outcomes of 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.” Multidisciplinary Head and Neck Cancer symposium, Scottsdale, Arizona, February 27-29, 2020.


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

Carryn M. Anderson, Christopher M. Lee, Deborah P. Saunders, Amarinthia Curtis, Neal Dunlap, Chaitali Nangia, Arielle S. Lee, Sharon M. Gordon, Philip Kovoor, Roberto Arevalo-Araujo, Voichita Bar-Ad, Abhinand Peddada, Kyle Colvett, Douglas Miller, Anshu K. Jain, James Wheeler, Dukagjin Blakaj, Marcelo Bonomi, Sanjiv S. Agarwala, Madhur Garg, Francis Worden, Jon Holmlund, Jeffrey M. Brill, Matt Downs, Stephen T. Sonis, Sanford Katz, and John M. Buatti

Journal of Clinical Oncology 2019 37:34, 3256-3265


Brock, et al., The radioprotector GC4419 ameliorates radiation induced lung fibrosis while enhancing the response of non-small cell lung cancer tumors to high dose per fraction radiation exposures. ASTRO 2018, Henry B. Gonzalez Convention Center, San Antonio, Texas, October 21 – 24, 2018.


 

References:

  1. Hoffbauer M, Fineberg J, Stattenfield R, Holmlund J. Cost of radiation-induced oral mucositis in head and neck cancer patients: an administrative claims analysis. JMCP October 2020;26(10-a Suppl):S31 (abs C48).
  2. Thompson JS, Chu Y, Glass J, Tapp AA, Brown SA. The manganese superoxide dismutase mimetic, M40403, protects adult mice from lethal total body irradiation. Free Radic Res. 2010;44(5):529-540.
  3. Coleman MC, Olivier AK, Jacobus JA, et al. Superoxide mediates acute liver injury in irradiated mice lacking sirtuin 3. Antioxid Redox Signal. 2014;20(9):1423-1435.
  4. Sishc BJ, et al. Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide. Sci Transl Med. 2021;13(593):eabb3768.
  5. Rahib L, et al. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Clin Cancer Res. 2014;74(11):2913-2921.
  6. American Cancer Society. Cancer Facts & Figures 2021. Atlanta: American Cancer Society; 2021.
  7. Ghaly M, Gogineni E, Herman J, Saif MW. New potential options for SBRT in pancreatic cancer. Cancer Med J. 2021 March;4(Suppl 3): 41–50.
  8. Galera Therapeutics, Inc. Galera announces final results from pancreatic cancer trial showing improvements on all efficacy parameters. Press Release. September 8, 2021. Accessed December 21, 2021. https://investors.galeratx.com/news-releases/news-release-details/galera-announces-final-results-pancreatic-cancer-trial-showing

 

Investigational Drugs – Not for Commercial Distribution