FDA Grants Breakthrough Therapy Designation to TERN-701 in Ph+ CP-CML

The FDA has granted breakthrough therapy designation to TERN-701, an investigational allosteric small molecule inhibitor, for treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic phase chronic myeloid leukemia (CP-CML).¹ This designation specifically applies to those who lack the T315I mutation and who have received prior treatment with 2 or more tyrosine kinase inhibitors (TKIs).

Breakthrough therapy designation is intended to expedite development and regulatory review of investigational agents that demonstrate substantial improvement over existing therapies for serious or life-threatening conditions. In CML, where sequential TKI therapy is standard, but resistance or intolerance remains a clinical challenge, new agents with differentiated mechanisms continue to be evaluated.

TERN-701 is an oral, highly selective allosteric inhibitor of BCR::ABL1 designed to target the myristoyl pocket,² distinguishing it mechanistically from ATP-competitive TKIs. This approach is conceptually similar to other allosteric inhibitors but may offer advantages in selectivity and tolerability, particularly in heavily pretreated populations.

“There remains an urgent need for CML treatments that offer improved efficacy, safety, and tolerability over current therapies,” said Scott Harris, chief development and operations officer at Terns Pharmaceuticals, in a news release.¹ “This designation from the FDA supports the significant potential of TERN-701 to be a best-in-disease therapy for patients [with CML] and offer substantial improvement based on the faster, deeper responses compared [with] prior TKIs and encouraging safety and tolerability profile observed to date.”

TERN-701 also holds an orphan drug designation from the FDA in CML, awarded in March of 2024.

Clinical Development of TERN-701: CARDINAL Trial

The designation is based on interim findings from the phase 1/2 CARDINAL trial (NCT06163430), which was initiated in early 2024 after clearance of TERN-701’s investigational new drug application in October 2023. This global, multicenter, open-label, 2-part dose-escalation and -expansion study is evaluating the safety, tolerability, pharmacokinetics, and antileukemic activity of TERN-701 administered once daily.³ The trial is enrolling an estimated total of 180 adult patients with CP-CML previously treated with at least 1 prior second-generation TKI such as bosutinib (Bosulif), dasatinib (Sprycel), or nilotinib (Tasigna), and who have experienced treatment failure, intolerance, or suboptimal response.

Importantly, responses with TERN-701 treatment have been reported in a population with a high baseline disease burden including those with prior exposure to multiple TKIs. According to interim data from the study, TERN-701 has demonstrated encouraging rates of major molecular response (MMR) and deep molecular response, including responses observed as early as 24 weeks. Of 32 efficacy-evaluable patients as of the June 30, 2025, data cut-off, 75% were in MMR by 24 weeks.²

Additionally, safety findings to date indicate that most treatment-emergent adverse events (TEAEs) have been low grade (74%), with relatively few discontinuations due to toxicity. The most common TEAEs recorded include diarrhea (22%), headache (18%), and nausea (16%). The incidence rates of grade 3 or higher TEAEs were all 10% or below, with the most common being neutropenia (7%) and thrombocytopenia (4%).

While early efficacy and safety signals are encouraging, longer follow-up and randomized data will be necessary to define the comparative benefit of TERN-701 relative to existing therapies, including other allosteric inhibitors and later-generation TKIs. Durability of response, long-term safety, and positioning within treatment algorithms remain key questions for future investigation.

REFERENCES

1. Terns Pharmaceuticals announces FDA breakthrough therapy designation granted to TERN-701 for certain patients with chronic myeloid leukemia. News release. Terns Pharmaceuticals. April 27, 2026. Accessed April 29, 2026. https://tinyurl.com/47wtu7mf

2. Jabbour E, Hughes T, Etten Van, et al. CARDINAL: A phase 1 study of TERN-701, a novel investigational allosteric BCR::ABL1 inhibitor for patients with previously treated CML. Blood. 2025;146(Supplement 1):901-901. doi:10.1182/blood-2025-901

3. A phase 1/2 clinical study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TERN-701 in participants with chronic myeloid leukemia (CARDINAL). ClinicalTrials.gov. Updated January 12, 2026. Accessed April 29, 2026. https://clinicaltrials.gov/study/NCT06163430