Terns Pharmaceuticals (TERN) Study Update summary

Background and Unmet Need in CML

• CML affects about 10,000 new US patients annually, with prevalence expected to triple by 2040; most require lifelong TKI therapy, but 40% switch by five years due to intolerance or resistance, and only half achieve deep molecular response after switching.

• Chronic use of active-site TKIs is associated with serious off-target adverse events, including cardiovascular issues.

• Allosteric TKIs, such as asciminib, have shown improved efficacy and safety, setting a new standard and making the class a key opportunity for CML treatment evolution.

• Next-generation allosteric BCR-ABL inhibitors may offer superior target coverage, selectivity, and patient convenience, aiming for deeper responses and fewer discontinuations.

TERN-701 Opportunity, Development, and Study Design

• TERN-701 is a novel, once-daily, food-independent allosteric BCR-ABL inhibitor designed for high potency, including against T315i, and optimized for patient convenience.

• The CARDINAL phase I study enrolls chronic phase, second-line-plus CML patients with prior TKI failure, suboptimal response, or intolerance, including those intolerant to asciminib.

• Interim phase I data in December 2024 will include 10-20 patients, with 5-10 having at least three months of treatment across at least two dose levels; six-month data in 2025 will inform registrational trial design.

• Early endpoints focus on safety, tolerability, and descriptive efficacy signals, such as hematologic response and BCR-ABL transcript changes, leveraging data from a parallel phase I study in China.

• The study is designed to inform dose optimization and future registrational strategy, with expansion cohorts planned for more robust efficacy and safety assessment.

Early Clinical Data Interpretation and Response Measures

• Early phase I data are best interpreted at the individual patient level, considering baseline disease biology, prior therapies, and BCR-ABL transcript levels.

• Early efficacy signals include stabilization or decline in BCR-ABL transcripts, especially in heavily pretreated or high-burden patients, with positive outcomes also seen in those intolerant to prior TKIs.

• Early data will focus on safety, tolerability, and descriptive efficacy, not major molecular response (MMR) rates.

• Number of prior TKIs alone is not a reliable indicator of disease refractoriness; context of resistance, intolerance, and disease progression is critical.

• Early data will be visualized using individual patient profiles, such as spaghetti plots or shift tables, to contextualize transcript changes.