Macrocycle start-ups emerge from stealth

Orbis Medicines emerged from stealth Feb. 29 with $28 million in seed funding. The company is the latest launched to turn cyclic peptide molecules into orally available drugs that could replace injected or intravenous ones.

“Macrocycles in their own right are quite amazing molecules . . . that can bind to all the challenging targets,” says Morten Døssing, who is board chair at Orbis and a partner at Novo Holdings, one of the investors in the start-up.

Døssing says the ability to impart properties like oral availability and cell permeability has been missing from the peptide molecule field. So he and colleagues at Novo got “very, very excited” when they saw work by Christian Heinis and Sevan Habeshian, chemists at the Swiss Federal Institute of Technology, Lausanne (EPFL). Because the chemists had developed ways to build large libraries of macrocylic compounds at small volumes, the molecules can be quickly made, tested, and optimized (Nat. Commun. 2022, DOI: 10.1038/s41467-022-31428-8; Nat. Chem. Biol. 2023, DOI: 10.1038/s41589-023-01496-y).

“When we saw that technology, we felt that this is exactly what we’ve been missing in the field,” Døssing says.

Investors are coming to similar conclusions about other macrocycle firms. The California start-up Insamo recently announced that it has secured $12 million in seed funding to develop small, orally available and cell-permeable cyclic peptides using artificial intelligence protein design expertise. The UK start-up Curve Therapeutics just raised about $52 million in series A funding for what it calls its “microcycle” platform.

Curve, which creates its molecules inside cell lines so that they can be screened against disease-causing proteins in their native state and environment, is based on work by Ali Tavassoli, a professor at the University of Southampton. Tavassoli, who now splits his time between academia and his role as Curve’s chief scientific officer, says the firm’s rigid small rings can sample every pocket of a target protein; from those results, the team can choose to build drugs based on peptides or small molecules.

Tavassoli agrees that the cyclic peptide space is getting hot. Orally administrable cyclic peptides in development, including Merck & Co.’s PCSK9 inhibitor and Chugai Pharmaceutical’s RAS inhibitor, have helped show what’s possible, he says.

Tavassoli and Døssing are keen to highlight how their approaches are different. Curve is focused on cancer targets such as hypoxia inducible factor. While the firm’s early work used cyclic peptides, its lead candidate in that program is a small molecule. Orbis, meanwhile, is identifying top-selling antibody or peptide drugs—which are typically injected—that could be replaced with cyclic peptides taken orally, Døssing says.

“I think there will be a future where you don’t make an antibody, you make a macrocycle,” Døssing says. “That’s why there’s so much excitement around it.”