Summary of Septerna Conference Call Company Overview - **Company**: Septerna (NasdaqGM:SEPN) - **Focus**: Drug discovery targeting G protein-coupled receptors (GPCRs) using the Native Complex Platform - **Financial Position**: Cash runway into at least 2029 [4][4][4] Key Programs SEP631 - **Type**: MRGPRX2 inhibitor, currently in Phase 1 clinical trials - **Indication**: Mast cell-driven diseases - **Expected Readouts**: First half of the upcoming year [3][4][5] - **Mechanism**: Targets MRGPRX2, leading to mast cell degranulation through an IgE-independent pathway [5][6] - **Profile**: - High potency (single-digit nanomolar to high picomolar) - Excellent oral bioavailability with once-daily dosing projected - Good preclinical safety profile [6][6][11] - **Phase 1 Trial Design**: Randomized placebo-controlled, includes skin challenge with Icatibant [8][9][17] SEP479 - **Type**: PTH1 receptor agonist for hypoparathyroidism, expected to enter the clinic in the first half of next year [3][28] - **Challenges**: Historically difficult target for small molecules; previous candidate (SEP786) faced issues with bilirubin increases [29][30] - **Current Status**: - New compound shows no UGT1A1 inhibition or bilirubin increase - Predicted human half-life of 40-80 hours, aiming for once-daily oral dosing [30][31] - **Clinical Goals**: - Aim for serum calcium increases of about 1 mg/dL in Phase 1 trials - Final IND enabling studies wrapping up, including a 28-day GLP-tox study in monkeys [33][34][40] Future Directions - **Phase 2 Strategy**: Plans to move into chronic spontaneous urticaria (CSU) trials post-Phase 1 [22][26] - **Exploration of Other Indications**: Potential for expansion into asthma and pain-related conditions involving mast cells [26][26] - **Collaboration with Novo**: Developing a TSH receptor negative allosteric modulator, with hopes for a development candidate next year [41][42] Additional Insights - **Safety Profile**: SEP631 has shown no liver involvement in preclinical studies, distinguishing it from other X2 agonists [11][12] - **Market Opportunities**: Significant market potential for both SEP631 and SEP479 due to their targeted mechanisms and the unmet medical needs in their respective indications [4][4][28]