G protein-coupled receptors (GPCRs) are the largest family of proteins targeted by approved drugs. Some 700 approved drugs target GPCRs, with 80 percent of those treatments pursuing just six subfamilies of GPCRs, including receptors for the neurotransmitters serotonin, dopamine, histamine, and acetylcholine. That leaves a vast universe of undruggable GPCRs waiting to be discovered for targeting.
Unlocking those opportunities is the quest of Septerna Therapeutics, a two-year-old startup that emerged from stealth mode by announcing the completion of a $100-million Series A financing.
“In terms of the whole landscape of GPCR biology, our thinking is that at least 90% of the opportunities are probably still out there, as crazy as that might sound!” said Jeffrey Finer, MD, PhD, Septerna’s CEO. “There’s not only new approaches to new GPCRs that have never been done before, but there’s a lot of opportunity space around different mechanisms for some of the old favorite GPCRs.”
Of those roughly 700 approved drugs that target GPCRs, all but two target the receptors in their orthosteric sites. However, many allosteric sites on the receptors have generally not been targeted, said Robert Lefkowitz, MD, a Nobel laureate honored for his pioneering research in GPCRs, and one of Septerna’s three scientific co-founders.
“There was a big boom in the ‘90s and the early 2000s in drug development using standard methods to screen drugs—typically libraries of about maybe a couple of million compounds —and using whole cells and laborious signaling assays to do the screening,” said Lefkowitz, the James B. Duke professor of Medicine and professor of Biochemistry and Chemistry at Duke University, and an Investigator of the Howard Hughes Medical Institute.
“But now over the last decade, a whole new suite of methods is developing,” said Lefkowitz, co-winner of the 2012 Nobel Prize in Chemistry with one of his then-postdocs, Brian K. Kobilka, MD. (Kobilka is now Hélène Irwin Fagan Chair of Cardiology and a professor at Stanford University School of Medicine, whose lab focuses on characterizing the structure & mechanism of activation of GPCRs.)
Added Finer: “We think that the field is actually prime for a second golden age of GPCR drug discovery. Septerna is poised right now to kick off that second golden age and to lead the way.”
Many of the tools that have sparked renewed interest in GPCRs were developed in Lefkowitz’s lab, which focuses less on drug discovery but more on understanding the basic properties of GPCRs.
Beyond on-off switches
“We were following leads that indicated that the receptors could actually exist in many different conformations, which could do different things, rather than being simple on-off switches, which could exist in just an inactive and an active conformation,” Lefkowitz said. “We were looking for probes that we could use to stabilize the receptors in these different conformations for us to study.”
In the course of doing that, Lefkowitz and colleagues developed a novel technology to purify the receptors in native form, without any stabilizing mutations in them, put them back into a natural lipid environment, just as they would normally be in the cell, then combine them with their natural signaling transducers called G proteins, or another class of proteins called arrestins.
Lefkowitz and colleagues took these complexes, incubating them with DNA-encoded small molecule libraries totaling billions of compounds.
“We were able to incubate the receptors with these libraries, and get molecules to bind to the receptors themselves, then figure out using these little DNA tags, which were essentially barcodes, to see what had bound,” Lefkowitz explained. “We were basically using the whole natural receptor as a target rather than looking just at the orthosteric site, and with much larger libraries. So we were using essentially these so-called affinity methods, which was a whole new approach to GPCR drug discovery.”
“Some of my very best postdocs, who had developed these approaches, they started trying to pitch me on maybe starting a company to do this,” Lefkowitz recalled. “And I was enthused.”
Around the same time, Finer also thought about starting up a GPCR drug developer, so he visited Lefkowitz—among a group of 100 experts worldwide—to learn more about the science and especially recent developments. The two first met a decade earlier, when Finer was a biotech executive researching the GPCR field.
“Within Third Rock, our approach is really to build companies that can be transformative companies, that can take on a big area of science and break it open and create not just one drug, but potentially a whole pipeline of future therapeutics,” Finer said.
“Some of my colleagues at Third Rock and I were seeing, essentially a really timely opportunity. There was a convergence of new technologies that we saw. We started to think we could take a whole new approach to GPCR drug discovery,” Finer said. “It was very clear to me that there were technologies that had been developed just in the preceding couple of years that just weren’t available during the first era of GPCR drug discovery.”
Postdocs to Portmanteau
Finer and Lefkowitz agreed to launch Septerna early in 2020, starting up just as the COVID-19 pandemic started to shut the world down. Several of Lefkowitz’s postdocs joined them in forming Septerna, whose name is a portmanteau: “Sept” comes from the prefix for seven, a nod to the seven transmembrane domains of GPCRs that gives them their alternative name of seven-transmembrane receptors. “Terna” comes from the ternary complex formed by GPCRs with cognate G proteins and their ligands, a model that Kobilka and a colleague described in 2009 as “an important landmark for drug discovery.”
The ternary complex model—articulated in a 1980 paper published by Lefkowitz and colleagues—underpins the Native Complex™ platform, which is designed to recapitulate GPCRs outside of cells, complete with their native structure, function, and dynamics. The platform develops modular assemblies called native complexes that allow use of different transducer-and-ligand combinations to construct multiple different states for each receptor.
These native complexes are designed to enable rapid screening of potentially billions of compounds and rapid solution of GPCR-ligand structures to enable structure-based drug design and industrial-scale drug discovery.
“The heart of the native complex is the ability to take the receptor out of the cell, reconstitute it, and recapitulate it in its normal function,” Finer explained. “These are completely native receptors—they don’t have any mutations, no truncation, nothing to stabilize them in any artificial way. We found ways to take them out of the cells, put them in back into a membrane environment, and combine them with a transducer and a ligand.
The components can be mixed and matched in modular fashion, Finer said, allowing any receptor to be combined with one of many different G proteins or other transducers or ligands. The ligands can be the endogenous ligand, or a chemical compound that Septerna could make outside the cell, and fully control.
“They’re modular but, most importantly, they open up a whole toolbox of technologies that really weren’t usable unless you could actually purify proteins,” Finer said.
One technology is structural biology: Septerna’s platform is designed to allow high-resolution imaging of structures of the receptor with its transducer, and chemical compounds: “That’s creating tremendous opportunities for structure-based drug design,” Finer said. Another technology is affinity-based approaches allowing for screening billions of compounds to find binders.
“This Native Complex platform has essentially opened up a toolbox for modern direct discovery technologies that just weren’t accessible before,” Finer said.
Added Lefkowitz: “There’s a lot of special sauce involved here. It’s not like you can look up how to do this in a cookbook.”
Chasing GPCR opportunities
Septerna is not the only company sensing an opportunity by chasing new GPCR targets, in hopes of equaling if not surpassing the successes of marketed drugs. They range from blockbusters like Eli Lilly’s once-weekly type 2 diabetes drug Trulicity® (dulaglutide; $4.588 billion in Q1-Q3 2021) to smaller sales generators such as Amgen/Novartis’ Aimovig® (erenumeb; a combined $235 million) and Kyowa Kirin’s Poteligeo (mogamulizumab-kpkc; ¥11 billion [$95.7 million]). GPCRs are attractive to drug developers since they regulate virtually all metabolic processes, including glucose and energy homeostasis.
Among drug developers pursuing new GPCR-targeting drugs, Sosei Heptares has launched three GPCR-focused collaborations based on its StaR® protein platform in the past two-and-a-half years—with Genentech in 2019 (up to $1 billion), Neurocrine Biosciences in November (up to $2.6 billion), and in January, with Verily and its Immune Profiler target discovery tool (value undisclosed).
Some smaller biopharmas also specialize in GPCR drug development, including Tectonic Therapeutics (GEODe platform), and Confo Therapeutics (ConfoBodies). In September, AbCellera Biologics acquired TetraGenetics for an undisclosed price to expand its capabilities for expression and purification of GPCRs and other transmembrane proteins.
“A lot of the other companies are using approaches that we don’t think are going to be as impactful as ours,” Finer said. “It’s really critical to have the receptor and have its ability to be fully dynamic and have all of its forms.”
Septerna says proceeds from the Series A financing will enable it to advance its pipeline of small molecule GPCR-targeting treatments, which span multiple therapeutic areas and have been developed through the Native Complex platform.
Septerna is initially pursuing four therapeutic areas. Two programs are in the area of endocrine disease, one of which focuses on a CNS target for “a neurology type of indication.” The other two areas are metabolic disease and inflammation: “There’s a lot of inflammation oriented GPCRs, so it’s an area of interest for us,” he explained.
“These are still discovery-stage programs, but they’re discovery-stage programs we’ve actually already started on. We’ve been working on at least three of these for about a year or more already,” Finer said. “These are in mid-stage drug discovery. We think we’ve got a shot at getting to our first clinical development candidate certainly within two years, if not sooner.”
Finer is also a venture partner at Third Rock Ventures, which led the Series A financing with what the startup calls “significant” participation by Samsara BioCapital, BVF Partners, Invus Financial Advisors, Catalio Capital Management, Casdin Capital, and Logos Capital.
Besides its investor syndicate, Septerna brings with it a staff of 23, including Finer and nine other announced senior executives, plus a trio of scientific advisors including Lefkowitz, and several onetime postdocs of Lefkowitz.
Septerna plans to double its staff this year. “It’ll be mostly expansion in R&D,” Finer said. “The company right now is a largely R&D company, but we will be adding a few business people as well.”
Joining Finer among Septerna’s senior executives are Alan Ezekowitz, MD, DPhil, chief medical officer; Dodzie Sogah, PhD, chief operating officer; Uwe Klein, PhD, senior vice president biological sciences; Daniel Long, DPhil, senior vice president drug discovery; Richard Hansen, PhD, vice president technology; Christopher Heise, PhD, vice president discovery biology; Amer Mirza, PhD, vice president disease biology; Kara Halvorsen, head of human resources; and George Xu, PhD, director corporate strategy and portfolio development.
Joining Lefkowitz as scientific advisors are Arthur Christopoulos, PhD, professor of Analytical Pharmacology, dean of the Faculty of Pharmacy & Pharmaceutical Sciences, and director of the Neuromedicines Discovery Centre at Monash University, Australia; and Patrick Sexton, PhD, DSc, professor, Drug Discovery Biology at Monash and director of the ARC Centre for Cryo-electron Microscopy of Membrane Proteins.
The company is also tapping into the expertise of four professors with expertise in GPCR biology, technology, and drug discovery: Bryan Roth, MD, PhD, of the University of North Carolina School of Medicine; Aashish Manglik, MD, PhD, of the University of California, San Francisco; Craig Lindsley, PhD, of Vanderbilt University; and Ron Dror, PhD, of Stanford University.
The Series A financing, Finer said, gives Septerna a runway of approximately two years: “We’ve built the runway to get us to at least to our first development candidate.”
“I would be excited about building a company that has a dozen or more therapeutics down the road,” Finer added. “But you have to walk before you can run. As an early-stage company, we’re laser focused on our initial set of programs, and getting to the near-term milestones with those.”
As Septerna matures and its staff grows and delivers early successes, Finer added: “I think the opportunity space is absolutely huge. But we haven’t yet decided exactly how thick to build that pipeline over time.”