About 50,000 people in the U.S. are diagnosed annually with head, neck, nasal and oral cancers. Most are treated with radiation, and of those, 70-80 percent develop a painful and debilitating side effect called severe oral mucositis (SOM). While some drugs are available to treat SOM once it develops, none can prevent it. But today, researchers are reporting on a new drug, called GC4419, that appears to do just that.
Although still in clinical trials, it has already been designated by the U.S. Food and Drug Administration as a “breakthrough therapy.”
“It is exciting to publicly report on the structure and synthesis of GC4419 for the first time,” says Dennis P. Riley, Ph.D., leader of the study. “We believe GC4419 has the potential to address an important unmet medical need in the treatment of cancer patients undergoing radiation therapy, and we look forward to commencing a Phase 3 trial with GC4419 in head and neck cancer patients this year.”
Oral mucositis (OM) is a painful and problematic complication during cancer treatment, especially radiation therapy, which breaks down the epithelial cells lining the mouth. Patients suffering from OM experience severe pain, inflammation, ulceration and bleeding. Most patients receiving chemoradiotherapy develop SOM, as defined by the World Health Organization as grade 3 or 4 of OM. In the most severe cases, patients can’t swallow or consume liquids or solid food, often leading to the use of feeding tubes and narcotic analgesics. Patients are also susceptible to infections that can lead to hospitalization.
Radiation therapy creates elevated superoxide radical levels, which are believed to be responsible for most of the side effects associated with this treatment, including OM. “The synthetic enzyme we designed and made mimics the function of the naturally occurring superoxide dismutase, an enzyme that converts superoxide to molecular oxygen and hydrogen peroxide,” says Riley, who is with Galera Therapeutics. “Hydrogen peroxide is very toxic to cancer cells but not to normal cells. Thus, we create two opportunities to improve radiation therapy: reducing toxicity for normal cells while increasing the toxicity to the cancerous ones.”
Designing and creating the synthetic superoxide dismutase was complex, and Riley’s team tried many variations of synthetic enzyme mimics before settling on GC4419. The research began decades ago when Riley worked at Monsanto/Searle. The molecules his team were working with had four chiral carbon centers, which meant there were a very large number of potential mimics.
“We had to figure out which isomer would work best and be the most ‘druggable,’” he reports. “Our current synthesis involves using a template to make the 15-membered macrocylic ring complex in a single GMP [Good Manufacturing Practice] step. It uses pyridine-2,6- dicarboxyaldehyde, manganese(II) chloride and a linear tetramine synthesized from S,S-1,2 diaminocyclohexane. It is an elegantly simple ‘one-pot’ synthesis that yields the desired molecule with more than 99.5 percent chemical purity.”
GC4419 successfully completed Phase 1 and 2 clinical trials, showing safety and efficacy in preventing SOM in head and neck cancer patients undergoing radiation therapy. If further clinical trials are successful and GC4419 gets FDA approval, Riley says, “there’s no reason it could not be used to prevent side effects from radiation treatment of other cancers. You can think of pancreatic cancer, for example, in which you might want to use high-dose radiation for locally advanced disease, but the pancreas is too close to other organs that cannot handle the side effects of radiation. We are currently studying GC4419’s anti-tumor effect in a Phase 1/2 clinical trial in pancreatic cancer at MD Anderson Cancer Center. If successful, this drug has the potential to change the management of radiation therapy since 70 percent of all solid tumors are treated with radiation.”
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The Latest on: GC4419
- Galera Therapeutics raises $150M Series C round to fund clinical development on September 20, 2018 at 9:10 am
The company plans to use the funding to advance clinical development of its lead drug candidate, GC4419, and to fund a registrational Phase III trial in patients with severe oral mucositis. According ... […]
- New drug could prevent debilitating side effect of cancer treatment on August 20, 2018 at 2:09 am
Space-filling structure depiction of GC4419 based on X-ray crystal structure determination. Credit: Dennis Riley About 50,000 people in the U.S. are diagnosed annually with head, neck, nasal and oral ... […]
- Anti–Oral Mucositis Drug Granted Breakthrough Status on March 8, 2018 at 4:00 pm
The US Food and Drug Administration (FDA) recently granted Breakthrough Therapy designation to GC4419 (Galera Therapeutics) for reduction of the duration, incidence, and severity of severe oral mucosi... […]
- Galera Therapeutics Receives FDA Breakthrough Therapy Designation for GC4419 for the Reduction of Severe Oral Mucositis on February 27, 2018 at 11:30 pm
MALVERN, Pa., Feb. 28, 2018 (GLOBE NEWSWIRE) -- Galera Therapeutics, Inc., a clinical-stage biotechnology company developing drugs targeting oxygen metabolic pathways with the potential to transform c... […]
- Galera Therapeutics Announces Promising Innovative Medicines Designation from the United Kingdom’s Medicines and Healthcare Products Regulatory Agency for GC4419 for the ... on July 31, 2017 at 5:11 am
MALVERN, Pa.--(BUSINESS WIRE)--Galera Therapeutics, Inc., a clinical stage biotechnology company announced today that GC4419 has received a Promising Innovative Medicines (PIM) designation in the Unit... […]
- Galera Therapeutics Receives $15M from Sofinnova Ventures on November 28, 2016 at 7:40 am
In conjunction with this financing, Mike Powell, PhD, General Partner at Sofinnova, will join the Galera Board of Directors. The company intends to use the proceeds to prepare its lead product candida... […]
- Galera Therapeutics Announces Presentation of One-Year Follow-up Data from a Phase 1b/2a Study of GC4419 In the Reduction of Severe Oral Mucositis on September 27, 2016 at 10:31 am
MALVERN, Pa.--(BUSINESS WIRE)--Galera Therapeutics, Inc., a clinical-stage biotechnology company developing new treatments for cancer patients, today announced the presentation of final data, includin... […]
- FDA fast-tracks Galera drug on January 18, 2016 at 5:50 am
Galera Therapeutics Inc., a Malvern biotechnology company, said that the Food and Drug Administration recently granted "fast track" status to its investigational drug compound, known as GC4419, to red... […]
- Malvern Company's Anti-Chemotherapy Drug Granted 'Fast Track' Status on January 7, 2016 at 10:41 am
MALVERN, PA - (BUSINESS WIRE) Galera Therapeutics, Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for GC4419, an investigational drug candida... […]
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