A Booster For Biotech

New drugs can be delivered without shots

For all the advances against disease in recent years, one archaic instrument has remained stubbornly resistant to progress: the needle. Biotechnology has actually made the hypodermic even more prevalent, by creating large-molecule drugs that can't be absorbed in pill form. As David M. Steinberg, managing director at Volpe Brown Whelan LLC, says: "The holy grail for the biotech industry is drugs that don't require injections."

The prize may finally be within reach--a number of technologies are expected to start hitting the market next year. More than 100 so-called drug-delivery companies are developing everything from transdermal patches that can deliver painkillers at the touch of a tiny computer to drug-containing molecules that release medicine over time. There are high-tech inhalers that push the medicine through the lungs and biotech drugs that can be taken in a drink.

LESS OW. All these advances promise less pain. And that can translate into better outcomes, because patients are more likely to take their medicine. "This will be significant for the growth of biotech," says William D. Young, chief operating officer at Genentech Inc.

For drug-delivery companies, demand is also driven by the heat on traditional medicines. New drug-delivery systems for existing drugs can give life to older products such as the painkiller fentanyl, recently turned into a lozenge. They can also protect big blockbuster franchises from copycat competitors. Analyst Ian C. Sanderson of SG Cowen Securities Corp. figures that the opportunity for the new versions of existing drugs, combined with the expanding biotech market, will drive sales of drugs using the new delivery systems from $9.8 billion in 1997 to more than $30 billion by 2007.

The need for new delivery systems is in large part a function of biology. For years, drugmakers have churned out small chemical molecules that are able to pass through stomach membranes into the bloodstream, making them ideal as pills. But biotech products are based on proteins and peptides--large molecules that often cannot be absorbed through the stomach.

Besides, since we live on proteins, the body has efficient mechanisms for breaking them down. The end result: They don't last long in the body. Consequently, almost all biotech drugs are delivered directly to the blood through frequent injections--a notoriously unpopular method with patients. "Many companies steer away from protein drugs because they think the market will be limited," says Robert B. Chess, co-chief executive officer of drug-delivery company Inhale Therapeutic Systems Inc.

One of the first advances in protein drug delivery could hit the market next year. Alkermes Inc. of Cambridge (Mass.) has teamed up with Genentech to develop a sustained-release version of human growth hormone, used to treat children who don't produce enough themselves. In Alkermes' Prolease system, the protein is freeze-dried and placed in tiny particles of a biodegradable sponge-like polymer. The medicine sits in the little holes throughout--once injected, water hits the pores on the outer layer, releasing the drug. As the water seeps further down, the drug is released from each successive layer of pores. Alkermes CEO Richard F. Pops says a Prolease injection can release human growth hormone for up to one month, replacing daily shots.

But the ideal is no needles at all. The first needle-free, big-molecule delivery systems are likely to use the deepest part of the lung, where the large surface area and thin tissue lining are ideal for drug absorption. But the proteins need to be stabilized so they can last in an inhaler for long periods, and must be pumped out in just the right size. Too small and the particles are exhaled, too large and they stick in the throat.

A number of companies are rushing to bring deep-lung systems to market. Leader Inhale Therapeutic has found a way to stabilize big molecules in powder form and pump them into the lung using a soda-can-size inhaler. Its first product, inhaled insulin, is in final testing and could be approved in 2001. Competitor Aradigm Corp. has an inhaled-liquid system that is in the second phase of testing for insulin and morphine.

Other methods try to get around the protein-dicing enzymes in the stomach. One owes much to a chance discovery made 12 years ago. A researcher with diabetes at Emisphere Technologies Inc. was working on a project to mask the taste of fish oil. On a whim, he decided to feed one compound along with insulin to rats, and noticed a change in the animals' blood sugar. Instead of breaking down in the stomach, the insulin reached the bloodstream.

The discovery led to years of study on how different substances, when attached to a large molecule, can change its shape--making it tougher for stomach enzymes to latch on. Emisphere, with pharmaceutical partner Elan Corp., is hoping to soon enter final human testing of an oral version of the anticlotting drug heparin--now typically given as several injections a day. Analysts figure oral heparin could be on the market as early as 2001.

Big drugmakers will be calling on drug-delivery companies for help in defending older treatments, too. Over the next few years, key patents will expire on some blockbuster drugs while other products could lose exclusivity in legal challenges from rivals. In either case, the result is likely to be the rollout of cheap, generic versions. Drugmakers have fended off generics in the past by developing a more convenient delivery form--going from a three-times-a-day pill to a once-a-day tablet, for example.

Case in point: SmithKline Beecham's $2 billion antidepressant, Paxil. The company says it has patent protection on Paxil in the U.S. through 2006, but Canadian drugmaker TorPharm is challenging that claim. If SmithKline loses, it has a backup: The company has signed a deal with drug-delivery company SkyePharma PLC to come up with a new form of Paxil. SkyePharma uses sponge-like polymer tablets to control exactly where and when the drug is released in the gut. While the two companies won't comment on how the new Paxil will be superior to the old, SG Cowen analyst Sanderson figures it may reduce nausea by releasing the drug at a different point in the intestinal tract.

SAFETY PEG. New delivery systems may also make toxic drugs safer. Drug-delivery company Enzon Inc. has a system that attaches strands of a polymer called polyethylene glycol (PEG) to proteins. It's also testing the method with Camptothecin, a highly toxic small-molecule anticancer compound. In mice, it seems the PEG version of Camptothecin attacks tumors and not healthy tissue. One theory: The PEG version is too large to pass out of normal blood vessels, but blood vessels in tumors are often leaky, so the altered Camptothecin may seep through their walls into the tumor.

Enzon is seeking permission to begin testing the PEG Camptothecin in humans. It may take years for this and other new delivery methods to reach patients, but scientists are confident they will eventually supplant the needle. Look for a future when the words "Take your medicine" will lose their sting.