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]

Summary of Septerna's Conference Call Company Overview - **Company**: Septerna - **Focus**: G protein-coupled receptors (GPCRs) and small molecule discovery using the Native Complex platform - **Financial Position**: Well-capitalized with an operating cash runway into at least 2029 [2][2][2] Key Programs 1. **SEP479 Program** - **Target**: Parathyroid hormone receptor agonist for hyperparathyroidism - **Clinical Development**: Anticipated entry into the clinic in the first half of next year [3][3][9] - **Pharmacodynamics**: Demonstrated ability to normalize serum calcium and phosphate levels in preclinical studies with low dosing (0.15 mg/kg) [7][7][8] - **Safety Profile**: Improved pharmaceutical properties compared to previous candidate SEP786, which was discontinued due to safety issues related to bilirubin levels [6][14][15] - **Half-Life**: Predicted human half-life of 40-80 hours, supporting once-daily dosing [7][17][17] 2. **SEP631 Program** - **Target**: MRGPRX2 negative allosteric modulator for mast cell-driven diseases, including chronic spontaneous urticaria - **Clinical Development**: Currently in phase one trial, with data expected in early 2026 [9][12][25] - **Pharmacodynamics**: Demonstrated complete inhibition of extravasation in preclinical models [11][11] - **Differentiation**: Unique profile as an insurmountable negative allosteric modulator, potentially offering a long duration of action [10][19] 3. **Thyroid-Stimulating Hormone Receptor Program** - **Target**: Graves' disease and thyroid eye disease - **Market Opportunity**: Significant unmet need with a large market size; current treatments are outdated [26][26][27] - **Mechanism**: Utilizing an insurmountable negative allosteric modulator approach to inhibit receptor activation by various antibodies [27][28] Collaborations and Financials - **Collaboration with Novo Nordisk**: Announced a significant collaboration in May, including $195 million upfront and full support for R&D costs [4][4] Market Context and Competitive Landscape - **Mast Cell Indications**: Potential to target multiple mast cell-driven diseases, with chronic spontaneous urticaria as the initial focus [21][21] - **Competitive Landscape**: Acknowledgment of a crowded market for chronic spontaneous urticaria treatments, with a focus on differentiating SEP631 from existing therapies [22][22][19] Future Outlook - **Pipeline Expansion**: The platform has broader applications for GPCRs, with potential for a deep pipeline of products targeting various therapeutic areas [29][30] - **Clinical Trials**: Plans to initiate trials for SEP631 in chronic spontaneous urticaria following successful phase one results [25][25] Conclusion - **Overall Sentiment**: Positive outlook on the progress of Septerna's programs, with a focus on advancing clinical development and addressing significant market needs in the biopharma space [30][30]