The multimodal mechanism of action of brequinar has the potential to treat COVID-19 by depleting the host nucleotide pool to block viral RNA synthesis
CAMBRIDGE, Mass., September 1, 2020 – Clear Creek Bio, Inc. announced today that the company has received U.S. Food and Drug Administration (FDA) clearance on an Investigational New Drug (IND) application for brequinar for the treatment of COVID-19 and has dosed the first patient in a Phase 1 clinical study. Brequinar is an orally available, potent, and selective small molecule DHODH inhibitor that blocks host cell de novo pyrimidine biosynthesis, which is essential for DNA and RNA synthesis. In vitro and in vivo studies have shown that brequinar has potent antiviral activity against a broad spectrum of viruses, including SARS-CoV-2, the novel coronavirus that causes COVID-19 (1,2).
“In preclinical studies, brequinar has demonstrated compelling antiviral activity against a broad spectrum of RNA viruses, most importantly SARS-CoV-2,” said Vikram Sheel Kumar, M.D., Cofounder, President, and Chief Executive Officer of Clear Creek Bio. “With the urgent need today, we are focused on rapidly developing brequinar as a potential treatment for COVID-19.”
The randomized, open label, multi-center study will enroll up to 24 patients hospitalized with COVID-19 to assess the preliminary efficacy, safety, and tolerability of brequinar. The study will assign participants in a 1:2 ratio to standard of care or standard of care plus five once-daily oral doses of 100 mg brequinar.
David Sykes, M.D., Ph.D., scientific cofounder of Clear Creek Bio and Assistant Professor, Harvard Medical School, commented, "Viruses hijack the host cell's transcriptional machinery and steal from the nucleotide pool. Because viruses depend on the level of intracellular ribonucleotides, they are susceptible to treatment with brequinar. We believe that the temporary depletion of the host pyrimidine pool following treatment with brequinar will cripple viral replication while sparing the host cell, providing an important therapeutic window."
Brequinar is designed to provide broad spectrum, mutation-resistant antiviral activity either as a standalone therapy or combined to complement and enhance direct-acting antiviral drugs. Additional in vitro data has shown that brequinar led to increased effects of other antiviral therapies, including nucleoside analogs that are currently being evaluated for the treatment of COVID-19, potentially indicating that brequinar could be used in combination therapies (3).
“It’s exciting to learn that clinical trials of the potential innovative SARS-CoV-2 therapy, brequinar, are starting,” said James Cunningham, M.D., Associate Professor, Medicine, Harvard Medical School. “Brequinar is promising because it limits the supply of a critical nutrient required for SARS-CoV-2 growth and transmission. Through this mechanism, brequinar may reduce virus resistance, promote synergy with other anti-SARS-CoV-2 drugs, and prove to be effective against other pathogenic RNA viruses.”
“We urgently need antivirals that can fight SARS-CoV-2 and treat COVID-19,” said Gerard J. Criner, M.D., FACP, FACCP, a principal investigator for the COVID-19 clinical trial; Director, Temple Lung Center; and Chair and Professor, Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University.
The clinical trial is currently recruiting at four sites in Hartford, Jacksonville, Philadelphia, and Tampa. For more info on the clinical trial, please visit https://clinicaltrials.gov/ct2/show/NCT04425252.
About Clear Creek Bio
Clear Creek Bio is a private biotech company focused on developing novel therapies to address infectious disease and cancer. The company’s lead drug candidate, brequinar, is a dihydroorotate dehydrogenase (DHODH) inhibitor with high potency and short half-life. In addition to its potential as a broad spectrum antiviral, the company is evaluating brequinar as a potential treatment for acute myeloid leukemia.
References
- Rui Xiong, et al. Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. August 2020. https://doi.org/10.1007/s13238-020-00768-w
- Shi-fang Li, et al. Antiviral activity of brequinar against foot-and-mouth disease virus infection in vitro and in vivo. August 2019. https://doi.org/10.1016/j.biopha.2019.108982.
- Clear Creek Bio, unpublished data, manuscript in preparation.
