A Miracle Drug's Second Coming

But, Genentech isn't overhyping its clot-busting drug this time

A decade ago, Wall Street had the heart-attack drug TPA pegged as biotech's first billion-dollar blockbuster. Pioneered by Genentech Inc., the gene-spliced clotbuster promised to save lives and revolutionize treatment, too.

That promise proved elusive: Doctors worried about TPA's potent side effects, hospitals fretted over its high cost, and many patients didn't arrive at the hospital fast enough for it to be useful. Last year, Genentech sold just $301 million worth of TPA--and only after spending tens of millions on studies to prove its value over cheaper rivals.

OPEN DOOR. Now, in a remarkable case of deja vu, TPA is again being hailed as a wonder drug--this time, as the first treatment ever for stroke. Encouraged by new studies, doctors envision using the clotbuster right after a stroke to restore the flow of blood and oxygen to brain tissue before irreparable damage is caused. "We've finally opened the door," says Dr. Patrick D. Lyden, a neurologist at the University of California at San Diego who says he's "spent a decade treating an illness for which there is no treatment."

On June 6, an advisory committee to the Food & Drug Administration will review Genentech's application to sell TPA as a stroke treatment. The application has received fast-track status and hopes are high. But this time, Wall Street's predictions are modest at best. Despite the great promise, the marketing hurdles in the use of TPA for stroke will be even more complex than they were for heart attacks.

Each year, half a million Americans suffer strokes--disruptions in blood flow to the brain that kill or damage brain cells. Strokes are the third-biggest killer, after heart attacks and cancer, and the leading cause of disability in the U.S. While about 17% of strokes are caused by a ruptured blood vessel, the vast majority are ischemic: They occur when a blockage in an artery robs the brain of blood and oxygen. Only about 20% of those who have strokes die from them, but many suffer paralysis and impaired speech and vision.

The good news is that a slew of companies have targeted stroke as the next great opportunity for breakthrough drugs. TPA is the first: In a study published last December, researchers at the National Institutes of Health's division of stroke and trauma showed that if TPA is given within three hours of the onset of a stroke, the incidence of complete recovery increases by 50%.

Unfortunately, despite the likelihood that TPA could be approved for use in stroke by next year, a rash of dramatic recoveries is unlikely for some time. Fewer than 10% of all stroke victims currently make it to the hospital in time to be treated with TPA. Most patients--and hospitals--do not treat stroke as an emergency in which prompt intervention matters. Stroke symptoms are not as dramatic or painful as a heart attack. And brain damage or advanced age can impair patients' understanding.

But delays plague the entire system: Paramedics aren't primed to diagnose stroke patients and rush them in; emergency rooms often "park" stroke patients, and facilities are not organized to perform the brain scans needed before a patient can get TPA.

Even TPA's biggest advocates admit that many neurologists are nervous about the drug's side effects. Studies clearly show that more lives are saved with the treatment than without. But in about 7% of cases, the drug causes bleeding in the brain, which is often fatal. That means doctors who give it will inevitably be iilling some patients who otherwise would have lived. More conservative neurologists are "quite hesitant" to make these quick trade-off calls that surgeons and trauma physicians regularly face, explains Dr. John R. Marler, an NIH neurologist who is a strong supporter of the drug.

All told, analysts are skeptical that Genentech can quickly build a blockbuster market for the drug. If approval comes by 1997, for example, analyst Reijer Lenstra of Smith Barney Inc. expects stroke usage to add just $22 million in TPA sales in 1998. "At one of the trial centers, only 1% of stroke patients arrived at the hospital within the three-hour time limit," Lenstra says.

Genentech's overestimate of the use of TPA for heart attacks created a gap in revenue projections that led to the company's having to sell a majority stake to Roche Holdings Ltd. in 1990. To build market share, Genentech has had to help educate doctors and patients on the importance of hurrying to the hospital. And only time and experience made physicians more comfortable with the risk of bleeding.

This time the company's public posture has been cautious. Chief Executive Arthur D. Levinson will not give interviews about the drug. Greg Vontz, associate director of marketing who was there for TPA's launch, says the company's focus is on educating neurologists--not hyping the drug's prospects on Wall Street. "We have to get the relationships built in the hospitals. We didn't know that in 1987," he says.

HIGH PRICE. Indeed, Genentech was widely criticized for using high-pressure sales tactics on cardiologists and hospital pharmacies--and for pricing a typical dose of TPA at $2,200, about 10 times the cost of the competing drug, streptokinase. Studies have shown streptokinase works only slightly less well on heart attacks. Genentech won't say what it will charge stroke patients for TPA, but streptokinase won't be a competitor. It caused unacceptable brain hemorrhage rates in stroke-treatment trials.

Genentech is facing other competition, however. Interneuron Pharmaceutical Inc., based in Lexington, Mass., is testing a so-called neuroprotective agent called citicoline. Instead of breaking up blood clots, this drug seems to reduce levels of the toxic substances that contribute to brain cell damage in a stroke's aftermath.

In theory, the agents should be complementary. But Interneuron's trials have shown patient recovery numbers similar to Genentech's, and they were achieved within 24 hours of patients appearing at the hospital, with no serious side effects observed, including bleeding. The company has been quick to compare the agents in terms of how they'll go over with doctors. With TPA, neurologists will have to come to the hospital in the middle of the night--something they're not used to, says Interneuron CEO Glenn L. Cooper. "Sometimes those practical things have a big impact."

Some researchers are frustrated by such talk. They say TPA has proven itself in a large, well-run trial and is much closer to approval. Physicians shouldn't be scared off, says James Grotta, director of the stroke program at the University of Texas at Houston. He finds Interneuron's comparison of the agents "inflammatory and irresponsible." Genentech, meanwhile, is trying to extend the window of time during which TPA can be given effectively. And it's testing another agent called TNK, which could be faster and easier to administer for heart attacks or strokes.

Many of the hospitals that participated in the NIH trial are trying to get stroke patients treated more aggressively. Some are instituting "code stroke" procedures that would set emergency personnel in action much as a yell of "code blue" does for heart attacks. Groups such as the National Stroke Assn. are trying to urge the public to learn the symptoms of stroke (table) and call 911 as soon as they appear.

But for Genentech to succeed with this new application will require a remarkable coordination of doctors, hospitals, paramedics, and patients. That's likely to take years, even if a humbler Genentech does everything right this time around. Medicine is on the brink of the first meaningful treatment for stroke in history. But the curious reality is that making a difference for scores of patients is likely to be agonizingly slow.

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