Trethera Corporation has secured a combined $5.3 million in Small Business Innovation Research (SBIR) grants from the National Institute of Health to advance its lead drug candidate TRE-515, a first-in-class deoxycytidine kinase (dCK) inhibitor, across multiple therapeutic areas. The clinical-stage biopharmaceutical company announced two separate awards in August 2025: $2.3 million to study TRE-515 combined with radiation therapy for metastatic castration-resistant prostate cancer (mCRPC), and $3 million to advance the compound for systemic lupus erythematosus treatment.
Targeting Metabolic Vulnerabilities in Cancer and Autoimmune Disease
TRE-515 represents a novel therapeutic approach that inhibits deoxycytidine kinase, the rate-limiting enzyme in the nucleoside salvage pathway responsible for generating DNA precursors. By blocking this pathway, the drug deprives diseased cells of the DNA building blocks needed for uncontrolled proliferation while sparing healthy cells that rely on regulated cell division.
"Our ongoing research shows TRE-515's unique mechanism of inhibiting nucleotide metabolism has the potential to address multiple autoimmune and oncology indications," said Dr. Ken Schultz, Chairman and CEO of Trethera and principal investigator on the lupus grant.
The compound has demonstrated a favorable safety profile and early signs of clinical benefit in ongoing first-in-human oncology trials, with no toxicity observed in dose escalation studies according to NIH peer review summaries.
Prostate Cancer Combination Strategy
The $2.3 million prostate cancer grant will fund preclinical testing of TRE-515 combined with standard-of-care radiation therapy in mCRPC mouse models. This combination approach aims to exploit a metabolic vulnerability where cancer cells must gather additional DNA building blocks to repair radiation-induced damage.
"Combining radiation with TRE-515 synergistically cripples the ability of cancer cells to recover from DNA damage and enhances the therapeutic response," the company explained. The research addresses a significant unmet need, as current FDA-approved targeted radiation therapies for mCRPC have a 29.8% response rate, meaning seven in ten men experience no clinical benefit from treatment.
Globally, 1.5 million men are diagnosed with prostate cancer annually, with over 40,000 deaths each year. The disease claims 70% of mCRPC patients within five years of diagnosis, highlighting the urgent need for more effective treatments.
"Prostate cancer remains the second leading cause of cancer related death in men, with limited effective therapies once the disease becomes resistant and metastatic," said Dr. Michael Shepard, Trethera Scientific Advisory Board member and Lasker Prize Laureate. "A novel, first-in-class drug such as TRE-515, paired with radiation, could redefine treatment for this devastating disease."
Lupus Treatment Development
The $3 million lupus grant builds on successful Phase I research that demonstrated increased dCK activity is associated with lupus in mouse models and that blocking dCK with TRE-515 stops disease progression. The funding will support advanced toxicology, pharmacology, and efficacy studies with the goal of initiating clinical trials in lupus patients.
Lupus affects over 3 million people globally and is driven by autoreactive immune cells that can impact vital organs including the kidneys, brain, and lungs. Approximately 35-50% of patients develop organ damage within five years of diagnosis. Current treatments have response rates of less than 50% with limited durability and are associated with serious side effects.
"Lupus remains a chronic, debilitating disease with limited therapeutic choices, many of which are associated with heightened infection risk," said Dr. Larry Steinman, Trethera Scientific Advisory Board member and distinguished immunologist at Stanford University. "A novel, first-in-class agent such as TRE-515 offers a differentiated mechanism of action, potentially improving patient outcomes while reducing treatment burden."
Strong Scientific Validation
The NIH peer review panels provided strong endorsements for both programs. For the prostate cancer grant, reviewers noted "strong preliminary data supports the premise that TRE-515 is an effective and specific dCK inhibitor... will likely lead to proof of concept that combining TRE-515 with radiation will be an effective approach for preventing resistance... opens new opportunities to apply this inhibitor to a broad range of cancers... has very strong commercial potential."
For the lupus program, the panel commented, "The potential for broad immunomodulation without general immunosuppression is compelling... the premise of the proposal is strong and significant... the preclinical data are impressive and support the potential of TRE-515 to impact autoimmune disease... the innovative aspects include a novel mechanism of action, a highly selective agent, and the use of novel PET imaging and biomarker assays."
Regulatory Recognition
The NIH grants complement recent regulatory recognition for TRE-515. The FDA has designated the compound as a Fast Track drug for prostate cancer and granted Orphan Drug status for two autoimmune neurologic diseases. The prostate cancer grant announcement came less than a month after receiving FDA Fast Track designation for the same indication.
"Securing this NIH grant continues our prostate cancer momentum, coming less than a month after receiving FDA Fast Track designation for the same indication. Such dual validations are rare and substantiate the strength of our scientific rationale and clinical observations," Schultz noted.
