Medicine by Special Delivery, Cusp of a Health Revolution
Research Finding Novel Ways to Administer Drugs
By Justin Gillis
Washington Post Staff Writer
Sunday, November 29, 1998; Page A01
Frank Rabanzo, a mechanic for the San Diego utility company, pulled into Denny's with his family not long ago. He's a diabetic and needed insulin before he could eat a hamburger. For many diabetics, that would have meant sneaking into the bathroom and jabbing a needle into a thigh.
Not for Rabanzo. He whipped out a little aerosol device, breathed some white powder into his lungs, and moments later was ready to eat. "I got a few looks, but for all anybody knew I was taking my asthma medicine," he said.
Rabanzo is on the cutting edge of medical technology, as one of just a handful of people in America using insulin inhalers. But he may not be alone for long. Several companies are working to bring such inhalers to market. And the inhalers are just one small part of a broader trend: Companies are spending billions to find creative new ways to get drugs into the body.
They're developing patches with tiny batteries in them to push drugs through pores in the skin. They're selling nearly painless injectors that look like small pens. They're designing "smart" pills that release medicine in response to signals from the body. To lessen side effects, they're coating drugs with microscopic fat layers that dissolve when the compound reaches its target in the body.
They're creating fruits and vegetables that people would eat to gain immunity from common diseases. They're trying to formulate vaccine gels that could simply be rubbed on the skin, a potential breakthrough for any child afraid of shots and possibly a lifesaver in poor countries.
Some of this research goes back decades, but it has reached a torrid pace lately as scientists take advantage of new insights into the way the body works. A pharmaceutical-industry trade publication, MedAdNews, recently counted 106 public companies around the world involved in such research. "Drug delivery" has become one of the hottest branches of pharmaceutical science.
Revenue is rising fast at many of these companies as their work finally begins to pay off. SBC Warburg Dillon Read Inc., an investment firm, has projected that sales of products using novel drug-delivery techniques will go from less than $10 billion in 1995 to nearly $40 billion in 2005. Predictions like that have sparked intensive interest on Wall Street in some of these companies.
The research promises to change the lives of people all over the world, starting in places like Temple, a town on the plains of central Texas. There, researchers are spraying a new influenza vaccine up the noses of children in hopes of showing that flu transmission can be shut down in an entire city.
Flu is perhaps the only remaining illness that is capable of sweeping around the planet and killing millions. Yet many people won't go to the doctor every year for flu shots. That's partly because shots hurt. Replacing them with an easy-to-use nasal vaccine could become an important weapon. Children are thought to be prime agents in transmitting flu, so immunizing most of them might protect a whole community.
"The underlying goal is to develop practices that could be used in the face of a pandemic," said Paul Glezen, a Baylor University epidemiologist leading the Temple study. "When that happens, there's going to be a limited amount of time to deliver a lot of vaccine."
The nasal vaccine, based on decades of work funded by the U.S. military and the National Institutes of Health, is under commercial development by Aviron, a company in Mountain View, Calif. It is probably several years from final approval, though so far it seems to work well. Some experts hope that eventually the vaccine will be sold without a prescription to make it as easy as possible for people to protect themselves.
It's not the only effort to design friendlier vaccines. In a laboratory in Washington, a restaurant janitor named Matthew Ingram -- "just being a good Samaritan," he said -- stuck out his arm not long ago so doctors could swab on a bit of gel designed to penetrate the skin and induce immunity to a germ.
If the preliminary results hold up in more advanced tests, mass vaccination campaigns in poor countries could become more practical.
Much of the work on this gel vaccine was done at the Walter Reed Army Institute of Research. The discoverer of the technique, former Army researcher Gregory Glenn, has formed Iomai Corp. in Washington to try to commercialize it. The technique involves mixing standard vaccines with a poison produced by germs. On the surface of the skin the poison does no harm, but it does seem to wake up the immune system and prompt it to react aggressively to the nearby vaccine molecules. The technique works well in animals and has entered the early stages of human testing. Iomai has yet to sell shares to the public, but a half-dozen large pharmaceutical companies have beaten a path to its door, eager to have access to the technology if it holds up.
Glenn, who published news of his research in the journal Nature in February, emphasizes the need for extensive testing. But he acknowledges that the possibilities are exciting, especially for poor countries where there aren't enough doctors, nurses or clean needles to mount mass immunization campaigns. Gel-based vaccinates might be so easy to use that village healers could be taught to administer them.
"It waves in your face this possibility of eradicating diseases," Glenn said. "That's why there's so much interest."
Some of the most compelling drug-delivery research is aimed at helping diabetics. About 15.7 million Americans, nearly 6 percent of the population, have some form of diabetes. Not all of them need to take insulin shots, but many people who need to won't do it, or won't do it often enough, because of the inconvenience of needles. Even when they can find a place to inject themselves during a busy day at work or school, it's not a pleasant thing to do. Some diabetics talk of encounters with strangers in the bathroom who assume they're junkies.
The consequence is that diabetes isn't nearly as well controlled as it could be. It's a serious disease that, in its advanced stages, can make people extremely sick or kill them. Impotence, amputation and other problems are potential consequences of the disease, which kills about 190,000 Americans a year.
Even before inhaleable insulin, the drug-delivery industry was delivering for diabetics. If they're willing to wear a device the size of a pager, they can have insulin delivered through a small needle that remains embedded in the skin. These "insulin pumps" have been available for years, but they have grown smaller and more reliable, and far more people are using them.
Still, many people don't want to or need to wear an insulin pump. That's where Inhale Therapeutic Systems Inc. of San Carlos, Calif., comes in.
Turning insulin into a powder that can be breathed into the lungs may sound simple, but it hasn't been. Insulin is a human protein, a large molecule that normally circulates in the bloodstream and regulates blood sugar. Some oral drugs are available to help diabetics, whose bodies produce too little insulin or don't use it properly. But insulin itself can't be taken by mouth because such a large molecule would be destroyed in the digestive tract.
Inhale Therapeutic Systems had to create a form of insulin that could be turned into dry particles, then it had to get those particles into just the right size so they would stick to and be absorbed in the lungs without doing harm. And it had to devise a way to deliver precise doses by means of an inhaler that even children could operate.
The research has taken years and has cost millions of dollars. Final tests are beginning at 117 places across the country. Nobody knows how well the product will hold up in these tests, but patients who are using it say they're getting good control of their blood sugar. Some people can operate the inhaler in a few moments -- the company has had reports of patients giving themselves insulin while stopped at traffic lights, and it says one man used the inhaler in the middle of a game at the Orange Bowl in Miami.
Inhale Therapeutic Systems is collaborating with two giant drug firms, Pfizer Inc. and Hoechst Marion Roussel AG, and it's clear that the three companies are out to change diabetes treatment for millions. Anticipating final approval of the product, they recently announced plans to build one of the world's largest insulin factories in Germany. Other drug firms are playing catch-up to develop their own inhaled forms of insulin.
Like insulin, many of the hottest new drugs being developed in the nation's research laboratories are proteins, which means they can't be taken in pill form. Yet many of them need to be taken at regular intervals, ideally in a way that maintains consistent blood levels throughout the day. This is prompting a marriage between biotechnology firms, which discovered many of the proteins, and the drug-delivery industry, which has the means to get them into the body.
The result is likely to be a flood of specialized pumps, patches, implants and other devices. Patches under development use tiny electric currents or high-frequency sound waves that push the drugs through the skin into the body. Already, people can use patches to supplement low levels of hormones, such as testosterone.
Much work in the drug-delivery industry involves manipulating drugs to decrease side effects. For instance, several companies have focused on the injectable drug amphotericin B, which fights fungal infections. The drug's side effects are so bad that people who have taken it sometimes call it "amphoterrible," yet it's often the only choice to combat a life-threatening infection.
Drug-delivery companies have created forms of the drug in which tiny particles of it are coated in thin layers of fatty compounds called lipids. By hiding the drug from most organs, this technique lessens side effects. Yet at sites of infection, the fat layers peel away and the drug can do its job of fighting a fungus.
"We've substantially reduced the toxicity," said Crispin Eley, a vice president at NeXstar Pharmaceuticals Inc. of Boulder, Colo., which won federal approval last year to sell a lipid version of amphotericin.
It's only a matter of time, researchers say, before a good bit of the population will be dependent on gadgets developed by the drug-delivery industry. Ultimately, the devices probably will be able to measure how much of a drug a person needs at a given moment and simultaneously deliver the correct dose. And today's pager-sized pumps may shrink to a point that they could be implanted beneath the skin and refilled through a pore.
"I would say 10 to 20 years from now, people may be implanted with a programmable delivery system that includes a computer and sensors," said Gordon L. Amidon, president of the American Association of Pharmaceutical Scientists. "Once a week or once a month we connect it to the telephone, call the doctor's office and we're evaluated and reprogrammed."
The biggest drawback to these new technologies is likely to be cost. An insulin pump, for instance, can easily run $4,000. Yet drug-delivery companies contend that if they can reduce the hospitalizations and other problems associated with severe diseases such as diabetes, they can save money for the country and patients in the long run.
When Rabanzo, the San Diego diabetic, learned that he might need insulin shots to control his illness, he fretted. How was he supposed to give himself injections during the workday in the middle of a garage full of diesel mechanics? He jumped at the chance to enroll in a test of the insulin inhaler, and he's thrilled with the results.
"It's amazing," he said. "My mother-in-law had to go in the hospital, and they were putting medicine patches all over her. If they can administer medicine more easily and have it react more quickly, it's going to help a lot of people."
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