# EDGAR Filing Document

**Accession Number:** 0001984086
**File Stem:** 0001193125-26-152045
**Filing Date:** 2026-4
**Character Count:** 47094
**Document Hash:** 64b124a0dd0e5afec80373e99738fe5b
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001193125-26-152045.hdr.sgml**: 20260413

**ACCESSION NUMBER**: 0001193125-26-152045

**CONFORMED SUBMISSION TYPE**: 8-K

**PUBLIC DOCUMENT COUNT**: 55

**CONFORMED PERIOD OF REPORT**: 20260413

**ITEM INFORMATION**: Regulation FD Disclosure

**ITEM INFORMATION**: Financial Statements and Exhibits

**FILED AS OF DATE**: 20260413

**DATE AS OF CHANGE**: 20260413

**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:** 26856539

**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): April 13, 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 April 13, 2026, Septerna, Inc. (the "Company") issued a press release titled "Septerna Announces Initiation of Phase 1 Clinical Trial of SEP-479, an Oral Small Molecule PTH1R Agonist for the Treatment of Hypoparathyroidism." A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.

On April 13, 2026, the Company also updated its corporate presentation for use in meetings with investors, analysts and others. A copy of the updated corporate presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K, which is incorporated herein by reference.

The information in Item 7.01 of this Current Report on Form 8-K, including the accompanying Exhibit 99.1 and Exhibit 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 9.01. Financial Statements and Exhibits.
(d) Exhibits

---

| | |
|:---|:---|
| 99.1 | [Press Release issued by Septerna, Inc. on April 13, 2026, furnished herewith.](d57504dex991.htm) |
| 99.2 | [Corporate Presentation of Septerna, Inc., dated April 2026, furnished herewith.](d57504dex992.htm) |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document). |

---

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#### 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: April 13, 2026 | By: | /s/ Jeffrey Finer, M.D., Ph.D. |
|  |  | Jeffrey Finer, M.D., Ph.D.<br> Chief Executive Officer |

---

## Exhibit 99.1

**Exhibit 99.1**![LOGO](g57504g0413021359593.jpg)

**Septerna Announces Initiation of Phase 1 Clinical Trial of SEP-479, an Oral Small Molecule PTH1R Agonist for the Treatment of Hypoparathyroidism** 

*Trial Designed to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SEP-479 in Healthy Volunteers* 

*Data Anticipated in Late 2026 or Early 2027* 

**SOUTH SAN FRANCISCO, Calif. – April 13, 2026** – Septerna, Inc. (Nasdaq: SEPN), a clinical-stage biotechnology company pioneering a new era of G protein-coupled receptor (GPCR) drug discovery, today announced the dosing of the first participants in its Phase 1 clinical trial of SEP-479, its potent oral small molecule PTH1R agonist being developed for the treatment of patients with hypoparathyroidism. The Phase 1 clinical trial is a single-ascending dose (SAD) and multiple-ascending dose (MAD) clinical trial to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SEP-479 in healthy adult volunteers.

"Hypoparathyroidism is a lifelong condition that patients must manage with either high doses of calcium supplements several times a day or daily parathyroid hormone (PTH) injections, both of which can place a substantial burden on patients over time," said Jeffrey Finer, M.D., Ph.D., Chief Executive Officer and Co-founder of Septerna. "We are encouraged by the preclinical data for SEP-479, which underscore its potential to be a disease modifying therapy for hypoparathyroidism by directly targeting the PTH receptor to provide patients full-day calcium control and relief from their debilitating symptoms. Based on these findings, we believe SEP-479 has the potential to be differentiated as a once-daily oral therapy for patients, and we look forward to advancing our Phase 1 trial as rapidly as possible."

The randomized, placebo-controlled Phase 1 clinical trial is expected to enroll up to 150 healthy adult participants. Dosing is underway in the SAD portion of the clinical trial, which will evaluate the safety and tolerability of SEP-479 at escalating oral doses. The MAD portion of the clinical trial is designed to evaluate the safety and tolerability of once-daily oral dosing of SEP-479 over multiple days of treatment, with secondary and exploratory endpoints including PK and PD, with the latter assessed by changes in endogenous PTH and serum calcium, as well as other biomarkers. Septerna anticipates reporting data from the trial in late 2026 or early 2027.

**About SEP-479** 

Septerna is developing SEP-479, a potent oral small molecule parathyroid hormone 1 receptor (PTH1R) agonist for the treatment of patients with hypoparathyroidism. In preclinical studies, SEP-479 demonstrated activity comparable to PTH peptides in cell-based assays and in vivo models, normalized serum calcium in a rat model of hypoparathyroidism and increased serum calcium with reductions in endogenous PTH in a non-human primate PK/PD study. SEP-479 was generally well tolerated in 28-day GLP toxicology studies in rats, dogs and non-human primates.

**About Hypoparathyroidism** 

Hypoparathyroidism is a debilitating endocrine disease caused by a deficiency of the parathyroid hormone (PTH) that results in a range of symptoms, including muscle cramps, fatigue, cognitive dysfunction, and life-threatening complications, such as cardiac arrhythmias, seizures, and renal failure. Current therapies include high doses of calcium and vitamin D supplements orally several times daily or daily PTH injections. There remains a need for treatment options designed to functionally replace PTH that offer more convenient modes of administration for patients compared to lifelong daily injections.

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![LOGO](g57504g0413021359593.jpg)

**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 potential of SEP-479 preclinical data to translate into similar clinical safety, pharmacokinetic, and pharmacodynamic findings; the estimated availability of SEP-479 Phase 1 clinical data in late 2026 or early 2027; the potential for SEP-479 to be a differentiated once-daily oral therapy for patients with hypoparathyroidism; 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: the risk that SEP-479 preclinical data does not turn out to be predictive of future clinical outcomes for SEP-479; risks related to clinical development outcomes for SEP-479 including unexpected safety, pharmacokinetic, or pharmacodynamic findings; risks related to the actual timing of future availability of clinical data for SEP-479 including that the actual timing of enrollment and completion of the study may differ from management's current estimates; the scope of protection Septerna is able to establish and maintain for intellectual property rights covering its Native Complex Platform<sup>®</sup> and its product candidates (including SEP-479); and general economic, industry and market conditions. 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, 2025, 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

![Slide 1](g57504ex99_2s1g1.jpg)

Pioneering a New Era of GPCR Drug Discovery April 2026 Nasdaq: SEPN Corporate Presentation Exhibit 99.2

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![Slide 2](g57504ex99_2s2g1.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 SEP-479 in clinical development, including the anticipated availability of Phase 1 clinical study data in late 2026 or early 2027; the continued advancement of SEP-631, including the plan to initiate a Phase 2b clinical study in chronic spontaneous urticaria in the second half of 2026 subject to the successful completion of long-term preclinical toxicology studies and regulatory filings; the role of MRGPRX2 in mast cell-driven diseases; the ability of preclinical or Phase 1 safety and efficacy observations to successfully translate into positive clinical outcomes; the timing, progress and results of conducting our research and development programs, including our plans to advance the TSHR research 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 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, 2025, 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.

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![Slide 3](g57504ex99_2s3g1.jpg)

Septerna: Pioneering a New Era of GPCR Drug Discovery with Oral Small Molecules Native Complex Platform® designed to unlock the full potential of GPCR therapies Iterative structure-based drug design to rapidly optimize and validate programs in animal models Portfolio strategy to drive value creation Validated targets + early clinical readouts + multi-billion $ market opportunities Well-capitalized Cash runway expected to support operating plans at least into 2029 Discovery Stage TSHR NAM: Potential disease-modifying treatment for Graves' disease and TED; progressing multiple lead compounds toward development candidate selection Incretin Receptor Agonists: Potential multi-billion $ collaboration with Novo Nordisk for oral small molecules for metabolic diseases Lead Programs SEP-479 PTH1R Agonist: Potential first-in-class oral small molecule for hypoparathyroidism; Phase 1 in healthy volunteers initiated with SAD/MAD data anticipated in late 2026 or early 2027 SEP-631 MRGPRX2 NAM: Pipeline-in-a-product opportunity for mast cell-driven diseases; Phase 1 SAD/MAD demonstrated robust PD with QD dosing; targeting initiation of Phase 2 trial in CSU in 2H 2026 GPCR: G protein-coupled receptor; NAM: negative allosteric modulator; TED: thyroid eye disease; CSU: chronic spontaneous urticaria

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![Slide 4](g57504ex99_2s4g1.jpg)

GPCR Drug Discovery Success Has Been Highly Concentrated to a Small Fraction of GPCRs Historically productive target class, yet substantial untapped opportunity to expand the number of druggable GPCRs >70% of GPCR drugs target 6 small subfamilies of GPCRs ~1/3 of all FDA-approved drugs (~500 approved products) target GPCRs ~75% of potential GPCR targets remain undrugged Our focus: Unlocking difficult-to-drug GPCRs with our Native Complex Platform®

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![Slide 5](g57504ex99_2s5g1.jpg)

Proprietary Native Complex Platform® Today's GPCR Drug Discovery Challenge Several new small molecule drug discovery technologies have largely been inaccessible to GPCRs Inability to isolate fully functional GPCR proteins significantly limits use of modern discovery tools G protein Lipid Bilayer Ligand GPCR Native Complex Platform® : Industrialized Workflows to Unlock Difficult-to-Drug GPCRs Native Complexes Retain GPCR natural structure, function, and dynamics High-Resolution GPCR Structures Technologies to Screen Billions of Compounds Discovery of new leads with relevant modes of action Novel binding pockets and new insights into GPCR modulation Structure-Based Drug Design & Optimization <1 year from initiation of med chem to activity in animal models for each program to date

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![Slide 6](g57504ex99_2s6g1.jpg)

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

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![Slide 7](g57504ex99_2s7g1.jpg)

Targeting PTH1R for Hypoparathyroidism SEP-479: Oral Small Molecule PTH1R Agonist

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![Slide 8](g57504ex99_2s8g1.jpg)

Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement Hypoparathyroidism: Low PTH leads to low blood calcium ~70K patients in US; ~140K patients in EU Challenging patient symptoms Muscle cramps, tingling, brain fog Life-threatening complications: cardiac arrhythmias, seizures Standard-of-care limitations Calcium supplements (high doses several times per day) and Vitamin D do not fully resolve symptoms and lead to complications including calcifications and renal impairment Approved injectable PTH therapy will require life-long daily injections PTH: Parathyroid Hormone Our Strategy: Functionally replace PTH with oral small molecule PTH1R agonist to normalize serum calcium PTH: Master Regulator of Blood Calcium

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![Slide 9](g57504ex99_2s9g1.jpg)

SEP-479: Discovered with Native Complex Platform™ as Potent Oral PTH1R Agonist for Hypoparathyroidism Multiple PTH1R agonists with distinct binding sites identified and optimized in parallel to candidate quality molecules Native Complex Hit Identification and Structure-Based Optimization Rapid Iterative Structure-Based Drug Discovery <1 year from initiation of medicinal chemistry to activity in an animal model PTH1R PTH G protein SEP-479: Clinical Candidate Potent oral small molecule PTH1R agonist Demonstrated comparable effects to PTH peptides in cell-based assays and in vivo models Normalized serum calcium in preclinical rat surgical model of hypoparathyroidism Monkey PK/PD study demonstrated robust decreases in endogenous PTH and increases in serum calcium Excellent pharmaceutical properties; projected to achieve full-day HypoPT control with QD dosing Generally well tolerated in GLP toxicology studies Phase 1 in healthy volunteers is in progress

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![Slide 10](g57504ex99_2s10g1.jpg)

SEP-479: A Potent PTH1R Agonist Normalized Serum Calcium and Phosphate in Rat Hypoparathyroidism Model PO: oral dosing QD: once daily dosing BID: twice daily dosing Surgery to remove parathyroid glands Rat Decreased serum calcium (hypocalcemia) Oral small molecule PTH1R agonist Normalize serum calcium Rat surgical model of hypoparathyroidism SEP-479: 28-day Oral QD Dosing Sustained Normalization of Serum Ca2+ Levels Sustained Normalization of Serum Phosphate Levels

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![Slide 11](g57504ex99_2s11g1.jpg)

SEP-479 Lowered Endogenous PTH and Increased Serum Calcium In Healthy Cynomolgus Monkey Pharmacodynamic Study In healthy animals (and humans) with normal parathyroid gland function: Treatment with PTH agonists leads to rapid suppression of endogenous PTH secretion to maintain normal calcium levels When feedback suppression of endogenous PTH reaches its limits, PTH agonist therapy at higher doses leads to calcium increases SEP-479: 7-day Healthy Cynomolgus Monkey Pharmacodynamic Study Serum Ca2+ Levels Serum PTH Levels Lessons from PTH peptide clinical trials: Doses in healthy subjects that increase calcium ~0.5-1 mg/dL translated to relevant therapeutic pharmacology in hypoparathyroidism patients

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![Slide 12](g57504ex99_2s12g1.jpg)

SEP-479 Preclinical Profile Supported Advancement into Phase 1 Potent oral small molecule PTH1R agonist Demonstrated effects comparable to PTH peptides in cell-based assays and in vivo models Pharmacokinetic studies Demonstrated high oral bioavailability and long half-life following oral dosing across preclinical species (mouse, rat, dog, cyno) Projected human half-life is approximately 40-80 hours with potential to support QD human dosing Non-clinical safety studies Generally well tolerated in three non-clinical safety studies (28-day GLP toxicology in rats, dogs, cyno) Dose-limiting effect in each species was on-target hypercalcemia, as expected for a PTH1R agonist

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![Slide 13](g57504ex99_2s13g1.jpg)

SEP-479 Phase 1 Study in Healthy Volunteers is in Progress Study design: Randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) trial in healthy adult volunteers Will also include a cross-over food effect study Estimated enrollment: up to ~150 subjects (in Australia) Single ascending dose Multiple ascending dose SEP-479 x 1 SEP-479 x 1 Safety / tolerability PK PTH, Ca2+ Other biomarkers # cohorts TBD SEP-479 x 1 Randomization SEP-479 : placebo Safety / tolerability PK PTH, Ca2+ Other biomarkers Randomization SEP-479 : placebo SEP-479 QD x 7+ # cohorts TBD SEP-479 Phase 1: Illustrative Schematic Endpoints Endpoints SEP-479 QD x 7+ SEP-479 QD x 7+ Translation of healthy volunteer studies to hypoparathyroidism patients: Healthy subjects and hypoparathyroidism patients both have intact PTH1R in the bone and kidneys to control serum calcium Injectable PTH peptide trials: changes in serum calcium translated well from healthy volunteers to hypoparathyroidism patients Objectives for SEP-479 during dose escalation in healthy volunteers: On-target pharmacology to be confirmed initially with decreases in endogenous PTH, and at higher doses, with increases in serum calcium Anticipate SEP-479 SAD / MAD results in late 2026 or early 2027

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![Slide 14](g57504ex99_2s14g1.jpg)

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

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![Slide 15](g57504ex99_2s15g1.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

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![Slide 16](g57504ex99_2s16g1.jpg)

SEP-631: MRGPRX2 NAM with a Potentially Differentiated Profile for Mast Cell-Driven Diseases SEP-631 is a negative allosteric modulator (NAM) Binds to a novel allosteric site, distinct from the agonist binding pocket Potently inhibits MRGPRX2 activation with an insurmountable NAM profile Very high binding affinity (Ki ~0.5 nM) Slow dissociation rate (t1/2 > 2 hours) Locks MRGPRX2 in a state that prevents binding of all agonists, even at high agonist concentrations Potent inhibition of MRGPRX2-induced degranulation for both mast cell lines and primary human skin mast cells PK profile across species projected to once-daily oral dosing in humans SEP-631 Induces a Structural Change in MRGPRX2 That Completely Closes the Agonist Binding Pocket Extracellular view Transmembrane view MRGPRX2 Agonist binding pocket Extra- cellular loop Agonist\* MRGPRX2 + SEP-631 Agonist pocket no longer exists \*Cortistatin-14

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![Slide 17](g57504ex99_2s17g1.jpg)

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

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![Slide 18](g57504ex99_2s18g1.jpg)

SEP-631 Preclinical Profile SEP-631 Preclinical Data Supports Potential Best-in-Class 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

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![Slide 19](g57504ex99_2s19g1.jpg)

SEP-631 Phase 1 Study Design Goal: Evaluate the safety, tolerability, PK, PD (with an icatibant skin challenge), and food effects 120 healthy adult volunteers, double-blind, randomized, and placebo-controlled SAD/MAD study design 10 mg 30 mg 90 mg 200 mg 300 mg 400 mg Single ascending dose n=8 / cohort Randomization 6:2 (SEP-631:placebo) Key endpoints Safety / tolerability PK Randomized open-label crossover 5-day washout 200 mg Fed 200 mg Fed 200 mg Fasted 200 mg Fasted Part A. SEP-631 PO single dose (SAD) Part B. SEP-631 PO QD for 10 days (MAD) Multiple ascending dose n=16 / cohort Randomization 12:4 (SEP-631:placebo) 10 mg 30 mg 90 mg 200 mg Key endpoints Safety / tolerability PK PD: skin challenge Part C. SEP-631 PO single dose crossover Food effect n=8 Key endpoints Safety / tolerability PK (fasted vs fed) Skin Challenge (Pre-dose) Skin Challenge Objective (Post-dose) SEP-631 dosing QD x 9 days H P L H N L H N L L = icatibant 10 µg/mL; H = icatibant 100 µg/mL; N = negative control (saline); P = positive control (histamine) H P L

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![Slide 20](g57504ex99_2s20g1.jpg)

SEP-631: Adverse Event Profile Comparable to Placebo and Pharmacokinetics Support Once-Daily Oral Dosing Pharmacokinetics Elimination half-life of SEP-631 is approximately 24 hours, supporting once-daily (QD) dosing Food Effect Study SEP-631 with high-fat, high-calorie meal resulted in similar exposure to fasted conditions (AUC and Cmax) Multiple Dose Pharmacokinetics (Day 10) Safety Rate of TEAEs with SEP-631 was comparable with placebo No severe or serious events were reported 3 events of mild transaminase elevations (<1.5x ULN) observed; not dose-dependent and comparable to placebo rates SEP-631 was well tolerated with a PK profile that supports QD oral dosing and without food restrictions

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![Slide 21](g57504ex99_2s21g1.jpg)

Pharmacodynamics Assessed Using an Icatibant Skin Challenge Icatibant is a selective MRGPRX2 agonist that induces a skin wheal response following intradermal injection Skin challenge performed at baseline (Day –1) and steady-state (Day 9) following SEP-631 or placebo treatment Skin challenge agents: saline (injection negative control), histamine (wheal positive control), and icatibant at 10 μg/mL and 100 μg/mL Wheals imaged using a precision image-based detector (AllergyScope™) Saline Histamine Icatibant 10 µg/mL Icatibant 10 µg/mL Icatibant 100 µg/mL Icatibant 100 µg/mL Forearm Intradermal Injection Pattern AllergyScopeTM Detector Baseline Skin Challenge (Day -1)

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![Slide 22](g57504ex99_2s22g1.jpg)

SEP-631 Inhibits Icatibant Wheal Formation in Dose-Dependent Manner to Complete Inhibition Nominal p-values comparing each SEP-631 dose level to placebo for change from baseline are based on an ANCOVA model including a fixed effect for treatment group and baseline wheal response as a covariate 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

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SEP-631 Preclinical Profile Translated Well to Phase 1 Clinical Trial Results SEP-631 Preclinical Profile Robust SEP-631 Phase 1 Results Subnanomolar binding affinity Slow receptor off-rate kinetics Target Coverage Estimated high receptor occupancy (>99%) Excellent oral PK across preclinical species Pharmacokinetics Confirmed QD oral dosing (half-life ~24 hrs) No food effect, excellent dosing flexibility Insurmountable NAM blocks agonist binding pocket for all MRGPRX2 agonists tested Pharmacodynamics Full inhibition of icatibant-induced skin wheal formation at both high and low icatibant doses Generally well-tolerated in GLP tox studies Low DDI risk based on in vitro profiling Safety All AEs considered mild or moderate No LFT abnormalities or other observations Translation 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

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SEP-631: Initial Phase 2 Development Strategy Broad opportunity across a range of allergic and inflammatory diseases where mast cells are implicated in disease pathophysiology Mast cells reside in organ systems throughout the body contributing to pain, itch, and inflammation Our 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 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, and Asthma

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Chronic Spontaneous Urticaria (CSU): High Disease Burden, Large Patient Population CSU is an undertreated dermatology condition characterized by itchy and painful wheals and angioedema Significant burden of disease; patients experience1: Disease Burden % CSU Patients High to very high impact on their daily life ~40% Mod-to-severe pain / discomfort ~60% Mod-to-severe anxiety / depression ~50% Miss work at least once per week ~20% ~40% of patients are refractory to first-line high-dose antihistamines2-4 High unmet need for safe second-line oral treatment options Growing commercial opportunity: ~2-3M CSU patients in the US5 CSU Skin Wheals and Angioedema 1. ASSURE study, 2. 2022 Kaplan, et al CSU Review article, 3. AWARE study, 4. Guillen et al , 5. GA2LEN 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 Randomization SEP-631 Dose #2 PO QD Placebo SEP-631 Dose #3 PO QD SEP-631 Dose #4 PO QD SEP-631 Dose #1 PO QD Day 1 Week 12 Primary Endpoint: Change from baseline in UAS7 at Week 12 Key Secondary Endpoints: Safety / Tolerability UAS7≤6 and UAS7=0 Change in ISS7 Change in HSS7 Patient Population: Adults 18 to 65 years Moderate to Severe CSU Remain symptomatic on second-generation H1 antihistamine UAS7: Urticaria Activity Score over 7 days; ISS7: Itch Severity Score over 7 days; HSS7: Hives Severity Score over 7 days Following initiation of the CSU study, we plan to pursue an open-label Chronic Inducible Urticaria (CIndU) study

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Atopic Dermatitis Interstitial Cystitis Migraine Asthma 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 >10M moderate to severe AD patients1,2 MRGPRX2 could play a central role in itch resolution Safe, oral treatment would grow market ~1-4M interstitial cystitis patients3 No compelling treatment options Bladder has second highest level of MRGPRX2 expression after skin ~15-25M moderate-to-severe migraine patients4; ~40% would benefit from preventative treatment5 Current therapies provide only modest efficacy and drug cycling is common ~1-3M severe asthma patients6,7 High unmet need for safe, oral treatment Estimates are US addressable patients. 1. National Eczema Association, 2. 2019 Fuxench, et al, 3. 2022 Anger, et al, 4. 2024 Cohen, et al, 5. 2021 American Headache Society Consensus Statement, 6. ACAAI, 7. 2020 Wang, et al

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Oral Small Molecule Targeting TSHR for Graves' Disease and TED TSHR NAM Program

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No Disease-Modifying Therapies for Graves' Disease and Thyroid Eye Disease (TED) Graves' Disease & TED Pathophysiology: Autoantibodies activate TSHR in thyroid gland and in orbital fibroblasts behind the eyes Graves' Disease >2M patients in US Standard-of-care: antithyroid drugs, radioactive iodine, thyroidectomy TED Develops in ~50% of Graves' disease patients TEPEZZA® (anti-IGF-1R) decreases proptosis but requires multiple IV infusions; serious side effects (e.g., hearing loss) Challenge: Each Patient Has Unique Autoantibodies High-affinity, frequently polyclonal, high titer

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Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves' Disease Model Selective TSHR NAMs Blocked activation of TSHR by patient-derived autoantibodies Insurmountable NAM profiles in cell-based assays Preclinical Leads Inhibited Diverse Patient Autoantibodies Fully inhibited several Graves' patient polyclonal serum samples in primary orbital fibroblasts Reversed Graves' Animal Disease Model Effects Normalization of thyroid hormone T4 Reduction in thyroid weight Reversal of proptosis Lead optimization is ongoing towards selection of a development candidate Agonist mAb + Vehicle Agonist mAb + SP-1351 Isotype mAb control + Vehicle TSHR Activating Antibody Mouse Thyroid Hormone Levels Thyroid Size Eye Proptosis (bulging) TSHR Activating Ab +TSHR NAM Reversal of Thyroid and Eye Manifestations 6 weeks 1 week

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Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR and Other Targets for Obesity, Diabetes, and Other Cardiometabolic Diseases Metabolic Programs

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Collaboration with Novo Nordisk for Oral Small Molecules for Metabolic Diseases Septerna and Novo commenced four initial R&D programs targeting five GPCRs Includes GLP-1, GIP and glucagon receptors Collaboration includes Septerna's preclinical, selective, oral, small molecule GIP receptor agonists Potential multi-billion $ opportunity $195M upfront payment received in July '25 ~$500M in R&D, regulatory and commercial milestones for each program Mid-to-high single-digit tiered royalties based on global product sales Opt-in right for worldwide profit-share for one program Novo responsible for coverage of all collaboration R&D expenses Collaboration Objective: discover, develop and commercialize multiple novel mono-, dual-, or triple-acting oral small molecule drug candidates directed to obesity, type 2 diabetes and other cardiometabolic diseases

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Building a World-Class GPCR-Focused Biotechnology Company

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Proven Leaders in GPCR Drug Development and Company Building Senior Leadership Jeff Finer, MD PhD CEO Liz Bhatt, MS MBA President & COO Gil Labrucherie, CFA JD CFO Samira Shaikhly CPO Jae Kim, MD CMO Uwe Klein, PhD SVP Biological Sciences Dan Long, DPhil SVP Drug Discovery Board of Directors Jeff Finer, MD, PhD, CEO Jeff Tong, PhD, Third Rock Ventures Alan Ezekowitz, MD, DPhil, Third Rock Ventures Abe Bassan, Samsara BioCapital Jake Simson, PhD, RA Capital Bernard Coulie, MD, PhD, MBA, Independent Director Shalini Sharp, MBA, Independent Director Keith Gottesdiener, MD, Independent Director Academic Co-Founders Robert J. Lefkowitz, MD, Duke University Medical Center Arthur Christopoulos, PhD, Monash University Patrick Sexton, PhD, DSc, Monash University Drug Discovery Advisory Board Ruth Wexler, PhD, formerly with BMS John Lowe, PhD, formerly with Pfizer Craig Lindsley, PhD, Vanderbilt, formerly with Merck Tom Baillie, PhD, DSc, formerly with Merck David Lacey, MD, formerly with Amgen Mark Wilson, JD CLO

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Septerna: Pioneering a New Era of GPCR Drug Discovery Portfolio of oral small molecule GPCR-targeted programs Multi-product pipeline, each with a multi-billion $ market opportunity Native Complex Platform® drives rapid compound identification and portfolio expansion Well-capitalized with cash runway expected to support operating plans at least into 2029 \* Pending successful completion of regulatory submissions Wholly-Owned Programs Development Status Program / Target Mode of Action Discovery IND-enabling Phase 1 Phase 2 SEP-479 (PTH1R) Agonist SEP-631 (MRGPRX2) Negative Allosteric Modulator TSHR Program Negative Allosteric Modulator Partnered Programs Partner Metabolic Programs GLP-1R, GIPR, GCGR + Undisclosed Obesity and Other Cardiometabolic Diseases Undisclosed Undisclosed Phase 2 initiation\* anticipated in 2H 2026 Anticipate Phase 1 data in late 2026 or early 2027

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Pioneering a New Era of GPCR Drug Discovery

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Appendix

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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 TEAE, treatment-emergent adverse event as number (%) Pooled placebo (n=12) SEP-631 Single Dose 10 mg (n=6) 30 mg (n=6) 90 mg (n=6) 200 mg (n=6) 300 mg (n=6) 400 mg (n=6) Pooled SEP-631 (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)

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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 TEAE, treatment-emergent adverse event as number (%) Pooled placebo (n=15) SEP-631 Multiple Dose (10 Days) 10 mg (n=12) 30 mg (n=12) 90 mg (n=12) 200 mg (n=12) Pooled SEP-631 (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)

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Native Complex Platform® is a Highly Efficient Platform for GPCR Structure-Based Drug Design cryo-EM = cryogenic electron microscopy GPCR cryo-EM now achieving resolutions relevant for structure-based drug design Native Complex cryo-EM enables rapid and iterative lead optimization Applies to a broad range of lead candidate modes of action (e.g., agonists, antagonists, allosteric modulators) >150 high-resolution cryo-EM structures determined to date, fueling our drug discovery programs New Small Molecule Ligand New Ligand-Bound GPCR Structure ~1-2 weeks Native Complex Cryo-EM Structure-Based Design Rapid Iterative Cycle Apo (no ligand) Agonist Positive Allosteric Modulator Antagonist Negative Allosteric Modulator GPCR A 4 8 12 16 20 B C D E F G # Structures 24 Native Complex High-Resolution GPCR Structures

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SEP-786: First Clinical PTH1R Agonist Discontinued in Phase 1 in February 2025 Due to Unanticipated Events SEP-786 Phase 1 SAD/MAD trial in healthy volunteers discontinued 2 unanticipated severe (Grade 3) events of elevated unconjugated bilirubin levels in MAD Both events were reversible and without liver injury (normal AST, ALT, GGT), cholestasis, or hemolysis Not predicted by preclinical studies including 28-day GLP toxicology studies in rats and dogs Early signals of on-target pharmacology seen for SEP-786 prior to trial discontinuation Observed initial increases in serum calcium and decreases in endogenous PTH (as anticipated for healthy subjects) Observed human half-life of ~18 hours would have likely supported QD or BID oral dosing \*Note: UGT1A1 is not routinely tested if glucuronidation is not the major drug metabolism pathway Investigation into the mechanism of unconjugated hyperbilirubinemia Post Clinical Discontinuation Findings: SEP-786 is a potent UGT1A1 inhibitor\* which is a known mechanism for increases in unconjugated bilirubin In a cynomolgus monkey study with SEP-786 (conducted after clinical discontinuation), elevated unconjugated bilirubin was observed Bilirubin Bile Canaliculus Hepatocyte Hepatocyte Bilirubin Conjugated Bilirubin UGT1A1 OATP1B1 / OATP1B3 MRP2 SEP-786