Terns Pharmaceuticals has announced encouraging early data from its Phase I clinical trial of TERN-701, a small molecule allosteric BCR-ABL inhibitor, in patients with relapsed or refractory chronic myeloid leukemia (CML). The CARDINAL trial (NCT06163430) evaluated the safety and efficacy of TERN-701 in heavily pre-treated patients, many of whom had failed multiple tyrosine kinase inhibitors (TKIs).
The data, presented by Terns, revealed a cumulative major molecular response (MMR) rate of 50% at three months in patients without the T315I mutation. The trial also demonstrated a favorable safety profile, suggesting TERN-701 could offer a valuable new treatment option for CML patients who have exhausted other therapies.
Novel Allosteric Inhibition
TERN-701 represents a new class of CML drugs known as allosteric BCR-ABL inhibitors. Unlike traditional TKIs that bind to the ATP-binding site of the BCR-ABL protein, TERN-701 binds to a non-active site, modulating protein activity through conformational change. This mechanism is similar to asciminib (Scemblix), the first allosteric inhibitor approved for CML.
Amy Burroughs, CEO of Terns, highlighted the potential advantages of TERN-701, stating, "TERN-701 has the potential to demonstrate improved efficacy, safety, and ease of use...[allowing] for unified dosing across all CML patients."
Phase I Trial Results
The Phase I dose-escalation study enrolled 15 patients with relapsed/refractory CML who had previously received at least one second-generation TKI. Patients were treated with TERN-701 at doses of 160mg, 320mg, and 400mg once daily.
Key efficacy findings included:
- Seven of eight patients with baseline BCR-ABL transcript levels > 1% experienced decreases in BCR-ABL levels.
- A cumulative MMR rate of 50% (5/10) in non-T315I mutation patients with at least three months of treatment.
- 100% (4/4) of patients with MMR or better at baseline maintained their response.
Importantly, TERN-701 demonstrated a promising safety profile. There were no dose-limiting toxicities reported through the 400mg dose level, no adverse event-related treatment discontinuations or dose reductions, no Grade 3 or higher treatment-related adverse events, and no treatment-related serious adverse events.
Next Steps
The CARDINAL trial is now enrolling patients in the dose expansion phase, with a target of 20 patients at each of two, as-yet undetermined, dose levels. The primary endpoint for this phase is efficacy, with safety as the secondary endpoint. Terns anticipates beginning the dose expansion phase in the first half of 2025. These findings suggest that TERN-701 could provide a valuable treatment option for patients with CML, particularly those who have failed prior TKI therapies.
