Dose escalation with oral TRE-515 has reached 1,440 mg once daily—36-fold above the starting dose of 40 mg—without dose-limiting toxicities. Early antitumor activity was observed in the lowest cohorts (40–80 mg), including a patient maintaining disease control for more than 250 days. Across 33 patients treated, several remain on therapy.
Trethera has completed enrollment of the Phase 1 dose-escalation study in advanced solid tumors (NCT05055609), positioning the company to lock safety, PK/PD, and preliminary activity readouts and to nominate a recommended Phase 2 dose. The protocol’s primary aim is safety and tolerability, with secondary objectives including PK/PD characterization, antitumor activity, and exploratory biomarkers of target engagement for the deoxycytidine kinase (dCK) pathway. The company plans to present the Phase 1 findings at an upcoming scientific conference. During the study period, TRE-515 secured multiple U.S. patents extending exclusivity to February 2045, an FDA Fast Track designation for use with radiation in prostate cancer, a $2.3 million NIH grant supporting that combination, and Orphan Drug designations in acute disseminated encephalomyelitis and optic neuritis.
Strategically, Trethera is angling to establish first-mover status in dCK inhibition, aiming to exploit tumors and autoimmune settings reliant on the nucleoside salvage pathway. The wide apparent therapeutic window and early disease-control signals create room to select an exposure based on pharmacology rather than toxicity ceilings. Still, the pivotal question is where the drug will compete. The Fast Track path in prostate cancer, specifically as a radiation combination, suggests a deliberate pivot toward modalities where metabolic stress can amplify therapeutic effect and where randomized evidence may be achievable. At the same time, orphan designations in immune-mediated neurologic diseases signal broader ambitions that could strain resources if pursued in parallel, particularly for a private company.
For sites and CROs, an oral monotherapy with manageable toxicity is operationally straightforward and could support sustained on-study retention; however, the exploratory biomarker plan introduces complexity. If Trethera leans on dCK activity, salvage pathway gene expression, or deoxyribonucleotide pool metrics to enrich responders, central lab capacity and assay standardization will become gating factors for Phase 2 activation. The radiation-combination program will integrate radiation oncology departments and enhance coordination across scheduling, imaging, and multidisciplinary oversight, thereby modifying the site mix and operational cadence. Vendors focused on translational assays and digital PK/PD workflows may find a near-term opportunity if the company formalizes a biomarker-driven selection strategy. Regulators will expect a straightforward mechanistic narrative tied to prospectively defined biomarker endpoints, particularly as the FDA continues to push for enrichment and clinically meaningful endpoints in the development of solid tumors.
Next, the field will look for a declared recommended Phase 2 dose, the shape of expansion cohorts, and evidence that pharmacodynamic effects correlate with clinical benefit. Indication triage is a near-term decision: remain tumor-agnostic to validate the mechanism or concentrate on prostate cancer to leverage Fast Track and NIH funding. Combination strategy beyond radiation—chemotherapy, PARP, ATR/CHK1, or immunotherapy—will be scrutinized for overlapping myelosuppression and radiosensitization risks. The durability of disease control, not just the absence of early DLTs, will determine whether TRE-515 can maintain tolerability over months of exposure. Watch for biomarker assay readiness, the design of any randomized components in prostate cancer, and signs of partnering or financing that signal how aggressively Trethera can prosecute multiple indications under a 2045 IP runway.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
