For a certain hormone deficiency inadequately managed with calcium and vitamin supplements, the only FDA-approved therapy is a daily injection that’s in limited supply and is set to exit the market soon. Septerna Therapeutics is developing a drug that could offer patients a new and potentially safer oral treatment option. The startup now has $150 million to support plans that include advancing this small molecule to its first tests in humans.

The Series B financing announced Tuesday was led by RA Capital Management.

South San Francisco-based Septerna is developing a treatment for hypoparathyroidism, a rare disease characterized by insufficient amounts of hormone from the parathyroid glands. Parathyroid hormone is important for regulating calcium and phosphate levels in the blood. Without enough of this hormone, patients experience fatigue, brain fog, and muscle weakness. In severe cases, the disease can cause seizures, heart rhythm problems, and kidney failure.

Standard hypoparathyroidism treatment is various doses of oral calcium and vitamin D supplements, which are intended to keep calcium and phosphate levels closer to normal. When those supplements aren’t enough, the Takeda Pharmaceutical drug Natpara is the only FDA-approved option. Natpara, marketed as Natpar outside the U.S., is an engineered version of parathyroid hormone. Use of Natpara comes with a higher risk of a type of bone cancer, but that’s not the main problem with the drug. It just hasn’t been available.

The FDA approved Natpara in 2015. Four years later, the FDA recalled the drug due to potential contamination from tiny rubber particles from the cartridge housing the injectable product. Takeda worked on changes it hoped could address FDA concerns, but in March 2022, the agency turned down the company’s application seeking approval. Last October, Takeda concluded “there is not a sustainable or viable path forward” for the product, adding that it plans to discontinue manufacturing of the drug in 2024.

Septerna’s drug candidate is a small molecule designed to activate the parathyroid hormone 1 receptor (PTH1R), sparking it to produce more of the deficient hormone. This receptor belongs to a family of receptors called G-protein coupled receptors (GPCRs), which are valuable as drug targets because of their role in a wide range of physiological processes.

Many GPCRs are considered undruggable. Septerna finds ways to drug them. The startup, which launched last year, is based on research from Duke University scientist Robert Lefkowitz, whose work in the GPCR field led to the 2012 Nobel Prize in Chemistry. Septerna’s platform, called Native Complex, isolates GPCR proteins outside of the cellular environment, enabling them to be studied. The company says this approach enables it to identify molecules that address a wide range of GPCR targets long thought to be undruggable.

Septerna is catching up to other companies trying to develop alternatives to Takeda’s hypoparathyroidism drug. Ascendis Pharma completed Phase 3 testing of TransCon PTH, a peptide drug. In May, the FDA rejected the company’s new drug application citing manufacturing issues for the proposed drug/device combination product. Amolyt Pharma is preparing for a Phase 3 test of eneboparatide, a peptide drug that activates the PTH receptor. Extend Biosciences has reached Phase 1 testing with EXT608, a drug that’s derived from parathyroid hormone and is intended to mimic the physiological effects of the hormone. MBX Biosciences is also in Phase 1 with a drug called MBX 2109. All of these drug candidate are injectable, which means that if all goes well with Septerna’s research, its drug would stand apart from the field.

In an email, CEO Jeffrey Finer said that as the company tested its technology against a variety of GPCR targets across various therapeutic areas, PTH1R “rapidly moved ahead of the rest in terms of its advancement.” The company’s other disclosed program is a small molecule that targets thyroid stimulated hormone receptor (TSHR).

“We think there is a tremendous opportunity for an oral small molecule PTH1R agonist for patients with hypoparathyroidism, as most other companies are focused on injectable peptides, which require daily injections,” Finer said. “Taken together, our PTH1R and TSHR programs show that with our Native Complex platform, we can drug most GPCR targets, even hard-to-drug targets, efficiently and effectively.”

With the latest financing, Septerna aims to advance its PTH1R agonist to clinical proof-of-mechanism. The cash will also support development of the TSHR program and other assets in earlier stages of preclinical development.

RA Capital invests in both private and public companies, and its involvement can signal the type of investment that precedes an IPO. Septerna’s latest financing includes other so-called crossover investors. Additional participants in the round include earlier investors Third Rock Ventures, Samsara BioCapital, Invus, Catalio Capital Management, BVF Partners, Casdin Capital and Logos Capital. Disclosed new investors in the round include Deep Track Capital, Goldman Sachs Asset Management, Vertex Ventures HC, Mirae Asset Financial Group, Driehaus Capital Management, Woodline Partners, and Soleus Capital.

Finer acknowledged the participation of crossover investors, but said Septerna’s goal was to have a strong, well-rounded syndicate, which in this case included some crossover investors. He added that in terms of future financings, the company will consider all manner of bringing in capital based on what’s right for Septerna, its investors, and the startup’s programs.

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