Terns Pharmaceuticals Announces Global Phase 1 Clinical Trial Design of TERN-701 for the Treatment of Chronic Myeloid Leukemia

Terns Pharmaceuticals, Inc. recently announced the US FDA’s clearance of its Investigational New Drug application and the design of the CARDINAL Trial, Terns’ global Phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of TERN-701 in participants with chronic myeloid leukemia (CML). TERN-701 is the Company’s proprietary, allosteric BCR-ABL tyrosine kinase inhibitor (TKI), designed to target the BCR-ABL myristoyl pocket.

“Allosteric BCR-ABL inhibitors comprise a novel class of therapy for CML that has been shown to have superior efficacy and improved safety compared to active-site inhibitors in prior studies. We are particularly pleased with our Phase 1 trial design for TERN-701 as it will recruit chronic CML patients who experienced treatment failure on at least one prior second-generation TKI. This will allow us to offer a novel investigational allosteric inhibitor to CML patients in as early as their second line of therapy, where there are currently no approved allosteric inhibitors,” said Emil Kuriakose, MD, Chief Medical Officer-Oncology at Terns Pharmaceuticals. “Importantly, we were able to leverage emerging early clinical data from the ongoing Phase 1 trial in China conducted by our partner, Hansoh, to inform the dose selection for the CARDINAL Trial. This enables us to accelerate our study and the overall development of this molecule, while enhancing our ability to best dose optimize TERN-701 for patients with CML. We are excited to continue the clinical development momentum of TERN-701, which we believe can offer a valuable alternative to the only FDA-approved allosteric BCR-ABL TKI for CML. We are well-positioned to report initial data from this global Phase 1 trial in the second half of 2024.”

The CARDINAL Trial is a global, multicenter, open-label, two-part Phase 1 clinical trial to evaluate the safety, PK, and efficacy of TERN-701 in participants with previously treated CML. Part 1 is the dose escalation portion of the trial that will evaluate once-daily TERN-701 monotherapy in approximately 24-36 adults living with CML to be enrolled in up to five dose cohorts. Participants will have chronic phase CML with confirmed BCR-ABL and a history of treatment failure or suboptimal response to at least one second generation TKI (nilotinib, dasatinib or bosutinib). Participants who are intolerant to prior TKI treatment (including asciminib) are also allowed. The primary endpoints for Part 1 are the incidence of dose limiting toxicities (DLTs) during the first treatment cycle, and additional measures of safety and tolerability. Secondary endpoints include TERN-701 PK and efficacy assessments, such as hematologic and molecular responses as measured by the change from baseline in BCR-ABL transcript levels. The starting dose is 160 mg QD (once-daily) with dose escalations as high as 500 mg QD and the option to explore a lower dose of 80 mg QD.

Part 2 is the dose expansion portion of the trial that will enroll approximately 40 patients, randomized to once-daily treatment with one of two doses of TERN-701 to be selected based on data from Part 1. The primary endpoint of the dose expansion portion of the trial is efficacy, measured by hematologic and molecular responses. Secondary endpoints include safety, tolerability and PK. The overall objective of the CARDINAL Trial is to select the optimal dose(s) of TERN-701 to move forward to a potential pivotal trial in chronic phase CML.

The CARDINAL Trial plans to enroll at sites in the U.S., Europe and other Terns global territories. Global site identification and trial start-up activities are ongoing, with the first patient screening expected in December 2023. More information about the TERN-701 global Phase 1 (CARDINAL Trial) trial may be found on clinicaltrials.gov when available.

TERN-701 is Terns’ proprietary, oral, potent, allosteric BCR-ABL TKI specifically targeting the BCR-ABL myristoyl pocket, which is in clinical development for chronic myeloid leukemia. Allosteric TKIs, which bind to the myristoyl-binding pocket, represent a novel treatment class for CML and have the potential to address the shortcomings of active-site TKIs, including off-target activity and limited efficacy against active site resistance mutations. TERN-701 aims to address the limitations of active-site TKIs with the goal of achieving improved tumor suppression through a combination of potent activity against BCR-ABL including a broad range of mutations and improved safety and tolerability profiles. Terns anticipates initiation of the CARDINAL Trial, a global Phase 1 trial for TERN-701, in the second half of 2023, with potential interim top-line readouts from initial cohorts in 2024. Hansoh’s Phase 1 trial (NCT05367700) evaluating the tolerability, efficacy, and pharmacokinetics of once-daily TERN-701 (HS-10382) for CML in China is ongoing.

CML is a cancer that occurs when the blood-forming cells of the bone marrow overproduce white blood cells. In the US, CML is an orphan indication with approximately 8,930 new cases expected to be diagnosed in 2023. As of 2020, the latest year for which statistics are available, an estimated 66,366 people are either living with or in remission from CML. Since the introduction of tyrosine kinase inhibitor (TKI) therapy in 2001, CML has been transformed from a life-threatening disease to a life-long chronic condition for most patients. Despite improvements in outcomes with active-site targeting TKIs, many patients do not achieve long-term disease control with these therapies due to resistance or intolerance, leading patients to cycle through prior generation treatments. As a result, physicians and patients are seeking additional efficacious therapies for people whose tolerability, co-morbidity and/or drug-drug interaction profiles change over time, limiting their available treatment options, quality of life and the effectiveness of mainstay therapies. Allosteric BCR-ABL TKIs are the only class of drug to show efficacy and tolerability benefits over active-site TKIs, and represent an important advancement in the treatment of CML.

Terns Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases, including oncology, NASH, and obesity. Terns’ pipeline includes two clinical stage development programs including an allosteric BCR-ABL inhibitor and a THR-β agonist, and preclinical small-molecule GLP-1 receptor agonist and GIPR modulator programs. For more information, visit www.ternspharma.com.