Trevena Inc.'s deal with a subsidiary of Forest Laboratories Inc. brings a $30 million equity investment in exchange for an option to license worldwide rights to TRV027, an angiotensin II Type I receptor (AT1R) biased ligand for acute decompensated heart failure (ADHF), after results are clear from a 500-patient Phase IIb trial, slated to begin by the end of the year.

If the option is exercised, New York-based Forest will make payments of up to $430 million, depending upon the achievement of development and commercial milestones, plus royalties, and will carry forward the development and commercialization of TRV027. No further details were disclosed.

"It's going to take a few years [to complete the trial]," said Rosamond Deegan, vice president of business development for King of Prussia, Pa.-based Trevena. The investment by Forest leads a Series C financing of $60 million. Existing investors participating in the round are Alta Partners, Healthcare Ventures, NEA, Polaris and Yasuda Enterprise Development Co.

Cash on hand "will enable us not only to complete the Phase IIb trials, but also move forward the other assets" behind TRV027, including a handful of candidates for pain.

"We're not necessarily looking at this as a one-off financing event for the company," Deegan added, calling Trevena's approach "flexible. We know that as a small, privately funded company, we can't take all four programs forward alone. We're probably going to look to partner at least one other program."

The program to be partnered, if Trevena gets its druthers, involves an oral compound for acute chronic pain, which "is really a suitable program for a larger company with a primary care focus, and Trevena would look to retain more of the specialty [central nervous system] indications. We're also, obviously, keeping an eye on the public markets. We think we're an attractive profile, ultimately, for a public company."

Specializing in G protein-coupled receptors (GPCRs), "we're the only company we know of that focuses exclusively on biased ligands," Deegan said. "It is an area that's getting a lot more attention, and so I think a lot of people do have their own programs or are trying to investigate the biased approach." Trevena's drug discovery platform is based upon the discoveries of Nobel Prize-winning GPCR pioneer Robert Lefkowitz, and his fellow Duke University researcher Howard Rockman.

Standard agonists and antagonists activate or inactivate the entirety of a receptor's signaling network, whereas Trevena's "biased" ligands selectively engage some signals while avoiding, or even inactivating, other signals mediated by the same receptor. "To put it in layman's terms, the technology enables us to really separate the good signaling from the signaling you don't want at the receptor, so it's much more specific, and a completely new mechanism in treating heart failure," Deegan told BioWorld Today.

TRV027, a beta-arrestin biased ligand of AT1R, combines the proven benefits of angiotensin blockade with new beta-arrestin-mediated biology to preserve cardiac and renal function. It may "really have beneficial effects in the three key organs involved" in ADHF, Deegan said. The compound apparently is able to relax vessels, improve cardiac performance and increase perfusion of the kidney, thereby improving function, for a "trifecta of effects," she said.

Called the Advanced Biased Ligand Explorer (ABLE) platform, Trevena's approach generates biological tracing of beneficial and adverse signaling pathways at specific receptors, and then identifies ligands that activate only the pathways associated with therapeutic benefit. ABLE includes diverse assays of GPCR function and regulation that can predict therapeutic utility and provide understanding of G protein and beta-arrestin-mediated mechanisms associated with responses.

Trevena last raised money in 2010 in its $35 million Series B round. The $25 million Series A round took place in 2008. (See BioWorld Today, March 5, 2008, and July 14, 2010.)