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Breathing Life Into an Idea

Times Staff Writer

Scientist John S. Patton jumped when a venture capitalist asked for evidence that Patton’s cash-starved company could make inhaled versions of injected drugs.

Patton, a former Genentech Inc. researcher, gathered up his drug-testing equipment and headed with his business partner, Robert M. Platz, to the offices of Onset Ventures, which were then in Palo Alto. Patton also brought with him his cousin, a nurse.

As Patton recalled it, he and Platz took deep breaths of a drug that regulates calcium, then sat in a conference room for hours as his cousin took blood samples.

The experiment was a success: It showed a drug that was normally injected could enter the bloodstream through the lungs. And investment dollars began flowing into Patton’s company, now called Nektar Therapeutics.

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Fourteen years later, Nektar and its partner, drug giant Pfizer Inc., are on the verge of launching the first inhaled insulin. A Food and Drug Administration advisory panel two weeks ago recommended approval of the drug, which could make life easier for millions of diabetics. The FDA is expected to act by early next year.

Despite concerns about safety -- the drug causes a slight decline in patients’ breathing capacity -- many on Wall Street think that inhaled insulin can become a blockbuster with more than $1 billion in annual sales. The drug, called Exubera, could reduce or eliminate the need for injections to control patients’ blood sugar.

A failed project at Genentech in the mid-1980s set the course for Exubera. Genentech wanted Patton to develop a pill form of human growth hormone, an injected drug. But Patton determined that large proteins like human growth hormone wouldn’t survive in the intestine, where food proteins are broken down.

He began exploring the lining of the lower half of the lungs as a possible way into the body. A simple experiment hinted that Patton was on the right track: When he sprayed human growth hormone into the mouth of a rat, the drug immediately entered the animal’s bloodstream.

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Genentech patented the discovery, but the big biotechnology company put the project on the shelf. Patton quit Genentech in 1990 and started the company that became Nektar with Platz, now an Amgen researcher.

Patton spent 13 months scouring Silicon Valley for investors, without success. Then he met Onset Ventures’ Terry L. Opdendyk, who became fascinated with the possibility of developing inhaled versions of biotechnology drugs.

“We thought it could be incredibility lucrative -- if it worked,” Opdendyk said.

An obstacle were the lungs themselves: They are designed to keep foreign objects out. The airway passages are covered with mucus to trap large molecules, and very small particles are exhaled before they can be absorbed. Scientists knew from studying lungs of coal miners that only particles of a certain size, 1 to 3 microns, could penetrate the lungs. The width of human hair is about 70 microns.

Asthma drugs are delivered to the lungs by metered-dose inhalers, but those devices are not useful for biotechnology drugs. The asthma inhalers fire the drug to the back of the throat, and only 5% to 10% of the medicine makes it into the lungs. Because biotechnology drugs were costly, Nektar would need a more efficient device.

After Onset invested in Nektar, it asked for additional experiments that could be used to attract other investors. Using themselves as guinea pigs, the scientists tested other drugs.

Once they became so nauseous after inhaling a drug that they raced to Onset Ventures’ restroom, Platz said. The company’s new chief executive at the time, Robert B. Chess -- now Nektar’s chairman -- participated in another experiment but fainted after his blood was drawn, Platz recalled.

“Terry didn’t believe in animal studies,” Platz said wryly.

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Eventually, Nektar decided to focus on inhaled insulin.

The drug was attractive because insulin was available to work on and the potential market was huge. But insulin also posed challenges. Nektar’s device had to deliver the same amount of drug every time. And no one knew whether inhaled insulin, delivered several times daily over many years, would cause lung damage.

To develop the product, Nektar drew on technologies used in such areas as mechanical engineering and food science. Spray dryers similar to those that make powdered milk convert insulin to a fine powder. The insulin is packaged in blister packs, which are loaded into an inhaler.

The device, about the size of a flashlight, uses a blast of air to deliver the insulin powder. “It’s really just a little air gun,” Patton said of the inhaler.

Nektar, based in San Carlos, north of Palo Alto, spent about six years perfecting the device. An early stumbling block was finding an efficient way to fill blister packs. Before engineers figured out how to automate the process, just about every Nektar employee, including the entire executive suite, helped package insulin by hand.

The fastest worker completed just 50 a day. “I was losing sleep over this,” Patton said. “It was a huge technical barrier.”

Patton reached for an inhaler and slid a clear plastic chamber into place. Then he inserted a blister pack and cocked the device, causing a needle to puncture the blister pack. Patton squeezed a button, and a blast of air whipped the insulin into a fine cloud that filled the chamber. “You just breathe it in,” Patton said.

The device might be easy to use, but not to carry around.

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David Kliff, a diabetic who publishes the Diabetic Investor newsletter, said patients wanted a smaller device, one that they could carry in their pockets. Diabetics use insulin before meals.

“I can’t imagine anyone whipping this out in a restaurant,” he said. “My wife says it looks like a bong.”

“Size and simplicity of the device are important,” said Carlos Paya, the Eli Lilly & Co. vice president leading development of a competing inhaled insulin. Lilly, working with Alkermes Inc. of Cambridge, Mass., is testing a smaller inhaler.

Because Exubera is licensed to Pfizer, Nektar won’t make a killing on the drug. The drug giant conducted most of the clinical trials and would market Exubera once it was approved. Nektar would provide the device and powdered insulin to Pfizer, and receive an undisclosed royalty on product sales.

The next big step for Nektar is to develop inhaled drugs on its own. One area that’s under consideration: inhaled antibiotics for respiratory infections. The company, which went public in 1994, plans to give investors an update on its drug development pipeline next week. Nektar has never been profitable.

Patton, now Nektar’s chief scientist, hasn’t forgotten about human growth hormone, a drug used to treat short children with a hormone deficiency.

“I still think it is a giant opportunity,” he said. “Maybe not as big as insulin, but close.”


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