TGRX-678

Asciminib has shown efficacy in heavily pretreated patients and in the first-line setting, but resistance and limited benefit after ponatinib highlight the need for new therapeutic options...TGRX-678 exhibits potent activity against wild-type and mutant ABL1, including T315I, synergism with orthosteric tyrosine kinase inhibitors (TKIs), central nervous system (CNS) penetration, and encouraging phase Ia/Ib clinical activity in heavily pretreated CML. Early but promising data are also emerging for TERN-701 from the CARDINAL trial...Key questions regarding durability, long-term safety, and optimal integration with ATP-competitive TKIs remain open. Ongoing trials will define the clinical role of these STAMPi and their potential to advance cure-directed strategies, including treatment-free remission.

P1, N=6, Completed, Shenzhen TargetRx, Inc. | Not yet recruiting --> Completed | Trial completion date: Dec 2025 --> Aug 2025

When combined with ponatinib, TGRX-678 synergistically re-sensitizes the highly resistant compound mutants and T315M to growth inhibition at clinically achievable concentrations...It also demonstrates a markedly improved in vivo pharmacokinetic (PK) profile and higher oral bioavailability compared to asciminib. Importantly, TGRX-678 penetrates the blood-brain barrier (BBB) and exhibits in vivo efficacy in a murine CNS blast crisis leukemia model. Collectively, these findings suggest that TGRX-678 is a novel BCR::ABL1 allosteric inhibitor with high selectivity, potency and unique pharmacologic features, which has the potential to treat relapse or refractory CML and Ph+ ALL, even with CNS involvement.

Today, the six approved BCR::ABL1 TKIs, five in frontline therapy (imatinib, dasatinib, bosutinib, nilotinib, and asciminib) and all six in later line therapy (including ponatinib), fulfill in one form or another these requirements. Third-generation TKIs that target the ABL1 kinase domain (olverembatinib and ELVN-001) or the myristoyl pocket (TGRX-678 and TERN-701) are under development...However, serious complications, such as graft-vs-host disease, or death could occur. This review summarizes relevant information concerning the management of CML in 2025, and addresses some CML treatment pathways that became entrenched in the management of CML in the first 15-20 years of TKI experience, which may need to be revisited.

P1, N=6, Not yet recruiting, Shenzhen TargetRx, Inc.

P1, N=76, Completed, Shenzhen TargetRx, Inc. | Active, not recruiting --> Completed | Trial completion date: Jul 2025 --> Feb 2025

P1, N=90, Active, not recruiting, Shenzhen TargetRx, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Sep 2026 | Trial primary completion date: Dec 2024 --> Mar 2026

P1, N=72, Active, not recruiting, Shenzhen TargetRx, Inc. | Not yet recruiting --> Active, not recruiting | Trial completion date: Feb 2025 --> Jul 2025

P2, N=40, Recruiting, Shenzhen TargetRx, Inc. | Not yet recruiting --> Recruiting | Trial completion date: Dec 2027 --> Apr 2028

P1, N=72, Not yet recruiting, Shenzhen TargetRx, Inc.

P2, N=40, Not yet recruiting, Shenzhen TargetRx, Inc.

P1, N=90, Recruiting, Shenzhen TargetRx, Inc. | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Jun 2024