Shelved Solutions – Part 4 of 5

From The Oregonian, October 6, 2004

Shelved Solutions is part 4 of 5 UNNECESSARY EPIDEMIC: A Five-Part Series by The Oregonian – 2004 / 2005
SEE – All five stories here.

This series of articles, written largely by Steve Suo, illuminated and encouraged Oregon’s legal strategy toward addiction which uses institutional punishment approach versus a medical approach which might offer an individual’s recovery as a primary goal. As of Spring of 2011, Oregon’s strategy has had no affect on the number of arrests or convictions for drug possession or distribution, and has resulted in thousands of deaths, and billions of misspent tax dollars.

Promising fixes to the meth scourge, including a cold pill impervious to abuse, go unpursued as . . .
Shelved solutions

Eight years ago at a laboratory in Texas, Warner-Lambert Co. began testing a possible cure for the methamphetamine epidemic: a new and improved cold medicine that could not be turned into the illicit stimulant.

The company was worried that federal regulators would soon ban or restrict sales of pseudoephedrine, the main ingredient used to make meth and Warner-Lambert products such as Sudafed, Actifed and Benadryl.

Warner-Lambert’s meth-proof alternative showed promise in animal testing, conducted at a university lab in Fort Worth. The company quickly applied for a patent. But that is where the product’s development ended.

Former company officials said they saw little chance of making a profit on the product. Federal approval of a new drug, which includes lengthy human trials, costs as much as $800 million, according to industry estimates. Warner-Lambert’s top-selling cold remedy, Sudafed, was grossing less than $100 million a year.

“It would be a long road and an expensive road,” said Robert G. Flynn, a former research vice president at the company.

A cold pill that could not be used to make meth would offer huge public benefits if it replaced existing products. Past constrictions in the flow of meth ingredients have radically altered the trade, disrupting the supply of meth for as long as a year, The Oregonian’s analysis of federal data shows.

Federal authorities never offered the pharmaceutical industry financial or other incentives to develop such a pill.

By the time Warner-Lambert had its patent, the threat of a ban on pseudoephedrine had receded. In 2000, Pfizer Inc. took over Warner-Lambert and did not pursue the new cold medicine.

Jay Kosminsky, a Pfizer spokesman, said Warner-Lambert’s formula was not enough of an improvement over existing products to merit further research.

Instead, Pfizer tried mixing Sudafed with chemicals that would make it harder for meth traffickers to extract pseudoephedrine. The company chose ingredients already approved for human use, which made it possible to avoid the lengthy testing required for new drugs.

After seven years of research, the company abandoned that project as unworkable this past summer, Kosminsky said.

Warner-Lambert’s new decongestant is a close chemical sibling of pseudoephedrine, the bulk of which is manufactured in nine overseas factories. Executives at two of the largest pseudoephedrine makers — India’s Emmellen Biotech and Malladi Drugs — say they could supply the new chemical if the vast U.S. market demanded it.

“I can supply large quantities, in tons,” said V.N. Gopalakrishnan, technical director at Malladi.

Fear of a ban

Pharmaceutical companies have known that cough and cold remedies could be misused ever since the federal government first threatened tighter regulations to deal with the meth problem.

“All manufacturers of these types of products are aware that these decongestant ingredients are related, on a technical, chemical basis, to more powerful abuse drugs,” Robert N. Anderson, an attorney for Nyquil maker Richardson-Vicks, wrote to Congress in September 1987.

But Anderson said Vicks’ research indicated that it would be impractical for meth cooks to extract ingredients from over-the-counter cold medicine because it “unnecessarily complicates the chemical process, and raises the cost dramatically.”

In fact, meth cooks did find it economical to extract the ingredients. The U.S. Drug Enforcement Administration responded in the 1990s with more attempts to control meth ingredients.

James D. Cope, former president of the Consumer HealthCare Products Association, said he warned the trade group’s members that the DEA would make pseudoephedrine a controlled substance unless they prevented their products from being misused.

“If you can put some chemical in to make it impossible or almost impossible, that’s a way of avoiding the federal sanctions,” Cope recalled telling the group, formerly known as the Proprietary Association. “Warner-Lambert was the leader in this.”

Warner-Lambert entered a joint venture with Burroughs Wellcome in the mid-1990s to market Burroughs Wellcome’s Sudafed and Actifed.

In a 1995 letter to DEA officials, David Long, Warner-Lambert’s vice president for regulatory affairs, said it was unlikely the company’s products would be used in meth labs. At the same time, Warner-Lambert’s scientists were studying how easily meth cooks could extract pseudoephedrine — and how to counteract that.

Some Warner-Lambert cold medicines combined pseudoephedrine and painkillers with inactive ingredients. In a November 1995 memo to Long, one company scientist explained that it was “rather straightforward” chemistry to dissolve the tablets and obtain pure pseudoephedrine.

Former Warner-Lambert executives say the company, which took over the two Burroughs Wellcome product lines in 1996, wanted to come up with a meth-proof cold medicine in case of a ban.

“The impetus of the research was related to finding decongestants that could not be manipulated,” said Flynn, the former research vice president.

“We obviously were well aware of what was going on relative to the methamphetamine issue,” said Lester Isbrandt, a former Warner-Lambert research vice president. “We immediately became concerned about it because of its impact on the sale of Sudafed.”

Warner-Lambert “had a huge pseudoephedrine franchise,” said a source familiar with the research program. “This was an insurance policy.”

The mirror image

The idea for the new decongestant came from the study of molecules.

Ephedrine, pseudoephedrine and methamphetamine are close molecular cousins; meth, in fact, is ephedrine minus a single oxygen atom.

As a result, their effects on the body are similar. All three shrink blood vessels in the nose and dilate airways in lungs, while unleashing adrenaline that stimulates the heart.

With meth, the latter effect is most pronounced. Removing the oxygen atom, it turns out, makes the molecule fit receptor cells in the human brain “like a key in the lock,” said Paul Doering, a professor of pharmacy at the University of Florida.

Each of the three related molecules also has a twin: a mirror image of the same atoms. Flipping the atomic pattern can have a huge effect on how a drug works. Mirror images can sometimes be even more effective than the original drug, producing the desired outcome with fewer side effects.

Drug companies also introduce mirror images to extend the life of an existing drug with a patent that’s close to expiring. For example, AstraZeneca created Nexium, the purple pill that fights indigestion, using a molecular mirror image of its product Prilosec, also marketed in purple.

At Warner-Lambert, a team led by researcher Anthony R. Booth was exploring ways to apply the mirror-image concept to improving the performance of ephedrine, pseudoephedrine and other drug ingredients that affect the central nervous system.

Booth’s team came up with a unique insight: Mirror-image pseudoephedrine could only be used to make mirror-image methamphetamine, a benign incarnation of the street drug with few stimulant effects. No amount of processing or lab magic could change that.

And, the new drug appeared to be a better cold medicine.

Warner-Lambert hired a team of researchers at the University of North Texas to test the drug in dogs and rats. The team found the drug remained an effective decongestant but had significantly fewer side effects, such as elevated blood pressure.

The research was complete by December 1997, said Michael Forster, one of the Texas researchers.

“It was essentially devoid of nervous system effects, as far as we could tell,” Forster told The Oregonian. “And yet it retained the nasal decongestant effects very well.”

Steep price

Back at Warner-Lambert headquarters in Morris Plains, N.J., executives discussed what to do next. They filed an initial patent application in July 1998, records show. But they were not sure whether to pursue additional research.

Sudafed was a hugely popular and safe product. Changing the formula would be costly, former executives said.

The U.S. Food and Drug Administration requires three phases of testing on thousands of human subjects. The FDA can impose even more extensive tests for over-the-counter products because consumers use them without a doctor’s guidance.

To make the new pseudoephedrine commercially viable, Warner-Lambert executives considered pitching it to the FDA as part of an anti-meth program. If the FDA required companies to sell only mirror-image pseudoephedrine, Warner-Lambert could reap substantial benefits.

“If you had the patent on the only drug that was effective for sinuses, I think it could be lucrative, especially if you had the patent, and everybody else had to come to you,” said Isbrandt, the former Warner-Lambert vice president. “That is kind of a pharmaceutical drug researcher’s dream.”

But the company never made that pitch with Booth’s idea.

Going to Plan B

While Booth’s mirror-image molecule was being tested in Texas, a second team, headed by Warner-Lambert scientist William Bess, went down another avenue.

Bess’ team mixed Sudafed with harmless ingredients such as guar gum, a common ice-cream thickener, that would create a sticky mess when meth cooks tried to extract the pseudoephedrine.

On this project, the company worked closely with the DEA.

“We had meetings in Washington,” said Isbrandt, “and we would be sending samples back and forth.”

Researchers tested the formula using a popular meth recipe found on the Internet. Ordinary Sudafed yielded 89 percent pure pseudoephedrine, but with the additives, no usable pseudoephedrine could be extracted.

Another bonus was that the additives were already FDA-approved chemicals, executives said. Unlike Booth’s decongestant, which would be considered a new drug, a cold medicine made with additives would not require costly clinical trials. The company could move the product quickly to market.

Keeping the costs low was important because executives had no guarantees from the government that they would be rewarded for their investment.

“We never had any strong indication coming back from the DEA or other sources saying if we had solved the problem, we would have owned the market,” Isbrandt said.

Warner-Lambert applied for a patent on the additives in April 1997. That November, a Warner-Lambert spokeswoman told a British magazine that the company was “now at the final stages of research into a global solution” to the pseudoephedrine problem.

But there was an obstacle. The harder researchers made it for meth cooks to extract pseudoephedrine from Sudafed, the harder it was for digestive fluids to break down the pills and absorb the decongestant.

“We were trying to do a balancing act, to make it difficult for a chemistry lab to get at it, but at the same time make it easy for the body to get at it,” Isbrandt said. “We kept trying to get at that sweet spot.”

At the same time, the original pressure on Warner-Lambert — the possibility that regulators might ban pseudoephedrine — was fading. Industry lobbyists persuaded Congress to exempt from regulation cold products in foil blister packages, which were considered harder for meth cooks to open in volume.

The DEA, which had been a major force behind previous pseudoephedrine rules, stopped pushing for additional powers.

Research ceases

The company received patents on both ideas: the additives in October 2000 and Booth’s mirror-image pseudoephedrine in December 2002.

Kosminsky, the Pfizer spokesman, said the Booth project ended before the company took over Warner-Lambert in 2000. He said Pfizer gave up on the additives that Bess’ team had studied after spending $12 million.

Pfizer plans to introduce a cold medicine in January made with the decongestant phenylephrine, which cannot be converted to meth. Kosminsky said the product will offer consumers an alternative in states that restrict retail sales of pseudoephedrine products.

The company will continue selling Sudafed nationwide.

Today, the National Institute of Drug Abuse spends $1 billion a year, much of it on developing drugs that will fight addiction to substances such as meth.

Yet in the past 15 years, Congress has never seriously debated financing research into a cold remedy that cannot be turned into meth. Pfizer’s patent on the mirror-image pill is a public record. Yet lawmakers have never discussed making it easier for Pfizer to get federal approval for its new drug.

Kosminsky said Pfizer would be open to such a proposal.

For now, experts say, drug companies have little incentive to pursue pseudoephedrine alternatives.

“If tomorrow there was no such thing as Sudafed,” Doering said, “people would probably be working 24/7 looking for something that could fill that need.”