By David Shook In 1995, the National Institute of Neurological Disorders & Stroke (NINDS) found that a drug called TPA rapidly dissolves blood clots in the arteries and capillaries. Within a few hours, a clot can trigger the cascade of events known as ischemic stroke, leading to death or severe brain damage for hundreds of thousands of people each year. Finally, an effective stroke treatment with blockbuster potential? Unfortunately, it hasn't turned out that way.
In 1996, biotech giant Genentech (DNA) began selling TPA under the trade name Activase, and it remains the only treatment on the market for acute symptoms. But Genentech considers Activase for stroke a commercial disappointment, despite what Dr. Hal Barron, the company's senior director of cardiovascular-pulmonary research, says were "pretty tremendous efforts in investment and education." Sales of the drug are slumping, and much of its revenue comes from its use for heart attack -- a market that has seen increased competition from other anticlotting agents.
"DISABLING DEFICITS." The drug's business failure is all the more poignant because it does seem to work. In patients who receive it within three hours of an episode, the chance of full recovery is 35%, compared to 20% for those who don't. "We're talking about patients with disabling neurological deficits recovering completely," says Dr. James Grotta, professor of neurology at the University of Texas at Houston Medical School.
So why isn't Activase a commercial hit? Only about 5% of patients who suffer ischemic stroke -- which accounts for 85% of strokes in adults -- receive the drug. This has nothing to do with difficulty administering it or expense. The reasons start with the fact that too many people still don't recognize the symptoms of stroke and the critical need to seek treatment within a few hours after the onset of symptoms. The reasons end with the pharmaceutical industry's unwillingness to design trials that adhere to the crucial three-hour time frame.
It's a chicken-and-egg conundrum, according to physicians involved in clinical trials. The pharmaceutical industry has resisted trials using the three-hour window because of the limited market for such drugs. Many people don't know they've suffered a stroke, so they don't make it to the emergency room in time.
CRUCIAL PERIOD. There's another problem: Since a stroke is really a complex chain of events, researchers still aren't sure where the best place in the brain is to intervene with drugs. But it's clear that dissolving the blood clots that lead to stroke and protecting the brain cells from their lethal effects must be done within a few hours. During that crucial period, brain cells can build up toxic levels of calcium or be irreversibly damaged by inflammation or other processes.
Given Activase's lackluster, several drugmakers now are trying to develop more effective stroke therapies, with trials involving a much longer window for treatment -- six hours or more after symptoms occur. What researchers mostly have learned, however, is that by the time six hours have passed, much of the damage from strokes is already done.
That's frustrating to many in the field of treating strokes. "I really don't understand the fixation on looking at the first application for a stroke drug at six hours. There have been 14 or 15 drug trials that have failed at this time frame," says Dr. John Marler, the lead clinical researcher in the NINDS trials of TPA. "Hundreds of thousands of brain cells die increasingly rapidly as the minutes pass. So you have to wonder when these companies are going to catch on to the fact that the only real success is in three hours or less."
INCONCLUSIVE RESULTS. The most recent stroke-drug failures involve compounds developed by Bristol-Myers Squibb (BMY) and AstraZeneca (AZN). Both compounds are categorized as neuroprotectants, which shelter the brain from the toxic effects of stroke rather than dissolving the blood clot that causes it. But both were tested in many patients who had suffered a stroke six hours or longer before diagnosis. This may have contributed to inconclusive results in the trials for both Bristol-Myers' drug, Maxipost, and Astra's drug, clomethiazole.
A second Maxipost trial isn't complete, but doctors involved in the studies say the drug probably won't produce compelling results the second time around, either. "It's unlikely that that trial is going to show anything significant," says Dr. David Tong, associate director of the Stanford Stroke Center. Bristol-Myers declined to comment other than to say the company hasn't given up: "Certainly, the program isn't dead," says Bristol-Myers' spokesman Brian Henry. "At this point, though, it's difficult for us to predict how things will turn out."
Marler, who studies TPA, isn't the only one getting frustrated that drug companies keep focusing on a six-hour window because they believe it's the only time frame that will allow them both to design an effective treatment and make money. "Despite millions of dollars spent and the advice of many stroke specialists, pharmaceutical companies continue to make mistakes in clinical-trial design created by the companies' marketing concerns. They want as large a market as possible, but with a very short time window, less of the drug can be sold," Grotta says. "In my experience, there's always this tension between the research side of a pharmaceutical company and the marketing side, and it always results in a compromise for the drug trial that ends in a disaster."
SIDE EFFECTS. The drug companies respond that it's not all their fault. Genentech's Barron says Activase's limited success shows how difficult it can be to get people into the emergency room within three hours. So a drug with such scant application may not find commercial success without better public-health education and fundamental changes in the way hospitals respond to stroke.
Besides, while TPA and neuroprotective agents may show promise, they also can have negative side effects if not administered properly. Too much TPA can lead to brain hemorrhages, while excessive amounts of neuroprotective agents can cause behavioral problems.
There's also the question of whether neuroprotectants are suitable for all patients who suffer a stroke. For instance, some people suffer a stroke deep inside the brain, while others have an attack on the outer cortex. Researchers still are trying to figure out if neuroprotectants are more effective in some parts of the brain than in others. "So far, we've seen the shotgun approach to these trials, which is treating everyone within a certain time window but with no differentiation between different types of ischemic stroke," says Stanford's Tong.
COMBO THERAPY. Despite the huge amounts of money spent on failed clinical trials, drug companies aren't giving up. Up to 500,000 Americans suffer a stroke each year. Pfizer, Bristol-Myers, and biotechnology company ICOS remain involved in clinical trials.
Many now see a future where emergency treatment for stroke will involve a combination therapy that busts open a stroke-causing clot while simultaneously protecting the brain from cell damage. However, no company has designed a clinical trial yet that combines these two forms of therapy within three hours after symptoms occur, stroke doctors say.
Better public awareness of stroke symptoms would help. Grotta's approach at the University of Texas involves training emergency room staff to diagnose and treat stroke victims as quickly as possible. That's easier with the use of MRI, CAT scans, and angiography now available in most hospitals. "We're able to treat 15% to 20% of [stroke] patients with TPA because we've organized our emergency room to respond very rapidly," Grotta says of his Houston-based stroke-response unit.
Outside the emergency room, "it's a matter of public education, organizing the community," he says. Adds Marler: "You've got to punch 911, get patients into the ambulance, and then into the hospital." Sadly, in the short term, saving millions from the debilitating effects of stroke may involve spending nearly as much money on education as on research and miracle cures. Shook covers biotechnology issues for BusinessWeek Online. Follow The Biotech Beat every week, only on BW Online