The Wall Street Journal -- January 25, 1999
Drugs:
Diabetes Drugs Near End of a Long Road
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By Robert Langreth
Staff Reporter of The Wall Street Journal
Capping one of the longest quests in drug-industry history, scientists have started final-stage human tests of the first medicines specifically developed to treat the crippling and sometimes deadly complications of diabetes.
Pfizer Inc. and Warner-Lambert Co. are testing a new type of diabetes drug that could prevent nerve and organ damage, the most common long-term consequences of the incurable disease. The effort is fraught with risk, as the companies aim to resurrect an earlier class of drugs that flopped in human trials 10 years ago.
Industry scientists have been chasing these drugs for three decades, in the face of an unusual hurdle: It can take a decade or more before permanent nerve and organ damage sets in for diabetics. So assessing the effect of any drug has been difficult.
While diabetics who take drugs that decrease their blood sugar do manage to avoid some of the disease's complications, scientists have long sought a more targeted treatment that would home in on nerves and kidney tissue and counter the havoc wreaked by high blood-sugar levels.
The diabetes-complications research is the longest-running research program at Pfizer. As the drug industry targets other slow-developing chronic diseases, such as Alzheimer's, longer-range programs are likely to become more common.
About 60% of the 16 million American diabetics suffer nerve damage, which causes pain and loss of sensation in the limbs and eventually can lead to amputation. Tens of thousands of diabetics suffer kidney failure or go blind.
Pfizer, of New York, and Warner-Lambert, of Morris Plains, N.J., are hopeful they have solved many of the problems that plagued previous attempts. Their new drugs are more potent than earlier ones and, in initial human tests, halted the progression of, and even partially reversed, nerve damage in diabetic patients.
A different approach, taken by Genentech Inc., South San Francisco, has also shown promising results in reducing symptoms of nerve damage in initial human tests. Genentech's agent is a genetically engineered version of a natural protein that promotes nerve growth.
It will be a year or more before the new drugs could hit the market, since they haven't completed large-scale testing and may still fail. But if successful, "these would be the first agents capable of affecting the natural history of the disease -- and potentially reversing it," says Howard Foyt, who directs clinical research into diabetes at Warner-Lambert. Dr. Foyt recalls treating a construction worker whose nerve damage was so severe, he accidentally rammed a nail into his foot and didn't notice it until he got home and found he couldn't take off his boot.
Research into drugs against diabetes complications began in the 1960s, when university scientists identified an enzyme that seemed to play a critical role in converting high levels of sugar in the blood of diabetics into other chemicals that accumulate in nerves and eyes and kidney cells, slowly damaging them.
This finding caught the attention of scientists at what is now American Home Products Corp., who began screening the company's compound collection against the enzyme. They soon found a compound that blocked it. Other companies, including Pfizer, began developing their own versions of the drugs, dubbed aldose reductase inhibitors.
But as the drugs moved into human trials, it became clear that testing them would be problematic over the extraordinarily long course of nerve and organ damage. More than one program was put on hold as drug-company researchers debated with the Food and Drug Administration how to test their drugs.
"If we were only treating rats, we'd have a lot of great drugs by now," says Douglas Greene, a physician and researcher at the University of Michigan Medical Center, in Ann Arbor, who has helped test many of the drugs, including Warner-Lambert's version. "But the field has moved slowly, because the complications are so chronic that every step has taken a long time."
Amid enormous expectations, American Home, Pfizer and others pressed ahead into large-scale human testing in the late 1980s. The results were disappointing. No aldose reductase drug showed unequivocal efficacy, despite encouraging signs.
Merck & Co. abandoned development of its drug in 1990. American Home's drug was turned down in the late 1980s by an FDA advisory panel. The company continued to test the drug for several more years before halting its development in 1996 and recalling it from several foreign countries where it was sold.
American Home has an improved, second-generation drug, but it has put the compound on the back burner. It won't comment on its diabetes program, other than to say the company is focusing on higher-priority projects.
Pfizer's first drug fell through because it turned out to cause a rare but dangerous skin rash in a few patients. Its failure was a big blow to Pfizer scientists, and the company came close to abandoning research in the area. At one point, Pfizer's once-large diabetes program had shrunk to a single researcher. But the company already had a second-generation drug, Alond, which doesn't cause the skin-rash problem, and it kept the diabetes program alive.
As researchers examined what had gone wrong, they made a discovery that helped explain the drugs' limited effectiveness in human studies. The first-generation drugs, it turned out, did a poor job of penetrating human kidney and nerve cells. To compensate, doctors should have been giving patients far higher doses.
Pfizer also realized its original expectations for the inhibitors had been inflated. "People had thought these drugs would help the blind to see and the lame to walk," says Pfizer's Thomas Beyer, who oversees testing of Alond. In retrospect, he says, a more realistic goal is to prevent further damage in patients with early signs of complications.
Now Pfizer and Warner-Lambert, a new entrant into the diabetes-research marathon, are testing a second generation of aldose reductase inhibitors for treating diabetic nerve damage. Most of the trials focus on patients with early-stage nerve problems, which are presumably more treatable.
So far, the new drugs, which are taken orally, appear to be working. Warner-Lambert's zenarestat, licensed from Japan's Fujisawa Pharmaceutical Co., improved nerve structure and nerves' ability to conduct electrical impulses in a test of about 200 patients. Tests of Pfizer's Alond showed similar results. Pfizer also has started a longer-term trial aimed at reducing kidney problems in diabetics.
Meanwhile, Genentech has been working on an unrelated, injected drug, called nerve-growth factor, to treat diabetic nerve damage. It helped reduce symptoms in an initial clinical test done on 250 patients. Ultimately, some scientists say, the two classes of medicines might be combined for a more powerful treatment.
Results of Genentech's final-phase test are expected in several months, while results from large-scale tests of Alond and zenarestat are about two years away.
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Diabetic Damage Existing drugs to lower blood sugar don't always prevent complications of diabetes. A new generation of experimental drugs aims to stop nerve and organ damage from occurring.
EYES:Diabetic retina disease causes 12,000 to 24,000 cases of blindness each year. HEART:Diabetics are more likely than others to die of heart disease. NERVES, digestion:Elevated blood sugar slowly damages nerves, causing pain and loss of sensation
in the limbs, and difficulty digesting food.
KIDNEYS:Diabetes is a leading cause of advanced kidney disease and transplants.Source: American Diabetes Association
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