Septerna Showcases GPCR Drug Discovery Data at ENDO 2024

Septerna, a biotech firm based in South San Francisco, is pioneering innovative oral small molecule medicines aimed at G protein-coupled receptors (GPCRs). Recently, the company showcased promising preclinical data from its parathyroid hormone 1 receptor (PTH1R) and thyroid stimulating hormone receptor (TSHR) programs at the Endocrine Society’s Annual Meeting (ENDO 2024) held in Boston, MA.

PTH1R Program Progress

The data from the PTH1R program highlighted that small molecule agonists can mimic the activity of native PTH peptides, engaging similar endogenous pathways in the kidney and bone. These agonists effectively maintained serum calcium and phosphate levels over a 28-day period with daily oral administration in a preclinical model of hypoparathyroidism. This suggests a potential oral alternative to injectable PTH peptides for treating hypoparathyroidism. The company plans to start a Phase 1 clinical trial with its leading PTH1R agonist candidate in healthy volunteers by late 2024.

Dr. Jeffrey Finer, Chief Executive Officer and Co-founder of Septerna, expressed excitement about the potential of their PTH1R agonist to revolutionize hypoparathyroidism treatment. He emphasized that the agonist is the only small molecule in development mimicking native PTH behavior, marking a significant advancement in the treatment landscape for this condition.

Detailed PTH1R Findings

The company’s presentation, “Characterization of a Novel Oral Small Molecule PTH1R Agonist: Proof of Concept for an Alternative to Injectable Peptide-based Therapy for Hypoparathyroidism,” by Dr. Jun Zhang, detailed the preclinical assessment. It showed that treatment with Septerna’s small molecule PTH1R agonist upregulated serum calcium levels in a dose-dependent manner in a surgical rat model mimicking hypoparathyroidism. This sustained control over calcium and phosphate levels over 28 days underscores the potential of their oral small molecule as a viable alternative to injectable treatments currently under development.

TSHR Program Insights

In parallel, Septerna presented data from its TSHR program, focusing on an oral small molecule antagonist that improved thyroxine (T4) hormone levels and histological parameters in a preclinical Graves’ disease model. The studies demonstrated that this antagonist blocks the stimulating effects of autoantibodies that drive Graves’ disease. Prolonged treatment with the TSHR antagonist reduced thyroid gland size and improved histological features associated with the disease.

Graves’ disease is characterized by the production of autoantibodies that activate the TSH receptor on thyroid cells, leading to excessive thyroid hormone production and hyperthyroidism. The data presented provides proof-of-concept for the effectiveness of TSHR-targeting small molecules in mitigating hyperthyroidism in Graves’ disease. Septerna is advancing several lead molecules towards selecting a development candidate for both Graves’ disease and thyroid eye disease (TED).

Septerna’s Mission and Future Directions

Founded in 2022, Septerna leverages its Native Complex Platform™ to replicate GPCRs outside the cellular environment, preserving their native structure and function. This platform aims to rapidly discover new small molecule drugs targeting GPCRs, addressing both well-validated and previously undruggable GPCRs.

Septerna’s PTH1R program targets hypoparathyroidism, a condition characterized by a deficiency of parathyroid hormone leading to severe symptoms like muscle weakness, tissue calcification, and potentially fatal complications. Current treatments are limited to supplements or daily injectable PTH peptides. Septerna’s oral PTH1R agonist has shown potential to normalize serum calcium levels, offering a promising oral alternative.

Similarly, the TSHR program targets Graves’ disease, an autoimmune condition causing hyperthyroidism and TED. Existing treatments are inadequate, focusing narrowly on the thyroid without preventing TED progression. Septerna’s TSHR antagonist aims to block all Graves’ autoactivating antibodies, providing a comprehensive oral treatment option.

In summary, Septerna’s innovative approach to targeting GPCRs with small molecule medicines holds promise for transforming treatments for conditions like hypoparathyroidism and Graves’ disease, potentially leading to more effective and convenient therapeutic options.

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