TERN-701 Receives FDA Orphan Drug Designation in CML

US FDA

The allosteric BCR-ABL TKI TERN-701 (HS-10382) has been granted orphan drug designation by the FDA for the treatment of patients with chronic myeloid leukemia (CML).¹

TERN-701 is an allosteric BCR-ABL TKI that targets the BCR-ABL myristoyl pocket.² Allosteric TKIs that bind to the myristoyl pocket may address the limitations of active-site TKIs, including limited efficacy against active-site resistance mutations and off-target activity. TERN-701 may induce improved tumor suppression through its potent activity against a range of BCR-ABL mutations and its improved safety and tolerability profiles.

TERN-701 is in clinical development for patients with previously treated CML in the phase 1, global, multicenter, open-label, 2-part CARDINAL trial (NCT06163430).² Interim data from the initial dose-escalation cohorts of the trial are expected in the second half of 2024.¹

“CML is a serious leukemia that requires chronic, lifelong treatment,” Emil Kuriakose, MD, chief medical officer of Terns Pharmaceuticals, stated in a news release.¹ “Allosteric TKIs are a novel class of inhibitors that are highly selective and have demonstrated significantly improved clinical efficacy, safety, and tolerability compared with prior-generation active-site TKIs. Orphan drug designation for TERN-701 underscores the FDA’s recognition of the unmet need for [patients] living with CML and Terns’ commitment to developing new treatment options.”

Patients 18 years and older will be eligible for enrollment in the CARDINAL trial if they have an ECOG performance status of 0 to 2; an established cytopathologically confirmed diagnosis of BCR-ABL1–positive chronic-phase CML, regardless of T315I mutation status; have experienced progression, suboptimal response, or treatment intolerance with prior treatment with active site–targeting TKIs; are intolerant to asciminib and do not have relapsing or resistant disease; and have adequate organ function.³

Patients will be excluded from enrollment if they have CML in blast or accelerated phase; received systemic antineoplastic therapy, including prior TKIs, interferon-alfa, therapeutic antibodies, and chemotherapy, or other experimental therapies 7 days prior to the first dose of TERN-701; or have completed prior anticancer therapy without resolution of all associated and clinically significant toxicity, defined as toxicity that has reduced to baseline levels or grade 2 or lower.

Part 1 of CARDINAL is a dose-escalation portion that will assess TERN-701 monotherapy administered once daily in approximately 24 to 36 patients across a maximum of 4 dose cohorts.^2,3 The starting dose of TERN-701 is 160 mg once daily, and dose escalations range as high as 500 mg once daily; patients may also have the option to receive a dose of 80 mg once daily.² The primary end points of part 1 of the study are the incidence of dose-limiting toxicities during the first treatment cycle, as well as additional safety and tolerability measures. Secondary end points include pharmacokinetic and efficacy assessments, such as molecular and hematologic responses measured by the change from baseline in BCR-ABL transcript levels.

Part 2 of CARDINAL is a dose-expansion portion that will randomly assign approximately 40 patients to receive once-daily treatment with 1 of 2 doses of TERN-701, which will be selected based on data from part 1. The primary end point of part 2 is efficacy per hematologic and molecular responses. Secondary end points include safety, tolerability, and pharmacokinetics.

The overall objective of CARDINAL is to identify the optimal dose or doses of TERN-701 to use in a potential pivotal trial in patients with chronic-phase CML.

CARDINAL plans to enroll at sites across the United States, Europe, and other Terns global territories. A phase 1 trial (NCT05367700) investigating the tolerability, efficacy, and pharmacokinetics of once-daily TERN-701 for patients with CML is also ongoing in China.

References

1. Terns Pharmaceuticals announces orphan drug designation granted to TERN-701 for the treatment of chronic myeloid leukemia. News release. Terns Pharmaceuticals, Inc. March 11, 2024. Accessed March 12, 2024. https://ir.ternspharma.com/news-releases/news-release-details/terns-pharmaceuticals-announces-orphan-drug-designation-granted
2. Terns Pharmaceuticals announces global phase 1 clinical trial design of TERN-701 for the treatment of chronic myeloid leukemia. News release. Terns Pharmaceuticals, Inc. October 16, 2023. Accessed March 12, 2024. https://ir.ternspharma.com/news-releases/news-release-details/terns-pharmaceuticals-announces-global-phase-1-clinical-trial
3. CARDINAL- a clinical study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TERN-701 in participants with chronic myeloid leukemia. ClinicalTrials.gov. Updated December 8, 2023. Accessed March 12, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06163430