Several years ago, in his eponymously named lab at the Duke University School of Medicine, renowned researcher Robert Lefkowitz was fighting the inevitable. He and his team were working out a new method to better understand one of the most important families of proteins in drug development. Lefkowitz wanted the research to remain academic, but as his lab began to generate exciting findings, in came pitches from postdoctoral students about starting a company.
"As I like to say, they dragged me kicking and screaming to the idea," Lefkowitz said in an interview with BioPharma Dive.
Fast forward, and Lefkowitz is now co-founder of Septerna, a biotechnology company that officially launched Thursday, equipped with $100 million in funding from some of the industry's most powerful venture investors.
Septerna's focus is on an expansive and diverse group of proteins called G protein-coupled receptors, or GPCRs, which provide an invaluable service to cells. If cells were like castles, then GPCRs would act as lookouts on the perimeter wall, relaying information about the outside environment and, in turn, spurring action internally. These proteins are involved in a wide variety of important functional processes — from sensory ones like sight, smelling and taste, to regulatory ones that govern the immune system and even cell growth.
The key roles GPCRs play have made them a prime target for drug developers. Estimates hold that about a third of all medicines approved by the Food and Drug Administration target or act through these proteins in some fashion. Included in that list is the diabetes medication Victoza, the schizophrenia treatment Vraylar, and the multiple sclerosis therapy Gilenya.

While many major pharmaceutical companies continue to develop such drugs, Lefkowitz has noticed a dwindling number of new approvals. "There was a tremendous outpouring of new drugs in the '90s and the '00s," he said, "and that's slowed down recently, I think primarily because the low-hanging fruit that was accessible" with the technologies of the time has been picked.
Septerna, though, believes it's come up with a technology that could reshape how these drugs are discovered and advanced.
Historically, isolating GPCRs has been difficult. These proteins are embedded in cellular membranes, and the methods often used to wedge them out can accidentally destroy them. GPCRs, while widely present, are also not made in large quantities by the cell. Lefkowitz points out the one that his lab has used most in its research is found in virtually every cell in mammals; and yet, in a large cow, he said that amounts to just about one milligram of protein.
Septerna claims to have developed an approach that addresses these problems, by mimicking the natural conditions surrounding GPCRs. The company aims to remove these proteins from their cells, purify them so they hold a specific shape and are free of mutations, then insert them back into a membrane, in an environment that also contains the molecules they normally interact with.
With GPCRs now fixed and in focus, Septerna can use large-scale drug screening techniques to test billions of compounds to see which ones dock onto spots on the receptor proteins. Those that do may then be investigated further as potential drugs.
Importantly, Septerna's says its approach isn't limited to just the main binding sites on these proteins, but other "pockets" as well. "That immediately, greatly enlarges the amount of real estate we could be looking at for developing new receptor-interacting molecules," Lefkowitz said.

Jeffrey Finer, Septerna's CEO and other co-founder, added that the company's platform "opens up a toolbox of technologies that really hadn't been usable by the GPCR class," both because they required purified proteins and because the proteins "are so complex and so difficult to handle." Finer is also a venture partner at Third Rock Ventures, the investment firm that led Septerna's Series A financing round.
Joining Third Rock in the round were Samsara BioCapital, BVF Partners, Invus Financial Advisors, Catalio Capital Management, Casdin Capital and Logos Capital. According to Finer, investors were especially interested in what specific proteins and diseases the company intends to target.
On that front, Septerna is launching with five drug discovery programs, though the company believes three of them have a shot at advancing to human testing within the "next couple of years," Finer said. Endocrine disorders are the focus of two programs, while the other three are for diseases related to metabolism, inflammation and the central nervous system.
Finer said he expects the $100 million from Third Rock and its other investors will be enough to fuel Septerna until its first drug candidate is selected for development. He also envisions the company's workforce approximately doubling — to a headcount of about 40 to 50 — by the end of the year.
But like many newly launched biotechs, Finer says the immediate priority is validating Septerna's technology and hitting key development milestones.
"As we've been building the company, we've gotten a lot of inbound interest. I got one today from a big pharma company that's interested in talking to us," he said. But "from a company standpoint, it's really important during this stage for us to focus on our initial programs."
For Third Rock, the debut of Septerna adds to a recent string of biotech launches. The firm, which in 2019 closed a life sciences investing fund worth more than three quarters of a billion dollars, has been a main backer to Abata Therapeutics, Flare Therapeutics and Faze Medicines, among others.