Trethera Awarded $3-Million NIH Grant to Advance First-In-Class Drug for the Treatment of Lupus

Trethera Corporation recently announced it has been awarded a $3-million Small Business Innovation Research (SBIR) grant from the National Institute of Health (NIH). The award evaluates Trethera’s lead candidate, TRE-515, for the treatment of systemic lupus erythematosus (SLE, or lupus) — a chronic and debilitating autoimmune disease. Trethera will leverage the funding to complete advanced studies, including toxicology, pharmacology, and efficacy testing, with the goal of initiating trials in lupus patients after the award conclusion.

TRE-515 inhibits deoxycytidine kinase (dCK), the key enzyme for the nucleoside salvage pathway that becomes activated and essential for the growth of abnormal cells in autoimmune diseases and cancer. Blocking this pathway deprives diseased cells of the DNA building blocks needed for uncontrolled proliferation. Because dCK is relatively conserved in the regulated cell division of healthy cells, inhibiting it with TRE-515 has demonstrated a superb safety profile and early signs of clinical benefit in an ongoing first-in-human oncology trial. Based on these observations, the NIH award will expand development into preclinical lupus models.

“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, principal investigator and Trethera CEO. “This Phase 2 grant builds on the momentum from our successful Phase 1 grant, which demonstrated increased dCK activity is associated with lupus in mouse models and blocking dCK with TRE-515 stops disease progression.”

“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.”

Figure 1. PET scan images showing presence of target enzyme dCK in normal mice (row A), and lupus diseased mice (row B).

Lupus is a disease driven by autoreactive immune cells. It can impact vital organs, including the kidneys, brain, and lungs, where approximately 35%-50% of patients develop organ damage within 5 years of diagnosis. Patients undergo periods of stable disease interspersed with flares that can cause irreversible organ damage. Current treatments can be effective but not curative, with response rates of less than 50% and limited durability, while being associated with serious side effects. Globally, lupus impacts over 3 million people a year.

In its written summary, the NIH peer review 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.”

Sources: Ann Rheum Dis.2021 Jan;80(1); Lancet.2019 8;393(10188); NatureMed.2008 14(783)
Note: Statements taken from the official NIH peer review written summary reflect their personal scientific assessment and are not official NIH endorsements.

Trethera is a clinical-stage, privately held, biopharmaceutical company dedicated to pioneering the development of novel treatments for autoimmune diseases and cancers. Founded by prominent UCLA scientists, Trethera is led by experienced management and board members. Trethera’s innovative approach to targeting nucleotide metabolism led to the development of TRE-515, an orally administered capsule. TRE-515 is a first-in-class clinical stage drug that inhibits deoxycytidine kinase (dCK), the rate-limiting enzyme in the nucleoside salvage pathway, one of two biosynthetic pathways that generate DNA precursors. It is believed that some forms of cancer may be preferentially dependent on the salvage pathway to support tumor growth, and certain autoimmune diseases might also respond to TRE-515 treatment. The FDA has designated TRE-515 a Fast Track drug for prostate cancer and an Orphan Drug for two autoimmune neurologic diseases. Trethera is developing TRE-515 for use as a monotherapy or in combination to precisely target a metabolic vulnerability of cancer or autoimmune diseases that will transform outcomes for patients. For more information, visit us at trethera.com.