Financial Data and Key Metrics Changes - The company has identified a new development candidate for its parathyroid hormone receptor program, moving forward after unexpected findings with a previous compound [3][5] - The new compound, SEP-479, shows significantly improved pharmaceutical properties compared to the discontinued SEP-786, with a lower effective dose in preclinical models [9][10] Business Line Data and Key Metrics Changes - The parathyroid hormone receptor program has transitioned to SEP-479, which has demonstrated the ability to normalize serum calcium levels in preclinical models [9][10] - The MRGPRX2 program has initiated a phase one trial with a randomized, placebo-controlled design, focusing on skin-based indications [14][15] Market Data and Key Metrics Changes - The company has formed a collaboration with Novo Nordisk, which includes a $195 million upfront payment and covers all R&D costs going forward, allowing the company to expand its programs without increasing its burn rate [46][47] Company Strategy and Development Direction - The company is focused on GPCR drug discovery, utilizing its Native Complex Platform to optimize compounds quickly and effectively [2][4] - The strategic partnership with Novo Nordisk aims to leverage their expertise in the metabolic space while pursuing multiple programs in parallel [46][47] - The company is exploring additional opportunities in areas such as osteoporosis, neurology, cardiovascular diseases, and respiratory diseases [50][51] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the connection between preclinical data and eventual patient data for PTH peptides, indicating a strong potential for the new compound [21][22] - The company aims to gather safety and pharmacokinetic data in phase one trials to inform future patient dosing strategies [23][24] Other Important Information - The company has completed additional studies on SEP-786 to understand its effects better, particularly regarding bilirubin metabolism [7][8] - The company is optimistic about the potential for once-daily dosing with SEP-479, which could significantly improve patient compliance [31][32] Q&A Session Summary Question: When did the company start to see issues with bilirubin in the SINOS study for SEP-786? - The company observed bilirubin issues within a couple of days in the SINOS study, similar to findings in patients [18] Question: What is the development plan for SEP-479? - The company plans to conduct a phase one study with hopes of seeing safety and pharmacokinetic properties that will inform patient dosing [20][22] Question: How does SEP-479 differ from SEP-786? - SEP-479 is a completely different structural series with no observed functional differences in assays, but it is expected to have a lower risk of off-target effects [29][30] Question: What is the expected timeline for the phase one trial? - The company anticipates starting the phase one trial in the first half of next year, with more precise timing to be communicated later [34] Question: What is the opportunity within mast cell diseases for the MRGPRX2 program? - The company sees potential in various mast cell-driven diseases, including chronic spontaneous urticaria and atopic dermatitis, and plans to pursue multiple lead indications [35][40]

Summary of Septurna (SEPN) 2025 Conference Call Company Overview - **Company**: Septurna - **Event**: 2025 Cantor Healthcare Conference - **CEO**: Jeff Feiner introduced the company and its updates on drug discovery platforms and lead programs [1][2] Industry and Market Context - **Industry**: Biopharmaceuticals focusing on G protein-coupled receptors (GPCRs) - **Market Opportunity**: GPCRs are a significant target class in drug discovery, with over 70% of approved GPCR drugs targeting just six subfamilies [6] Key Programs and Developments 1. Lead Programs - **SEP-479**: Next-generation parathyroid hormone receptor small molecule agonist for hyperparathyroidism, announced as a new development candidate [4][20] - **SEP-631**: Focused on MRGPRAX2 for mast cell-driven diseases, recently started Phase 1 trials [5][33] 2. Drug Discovery Platform - **Native Complex Platform**: A novel approach to drug discovery that allows for the isolation of fully functional GPCRs, enhancing the ability to design effective small molecules [3][7] - **Structural Biology**: Utilizes cryo-electron microscopy for rapid structure determination, enabling efficient structure-based design [9][10] 3. Therapeutic Areas - **Focus Areas**: Endocrinology, immunology, inflammation, metabolic diseases, and early-stage efforts in neurology [11][12] Clinical Insights SEP-479 - **Mechanism**: Aims to replace traditional injectable therapies for hypoparathyroidism with an oral small molecule [17] - **Efficacy**: Demonstrated effectiveness in animal models at significantly lower doses compared to previous compounds [25][26] - **Safety Profile**: No observed UGT1A1 inhibition, which was a concern with the previous candidate SEP-786 [32] SEP-631 - **Target**: MRGPRAX2, involved in mast cell activation pathways, with a focus on chronic spontaneous urticaria [34] - **Profile**: Designed as a negative allosteric modulator with a slow off-rate, showing promise in preclinical models [35][38] Collaborations and Financials - **Novo Nordisk Collaboration**: Involves five targets with an upfront payment of $195 million, significantly reducing Septurna's R&D costs [46] - **Financial Position**: Well-capitalized with operating capital projected to last until at least 2029 [4][48] Management and Governance - **Experienced Team**: Led by a seasoned management team and supported by a strong board of directors and advisory board [47] Conclusion - **Outlook**: Septurna is positioned for growth with a robust pipeline and strategic collaborations, focusing on innovative therapies for significant unmet medical needs [48]

Core Insights - Septerna, Inc. is a clinical-stage biotechnology company focused on G protein-coupled receptor (GPCR) drug discovery [1][2] - The company will participate in two upcoming investor conferences in September 2025, showcasing its commitment to engaging with investors [1] Company Overview - Septerna is advancing GPCR therapies to address significant unmet medical needs, utilizing its proprietary Native Complex Platform™ for drug discovery [2] - The company has developed a diverse pipeline of novel oral small molecule drug candidates across various therapeutic areas, including endocrinology, immunology, inflammation, and metabolic diseases [2]

Core Insights - Septerna, Inc. has initiated the Phase 1 clinical trial for SEP-631, a selective oral small molecule MRGPRX2 negative allosteric modulator aimed at treating chronic spontaneous urticaria (CSU) and other mast cell-driven diseases [1][2][4] Company Overview - Septerna is a clinical-stage biotechnology company focused on G protein-coupled receptor (GPCR) drug discovery, utilizing its proprietary Native Complex Platform™ to develop novel oral small molecule drug candidates [5] - The company aims to address significant unmet medical needs in various therapeutic areas, including endocrinology, immunology, inflammation, and metabolic diseases [5] Clinical Trial Details - The Phase 1 clinical trial will consist of a single-ascending dose (SAD) and multiple-ascending dose (MAD) study, enrolling approximately 150 healthy adult volunteers to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SEP-631 [3] - The SAD portion is currently underway, focusing on escalating oral doses, while the MAD portion will assess the safety and tolerability over a treatment period [3] Disease Context - Mast cell-driven diseases, such as CSU, affect millions globally and often result in inadequate symptom relief from existing therapies, highlighting the need for new treatment options [2] - CSU is characterized by spontaneous and persistent hives and angioedema, with mast cell activation playing a critical role in symptom development [2][4]

PART I. FINANCIAL INFORMATION [Item 1. Financial Statements (unaudited)](index=7&type=section&id=Item%201.%20Financial%20Statements%20(unaudited)) Unaudited H1 2025 financials reveal decreased assets to $415.2 million, a widened net loss of $46.3 million, and increased operating cash outflow [Condensed Balance Sheets](index=7&type=section&id=Condensed%20Balance%20Sheets) As of June 30, 2025, total assets decreased to $415.2 million from $456.6 million, primarily due to a drop in cash, while equity declined Condensed Balance Sheet Summary (in thousands) | Account | June 30, 2025 | December 31, 2024 | | :--- | :--- | :--- | | **Assets** | | | | Cash and cash equivalents | $189,311 | $238,196 | | Total current assets | $334,141 | $356,824 | | **Total assets** | **$415,231** | **$456,554** | | **Liabilities & Equity** | | | | Total current liabilities | $15,127 | $12,849 | | **Total liabilities** | **$37,674** | **$36,507** | | **Total stockholders' equity** | **$377,557** | **$420,047** | | Accumulated deficit | $(164,688) | $(118,374) | [Condensed Statements of Operations and Comprehensive Loss](index=8&type=section&id=Condensed%20Statements%20of%20Operations%20and%20Comprehensive%20Loss) Net loss for H1 2025 widened to $46.3 million from $30.6 million, driven by increased R&D and G&A expenses Statement of Operations Summary (in thousands, except per share data) | Metric | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :--- | :--- | :--- | | Revenue | $338 | $687 | | Research and development | $41,459 | $28,188 | | General and administrative | $13,767 | $6,054 | | **Total operating expenses** | **$55,226** | **$34,242** | | Loss from operations | $(54,888) | $(33,555) | | **Net loss** | **$(46,314)** | **$(30,607)** | | Net loss per share | $(1.05) | $(13.40) | [Condensed Statements of Cash Flows](index=10&type=section&id=Condensed%20Statements%20of%20Cash%20Flows) Net cash used in operating activities increased to $43.6 million in H1 2025, with minimal financing cash compared to prior year Cash Flow Summary (in thousands) | Activity | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :--- | :--- | :--- | | Net cash used in operating activities | $(43,630) | $(29,698) | | Net cash used in investing activities | $(5,660) | $(2,565) | | Net cash provided by financing activities | $405 | $74,952 | | **Net (decrease) increase in cash** | **$(48,885)** | **$42,689** | [Notes to Unaudited Condensed Financial Statements](index=12&type=section&id=Notes%20to%20Unaudited%20Condensed%20Financial%20Statements) Notes detail the company's IPO, a major collaboration with Novo Nordisk, and confirm sufficient capital for 12 months - The company is a biotechnology firm focused on GPCR oral small molecule drug discovery using its proprietary Native Complex Platform™[31](index=31&type=chunk) - In October 2024, the company completed its IPO, raising net proceeds of **$302.8 million**[35](index=35&type=chunk) - The company believes its cash, cash equivalents, and marketable securities of **$379.2 million** as of June 30, 2025, are sufficient to fund operations for at least **12 months**[40](index=40&type=chunk) - In May 2025, the company entered into a collaboration with Novo Nordisk, effective July 1, 2025, receiving a **$195.0 million** upfront payment in July 2025 and eligible for up to **$498.0 million** in milestones per R&D program, plus tiered royalties[52](index=52&type=chunk)[54](index=54&type=chunk) - A milestone related to the 2023 asset purchase agreement with Vertex was achieved in July 2025, resulting in a **$12.5 million** payment received in August 2025[57](index=57&type=chunk) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=29&type=section&id=Item%202.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses the GPCR platform, increased H1 2025 operating losses, and the Novo Nordisk collaboration, projecting funding into 2029 [Overview and Pipeline](index=29&type=section&id=Overview%20and%20Pipeline) Septerna, a biotechnology company, pioneers GPCR oral small molecule drug discovery with its Native Complex Platform™ and a pipeline in endocrinology, immunology, and metabolic diseases - The company's proprietary Native Complex Platform™ replicates the natural structure and function of GPCRs, enabling an industrialized, structure-based drug design approach[100](index=100&type=chunk) Development Pipeline Summary | Program / Target | Therapeutic Area | Development Status | | :--- | :--- | :--- | | **Wholly-Owned Programs** | | | | PTH1R Program | Endocrinology | Discovery | | SEP-631 (MRGPRX2) | Immunology and Inflammation | Discovery | | TSHR Program | Endocrinology | Discovery | | **Partnered Programs** | | | | Metabolic Programs (GLP-1R, etc.) | Obesity & Cardiometabolic | Partnered (Novo) | [Results of Operations](index=39&type=section&id=Results%20of%20Operations) Net loss increased to $46.3 million in H1 2025, driven by a $13.3 million rise in R&D expenses and a $7.7 million increase in G&A expenses Comparison of Results of Operations (in thousands) | Line Item | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | Change | | :--- | :--- | :--- | :--- | | Revenue | $338 | $687 | $(349) | | Research and development | $41,459 | $28,188 | $13,271 | | General and administrative | $13,767 | $6,054 | $7,713 | | **Net loss** | **$(46,314)** | **$(30,607)** | **$(15,707)** | Research and Development Expense Breakdown (in thousands) | Program | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | Change | | :--- | :--- | :--- | :--- | | PTH1R | $6,733 | $4,746 | $1,987 | | SEP-631 (MRGPRX2) | $3,765 | $874 | $2,891 | | Other programs | $9,996 | $2,153 | $7,843 | | Unallocated costs | $20,965 | $20,415 | $550 | | **Total R&D Expense** | **$41,459** | **$28,188** | **$13,271** | [Liquidity and Capital Resources](index=42&type=section&id=Liquidity%20and%20Capital%20Resources) With $379.2 million in cash as of June 30, 2025, bolstered by $195.0 million from Novo and $12.5 million from Vertex, the company projects funding into 2029 - The company historically financed operations through convertible notes, preferred stock, and its October 2024 IPO, which raised **$302.8 million** in net proceeds[143](index=143&type=chunk) - Management projects that its cash position of **$379.2 million** as of June 30, 2025, combined with the **$195.0 million** from Novo and **$12.5 million** from Vertex, will fund operations into **2029**[144](index=144&type=chunk) Summary of Cash Flows (in thousands) | Cash Flow Activity | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :--- | :--- | :--- | | Net cash used in operating activities | $(43,630) | $(29,698) | | Net cash used in investing activities | $(5,660) | $(2,565) | | Net cash provided by financing activities | $405 | $74,952 | [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=28&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) As a smaller reporting company, Septerna, Inc. is not required to provide the information requested under this item - The company is a smaller reporting company as defined by Rule 12b-2 of the Exchange Act and is not required to provide quantitative and qualitative disclosures about market risk[161](index=161&type=chunk) [Item 4. Controls and Procedures](index=28&type=section&id=Item%204.%20Controls%20and%20Procedures) Management concluded disclosure controls were effective as of June 30, 2025, with no material changes in internal control over financial reporting - Based on an evaluation as of the end of the period, the Principal Executive Officer and Principal Financial Officer concluded that the company's disclosure controls and procedures were effective at a reasonable assurance level[163](index=163&type=chunk) - No changes in internal control over financial reporting occurred during the quarter ended June 30, 2025, that have materially affected, or are reasonably likely to materially affect, internal controls[164](index=164&type=chunk) PART II. OTHER INFORMATION [Item 1. Legal Proceedings](index=29&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any legal proceedings deemed probable to have a material adverse effect on its business - The company is not currently involved in any litigation or legal proceedings expected to have a material adverse effect on its business, financial condition, or results of operations[168](index=168&type=chunk) [Item 1A. Risk Factors](index=29&type=section&id=Item%201A.%20Risk%20Factors) Updated risk factors include potential FDA disruptions, unfavorable global economic conditions, geopolitical instability, and healthcare legislative reforms impacting drug pricing - Risks include potential disruptions at the FDA and other agencies due to staffing reductions, funding shortages, or government shutdowns, which could delay product development and approval[170](index=170&type=chunk)[171](index=171&type=chunk) - Unfavorable global economic conditions, political instability, and geopolitical events such as military conflicts and trade tariffs could adversely affect the business, financial condition, and stock price[172](index=172&type=chunk)[173](index=173&type=chunk) - Healthcare legislative reforms, including the Inflation Reduction Act (IRA) and recent Executive Orders, may negatively impact the business by containing healthcare costs and affecting drug pricing and reimbursement[176](index=176&type=chunk)[179](index=179&type=chunk)[180](index=180&type=chunk) - Recent changes to U.S. tax law, such as the One Big Beautiful Bill Act (H.R.1), could materially affect the company's business and cash flow, particularly regarding the capitalization and amortization of R&D expenses[186](index=186&type=chunk) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=32&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) No unregistered sales occurred; IPO proceeds of $302.8 million are reallocated to advance other pipeline candidates after discontinuing the SEP-786 program - The company's October 2024 IPO generated net proceeds of **$302.8 million**[189](index=189&type=chunk) - The planned use of IPO proceeds has changed due to the discontinuation of the SEP-786 product candidate; funds will now advance other programs, including a next-generation PTH1R agonist and SEP-631[190](index=190&type=chunk) [Item 3. Defaults Upon Senior Securities](index=33&type=section&id=Item%203.%20Defaults%20Upon%20Senior%20Securities) Not applicable - No defaults upon senior securities were reported[192](index=192&type=chunk) [Item 4. Mine Safety Disclosures](index=33&type=section&id=Item%204.%20Mine%20Safety%20Disclosures) Not applicable - No mine safety disclosures were required[193](index=193&type=chunk) [Item 5. Other Information](index=33&type=section&id=Item%205.%20Other%20Information) No directors or officers adopted or terminated Rule 10b5-1 trading plans during the fiscal quarter ended June 30, 2025 - No directors or officers adopted or terminated a Rule 10b5-1 trading plan or other similar trading arrangement during the quarter[194](index=194&type=chunk) [Item 6. Exhibits](index=34&type=section&id=Item%206.%20Exhibits) This section lists exhibits filed with the Form 10-Q, including corporate governance documents, the Novo Collaboration Agreement, and certifications - The list of exhibits includes the Novo Collaboration Agreement, CEO/CFO certifications, and XBRL data files[196](index=196&type=chunk)

[Executive Summary](index=1&type=section&id=Executive%20Summary) This section summarizes Septerna's clinical advancements, financial strengthening, and key leadership changes [Key Business Progress and Milestones](index=1&type=section&id=Key%20Business%20Progress%20and%20Milestones) Septerna is actively advancing its clinical pipeline, initiating a Phase 1 trial for SEP-631 for mast cell diseases and progressing its PTH1R agonist program towards development candidate selection and a Phase 1 trial in early 2026 - Initiating Phase 1 Trial for SEP-631, MRGPRX2 NAM Program, for Mast Cell Diseases in **Q3 2025** [2](index=2&type=chunk)[3](index=3&type=chunk)[7](index=7&type=chunk) - Advancing selection of a next-generation oral small molecule PTH1R Agonist for clinical development in **Q3 2025**, with a Phase 1 trial planned for **H1 2026** [2](index=2&type=chunk)[3](index=3&type=chunk)[7](index=7&type=chunk) [Financial Outlook and Strategy](index=1&type=section&id=Financial%20Outlook%20and%20Strategy) The company's financial position has been significantly bolstered by the effective collaboration with Novo Nordisk, extending its cash runway well into 2029 - Updated cash runway expected to support operating plans at least into **2029**, bolstered by the Novo Nordisk collaboration [2](index=2&type=chunk)[3](index=3&type=chunk)[14](index=14&type=chunk) [Corporate Overview and Program Updates](index=1&type=section&id=Corporate%20Overview%20and%20Anticipated%20Milestones) This section covers Septerna's leadership, Novo Nordisk collaboration, and pipeline program advancements [Leadership Update](index=1&type=section&id=Leadership%20Update) Septerna announced the promotion of Liz Bhatt, MS, MBA, to President, effective August 1, 2025, recognizing her instrumental role in strategic partnerships and company growth - **Liz Bhatt**, COO, promoted to President, effective **August 1, 2025** [6](index=6&type=chunk) - Ms. Bhatt was instrumental in securing the multi-billion-dollar strategic partnership with Novo Nordisk and guiding Septerna through a successful IPO in **2024** [9](index=9&type=chunk) [Collaboration with Novo Nordisk](index=1&type=section&id=Collaboration%20Agreement%20with%20Novo%20Nordisk) The global collaboration and license agreement with Novo Nordisk became effective on July 1, 2025, initiating joint R&D efforts for cardiometabolic diseases and resulting in a $195 million upfront payment to Septerna - Global collaboration and license agreement with Novo Nordisk became effective on **July 1, 2025**, focusing on oral small molecule therapies for obesity, type 2 diabetes, and other cardiometabolic diseases [7](index=7&type=chunk) - Septerna received a **$195 million upfront payment** in **July 2025** in connection with the agreement's effectiveness [7](index=7&type=chunk) [Pipeline Program Updates](index=1&type=section&id=Pipeline%20Program%20Updates) Septerna provided updates on its key pipeline programs, including the initiation of a Phase 1 trial for SEP-631, progress towards a development candidate for its PTH1R agonist, and advancement of its TSHR NAM and discovery programs [SEP-631 MRGPRX2 NAM Program](index=1&type=section&id=SEP-631%20MRGPRX2%20NAM%20Program) Septerna is initiating a Phase 1 clinical trial for SEP-631, an oral small molecule for mast cell diseases, in healthy volunteers during Q3 2025 - Initiating a Phase 1 clinical trial for SEP-631 in healthy volunteers in **Q3 2025** to assess safety, tolerability, pharmacokinetics, and pharmacodynamics [7](index=7&type=chunk) - SEP-631 is a selective oral small molecule MRGPRX2 negative allosteric modulator (NAM) for mast cell diseases, including chronic spontaneous urticaria [7](index=7&type=chunk) [PTH1R Agonist Program](index=1&type=section&id=PTH1R%20Agonist%20Program) The PTH1R agonist program for hypoparathyroidism is on track to select a next-generation development candidate in Q3 2025, with a Phase 1 clinical trial planned for H1 2026 - Tracking towards selection of a next-generation PTH1R agonist development candidate in **Q3 2025** [7](index=7&type=chunk) - Plans to commence a Phase 1 clinical trial in **H1 2026**, following successful completion of preclinical development activities [7](index=7&type=chunk) - Goal is to provide full-day calcium control in hypoparathyroidism patients [7](index=7&type=chunk) [TSHR NAM Program](index=1&type=section&id=TSHR%20NAM%20Program) Septerna is making progress on its TSHR NAM program, moving multiple lead compounds closer to development candidate selection for Graves' disease and thyroid eye disease - Progressing multiple lead compounds closer to development candidate selection for a potential disease-modifying oral treatment for Graves' disease and thyroid eye disease [7](index=7&type=chunk) [Discovery Programs](index=1&type=section&id=Discovery%20Programs) The company continues to advance its discovery-stage programs across multiple therapeutic areas, leveraging its Native Complex Platform™ - Advancing discovery-stage programs utilizing its Native Complex Platform™ across multiple therapeutic areas [7](index=7&type=chunk) [Second Quarter 2025 Financial Results](index=3&type=section&id=Second%20Quarter%202025%20Financial%20Results) This section details Septerna's Q2 2025 financial results, including key highlights, statements of operations, and balance sheet [Summary Financial Highlights](index=3&type=section&id=Summary%20Financial%20Highlights) Septerna reported a net loss of $24.8 million for Q2 2025, with increased R&D and G&A expenses compared to the prior year, while its cash position was strengthened by the Novo Nordisk upfront payment Key Financial Highlights (Q2 2025 vs. Q2 2024) | Metric | Q2 2025 (Millions) | Q2 2024 (Millions) | Change (YoY) | | :----------------------- | :------------------ | :------------------ | :------------ | | Cash, cash equivalents, and marketable securities (as of June 30) | $379.2 | N/A | N/A | | R&D Expenses | $22.2 | $15.0 | +48.0% | | G&A Expenses | $6.9 | $3.4 | +102.9% | | Net Loss | $(24.8) | $(16.4) | +51.2% | - Cash, cash equivalents, and marketable securities totaled **$379.2 million** as of June 30, 2025. Following receipt of the **$195.0 million upfront payment** from Novo Nordisk in July, Septerna now expects its cash runway to extend at least into **2029** [14](index=14&type=chunk) [Condensed Statements of Operations](index=6&type=section&id=Condensed%20Statements%20of%20Operations) The condensed statements of operations show a net loss of $24.8 million for the three months ended June 30, 2025, an increase from $16.4 million in the prior year, driven by higher R&D and G&A expenses Condensed Statements of Operations (Unaudited, In thousands) | | Three Months Ended June 30, | | Six Months Ended June 30, | | :------------------------------------------ | :--- | :--- | :--- | :--- | | | **2025** | **2024** | **2025** | **2024** | | Revenue | $119 | $370 | $338 | $687 | | Operating expenses: | | | | | | Research and development | 22,188 | 15,035 | 41,459 | 28,188 | | General and administrative | 6,909 | 3,400 | 13,767 | 6,054 | | Total operating expenses | 29,097 | 18,435 | 55,226 | 34,242 | | Loss from operations | (28,978) | (18,065) | (54,888) | (33,555) | | Interest and other income, net | 4,140 | 1,515 | 8,574 | 2,746 | | Benefit for income taxes | — | 109 | — | 202 | | Net loss attributable to common stockholders | $(24,838) | $(16,441) | $(46,314) | $(30,607) | | Net loss per share attributable to common stockholders, basic and diluted | $(0.56) | $(7.03) | $(1.05) | $(13.40) | | Weighted-average shares outstanding, basic and diluted | 44,165,168 | 2,337,585 | 44,051,918 | 2,284,414 | [Condensed Balance Sheets](index=6&type=section&id=Condensed%20Balance%20Sheets) As of June 30, 2025, Septerna reported total assets of $415.2 million and total stockholders' equity of $377.6 million, with cash, cash equivalents, and marketable securities at $379.2 million Condensed Balance Sheets (Unaudited, In thousands) | | June 30, | | December 31, | | :------------------------------------------ | :--- | :--- | :--- | :--- | | | **2025** | | **2024** | | Cash, cash equivalents and marketable securities | $379,194 | | $420,789 | | Working capital | 319,014 | | 343,975 | | Total assets | 415,231 | | 456,554 | | Total liabilities | 37,674 | | 36,507 | | Additional paid-in capital | 542,024 | | 538,321 | | Accumulated deficit | (164,688) | | (118,374) | | Total stockholders' equity | 377,557 | | 420,047 | [About Septerna](index=3&type=section&id=About%20Septerna) This section describes Septerna's company profile, Native Complex Platform™, and GPCR drug discovery focus [Company Profile and Platform](index=3&type=section&id=Company%20Profile%20and%20Platform) Septerna is a biotechnology company focused on G protein-coupled receptor (GPCR) drug discovery, utilizing its proprietary Native Complex Platform™ to develop oral small molecule therapies across endocrinology, immunology and inflammation, and metabolic diseases - Septerna, Inc. is a biotechnology company pioneering a new era of GPCR drug discovery [11](index=11&type=chunk) - Utilizes its proprietary Native Complex Platform™ to discover and develop a deep pipeline of oral small molecule product candidates [11](index=11&type=chunk) - Initial therapeutic areas of focus include endocrinology, immunology and inflammation, and metabolic diseases [11](index=11&type=chunk) [Forward-Looking Statements](index=3&type=section&id=Forward-Looking%20Statements) This section outlines disclaimers for forward-looking statements, emphasizing risks and uncertainties for future results [Disclaimer and Risk Factors](index=3&type=section&id=Disclaimer%20and%20Risk%20Factors) This section serves as a disclaimer for forward-looking statements, highlighting that actual results may differ materially due to various risks and uncertainties, including those related to clinical trials, regulatory approvals, intellectual property, and economic conditions - The press release contains forward-looking statements regarding Septerna's beliefs and expectations, including program advancements, clinical trial initiations, and financial outlook [12](index=12&type=chunk) - These statements are subject to risks, uncertainties, and important factors that may cause actual events or results to differ materially [13](index=13&type=chunk) - Risks include uncertainties related to the Novo Nordisk collaboration, product candidates entering clinical trials, regulatory approvals, clinical development outcomes, intellectual property, and general economic conditions [13](index=13&type=chunk)

Core Insights - Septerna, Inc. is advancing its next-generation oral small molecule PTH1R agonist program for hypoparathyroidism, with plans to select a development candidate in Q3 2025 and initiate a Phase 1 clinical trial in H1 2026 [2][3] - The company is also initiating a Phase 1 clinical trial for SEP-631, an oral small molecule for mast cell diseases, in Q3 2025 [7] - Septerna's cash position is strong, with $379.2 million in cash and equivalents as of June 30, 2025, and an expected cash runway extending into 2029 following a $195 million upfront payment from Novo Nordisk [12][15] PTH1R Agonist Program - The PTH1R agonist program aims to provide full-day calcium control for patients with hypoparathyroidism, with a development candidate selection expected in Q3 2025 [3] - A Phase 1 clinical trial is planned to commence in the first half of 2026 after successful preclinical development [3] SEP-631 MRGPRX2 NAM Program - SEP-631 is a selective oral small molecule MRGPRX2 negative allosteric modulator for mast cell diseases, with a Phase 1 trial to assess safety and tolerability in healthy volunteers starting in Q3 2025 [7] Collaboration with Novo Nordisk - A global collaboration and license agreement with Novo Nordisk became effective on July 1, 2025, focusing on the discovery and development of oral small molecule therapies for obesity, type 2 diabetes, and other cardiometabolic diseases [7] - Septerna received a $195 million upfront payment as part of this collaboration [7] Business Highlights - The company continues to progress its TSHR NAM program, moving multiple lead compounds closer to development candidate selection for treating Graves' disease and thyroid eye disease [7] - Septerna's discovery-stage programs are advancing across various therapeutic areas utilizing its Native Complex Platform™ [7] Financial Results - For Q2 2025, Septerna reported R&D expenses of $22.2 million, up from $15.0 million in Q2 2024, and G&A expenses of $6.9 million, compared to $3.4 million in the same period [12] - The net loss for Q2 2025 was $24.8 million, compared to a net loss of $16.4 million in Q2 2024 [12][14]

Core Viewpoint - HC Wainwright has initiated coverage on Septerna, Inc., highlighting its innovative drug design platform targeting previously undruggable G protein-coupled receptors (GPCRs) [1][3] Company Overview - Septerna is focused on GPCR drug discovery through its proprietary Native Complex Platform, aiming to maximize the potential of GPCR therapies [1] - The company has a deep pipeline of oral small molecule product candidates targeting endocrinology, immunology and inflammation, and metabolic diseases [2] Financial Insights - Analyst Raghuram Selvaraju noted that Septerna trades at a discount to its cash position and recent partnership cash, presenting a risk-mitigated investment opportunity with multiple catalysts expected in the next 6 to 12 months [3][7] - HC Wainwright has set a Buy rating for Septerna with a price target of $26 [3] Drug Development - The leading drug candidate, SEP-631, is a selective oral small molecule MRGPRX2 negative allosteric modulator for mast cell diseases, including chronic spontaneous urticaria (CSU) [4] - SEP-631 could provide a unique treatment option for CSU patients due to its selective mast cell inhibition and potential for combination therapy [4] Market Potential - If SEP-631 can match the efficacy of Novartis and Roche's Xolair, which generated nearly $3.9 billion in sales in 2023, it could achieve blockbuster status [5] - Septerna has entered an exclusive global collaboration with Novo Nordisk for the development of oral small-molecule medicines for obesity, type 2 diabetes, and other cardiometabolic diseases, starting with four development programs [6] Valuation Perspective - HC Wainwright emphasized that the financial implications of the partnership suggest Septerna's implied enterprise value may be negligible or negative, indicating the company is undervalued [7]

Summary of Septerna (SEPN) 2025 Conference Call Company Overview - **Company**: Septerna (SEPN) - **Focus**: Development of drugs targeting G protein-coupled receptors (GPCRs) using a proprietary platform called the native complex platform [1][2] Portfolio Strategy - **Target Selection**: Focus on biologically and clinically validated targets with significant unmet needs and market opportunities [2] - **Current Programs**: Discussion of four main programs, including a parathyroid hormone receptor agonist, MRGPRX2, thyroid stimulating hormone receptor negative allosteric modulator, and an incretin receptor agonist [3][4] Financial Position - **Capitalization**: Well-capitalized following an IPO in October and a recent collaboration with Novo Nordisk, providing a strong financial position for ongoing research and development [3][54] Key Programs 1. **Parathyroid Hormone Receptor Agonist Program** - **Target**: Oral small molecules for hypoparathyroidism [16] - **Challenges**: Discontinued trial of first compound (SEP-786) due to unanticipated bilirubin levels, but ongoing investigation into next-generation compounds [23][24][26] - **Animal Model Results**: Promising results in normalizing calcium levels in hypoparathyroid rat models with new compounds showing lower dosing requirements compared to SEP-786 [29][31][34] 2. **MRGPRX2 Program** - **Target**: Mast cell diseases, including chronic spontaneous urticaria and allergic asthma [35][37] - **Compound**: SEP-631, a negative allosteric modulator showing potent inhibition of receptor activation and promising preclinical results [38][42] - **Clinical Timeline**: Expected to enter Phase 1 trials in Q3 [43] 3. **Thyroid Stimulating Hormone Receptor Program** - **Focus**: Treating Graves' disease and thyroid eye disease with a negative allosteric modulator [44] - **Mechanism**: Aiming for a universal approach to target multiple autoantibodies in patients [45][46] 4. **Incretin Receptor Agonist Program** - **Innovation**: Discovery of a novel binding pocket allowing for the development of multi-incretin receptor agonists [50] - **Preclinical Results**: Early-stage molecules showing weight loss effects comparable to existing treatments [52] Collaboration with Novo Nordisk - **Details**: Collaboration includes three known targets and two undisclosed targets, with an upfront payment of $195 million and Novo responsible for all R&D costs [53][54] Leadership and Future Outlook - **Team**: Experienced leadership with decades of industry experience and a strong advisory board [55] - **Market Potential**: Each program represents a significant market opportunity, with ongoing efforts to extend financial runway into early 2028 and beyond [56] Conclusion - **Overall Position**: Septerna is well-positioned in the GPCR drug discovery space with a robust pipeline and strategic collaborations, aiming to address significant unmet medical needs across various therapeutic areas [56]

Company Overview - Septerna, Inc. is a biotechnology company focused on G protein-coupled receptor (GPCR) drug discovery, utilizing its proprietary Native Complex Platform™ to enhance GPCR therapies [3] - The company has developed a deep pipeline of oral small molecule product candidates targeting three therapeutic areas: endocrinology, immunology and inflammation, and metabolic diseases [3] Upcoming Event - Jeffrey Finer, M.D., Ph.D., CEO and Co-founder of Septerna, will present at the Jefferies Global Healthcare Conference on June 5, 2025, at 3:45 p.m. ET in New York [1] - A live webcast of the presentation will be available on the company's website and will be archived for at least 30 days [2]