If Arena Pharmaceuticals Inc.’s future looks bright because of the recent approval of its Belviq, a potentially blockbuster drug to treat obesity, there’s opportunity to shine even more with continuing research and development around G protein-coupled receptors.
The science behind GPCRs, which garnered Brian Kobilka and Robert Lefkowitz a 2012 Nobel Prize in chemistry, plays a large role in Arena’s Sorrento Valley labs where researchers work to access these receptors and harness them to modulate human disease.
Founded in 1997, Arena has made inroads with GPCRs while developing Belviq since 2001. Following extensive Phase 1 and Phase 2 clinical trials and testing on about 8,000 patients in the Phase 3 clinical program, the drug gained U.S. Food and Drug Administration approval on June 27 of this year. As the first drug approved for weight management in 13 years, the market potential is huge. According to the Centers for Disease Control and Prevention, more than one-third of U.S. adults, 35.7 percent of the population, are obese. In 2008, medical costs associated with obesity were estimated at $147 billion, according to the CDCP.
Following the Drug Enforcement Administration scheduling process, Arena anticipates that Belviq will be available to patients in the U.S. in early 2013. Approvals are also being pursued in Europe as well as Asia and other parts of the Americas.
While Arena plans to study the possibilities of using Belviq in combination with other therapies or for other indications, Dominic Behan, co-founder and chief scientific officer of Arena, said there are several opportunities for the company to build on Belviq by evaluating its pipeline of internally discovered drug candidates.
“Belviq is just the beginning,” Behan said. “By targeting GPCRs, we have a tremendous opportunity to address a number of diseases in a meaningful way.”
A Life-Threatening Disease
One of Arena’s compounds in development is for the treatment of pulmonary arterial hypertension, or PAH. This life-threatening disease is considered an orphan disease because of its rarity, but Behan said it’s an important disease because there is an estimated five-year survival rate of only 57 percent from diagnosis. PAH occurs when the arterial blood vessels that supply blood between the heart and the lung become blocked. Behan said Arena is working on an oral, once-daily therapy that targets a GPCR receptor to address this disease.
“By stimulating the receptor we can open up the pulmonary arterial vessels and blood can pass through and be oxygenated,” he said.
Behan said until the human genome was cloned in the 1990s, researchers didn’t realize there were hundreds of these receptors in the body. Now about half of all known drugs on the market target the G protein-coupled class of receptors, according to Behan.
But challenges remain in understanding where the receptors can be expressed in the body and identifying how they affect individual organs and tissues, he said.
Think of receptors as a lock that provides a gateway of communication to cells when they are accessed by hormones and other molecules that act as “keys” to the lock. Depending on how a receptor talks to a cell, for example, Behan said it can result in the production of insulin which can result in glucose control.
“We identified a receptor in the pancreas that induced insulin,” Behan said. “It was present in the cell type responsible for producing insulin. We showed that small molecules that interact with this receptor in animals can stimulate insulin secretion. In that case, it was for glucose control.”
In the process of discovering Belviq, Arena became interested in the serotonin 2C receptor. Expressed in neurons in the hypothalamus area of the brain, this receptor is important for stimulating hunger and creating a sense of satiety, or fullness.
“We hypothesized that if we could selectively stimulate the receptor we could regulate food intake,” Behan said. “We didn’t want to activate other receptors, that would lead to side effects. We wanted to selectively isolate the serotonin 2C receptor and avoid the other receptors.”
With about half the team of 200 San Diego-based Arena employees directly involved in developing Belviq and the remaining staff involved in supporting the project, Cindy McGee, vice president of investor relations and alliance management for Arena, said Belviq exemplifies what can be achieved through teamwork.
“Belviq is a great example of what can be achieved through innovation,” McGee said. “Our team’s dedication to this program delivered an important new treatment to patients.”
Joe Panetta, CEO of the local life sciences trade group Biocom, said Belviq’s approval was a win for the entire San Diego life sciences community. Drug development is tough, he said, and there are so many drugs and companies that never make it, so the entire community celebrates when one does.
Panetta added that Arena faced an uphill battle because the safety bar has been set very high for obesity drugs in the U.S.
“The company faced a number of setbacks along the path to approval, yet company leadership believed in the drug and had the tenacity and determination to do what it took to get it approved,” Panetta said, in an email statement. “One of the most important lessons that other entrepreneurs can learn from the Arena team is the importance of working closely with the FDA. It is important to get clarity about what will make a drug approvable and how to address that through good clinical trial design. Communication with the FDA early and often in the drug development process will alert you to any perceived shortcomings of the clinical data supporting the drug so that they can be overcome.”