# EDGAR Filing Document

**Accession Number:** 0001984086
**File Stem:** 0001193125-26-084142
**Filing Date:** 2026-3
**Character Count:** 48035
**Document Hash:** 8d32a92b18e67040c8877541cb9534dc
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001193125-26-084142.hdr.sgml**: 20260302

**ACCESSION NUMBER**: 0001193125-26-084142

**CONFORMED SUBMISSION TYPE**: 8-K

**PUBLIC DOCUMENT COUNT**: 43

**CONFORMED PERIOD OF REPORT**: 20260301

**ITEM INFORMATION**: Regulation FD Disclosure

**ITEM INFORMATION**: Other Events

**ITEM INFORMATION**: Financial Statements and Exhibits

**FILED AS OF DATE**: 20260302

**DATE AS OF CHANGE**: 20260302

**FILER**: 

**COMPANY DATA:**
- **COMPANY CONFORMED NAME:** Septerna, Inc.
- **CENTRAL INDEX KEY:** 0001984086
- **STANDARD INDUSTRIAL CLASSIFICATION:** PHARMACEUTICAL PREPARATIONS [2834]
- **ORGANIZATION NAME:** 03 Life Sciences
- **EIN:** 843891440
- **STATE OF INCORPORATION:** DE
- **FISCAL YEAR END:** 1231

**FILING VALUES:**
- **FORM TYPE:** 8-K
- **SEC ACT:** 1934 Act
- **SEC FILE NUMBER:** 001-42382
- **FILM NUMBER:** 26703405

**BUSINESS ADDRESS:**
- **STREET 1:** 250 EAST GRAND AVENUE, SUITE 65
- **CITY:** SOUTH SAN FRANCISCO
- **STATE:** CA
- **ZIP:** 94080
- **BUSINESS PHONE:** 650-338-3533

**MAIL ADDRESS:**
- **STREET 1:** 250 EAST GRAND AVENUE, SUITE 65
- **CITY:** SOUTH SAN FRANCISCO
- **STATE:** CA
- **ZIP:** 94080

?xml version='1.0' encoding='ASCII'? 8-K

### UNITED STATES

### SECURITIES AND EXCHANGE COMMISSION

#### WASHINGTON, D.C. 20549

### FORM 8-K

#### CURRENT REPORT

#### Pursuant to Section 13 or 15(d)

#### of the Securities Exchange Act of 1934

#### Date of Report (Date of earliest event reported): March 1, 2026

## Septerna, Inc.

#### (Exact name of Registrant as Specified in Its Charter)

---

| | | |
|:---|:---|:---|
| **Delaware** | **001-42382** | **84-3891440** |
| **(State or Other Jurisdiction<br>of Incorporation)** | **(Commission**<br> **File Number)** | **(IRS Employer<br>Identification No.)** |
| **250 East Grand Avenue** |  |  |
| **South San Francisco, California** |  | **94080** |
| **(Address of Principal Executive Offices)** |  | **(Zip Code)** |

---

#### Registrant's Telephone Number, Including Area Code: 650 338-3533

#### Not Applicable

#### (Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

#### Securities registered pursuant to Section 12(b) of the Act:

---

| | | |
|:---|:---|:---|
| **Title of each class** | **Trading<br>Symbol(s)** | **Name of each exchange**<br> **on which registered** |
| Common Stock, par value $0.001 per share | SEPN | The Nasdaq Stock Market LLC |

---

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

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| | |
|:---|:---|
| **Item 7.01** | **Regulation FD Disclosure.**  |

---

On March 1, 2026, Septerna, Inc. (the "Company") issued a press release entitled "Septerna Announces Positive Phase 1 Data for SEP-631, an Oral MRGPRX2 NAM for the Treatment of Mast Cell-Driven Diseases, and Outlines Initial Phase 2 Development Strategy." A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K, which is incorporated herein by reference.

The Company will host a conference call and webcast on March 2, 2026, at 8:00 a.m. ET to discuss the Phase 1 results and initial Phase 2 development strategy for SEP-631. The live webcast will be available in the investors section of the Company's website at www.septerna.com. A replay will be available shortly after the event and will be archived for at least 30 days. A copy of the slides that will be presented at the conference call and webcast is furnished as Exhibit 99.2 to this Current Report on Form 8-K, which is incorporated herein by reference. Reference to the Company's website is for inactive textual reference only and the information contained in, or that can be accessed through, the website should not be deemed incorporated by reference into this Current Report on Form 8-K.

The information in Item 7.01 of this Current Report on Form 8-K, including the accompanying Exhibits 99.1 and 99.2, is intended to be furnished and shall not be deemed "filed" for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the "Exchange Act"), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, regardless of the general incorporation language of such filing, except as shall be expressly set forth by specific reference in such filing.

---

| | |
|:---|:---|
| **Item 8.01.** | **Other Events**  |

---

On March 1, 2026, the Company announced positive results from its Phase 1 clinical trial evaluating SEP-631, a potent and selective oral negative allosteric modulator ("NAM") of Mas-related G protein-coupled receptor X2 ("MRGPRX2"), and outlined initial Phase 2 development strategy.

#### Phase 1 Results
SEP-631 was evaluated in a randomized, double-blind, placebo-controlled Phase 1 trial in healthy volunteers, including single-ascending dose, multiple-ascending dose and food-effect cohorts. The study assessed safety, tolerability, pharmacokinetics ("PK") and pharmacodynamic ("PD") activity.

SEP-631 was well-tolerated across all doses studied:

• Adverse event profile comparable to placebo

• No severe or serious adverse events

• No clinically meaningful laboratory or ECG abnormalities

SEP-631 demonstrated a PK profile supportive of convenient once-daily oral dosing, including:

• Half-life of approximately 24 hours

• No clinically meaningful effect of food on exposure, supporting dosing without food restrictions

PD activity was assessed using icatibant-induced skin wheal formation, an established skin test used to measure mast cell activation and target engagement, as a translational model of MRGPRX2-mediated mast cell activation. Use of short-wave infrared imaging technology enabled accurate and precise measurement of the skin test wheals. SEP-631 produced robust suppression of wheal formation across evaluated dose levels, with complete inhibition observed at doses as low as 10 mg once daily following the 10 µg/mL icatibant challenge. Following the 100 µg/mL icatibant challenge, inhibition was dose-dependent, with progressively greater suppression observed at increasing SEP-631 doses with near to complete inhibition achieved at 90 and 200 mg once daily. These findings are consistent with the insurmountable NAM mechanism of SEP-631 observed preclinically and support potent target engagement and functional blockade of MRGPRX2 signaling in humans, providing clinical proof-of-mechanism.

#### Phase 2 Development Strategy
The Company also announced its plans to initiate a Phase 2b clinical trial of SEP-631 in chronic spontaneous urticaria ("CSU") in the second half of this year, following the completion of ongoing long-term toxicology studies.

The planned Phase 2b study will be a randomized, double-blind, placebo-controlled, global trial evaluating once-daily oral SEP-631 in adult patients with moderate-to-severe CSU who remain symptomatic despite treatment with second-generation antihistamines. Following the CSU study initiation, the Company also plans to pursue an open-label study in chronic inducible urticaria, specifically in patients with symptomatic dermatographism.

Beyond urticaria, the Company is evaluating additional mast cell-driven diseases with high unmet medical need and evidence of MRGPRX2 expression, and has initially prioritized atopic dermatitis, interstitial cystitis, migraine and asthma for further assessment.

------

#### Forward-Looking Statements
*This Current Report on Form 8-K contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about the Company's beliefs and expectations regarding: the continued advancement of SEP-631, including the plan to initiate a Phase 2b clinical study in CSU in the second half of 2026 subject to the successful completion of long-term preclinical toxicology studies; the role of MRGPRX2 in mast cell-driven diseases; the potential of SEP-631 to provide a convenient oral treatment option for patients with CSU and other mast cell-driven diseases; expectations regarding the anticipated once-daily dosing frequency of SEP-631; the ability of the SEP-631 Phase 1 safety and efficacy observations to successfully translate into clinical outcomes in patients; the potential of its proprietary Native Complex Platform<sup>®</sup>; the size and growth potential of the markets for its current and future product candidates; its expectations regarding strategic plans for its business, product candidates, and technology; and the scope of protection it is able to establish and maintain for intellectual property rights covering its Native Complex Platform<sup>®</sup> and its product candidates. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "objective," "ongoing," "plan," "predict," "project," "potential," "should," or "would," or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward looking statements contain these identifying words.* 

*Any forward-looking statements in this Current Report on Form 8-K are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this Current Report on Form 8-K, including, without limitation, risks associated with: Company's product candidates successfully entering and advancing through clinical trials (including SEP-631) including uncertainties related to opening INDs and other regulatory approvals; risks related to clinical development outcomes including unexpected safety or efficacy findings; the results of preclinical studies including the long-term toxicology studies for SEP-631, or clinical studies not being predictive of future clinical outcomes; risks related to the timing of initiating clinical studies and future availability of clinical data; and the scope of protection Company is able to establish and maintain for intellectual property rights covering its Native Complex Platform<sup>®</sup> and its product candidates. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Company's Annual Report on Form 10-K for the year ended December 31, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Company's views only as of today and should not be relied upon as representing its views as of any subsequent date. The Company explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.* 

---

| | |
|:---|:---|
| **Item 9.01.** | **Financial Statements and Exhibits.**  |

---

(d) Exhibits

---

| | |
|:---|:---|
| 99.1 | [Press Release issued by Septerna, Inc. on March 1, 2026, furnished herewith.](d44190dex991.htm) |
| 99.2 | [Corporate Presentation of Septerna, Inc., dated March 2, 2026, furnished herewith.](d44190dex992.htm) |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document). |

---

------

#### SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

---

| | | |
|:---|:---|:---|
|  |  | Septerna, Inc. |
| Date: March 2, 2026 | By: | /s/ Jeffrey Finer, M.D., Ph.D. |
|  |  | Jeffrey Finer, M.D., Ph.D. |
|  |  | Chief Executive Officer |

---

## Exhibit 99.1

**Exhibit 99.1**![LOGO](g44190img1.jpg)

**Septerna Announces Positive Phase 1 Data for SEP-631, an Oral MRGPRX2 NAM for the Treatment of Mast Cell-Driven Diseases, and Outlines Initial Phase 2 Development Strategy** 

*SEP-631 Demonstrated Robust, Dose-Dependent Inhibition of Icatibant-Induced Skin Wheal Formation, with Complete Inhibition Observed at Doses as Low as 10 mg Once-Daily* 

*Well-Tolerated Across All Doses Studied with an Adverse Event Profile Comparable to Placebo; Pharmacokinetic Profile Supports Once-Daily Oral Dosing* 

*Phase 2 Development Planned to Begin with Chronic Spontaneous Urticaria in the Second Half of 2026* 

*Company to Host Conference Call and Webcast on Monday, March 2, 2026, at 8:00 a.m. ET* 

**SOUTH SAN FRANCISCO, Calif. – March 1, 2026** – Septerna, Inc. (Nasdaq: SEPN), a clinical-stage biotechnology company pioneering oral small molecule GPCR-targeted medicines, today announced positive results from its Phase 1 clinical trial evaluating SEP-631, a potent and selective oral negative allosteric modulator (NAM) of Mas-related G protein-coupled receptor X2 (MRGPRX2). Based on these results, Septerna plans to advance SEP-631 into Phase 2 development for chronic spontaneous urticaria (CSU) and continue evaluation of additional mast cell-driven indications.

"These data mark an important milestone for the SEP-631 program and more broadly for our Native Complex Platform<sup>®</sup>, which enables new approaches to GPCR drug discovery by reconstituting functional GPCR complexes outside of cells," said Jae Kim, M.D., chief medical officer of Septerna. "Importantly, the robust inhibition of icatibant-induced wheal formation observed is consistent with the differentiated insurmountable NAM mechanism we characterized preclinically and provides clinical proof-of-mechanism for the MRGPRX2 pathway. Overall, we believe the strength and consistency of these results position SEP-631 as a potentially differentiated oral treatment for patients living with mast cell-driven diseases. With a clear path into Phase 2 development in chronic spontaneous urticaria, we are focused on translating this early validation into meaningful outcomes for patients and exploring additional high-need indications where MRGPRX2 biology is implicated."

**Phase 1 Results** 

SEP-631 was evaluated in a randomized, double-blind, placebo-controlled Phase 1 trial in healthy volunteers, including single-ascending dose, multiple-ascending dose and food-effect cohorts. The study assessed safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) activity.

SEP-631 was well-tolerated across all doses studied:

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• Adverse event profile comparable to placebo

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• No severe or serious adverse events

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• No clinically meaningful laboratory or ECG abnormalities

------

![LOGO](g44190img1.jpg)

SEP-631 demonstrated a PK profile supportive of convenient once-daily oral dosing, including:

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• Half-life of approximately 24 hours

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• No clinically meaningful effect of food on exposure, supporting dosing without food restrictions

Pharmacodynamic activity was assessed using icatibant-induced skin wheal formation, an established skin test used to measure mast cell activation and target engagement, as a translational model of MRGPRX2-mediated mast cell activation. Use of short-wave infrared imaging technology enabled accurate and precise measurement of the skin test wheals. SEP-631 produced robust suppression of wheal formation across evaluated dose levels, with complete inhibition observed at doses as low as 10 mg once daily following the 10 µg/mL icatibant challenge. Following the 100 µg/mL icatibant challenge, inhibition was dose-dependent, with progressively greater suppression observed at increasing SEP-631 doses with near to complete inhibition achieved at 90 and 200 mg once daily. These findings are consistent with the insurmountable NAM mechanism of SEP-631 observed preclinically and support potent target engagement and functional blockade of MRGPRX2 signaling in humans, providing clinical proof-of-mechanism.

**Phase 2 Development Strategy** 

Septerna plans to initiate a Phase 2b clinical trial of SEP-631 in chronic spontaneous urticaria (CSU) in the second half of this year, following the completion of ongoing long-term toxicology studies.

The planned Phase 2b study will be a randomized, double-blind, placebo-controlled, global trial evaluating once-daily oral SEP-631 in adult patients with moderate-to-severe CSU who remain symptomatic despite treatment with second-generation antihistamines. Following the CSU study initiation, the company also plans to pursue an open-label study in chronic inducible urticaria (CIndU), specifically in patients with symptomatic dermatographism.

Beyond urticaria, Septerna is evaluating additional mast cell-driven diseases with high unmet medical need and evidence of MRGPRX2 expression, and has initially prioritized atopic dermatitis, interstitial cystitis, migraine and asthma for further assessment.

**Conference Call and Webcast Information** 

Septerna will host a conference call and webcast on Monday, March 2, 2026, at 8:00 a.m. ET to discuss the Phase 1 results and initial Phase 2 development strategy for SEP-631. The live webcast will be available in the investors section of the company's website at www.septerna.com. A replay will be available shortly after the event and will be archived for at least 30 days.

**About SEP-631** 

Septerna is developing SEP-631, a selective oral small molecule Mas-related G protein-coupled receptor X2 (MRGPRX2) negative allosteric modulator (NAM) for the treatment of patients with chronic spontaneous urticaria (CSU) and other mast-cell driven diseases. MRGPRX2 is known to play an important role in mast cell activation and degranulation which, in combination with other inflammatory mediators, lead to debilitating symptoms for patients. In a Phase 1 clinical

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![LOGO](g44190img1.jpg)

trial, SEP-631 demonstrated favorable tolerability, once-daily pharmacokinetics and pharmacodynamic evidence of MRGPRX2 pathway inhibition. Septerna plans to advance SEP-631 into Phase 2 development in CSU and chronic inducible urticaria and is evaluating its potential in additional mast cell-driven indications, including atopic dermatitis, interstitial cystitis, migraine and asthma.

**About Septerna** 

Septerna, Inc. is a clinical-stage biotechnology company with a world-class team of GPCR experts and drug developers advancing cutting-edge science to unlock the full potential of GPCR therapies for patients with significant unmet needs. The company's proprietary Native Complex Platform<sup>®</sup> is designed to enable new approaches to GPCR drug discovery and has led to the development of a diverse pipeline of novel oral small molecule drug candidates. Septerna is advancing programs in endocrinology, immunology and inflammation, metabolic diseases and additional therapeutic areas, both independently and with partners. For more information, please visit www.septerna.com.

**Forward-Looking Statements** 

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Septerna's beliefs and expectations regarding: the continued advancement of SEP-631, including the plan to initiate a Phase 2b clinical study in CSU in the second half of 2026 subject to the successful completion of long-term preclinical toxicology studies; the role of MRGPRX2 in mast cell-driven diseases; the potential of SEP-631 to provide a convenient oral treatment option for patients with CSU and other mast cell-driven diseases; expectations regarding the anticipated once-daily dosing frequency of SEP-631; the ability of the SEP-631 Phase 1 safety and efficacy observations to successfully translate into clinical outcomes in patients; the potential of its proprietary Native Complex Platform<sup>®</sup>; the size and growth potential of the markets for its current and future product candidates; its expectations regarding strategic plans for its business, product candidates, and technology; and the scope of protection it is able to establish and maintain for intellectual property rights covering its Native Complex Platform<sup>®</sup> and its product candidates. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "objective," "ongoing," "plan," "predict," "project," "potential," "should," or "would," or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward looking statements contain these identifying words.

Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: Septerna's product candidates successfully entering and advancing through clinical trials (including SEP-631) including uncertainties related to opening INDs and other regulatory approvals; risks related to clinical development outcomes including unexpected safety or efficacy findings; the results of preclinical studies including the long-term toxicology studies for SEP-631, or clinical studies not being predictive of future clinical outcomes; risks related to the timing of initiating clinical studies and future availability of clinical data; and the scope of protection Septerna is able to establish and maintain for intellectual property rights covering its

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![LOGO](g44190img1.jpg)

Native Complex Platform<sup>®</sup> and its product candidates. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Septerna's Annual Report on Form 10-K for the year ended December 31, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Septerna's views only as of today and should not be relied upon as representing its views as of any subsequent date. Septerna explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.

**Investor Contact:** 

Renee Leck, THRUST

renee@thrustsc.com

**Media Contact:** 

Carly Scaduto, THRUST

carly@thrustsc.com

## Exhibit 99.2

![](g44190ex99_2p1g1.jpg)

Exhibit 99.2 Phase 1 Results\* for SEP-631, a Novel Oral Small Molecule MRGPRX2 Negative Allosteric Modulator (NAM) for Mast Cell-Driven Diseases March 2, 2026 Nasdaq: SEPN \*Data presented at the 2026 American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting© 2026 SEPTERNA

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![](g44190ex99_2p2g1.jpg)

Forward-Looking Statements This presentation contains express or implied forward- looking statements of Septerna, Inc. (the "Company," "we," or "our") within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. All statements other than statements of historical facts contained in this presentation, including statements regarding our business strategy, plans, estimated R&D program milestones and objectives of management are forward-looking statements. Such forward-looking statements include, but are not limited to, statements regarding: the continued advancement of our PTH1R agonist program, including the planned initiation of a Phase 1 clinical trial for SEP-479 in the first half of 2026 subject to successful completion of regulatory submissions; the continued advancement of SEP-631, including the plan to initiate a Phase 2b clinical study in CSU in the second half of 2026 subject to the successful completion of long-term preclinical toxicology studies; the role of MRGPRX2 in mast cell-driven diseases; the timing, progress and results of conducting our research and development programs, including our plans to advance the TSHR program; the intended and potential benefits of the collaboration with Novo Nordisk, including our ability to jointly discover, develop and commercialize multiple potential oral small molecule therapies for obesity, type 2 diabetes, and other cardiometabolic diseases and the potential resulting milestones and royalties (if any); our ability to demonstrate, and the timing of, preclinical proof-of-concept in vivo and ex vivo for multiple programs; the potential of® our proprietary Native Complex Platform ; the ability of preclinical or Phase 1 safety and efficacy observations to successfully translate into clinical outcomes; the size and growth potential of the markets for our current and future product candidates; our expectations regarding strategic plans for our business, product® candidates, and technology; the scope of protection we are able to establish and maintain for intellectual property rights covering our Native Complex Platform and our product candidates; our ability to maintain existing collaborations and to identify and enter into future license agreements and collaborations; and the accuracy of our estimates regarding expenses and capital requirements, including our expected cash runway at least into 2029. Such forward-looking statements reflect the current views of the Company and are subject to known and unknown risks and other factors, which are, in some cases, beyond the Company's control. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties set forth in the section titled Risk Factors in our most recent Annual Report on Form 10-K for the year ended December 31, 2024, as well as any subsequent filings with the Securities and Exchange Commission. Certain information in this presentation (including market data and statistical information) and statements made orally during this presentation are the good faith estimates of management and have been obtained from various sources (including third-party sources such as independent industry publications, governmental publications, and reports by market research firms), and we do not guarantee the accuracy or completeness of such information. No representations or warranties (expressed or implied) are made about the accuracy of such forward-looking statements, and there can be no assurance as to the reliability or correctness of such projections and actual results may vary materially from those projected. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.© 2026 SEPTERNA 2

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![](g44190ex99_2p3g1.jpg)

Agenda • Septerna: Building a World-Class GPCR-Focused Biotechnology Company • SEP-631: Oral Small Molecule MRGPRX2 Negative Allosteric Modulator (NAM) • SEP-631: Phase 1 Healthy Subject Trial Results • Safety, Pharmacokinetics, and Pharmacodynamics (with Icatibant Skin Challenge) • SEP-631: Broad Opportunity in Mast-Cell Driven Diseases • Question & Answer Session Jeff Finer, MD, PhD Liz Bhatt, MS, MBA Jae Kim, MD Gil Labrucherie, CFA, JD CEO President & COO CMO CFO© 2026 SEPTERNA 3

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![](g44190ex99_2p4g1.jpg)

Septerna: Pioneering a New Era of GPCR Drug Discovery with Oral Small Molecules • GPCR drug discovery has been concentrated to a small number of targets - our strategy is to unlock difficult-to-drug GPCRs® • Our Native Complex Platform enables us to • Growing portfolio of clinical programs rapidly discover and optimize small molecules focused on validated targets, early clinical using iterative structure-based drug design readouts, and large commercial opportunities • SEP-631 is a MRGPRX2 NAM with the potential to be a pipeline-in-a-product for mast cell-driven diseases New Chemical Rapid Matter Candidate Discovery Optimization • SEP-479 is a PTH1R agonist that has the potential to be the first oral PTH replacement therapy for hypoparathyroidism patients • Well-capitalized with cash runway to drive research and development pipelines at least into 2029© 2026 SEPTERNA 4

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![](g44190ex99_2p5g1.jpg)

Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs Wholly-Owned Programs Development Status Program / Target Therapeutic Area Discovery IND-enabling Phase 1 Phase 2 Mode of Action Indications / US Patient Population \* Phase 1 initiation Anticipate Phase 1 Endocrinology SEP-479 (PTH1R) anticipated in topline data in Hypoparathyroidism: ~70k 1H 2026 late 2026 / early 2027 Agonist Immunology and Inflammation \* Phase 2 initiation SEP-631 (MRGPRX2) anticipated in CSU: ~1.5mm 2H 2026 Negative Allosteric Modulator Other mast cell diseases Endocrinology TSHR Program Graves' disease: ~2mm Negative Allosteric Modulator Thyroid eye disease: ~1mm Research Areas: Neurology, Women's Health, Cardiovascular Disease and Respiratory Disease Partnered Programs Partner Metabolic Programs Obesity and Other Cardiometabolic Diseases GLP-1R, GIPR, GCGR + Undisclosed Undisclosed Undisclosed© 2026 SEPTERNA 5 \* Pending successful completion of regulatory submissions

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![](g44190ex99_2p6g1.jpg)

SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell-Driven Diseases© 2026 SEPTERNA

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![](g44190ex99_2p7g1.jpg)

MRGPRX2 is a Key Regulator of Mast Cell Degranulation Activated by Several Endogenous Ligands MRGPRX2 is activated by a host of endogenous agonists leading to IgE-independent mast cell degranulation • Include several neuropeptides and immune ligands Mast cell degranulation leads to release of mediators which cause pain, itch, inflammation, and edema • Pain and itch are driven by mast cells co-localized with sensory neurons • Inflammation and edema are driven by mast cell mediator effects on tissue capillaries leading to vasodilation, vascular permeability, and leukocyte recruitment Targeting MRGPRX2 has the potential to disrupt feedback loops that drive these effects© 2026 SEPTERNA 7

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![](g44190ex99_2p8g1.jpg)

Broad Opportunity for New Medicines Targeting Several Mast Cell-Driven Diseases Mast cells are key mediators of allergic and inflammatory diseases • Reside in organ systems throughout the body Degranulation results in the release of an array of mediators which result in pain, itch, and inflammation • Contributes to pathophysiology of several diseases Targeting MRGPRX2, which leads to IgE-independent mast cell degranulation, has multi-indication potential • Breadth of potential represents a pipeline-in-a-product opportunity© 2026 SEPTERNA 8

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![](g44190ex99_2p9g1.jpg)

SEP-631: MRGPRX2 NAM with a Potentially Differentiated Profile for Mast Cell-Driven Diseases SEP-631 Induces a Structural Change in MRGPRX2 SEP-631 is a negative allosteric modulator (NAM) That Completely Closes the Agonist Binding Pocket • Binds to a novel allosteric site, distinct from the agonist binding pocket MRGPRX2 MRGPRX2 Potently inhibits MRGPRX2 activation with an + SEP-631 insurmountable NAM profile • Very high binding affinity (Ki ~0.5 nM) Extracellular view • Slow dissociation rate (t > 2 hours) 1/2 Agonist Locks MRGPRX2 in a state that prevents binding of Extra- binding Agonist pocket cellular Agonist\* all agonists, even at high agonist concentrations pocket no longer exists loop • Potent inhibition of MRGPRX2-induced degranulation for both mast cell lines and primary human skin mast cells Transmembrane view PK profile across species projected to once-daily oral dosing in humans© 2026 SEPTERNA 9 \*Cortistatin-14

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SEP-631 Inhibited MRGPRX2 Activation in Humanized Mouse Translational Model Human MRGPRX2 Knock-in (KI) SEP-631 Potently Inhibited Skin Extravasation Mouse Model of Skin Extravasation Knock-in Mouse Cortistatin-14 (0.7 µg/ml) Icatibant (10 µg/ml) mMRGPRB2 KO hMRGPRX2 KI Treat with oral MRGPRX2 NAM (SEP-631) or vehicle Administer Evans Blue dye Intradermal skin challenge with cortistatin-14 or icatibant (MRGPRX2 agonists) Measure extravasation of dye into skin SEP-631's insurmountable NAM profile translated to complete inhibition of MRGPRX2-mediated skin Extravasation No extravasation extravasation in a preclinical urticaria translational model (no MRGPRX2 inhibition) (MRGPRX2 inhibition)© 2026 SEPTERNA 10 KO: gene knockout KI: gene knock-in

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SEP-631 Preclinical Data Supports Potential Best-in-Class Profile SEP-631 Preclinical Profile Subnanomolar binding affinity and slow off-rate kinetics Insurmountable negative allosteric modulator mechanism closes off agonist binding pocket • Inability to activate receptor despite presence of high doses of endogenous agonists Potent inhibition of MRGPRX2 activation in knock-in animals and primary human mast cells Excellent oral PK across species • Projects to once-daily human dosing Excellent pharmaceutical properties • Low drug-drug interaction risk based on in vitro profiling • Low food effect risk based on preclinical studies Generally well-tolerated in pharmacology and GLP toxicology studies Convenient tablet formulation developed© 2026 SEPTERNA 11

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First-in-Human, Proof-of-Mechanism Phase 1 Study of the Oral MRGPRX2 Antagonist SEP-631© 2026 SEPTERNA

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SEP-631 Phase 1 Study Design A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Food Effects of SEP-631 in Healthy Adult Volunteers Part A. SEP-631 PO single dose\* Key endpoints Randomization 400 mg Single 300 mg 6:2 ascending 200 mg (SEP-631:placebo) dose Safety / tolerability • Part A: randomized, double-blind, 90 mg 30 mg PK n=8 / cohort placebo controlled, single ascending 10 mg dose (SAD) study (n = 48) Part B. SEP-631 PO QD for 10 days Key endpoints Randomization Multiple • Part B: randomized, double-blind, 12:4 Safety / tolerability ascending 200 mg (SEP-631:placebo) dose 90 mg PK placebo controlled, multiple ascending 30 mg 10 mg n=16 / cohort PD: skin challenge dose (MAD) study (n = 64) Part C. SEP-631 PO single dose crossover • Part C: randomized, open-label, 2 period, 5-day Key endpoints Randomized 200 mg 200 mg washout crossover food effect study (n = 8) open-label Fasted Fasted Food effect crossover Safety / tolerability n=8 200 mg 200 mg PK (fasted vs fed) Fed Fed \*Sentinel dosing was used in SAD cohorts. Decisions for dose escalation and progression from single to multiple doses and food effect dosing were made by a Safety Review Committee© 2026 SEPTERNA 13

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Safety: Single Dose Adverse Event Profile Comparable to Placebo • Rate of TEAEs with SEP-631 was comparable with placebo • No severe or serious events were reported • 2 AEs of mild transaminase elevations (<1.5x ULN) observed with SEP-631 were not related to dose, and at rates comparable to placebo SEP-631 Single Dose Pooled Pooled placebo 10 mg 30 mg 90 mg 200 mg 300 mg 400 mg SEP-631 (n=12) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=36) Any TEAEs, n (%) 5 (41.7) 2 (33.3) 4 (66.7) 0 4 (66.7) 3 (50.0) 1 (16.7) 14 (38.9) Mild 5 (41.7) 2 (33.3) 3 (50.0) 0 4 (66.7) 2 (33.3) 1 (16.7) 12 (33.3) Moderate 0 0 1 (16.7) 0 0 1 (16.7) 0 2 (5.6) Severe 0 0 0 0 0 0 0 0 Serious TEAEs, n (%) 0 0 0 0 0 0 0 0 TEAEs in >1 subject, n (%): Headache 1 (8.3) 0 2 (33.3) 0 1 (16.7) 1 (16.7) 0 4 (11.1) Transaminases increased 1 (8.3) 1 (16.7) 1 (16.7) 0 0 0 0 2 (5.6) Dysmenorrhoea 0 0 1 (16.7) 0 0 1 (16.7) 0 2 (5.6)© 2026 SEPTERNA 14 TEAE, treatment-emergent adverse event as number (%)

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Safety: Multiple Dose Adverse Event Profile Comparable to Placebo • Rate of TEAEs with SEP-631 was comparable with placebo. • No severe or serious events were reported • One mild transaminase elevation (<1.5x ULN) observed with SEP-631 and one observed with placebo SEP-631 Multiple Dose (10 Days) Pooled Pooled placebo 10 mg 30 mg 90 mg 200 mg SEP-631 (n=15) (n=12) (n=12) (n=12) (n=12) (n=48) Any TEAEs, n (%) 10 (62.5) 3 (25.0) 6 (50.0) 5 (41.7) 4 (33.3) 18 (37.5) Mild 10 (62.5) 3 (25.0) 6 (50.0) 4 (33.3) 4 (33.3) 17 (35.4) Moderate 0 0 0 1 (8.3) 0 1 (2.1) Severe 0 0 0 0 0 0 Serious TEAEs, n (%) 0 0 0 0 0 0 TEAEs in >1 subject, n (%): Headache 4 (25.0) 0 2 (16.7) 2 (16.7) 1 (8.3) 5 (10.4) Dizziness 1 (6.3) 0 0 2 (16.7) 1 (8.3) 3 (6.3) Abdominal pain 0 2 (16.7) 0 1 (8.3) 0 3 (6.3) Nausea 1 (6.3) 0 0 1 (8.3) 1 (8.3) 2 (4.2) Fatigue 1 (6.3) 0 0 1 (8.3) 0 1 (2.1) Dermatitis contact 1 (6.3) 0 1 (8.3) 0 0 1 (2.1) ALT or Transaminases increased 1 (6.3) 0 0 0 1 (8.3) 1 (2.1) Dysmenorrhea 1 (6.3) 0 1 (8.3) 0 0 1 (2.1)© 2026 SEPTERNA 15 TEAE, treatment-emergent adverse event as number (%)

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SEP-631 Pharmacokinetics: Dose-Proportional, Support Once Daily Dosing, and Without Food Effects • Approximately dose-proportional exposures were observed across the evaluated dose range • Elimination half-life of SEP-631 is approximately 24 hours, supporting once-daily (QD) dosing • SEP-631 with high-fat, high-calorie meal resulted in similar exposure to fasted conditions (AUC and Cmax) Multiple Dose Pharmacokinetics (Day 10)© 2026 SEPTERNA 16

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Pharmacodynamics Assessed Using Icatibant Skin Challenge and AllergyScope Detector Forearm Intradermal Skin challenge performed at baseline (Day –1) and steady-state (Day 9) Injection Pattern following SEP-631 or placebo treatment Saline Histamine • Skin challenge agents: saline (injection control), histamine (wheal positive control), and icatibant at 10 μg/mL and 100 μg/mL (selective MRGPRX2 agonist at low and high Icatibant Icatibant concentrations; each performed in duplicate for average measurements) 10 µg/mL 10 µg/mL Wheals imaged using AllergyScope , a precision image-based detector Icatibant Icatibant 100 µg/mL 100 µg/mL • Utilizes short-wave infrared (SWIR) spectrum; images transmitted for central lab analysis and adjudication performed by 2 independent and blinded adjudicators at Johns Hopkins University TM Baseline Skin Challenge (Day -1) AllergyScope Detector Dynamic Range of saline - Icatibant: 0-3.7 mm© 2026 SEPTERNA Results depicted as average with error bars represented as standard deviation. Independent wheal measurements yielded between-reader precision of 6% coefficient of variation 17 relative to histamine positive control, indicating a high degree of reproducibility not otherwise possible with traditional manual skin test reading

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SEP-631 Inhibits Icatibant Wheal Formation in Dose-Dependent Manner to Complete Inhibition • SEP-631 completely inhibited icatibant 10 μg/mL-induced wheals at 10 mg QD, the lowest dose evaluated • SEP-631 inhibited icatibant 100 μg/mL-induced wheals in a dose-dependent manner, with near to complete inhibition at 90 and 200 mg QD Icatibant 10 µg/mL Icatibant 100 µg/mL Nominal p-values comparing each SEP-631 dose level to placebo for change from baseline are based on an ANCOVA© 2026 SEPTERNA 18 model including a fixed effect for treatment group and baseline wheal response as a covariate

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Phase 1 Results Support Further Development of SEP-631 SEP-631 was well-tolerated across all studied doses Pharmacokinetic profile of SEP-631 supports once-daily oral dosing • Elimination half-life of SEP-631 is approximately 24 hours SEP-631 treatment resulted in robust inhibition of icatibant-induced skin wheal formation across all studied doses, with complete inhibition observed at doses as low as 10 mg QD (10 µg/mL icatibant challenge) • Use of the AllergyScope detector enabled accurate, precise assessment of skin test wheals • Inhibition of skin wheals supports SEP-631 engagement with MRGPRX2 in the skin and indicates inhibition downstream signaling and blockade of mast cell degranulation No clinically meaningful effect of food on SEP-631 exposure, supporting SEP-631 dosing without food restrictions These Phase 1 results in healthy adult subjects support further clinical evaluation of SEP-631 in patients with mast cell-driven skin diseases, including CSU© 2026 SEPTERNA 19

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SEP-631: Broad Opportunity in Mast Cell-Driven Diseases© 2026 SEPTERNA

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SEP-631 Preclinical Profile Translated Well to Phase 1 Clinical Trial Results Translation SEP-631 Preclinical Profile Robust SEP-631 Phase 1 Results • Subnanomolar binding affinity Target Coverage • Estimated high receptor occupancy (>99%) • Slow receptor off-rate kinetics • Confirmed QD oral dosing (half-life ~24 hrs) • Excellent oral PK across preclinical species Pharmacokinetics • No food effect, excellent dosing flexibility • Insurmountable NAM blocks agonist binding • Full inhibition of icatibant-induced skin wheal Pharmacodynamics pocket for all MRGPRX2 agonists tested formation at both high and low icatibant doses • Generally well-tolerated in GLP tox studies • All AEs considered mild or moderate Safety • Low DDI risk based on in vitro profiling • No LFT abnormalities or other observations Potential Best-in-Class Profile of SEP-631: • Excellent potency with mechanism that provides broad insurmountable inhibition • Clean clinical safety profile • Convenient, once daily oral tablet with a flexible dosing schedule© 2026 SEPTERNA 21

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SEP-631: Initial Phase 2 Development Strategy Since the skin has the highest level of MRGPRX2 expression on mast cells, plan to rapidly advance into Chronic Urticaria studies • Targeting initiation of a Phase 2b Chronic Spontaneous Urticaria study in 2H 2026 • Pursue open-label Chronic Inducible Urticaria (CIndU) study in symptomatic dermatographism following initiation of the CSU study Exploring path forward in other high potential indications where tissue mast cells express MRGPRX2 including: • Atopic Dermatitis • Interstitial Cystitis / Bladder Pain Syndrome • Migraine • Asthma© 2026 SEPTERNA 22

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Chronic Spontaneous Urticaria (CSU): High Disease Burden, Large Patient Population • CSU is an undertreated dermatology condition characterized by CSU Skin Wheals and Angioedema itchy and painful wheals and angioedema 1 • Significant burden of disease; patients experience : Disease Burden % CSU Patients ~40% High to very high impact on their daily life ~60% Mod-to-severe pain / discomfort ~50% Mod-to-severe anxiety / depression ~20% Miss work at least once per week 2-4 • ~40% of patients are refractory to first-line high-dose antihistamines • High unmet need for safe second-line oral treatment options 5 • Growing commercial opportunity: ~2-3M CSU patients in the US 2© 2026 SEPTERNA 23 1. ASSURE study, 2. 2022 Kaplan, et al CSU Review article, 3. AWARE study, 4. Guillen et al , 5. GA LEN task force report

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Plan to Initiate Phase 2b Dose-Ranging Chronic Spontaneous Urticaria Study in 2H 2026 • Long-term GLP toxicology studies in rats and dogs to be completed by mid-year 2026 • Planned global, randomized, double-blind, placebo-controlled study to evaluate safety and exploratory efficacy of SEP-631 in CSU SEP-631 Dose #1 PO QD Primary Endpoint: Patient Population: • Change from baseline in • Adults 18 to 65 years SEP-631 Dose #2 PO QD UAS7 at Week 12 • Moderate to Severe CSU Key Secondary Endpoints: SEP-631 Dose #3 PO QD • Remain symptomatic on second-generation H1 • Safety / Tolerability antihistamine SEP-631 Dose #4 PO QD • UAS7≤6 and UAS7=0 • Change in ISS7 • Change in HSS7 Placebo Day 1 Week 12 • Following initiation of the CSU study, we plan to pursue an open-label Chronic Inducible Urticaria (CIndU) study© 2026 SEPTERNA 24 UAS7: Urticaria Activity Score over 7 days; ISS7: Itch Severity Score over 7 days; HSS7: Hives Severity Score over 7 days Randomization

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Exploring Opportunities for SEP-631 in Additional Indications with High Unmet Need • Indications characterized by mast cells playing a central role in disease pathology and evidence of MRGPRX2 expression on tissue-resident mast cells • Indications cover breadth of target organs and have different pathologies and unmet needs • Developing cost-efficient and right-sized clinical strategies to demonstrate SEP-631 benefit Atopic Dermatitis Interstitial Cystitis Migraine Asthma • >10M moderate to severe AD • ~1-4M interstitial cystitis • ~15-25M moderate-to-severe • ~1-3M severe asthma 1,2 3 4 6,7 patients patients migraine patients ; ~40% patients would benefit from • MRGPRX2 could play a • No compelling treatment • High unmet need for safe, oral 5 preventative treatment central role in itch resolution options treatment • Current therapies provide only • Safe, oral treatment would • Bladder has second highest modest efficacy and drug grow market level of MRGPRX2 cycling is common expression after skin Estimates are US addressable patients. 1. National Eczema Association, 2. 2019 Fuxench, et al, 3. 2022 Anger, et al, 4. 2024 Cohen, et al,© 2026 SEPTERNA 25 5. 2021 American Headache Society Consensus Statement, 6. ACAAI, 7. 2020 Wang, et al

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Building a World-Class GPCR-Focused Biotechnology Company© 2026 SEPTERNA

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Septerna: Building a World-Class GPCR-Focused Biotechnology Company® • SEP-631 Phase 1 results provides clear validation of Septerna's Native Complex Platform • Identification of novel binding pockets to mechanistically modulate GPCRs in therapeutically meaningful ways including unlocking new modes of action such as insurmountable NAMs to generate drug candidates with best-in-class profiles • Ability to use structure-based drug design to optimize clinical candidates with targeted pharmaceutical properties • Septerna is building a robust pipeline of GPCR-targeted medicines • Multi-product wholly-owned pipeline, each with a multi-billion $ market opportunity® • Leveraging Native Complex Platform to fuel additional programs through partnerships (Novo collaboration) • Well-capitalized with cash runway expected to support operating plans at least into 2029 Discovery Stage Phase 1 Ready Phase 2 Ready TSHR NAM SEP-479 SEP-631 Graves' Disease PTH1R Agonist MRGPRX2 NAM Hypoparathyroidism Mast Cell-Driven Diseases Several Others Multiple Indications© 2026 SEPTERNA 27

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Pioneering a New Era of GPCR Drug Discovery© 2026 SEPTERNA