May 15th, 2015:

http://www.washingtonpost.com/business/economy/pill-promises-a-safer-cheaper-way-than-chantix-to-quit-smoking/2015/05/15/8ce5590c-f830-11e4-9030-b4732caefe81_story.html

These laburnum trees growing in vast orchards in Bulgaria could be the source of a potential new stop-smoking drug that’s being tested now in the United States. (PHOTO COURTESY OF MARIA VUCHEVA /PHOTO COURTESY OF MARIA VUCHEVA )

Rick Stewart didn’t know about the laburnum trees growing in Bulgaria — and their potential to produce a drug for quitting smoking — back when he was the chief executive of the pharmaceutical company Amarin.

He was too deep inside the drug industry, a place often criticized for its short-sighted focus on profits. He had to fail first. Only then could he spot the opportunity in those yellow-flowering trees.

Now, with the help of the National Institutes of Health, Stewart is trying to introduce the laburnum-derived drug to the U.S. market. The pill works by interrupting tobacco cravings, much like Pfizer’s top-selling Chantix, but possibly without that drug’s high-profile side effects and at a much lower price. A recent run of positive studies have buoyed the pill’s prospects. Today, researchers are excited about what could be the first new treatment for smoking cessation to emerge in years.

“We need this,” said David Shurtleff, deputy director of the NIH Center for Complementary and Integrative Health, explaining why his agency is helping to get the drug approved.

But laburnum’s promise is not new. It was just overlooked — for decades — highlighting holes in how drugs are traditionally developed.

In 2007, Stewart had staked his job as the head of Amarin on a different drug. Miraxion was for treating Huntington’s Disease, and early on it showed signs of improving symptoms of the neurological disorder. But then the drug failed two late-stage trials. Investors in Amarin, a $240 million company based in New Jersey, were stunned. The company’s stock fell 80 percent. Stewart was out of a job.

“The CEO always falls on his sword,” Stewart, 56, says now.

But Miraxion did appear to help patients with Huntington’s — it just took longer than the six months allotted during the clinical trials. Yet the damage was done. This led Stewart and Anthony Clarke, who also lost his job after running the trials for Amarin, to wonder what other misunderstood drugs were out there. They went on a hunt.

“These drugs are uncared for or unwanted. They need tender loving care,” Stewart says. “And pharma, for whatever reason, can’t be bothered with them.”

They set up a tiny company outside London named Ricanto — a mash-up of their first names. They describe the firm’s focus as pharmaceutical asset optimization. They believed innovation was not limited to new drugs. Sometimes it’s just about rediscovering old ones.

Ricanto found a compounded drug used by a few European doctors for a rare autoimmune disorder and introduced it to a larger market. It then helped identify a treatment for severe childhood epilepsy and sold the drug rights to San Diego-based Zogenix in a $130 million deal.

In 2009, Stewart learned of the laburnum trees.

A co-worker told him about a company in Bulgaria named Sopharma that made a stop-smoking drug called Tabex. The pills contained cytisine, a natural compound found in the tree’s seeds. The drug was farmed from massive laburnum orchards in Bulgaria. Cytisine targeted brain receptors to block nicotine cravings. Its power had been recognized since at least the 1940s, when Russian soldiers in World War II, short on tobacco, reportedly turned to smoking the tree’s leaves. Some soldiers found they no longer needed cigarettes.

Sopharma began making the Tabex-branded cytisine pills in 1964, but they were available only in Central and Eastern Europe.

Stewart had never heard of the drug. But he was intrigued. He was also wary. Nearly 1 billion people smoke worldwide, according to the World Health Organization. Tobacco is blamed for 5 million deaths a year. A cheap, effective drug to help smokers quit would be huge. He wondered how others could have missed this opportunity.

There are only three treatment options for U.S. smokers looking to quit.

Chantix is the newest, debuting on the market in 2006. At the time, it was the first prescription drug approved for smoking cessation by the U.S. Food and Drug Administration in nearly a decade, since GlaxoSmithKline’s antidepressant Zyban. Aside from those two drugs, there also are the nicotine-replacement gums, lozenges and patches. But that’s it. The promise of treatments such as nicotine vaccines or other drugs had flamed out. Nothing new has come down the pike.

In 2008, Chantix (sold as Champix overseas) posted $846 million in worldwide sales. But that blockbuster number dropped 17 percent the next year when the FDA slapped a “black box” warning on Chantix and Zyban because of the risk of suicidal behaviors and other mental-health problems. Facing a wave of damaging publicity, Pfizer went on to settle 2,900 lawsuits for nearly $300 million. Chantix’s reputation is still suffering. Last year, it recorded $647 million in sales.

The risk of severe side effects alarmed Stewart.

Cytisine and Chantix work in similar ways. In fact, Pfizer chemists closely studied the plant product as they developed their synthetic drug. But Pfizer supercharged its derivative to increase efficacy. Stewart noted that Tabex had amassed a database of 5 million users in Eastern Europe without signs of Chantix-like side effects.

“Why aren’t we seeing the suicidality?” he recalls thinking.

One study suggested it was because cytisine is less potent. And many researchers today believe the worst side effects attributed to Chantix — such as suicidal thoughts — are unrelated to the drug. (A Pfizer study to be released later this year is expected by many to support this notion.) But stark differences between the two drugs are found in other severe reactions, including abnormal dreams, insomnia and nausea. These are rare for cytisine, but seen in up to 30 percent of Chantix users.

Stewart struck a deal with Sopharma. He wanted to get the drug approved in Western Europe and the United States. Instead of calling it Tabex, the pill would be named Extab.

But Stewart still faced a daunting problem with cytisine.

“There’s no money in it,” said Dr. Taylor Hays, director of the Nicotine Dependence Center at the Mayor Clinic in Rochester, Minn., who would love to see cytisine get a shot here. “And that’s what usually motivates people to try bringing it to market. The money is going to drive it.”

“It’s just frustrating to think that there’s something that could be helping people and we’re not using it,” said Dr. Nancy Rigotti, director of the Tobacco Treatment Unit at Massachusetts General Hospital.

A natural product like cytisine cannot be patented. That makes its market position harder to defend. And getting a drug approved requires millions of dollars. Drug companies say the cost of developing and getting approval for a new drug is $1 billion. This might explain why some companies have seen blockbuster profits with treatments for rare diseases, such as Genzyme’s drug for Goucher disease, which costs $300,000 a year.

“They’re fixated on patent protection and new drugs,” Stewart said.

Stewart is banking on two things to turn a profit with Extab. One is the limited cytisine supply. A competitor would need to plant vast orchards of laburnum trees — hundreds of thousands of them — and wait four years before the drug-containing seeds could be harvested.

The other thing is that Extab is new to the U.S. market. No one has ever tried to get it approved. So the drug would have five years of U.S. market exclusivity as a novel drug under the 1984 Hatch-Waxman Act. That’s less than the typical 20-year window for patented medicines. But it’s something.

“It’s a really old, novel drug,” Stewart says.

Still, he needed help getting the drug through the U.S. regulatory maze. He needed to get lucky. And he did.

British medical authorities offered to pay for and run a clinical trial of cytisine. In 2011, the findings were published in the New England Journal of Medicine, showing cytisine was 3.4 times more likely than placebo to help people quit smoking and stay that way for one year, on par with Chantix.

Then a review by University of Sheffield researchers compared cytisine with Chantix and concluded that while more investigation was needed, “Cytisine is estimated to be both more clinically effective and cost-effective than (Chantix).”

But the real turning point came in December, when another study was published in the New England Journal of Medicine. Researchers with New Zealand’s National Institute for Health Innovation found cytisine was superior to the nicotine-replacement gum or patch.

The drug now had two large-scale clinical trials under its belt.

But more work lies ahead.

“I’m either absolutely mad or I guess I really believe in it,” Stewart says.

European regulators and the FDA are considering what more they need, Stewart says.

In preparation, a lab in California recently started early-stage safety tests on Extab. The NIH is picking up the tab. The NIH’s Shurtleff said the agency wants to support promising drugs that don’t have a clear path to the marketplace, especially natural products.

“That’s where we come in and provide that capital,” he says.

It could take three to five more years for the FDA’s blessing. Stewart said he hopes to find a partner to help his small firm with the U.S. market. He also brushes off any suggestion that Extab would go head-to-head with Chantix, which is made by one of the world’s biggest drug firms. It’s a strategic move on his part.

“They’ll crush us,” he says.

Stewart estimated that Extab could see $400 million in annual sales worldwide five years after launch. Pfizer will notice that.

Currently, the cytisine supply comes from 100,000 laburnum trees planted in fields ringed by protective fences in Bulgaria. Stewart knows that will not be enough if all goes to plan — if the FDA approves, if Extab takes off. He will need to ramp up production.

He has plans to plant 300,000 more of those yellow-flowering trees, including some in the United States, orchards so large they would be impossible to miss.