We are a Phase 1 clinical biotech company developing oral small molecule drugs targeting G protein-coupled receptors (GPCRs) in numerous therapeutic areas. (Incorporated in Delaware)

Our lead product candidate is SEP-876, a clinical-stage oral small molecule agonist targeting PTH1R – parathyroid hormone 1 receptor (PTH1R) – which we are evaluating in a Phase 1 clinical trial to treat patients with hypoparathyroidism. We expect to report data from this trial in mid-2025.

Note: PTH1R is a historically difficult-to-drug small molecule target, yet we effectively leveraged our Native Complex Platform^TM to discover and optimize SEP-786 with desired drug-like properties.

We are also developing SEP-631, an oral small molecule MRGPRX2 negative allosteric modulator (NAM) to treat chronic spontaneous urticaria (CSU) currently in IND-enabling studies.

Chronic spontaneous urticaria (CSU) is a systemic inflammatory skin disease characterized by the spontaneous and persistent recurrence of itchy, painful hives, known as wheals, on the skin and angioedema, or swelling, that affects approximately 1.5 million patients in the United States. While there is no known trigger, the degranulation of mast cells and release of histamine and other inflammatory mediators lead to these debilitating symptoms. Patients are treated initially with antihistamines and non-responders may be treated with Xolair (omalizumab), an injectable anti-IgE monoclonal antibody. The targeting and blocking of IgE-mediated inflammation can effectively address symptoms; however, only an estimated 36% of these antihistamine-refractory patients respond to anti-IgE therapy. Mas-related G-protein coupled receptor member X2 (MRGPRX2) plays an important role in mast cell activation and degranulation. We believe an oral therapy that inhibits MRGPRX2 could provide a differentiated treatment option for patients with CSU given the selective inhibition of mast cells and potential for combination therapy.

SEP-631 is a selective, oral small molecule MRGPRX2 negative allosteric modulator (NAM) that we are developing initially for the treatment of CSU. We have initiated IND-enabling studies of SEP-631 and upon completion, we anticipate submitting for regulatory clearance to initiate a clinical trial.

In addition to CSU, we may develop SEP-631 for the treatment of other mast cell diseases. MRGPRX2 is highly and uniquely expressed on mast cells that drive multiple prevalent diseases, including allergic asthma, atopic dermatitis, interstitial cystitis, migraine, and prurigo nodularis. We believe SEP-631 could offer a novel oral treatment option for these patient populations.

Note: We are also developing a preclinical TSHR (thyroid stimulating hormone receptor) program to treat Graves’ disease and thyroid eye disease (TED).

TSHR Program – Oral Small Molecule TSHR NAM for Graves’ Disease and TED

Graves’ disease is one of the most prevalent autoimmune conditions affecting over 2 million patients in the United States and is the leading cause of hyperthyroidism, resulting in symptoms including anxiety, irritability, tremor, and fatigue. Treatments have remained largely unchanged over the past 70 years, and include anti-thyroid medications, radioactive iodine therapy to ablate thyroid gland function, and thyroidectomy surgery. These treatment options may initially address the underlying symptoms, but they are not disease-modifying and do not stop disease progression to thyroid eye disease (TED) for approximately 50% of Graves’ disease patients. TED is a serious, progressive and vision-threatening autoimmune condition that can lead to eye bulging, swelling, pain and blurred or double vision. Current treatments for TED, such as TEPEZZA (teprotumumab-trbw), an anti-IGF-1R human monoclonal antibody, are designed to help manage symptoms. Despite reaching global sales of $2.0 billion in 2022, TEPEZZA requires several intravenous (IV) infusions over several months and has risks of serious side effects, including hearing loss and metabolic issues, such as increased blood glucose or hyperglycemia.

These autoimmune conditions are caused by autoantibodies that bind to and activate the thyroid stimulating hormone receptor (TSHR) on thyroid cells in the thyroid gland (leading to Graves’ disease) and other cells including fibroblasts located behind the eyes (leading to TED). We believe an oral small molecule TSHR NAM could offer a novel disease-modifying treatment approach that directly addresses the pathobiology of both diseases by blocking TSHR overactivation caused by patients’ autoantibodies. We are advancing several lead compounds towards selection of a development candidate for IND-enabling studies.

Note: Net loss and revenue are for the 12 months that ended June 30, 2024.

(Note: Septerna Inc. upsized its IPO at pricing to 16.0 million shares – up from 15.28 million shares (15,277,778 shares) in the prospectus – and priced its IPO at $18.00 – the assumed IPO price in the prospectus – to raise $288.0 million on Thursday night, Oct. 24, 2024. Background: Septerna Inc. upsized its IPO to 15.28 million shares (15,277,778 shares) – up from 10.94 million shares (10,937,500 shares) originally – and raised the assumed IPO price to $18.00 – up from the price range of $15.00 to $17.00 in the original terms – to raise $275.0 million, according to an S-1/A filing dated Oct. 24, 2024.

(Background: Septerna Inc. disclosed the terms for its IPO in an S-1/A filing dated Oct. 21, 2024: The company is offering 10.94 million shares (10,937,500 shares) at a price range of $15.00 to $17.00 to raise $175.0 million, if the IPO is priced at the $16.00 mid-point of its range. Background: Septerna filed an S-1 on Oct. 2, 2024, without disclosing terms for its IPO. Estimated initial proceeds were $100 million, which was a placeholder figure.)