TGRX-678 / Shenzhen TargetRx - LARVOL DELTA

Efficacy of tgrx-678, a potent BCR::ABL1 allosteric inhibitor, in CML-CP and CML-AP patients harboring T315I mutation: Results from a phase 1 study (ASH 2025) - P1 | "35(66%) ptsreceived ≥ 3 prior TKIs; 24(45%) pts previously received ponatinib, olverembatinib, asciminib, and/or HS-10382 (STAMP inhibitor). Our study demonstrated that TGRX-678 achieved strong efficacy in patients with T315I-mutated CML in chronic or accelerated phase, with no clear dose–response relationship observed. Theseresults suggest that lower doses of TGRX-678 may offer comparable efficacy with potentially improvedsafety, particularly in heavily pretreated patients harboring T315I mutations."

Clinical • P1 data • Chronic Myeloid Leukemia • Diabetes • Dyslipidemia • Hypertriglyceridemia • Leukopenia • Metabolic Disorders • Neutropenia • Thrombocytopenia • ABL1

Numerous clinically-detected asciminib-resistant BCR::ABL1 mutations disrupt allostery and confer cross-resistance to the novel clinically-active allosteric TKI tgrx-678 (ASH 2025) - "Asciminib is clinically susceptible to a substantially larger number of drug-resistant mutantsthan 2G or 3G TKIs. All 22 BCR::ABL1 mutations tested conferred varying degrees of resistance toasciminib, with a majority retaining asciminib binding affinity. Several mutants displayed activation ofkinase activity and alteration of kinase structure, providing the first direct evidence for disruption ofallostery as the most common resistance mechanism of asciminib resistant-mutations."

Clinical • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ABL1

Safety and Efficacy of Tgrx-678, a Potent BCR-ABL Allosteric Inhibitor in Patients with Tyrosine Kinase Inhibitor (TKI) Resistant/Refractory Chronic Myeloid Leukemia (CML): Preliminary Results of Phase I Study (ASH 2023) - P1 | "There were 22 CML-CP and 23 CML-AP patients previous received 3rd Gen TKIs (ponatinib or HQP1351) or asciminib. Clinical activity of TGRX-678 was seen in all cohorts and across TKI-resistant mutations including T315I, providing a promising treatment option for CML CP/AP patients, including those who failed ponatinib or asciminib. Its unique PK properties might bring additional benefit to patients. TGRX-678 was well tolerated in heavily pretreated CML patients."

Clinical • P1 data • Anemia • Chronic Myeloid Leukemia • Dyslipidemia • Hematological Disorders • Hematological Malignancies • Hypertriglyceridemia • Leukemia • Neutropenia • Oncology • Thrombocytopenia • ABL1 • BCR

Tgrx-678, a Novel Allosteric Inhibitor of BCR-ABL1, Demonstrates Preclinical Anti-Leukemia Activity, High Oral Bioavailability and Synergism with Ponatinib to Suppress the Highly Resistant Compound Mutations (ASH 2023) - P1 | "ABL1 is subject to auto-inhibition mediated by myristoylation-triggered conformational change, which can be exploited to overcome resistance, as validated by allosteric inhibitors such as GNF2, GNF5 and asciminib. Furthermore, TGRX-678 and ponatinib synergize to overcome the clinically challenging resistance conferred by T315M or T315I-inclusive compound mutations. This data warrant further clinical investigation of TGRX-678 for the treatment of resistant or refractory CML patients."

Preclinical • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ABL1 • BCR

Tgrx-678 Penetrates Blood-Brain Barrier and Exhibits Preclinical Anti-Tumor Activity in Murine Ph+ CNS Leukemia and ALL Models (ASH 2024) - P2 | "Tumor regression was observed in all three dose groups (TGI= 119.5%, 124.7%, 125.6% post 21-day dosing, respectively). In conclusion, TGRX-678 can penetrate blood-brain barrier, and potently inhibit Ph+ leukemia cell growth in CNS and subcutaneous mouse model, suggesting TGRX-678's potential therapeutic applications in patients with Ph+ CNS leukemia and ALL."

Preclinical • Acute Lymphocytic Leukemia • Central Nervous System Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1

Safety and Efficacy of Tgrx-678, a Potent BCR::ABL1 allosteric Inhibitor, in Patients with Tyrosine Kinase Inhibitor Resistant and/or Intolerant Chronic Myeloid Leukemia: Updated Results of Phase 1 Study Tgrx-678 -1001 (ASH 2024) - P1, P2 | "Methods : In phase Ia, CML-CP and CML-AP patients who were R/I at least to imatinib, dasatinib and nilotinib were enrolled...Patients were heavily pretreated; 71 (66%) CP and 44 (88%) AP patients had received ≥ 3 prior TKIs; 40 (37%) CP and 30 (60%) AP patients had previously received ponatinib, olverembatinib, asciminib, and/or HS-10382 (a new STAMP inhibitor)...The updated data indicate promising efficacy in both CP and AP patients including those with the T315I mutation and those who failed 3G-TKI or STAMP inhibitors. Ongoing Phase 2 trials in China (NCT NCT06453902) and Phase 1 trials in US (NCT06088888) are further evaluating TGRX-678, underscoring the need for continued assessment."

Clinical • P1 data • Anemia • Chronic Myeloid Leukemia • Diabetes • Dyslipidemia • Hypertriglyceridemia • Leukopenia • Metabolic Disorders • Neutropenia • Thrombocytopenia • ABL1

TGRX-678 Pharmacokinetic Mass Balance (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Shenzhen TargetRx, Inc. | Not yet recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Aug 2025

Trial completion • Trial completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1. (PubMed, Blood) - "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."

Journal • Preclinical • Acute Lymphocytic Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • ABCG2 • ABL1

Management of chronic myeloid leukemia in 2025. (PubMed, Cancer) - "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."

Journal • Review • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • ABL1

TGRX-678 Pharmacokinetic Mass Balance (clinicaltrials.gov) - P1 | N=6 | Not yet recruiting | Sponsor: Shenzhen TargetRx, Inc.

New P1 trial • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-678-1002: TGRX-678 Phase I Oral Pharmacokinetic Study (clinicaltrials.gov) - P1 | N=76 | Completed | Sponsor: Shenzhen TargetRx, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Feb 2025

Trial completion • Trial completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-678-1001: TGRX-678 Chinese Phase I in Chronic Myelogenous Leukemia (CML) Patients (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Shenzhen TargetRx, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2025 ➔ Sep 2026 | Trial primary completion date: Dec 2024 ➔ Mar 2026

Enrollment closed • Trial completion date • Trial primary completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-678-1002: TGRX-678 Phase I Oral Pharmacokinetic Study (clinicaltrials.gov) - P1 | N=72 | Active, not recruiting | Sponsor: Shenzhen TargetRx, Inc. | Not yet recruiting ➔ Active, not recruiting | Trial completion date: Feb 2025 ➔ Jul 2025

Enrollment closed • Trial completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-678 Chinese Phase II in Chronic Myelogenous Leukemia (CML) Patients (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Shenzhen TargetRx, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Dec 2027 ➔ Apr 2028

Enrollment open • Trial completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-326 Phase I Oral Pharmacokinetic Study (clinicaltrials.gov) - P1 | N=72 | Not yet recruiting | Sponsor: Shenzhen TargetRx, Inc.

New P1 trial • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

Next Questions: Chronic Myeloid Leukemia (SOHO 2024) - "The Development of STAMP Inhibitors of ABL1 STAMP (Specifically TArgeting the Myristoyl Pocket) inhibitors target the ABL kinase by binding to a myristoyl site, which is distinct from the ATP-binding site of the kinase.3 This has several potential advantages when compared to the ATP-competitive TKIs (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib)...A significant improvement in the number of patients able to achieve TFR and the time required to achieve it will be the ultimate determinant of asciminib’s role as frontline therapy...There are now two more STAMP inhibitors in early clinical development, TERNS-701 and TGRX-678-STAMP inhibitors have the potential to be the biggest breakthrough in CML therapy since the development of imatinib...However, we need clinical trial proof that novel biomarkers can be applied and make a positive impact on patient outcomes. There is an urgent need for Pharma and Academia to collaborate to develop innovative clinical trials..."

IO biomarker • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • ASXL1 • DNMT3A • HAVCR2 • RUNX1 • TET2

TGRX-678 Chinese Phase II in Chronic Myelogenous Leukemia (CML) Patients (clinicaltrials.gov) - P2 | N=40 | Not yet recruiting | Sponsor: Shenzhen TargetRx, Inc.

New P2 trial • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-678 US Phase I for Subjects With Refractory or Advanced Chronic Myelogenous Leukemia (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Shenzhen TargetRx, Inc. | Not yet recruiting ➔ Recruiting | Initiation date: Mar 2024 ➔ Jun 2024

Enrollment open • Metastases • Trial initiation date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TKI treatment pattern and new therapy of CML (ICKSH 2024) - "Several studies show that asciminib(ABL001), the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), can quickly achieve a deep molecular response in CML-CP patients who have previously been resistant or intolerant to ≥2 types of TKIs. Olverembatinib (HQP1351), compared to the existing best available treatment, demonstrated superior efficacy and tolerability in patients with TKI-resistant CML-CP. Phase I study indicated that Tgrx-678 exhibited favorable clinical activity and tolerability in patients with TKI-resistant / refractory CML. New generation of TKIs, especially STAMP inhibitor hold promise in addressing CML resistance / intolerance after ≥2TKIs."

Chronic Myeloid Leukemia

TGRX-678 Chinese Phase I in Chronic Myelogenous Leukemia (CML) Patients (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Shenzhen TargetRx, Inc. | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

TGRX-678 US Phase I for Subjects With Refractory or Advanced Chronic Myelogenous Leukemia (clinicaltrials.gov) - P1 | N=90 | Not yet recruiting | Sponsor: Shenzhen TargetRx, Inc.

Metastases • New P1 trial • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR

TGRX-678 Chinese Phase I in Chronic Myelogenous Leukemia (CML) Patients (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Shenzhen TargetRx, Inc. | Trial completion date: Dec 2022 ➔ Jun 2024 | Trial primary completion date: Oct 2022 ➔ Dec 2023

Metastases • Trial completion date • Trial primary completion date • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR

TGRX-678 Chinese Phase I in Chronic Myelogenous Leukemia (CML) Patients (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Shenzhen TargetRx, Inc.

New P1 trial • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR