The Drug Refinery | January 10, 2011 Issue - Vol. 89 Issue 2 | Chemical & Engineering News
Volume 89 Issue 2 | pp. 22-23
Issue Date: January 10, 2011

The Drug Refinery

Trevena uses ‘biased ligands’ to fine-tune the effect of drugs on g-protein-coupled receptors
Department: Business
Keywords: Trevena, biotech, GPCR, arrestin
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IMPROVING DRUGS
Trevena scientists are exploiting recent discoveries about GPCR signalling.
Credit: Trevena
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IMPROVING DRUGS
Trevena scientists are exploiting recent discoveries about GPCR signalling.
Credit: Trevena

After Jonathan Violin completed his Ph.D. at the University of California, San Diego, he wanted to continue his research with a high-profile scientist working on G-protein-coupled receptors (GPCRs). Robert Lefkowitz, an expert in protein receptor biology at Duke University, was at the top of his list. Little did Violin know that his 2003 interview with Lefkowitz for a postdoc position would be so fateful: Their chat was a first step in founding Trevena, one of the more successful biotech start-ups of recent years.

Just three years after its formation, King of Prussia, Pa.-based Trevena has raised two rounds of financing and secured a sizable National Institutes of Health grant. More impressive, the biotech firm, with a staff of just 30 people, has a drug poised to enter midstage clinical trials and is readying a second candidate for testing.

Trevena is based on a new understanding of the biology of GPCRs, large proteins that span the cell membrane, sensing signaling molecules outside the cell and then turning on pathways inside it. Their ubiquity has made them popular targets for pharmaceutical development: About 40% of the drugs on the market today act on GPCRs. Well-known examples include Eli Lilly & Co.’s schizophrenia drug Zyprexa and Pfizer’s allergy treatment Zyrtec.

For years, the prevailing logic was that GPCRs use only one route, the G-protein pathway, for signaling and that a protein called β-arrestin would step in to stop that signaling. But Lefkowitz discovered that β-arrestin plays a second role: It is also involved in a long list of GPCR signaling pathways.

During the postdoc interview in 2003, Lefkowitz showed Violin an unpublished manuscript outlining the two pathways used by GPCRs: the established G-protein pathway and the newly discovered β-arrestin pathway. “I, like most people, had conceptually oversimplified how receptors work,” recalls Violin, who is now head of biology at Trevena. The paper “got me excited that there was this whole world of pharmacology that hadn’t been explored.”

The discovery meant that better control over the properties of a drug might be possible. Scientists could develop a “biased ligand”—a molecule that turns on the pathway associated with a desired pharmacological effect while deactivating the pathway associated with side effects.

Using the μ-opioid receptor, researchers in Lefkowitz’ lab demonstrated the potential of biased ligands. Drugs such as morphine that target the μ-opioid receptor are powerful analgesics but are also associated with serious gastrointestinal side effects. Lefkowitz’ group showed that morphine given to a mouse lacking β-arrestin works without producing the gastrointestinal effects. They concluded that the G-protein pathway is responsible for the analgesia whereas the β-arrestin pathway causes the unpleasant side effects.

Violin took a position in Lefkowitz’ lab, and over the next few years explored the mechanisms of biased ligands. During his postdoc, Violin went to night school to earn an M.B.A. The business degree would soon come in handy: He and other scientists in the lab were starting to realize that the assays they were building to screen for biased ligands might be the basis for a company.

In a sense, Trevena’s technology is part of the natural evolution of drug development as scientists unravel the nature of protein receptors. “Many years ago, receptors were just theoretical entities,” Violin says. Although researchers could link receptors with biological functions, the discovery that receptors exist in several forms, known as isoforms, enabled the development of more refined drugs.

Trevena’s biased-ligand approach takes that fine-tuning further. “It’s not always enough to separate the isoforms,” Violin says. “You also need to separate the ­signaling.”

By early 2007, with the help of Lefkowitz, Duke professor Howard Rockman, and Duke’s technology transfer office, Violin and two other senior scientists from the Lefkowitz lab had pulled together a business proposal. They started talking to venture capital groups and found that early interest in their idea was strong.

In September, one of the venture capitalists introduced Violin to Maxine Gowen, a former GlaxoSmithKline executive who subsequently agreed to become Trevena’s chief executive officer.

Gowen’s years of corporate know-how helped position Trevena in what was becoming a challenging financing environment for small biotech companies. During her last five years at GSK, Gowen had headed SR One, GSK’s venture capital arm, and led its new Center of Excellence for External Drug Discovery (CEEDD), where she was responsible for developing relationships with small companies.

“She came to us with a diverse set of viewpoints, having been an academic, in R&D, and in externalizing research,” Violin says. “She really could see all the perspectives we lacked.”

As Gowen took the helm, she also brought with her a view from the other side: Years of experience investing in or partnering with biotechs taught her how to build a solid company. The lessons from SR One and the CEEDD that she applied to Trevena included finding investors that were committed to its direction, never overpromising results, and populating the firm “with people who really know what they’re doing,” she says.

Notably, Gowen recruited several GSK scientists into leadership positions at Trev­ena. By March 2008, the fledgling biotech had closed on a $24 million financing round.

Trevena hit the ground running. After building assays based on the concepts developed at Duke, the company took several routes to finding potential biased ligands. Three different kinds of small-molecule collections were screened: focused libraries of compounds known to affect a specific receptor; a modest internal library composed of molecules generally known to interact with GPCRs; and a 5 million-compound library from Ligand Pharmaceuticals that was screened for standard GPCR-active ligands.

“We have found really great molecules with appropriate solubility and chemical properties to be good drugs or starting points,” Violin says.

The company has already completed Phase I studies of TRV120027 as a treatment for acute heart failure. The molecule represents an alternative therapeutic approach to angiotensin receptor blockers such as Merck & Co.’s Cozaar and Novartis’ Diovan, which inhibit both the G-protein and β-arrestin pathways. In contrast, Trevena’s drug inhibits G-protein but stimulates β-arrestin. In animal studies it had effects on heart rate and arterial pressure similar to the traditional blockers, but it also improved the ability of heart muscle to contract, which traditional blockers cannot.

Since Lefkowitz’ discovery of the complex biology of GPCRs, other scientists have become interested in exploiting its therapeutic potential. Trevena executives acknowledge the competition but argue that their company has a healthy head start with its proprietary assays.

Investors seem to agree. Last July, Trevena secured another $35 million in funding from many of the same investors that contributed to its initial round.

The money gives Trevena breathing room to complete Phase II trials of TRV120027 and to initiate human tests of a novel opioid. “At that point, we should have data that will make it a very interesting molecule for a partner,” Gowen says.

 
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