Biotech Firms Forge On In Race To Unearth Profits From SOD

Author: RENEE TWOMBLY, p. 1, 8-9. Since 1965, entrepreneurs have struggled to find a way to capitalize on the enzyme's anti-inflammatory properties Immunologist Mark Saifer was sure, even before it had a name, that the peculiar emerald-green protein could reduce inflammation. But Saifer and the other scientists who have acted on that conviction to build up DDI Pharmaceuticals Inc. of Mountain View, Calif., couldn't say why the protein, derived from bovine testicles, worked, much less how it could be converted into a drug or what diseases it could treat. "When we started we were really alone," says Saifer, who joined the company in 1970 and is now DDI's scientific director. "We were the only crazy believers in something that we didn't even know was an enzyme." AUTHOR: Robin Twombly, p.9 When a cell metabolizes oxygen to make energy, it forms oxygen molecules with an extra electron. That property allows these molecules, called superoxides, to bond easily to other chemical groups. But problems arise when these oxygen radicals invade a cell's membrane and attack its proteins and fats. Some scientists believe that they also can attack a cell's DNA, starting a chain reaction that increases the overall number of damaging radicals. To defend against these free radicals, the body manufactures antioxidant enzymes. The first of these, discovered in 1968, was called superoxide dismutase (SOD). SOD is one of a variety of enzymes that scavenge destructive free radicals by converting them to hydrogen peroxide, which can be metabolized into water and oxygen by the enzyme catalase. But scientists now think that the body makes only enough protective enzymes and chemicals to handle an average-sized attack on its cells. Over time, researchers theorize, the number of free radicals overwhelms the body's store of scavengers. The imbalance, they say, leads to degenerative diseases such as cancer, and to the aging process. Damage also can occur when blood supply to any tissue is impaired, resulting in oxygen deprivation. It is thought that, when blood flow is restored, the burst of oxygen and associated superoxides destroys tissue. Such injury occurs, for example, when clamps are removed after an organ has been transplanted or surgically removed. Also, conditions associated with inflammation, such as arthritis, may result in cellular production of superoxide and damage to tissue. Scientists believe that such damage may be prevented by inhibiting the production of those superoxides or by injecting SOD to accelerate their breakdown. --R.T. What the initial group of DDI scientists had stumbled onto in 1965 is the mechanism that the body uses to protect itself against the damage to cells and tissues caused by breathing oxygen. While oxygen is, of course, necessary for life, the free radicals it produces can be toxic if enzymes like the one spotted by DDI are destroyed. History has shown that those free radicals also can be toxic to investors. Hooked on the promise of a simple solution to a complex scientific problem, several companies poured millions of dollars over the past decade into futile searches for the answer. That list includes established pharmaceutical firms, such as New York-based Bristol-Myers Squibb Co., as well as smaller biotech enterprises, such as Chiron Corp. of Emeryville, Calif., and Bio-Technology General Corp. of New York. Both Chiron and Bio-Technology, however, are sufficiently impressed with the field's potential to be conducting clinical trials in Europe with different versions of the enzyme. The driving force in this biological roller-coaster ride is superoxide dismutase (SOD), part of a new class of antioxidant enzymes. Saifer's company hopes to become one of the first to bring its version of SOD onto the United States market, using its anti-inflammatory properties as a treatment for arthritis. Now derived from ground-up, USDA-grade beef liver, the enzyme--called orgotein--has already been injected into the joints of up to 3 million Germans at a cost of hundreds of dollars per treatment series. A more potent version of the same drug is in the final phase of human trials in the U.S., aimed at an audience of 17 million arthritis sufferers. DDI expects to prove to the U.S. Food and Drug Administration (FDA) that its enzyme will be safer than what many osteoarthritis patients now use--aspirin, ibuprofen, and other nonsteroidal anti-inflammatory agents. These drugs, although effective in reducing swelling, also are responsible for thousands of deaths each year as a result of ulcers and associated gastrointestinal bleeding, according to FDA. Obtaining FDA approval for its enzyme will represent the fulfillment of an enduring dream for a tiny, one-product firm that has stuck to its research guns despite two decades of red ink and persistent misgivings in the scientific community. And supporters of DDI's SOD believe that it may be just the first in a wave of antioxidant drugs to wash onto the market by the end of the decade. Arthritis isn't the only chronic disease that could be contained with antioxidants, according to experts. Cell damage due to oxygen toxicity is being implicated in a long and diverse list of killers, including heart and kidney disease, as well as stroke and cancer (see story on page 9). Some scientists even believe that oxygen is largely responsible for most of the effects of aging in humans. One thing is certain: Interest in SOD is skyrocketing among scientists. The number of journal articles "is increasing exponentially," according to Kelvin J.A. Davies, newly appointed chairman of Albany (N.Y.) Medical College. Another indication is the approximately 1,000 scientists who attended a six-day conference on free radical research last November in Pasadena, Calif. Davies, a toxicologist who organized the conference, says that "the field has undergone such an amazing expansion that it is now almost impossible to keep up with new developments." Therapeutic Potential Those developments are coming from hundreds of sources, including large pharmaceutical companies, medical centers, and universities. At first, scientists used SOD to investigate how cell damage occurs. Now, many have turned their attention to possible therapeutic uses of the enzyme. For example, the Upjohn Co. of Kalamazoo, Mich., is experimenting with a distant cousin of the enzyme to treat central nervous system injuries and stroke. Eli Lilly & Co. of Indianapolis is concentrating on oxygen radical scavengers for reperfusion injuries, which occur when blood flow to tissue is suddenly restored after being interrupted. Most of these companies have already begun clinical trials as well. The market for SOD products is diverse, and potentially quite lucrative, according to Decision Resources Inc., a Burlington, Mass., market analysis firm affiliated with Arthur D. Little Inc. of New York. In a report last year to investors on the financial outlook for SOD, the firm estimated that sales of first-generation SOD drugs for organ transplantation could reach $30 million by 1995, with another $70 million in sales for cardiovascular applications. But company officials believe that the real payoff for SOD is going to occur in second- and third-generation products, once the problem of administering the right dosage is ironed out. When that happens, the report concludes, "versions of SOD could become major drugs with multiple indications." "I am amazed at the number of diseases in which free radicals are proposed as part of the mechanism," says Joe McCord, a researcher at the University of Colorado Health Sciences Center in Denver who in 1968 discovered, with Irwin Fridovich of Duke University Medical Center, the role that SOD enzymes play in protecting cells. That potential is good news for DDI. "Now people are daily recognizing the role of SOD in the pathology of almost every major disease," says Saifer. "And at the end of the day, we may be the first to have a product." In the words of DDI president Henry Lerman, SOD is "a drug in search of a disease." Saifer acknowledges that the promise of a new class of drugs involving antioxidants is tempered by the difficulty of working with the enzyme. One major problem with axtioxidants is that they are extremely tricky to handle. With a half-life measured in minutes, they degrade quickly in the bloodstream, often before they reach the intended tissue cells. The enzymes are also very costly to produce. In addition, some patients have produced immune antibody responses to the enzymes. And many scientists believe that each disease might require a different antioxidant preparation. Worst of all, SOD's effectiveness has been hard to measure. Proving efficacy is essential in the clinical trials that SOD and other drugs must undergo in the U.S. In fact, DDI's European product, which the company licenses to a distributor, has so far been tested only to make sure it is safe, not to see how well it works. Despite these hurdles, DDI has begun to negotiate the long, difficult, and expensive route of winning approval from the FDA for a new product. Its anti-inflammatory drug is being tested in a double-blind, placebo control trial in clinics across the country. And Lerman, a former office products businessman from New York, acknowledges that his company doesn't yet have all the answers. "In this business, a lot of people say things that never come to fruition," notes Lerman. "We don't know it all, and we are very cautious. A lot of companies have deep pockets. Ours are very short, but that gives us an advantage in that we can't afford to waste money and time." In fact, it was that sense of urgency that led Lerman to take the helm at DDI. He arrived in the midst of a two-year proxy fight among the company's 9,000 stockholders to seize control of the firm, a battle that was eventually settled in court. The impetus for the uprising was the FDA's rejection in 1978 of the company's very first drug application. "It was a disaster," says Saifer. FDA officials wanted some changes, including a second clinical trial, he recalls, but the company refused to accept that verdict and spent more than a year trying to rewrite its report before it finally realized that it had to start over. Lerman wasted no time cracking the whip over the company's handful of employees. He lived in a local motel for two years, spending most of his waking hours at the office. Even now, one of his favorite admonitions is, "If you don't come in on Sunday, don't bother to come in on Monday." But Lerman has no regrets about adopting such a hard-nosed approach. "Ninety-nine out of 100 companies would have been down the tubes by now," says Lerman. "We survived through people's commitment, sweat, and more sweat." Despite 21 years of steady losses, DDI was able to sustain itself on $15 million derived from stock offered over the period 1968-78, according to Saifer. That amount has been supplemented by $5 million in the past three years from the sale of its SOD beef enzyme to Sterling Drug Inc. of New York and to Enzon Inc., a small drug development company in South Plainfield, N.J. And while it may not be a star financial performer, DDI has fared much better than several other companies in the rush to embrace SOD research during its previous heyday in the early 1980s. One such company was Chiron Corp., which in 1986 produced a recombinant SOD made in yeast. Working with kidney transplant patients, the company conducted clinical trials aimed at preventing oxygen damage once the surgical clamps had been removed from the transplanted organ. The results were disappointing. "We found no statistical differences in its use [compared with patients who did not receive the enzyme]," says Larry Kurtz, head of Chiron's office of corporate communications. Working with the German company Gruenenthal GmbH, Chiron spent $7 million on the kidney transplant project, which it has since abandoned. Bristol-Myers Squibb also invested millions in the attempt by Bio-Technology General to produce an SOD drug to treat reperfusion following kidney transplants and myocardial ischemia. Early positive results with animal models "pushed the partners into clinical trials without fully assessing the pharmacological aspects of the enzyme," says Ammon Gonenne, Bio-Technology's vice president of corporate development. The giant drug firm pulled out of the project several years ago after obtaining negative results from two clinical trials. While Bristol-Myers Squibb took an all-or-nothing approach, Bio-Technology General isn't willing to give up. Believing in the potential of the enzyme, the company is now conducting clinical trials in the United Kingdom and the Netherlands in which SOD products are used to treat patients with rheumatoid arthritis and ulcerative colitis. SOD is also being tested as a drug to prevent bronchopulmonary dysplasia, a chronic lung disorder in premature babies. Gonenne says the clinical trials are meant to find the proper dosage, dosing frequency, and timing. "There is very little doubt about the role of free oxygen radicals in a number of pathologies," he says. "Now we just have to be sophisticated and clever in using SOD." SOD research is proliferating internationally, according to Bruce Freeman, a biochemist at the University of Alabama. Freeman is working on delivering purified SOD to the lungs of premature infants through artificial membranes. "SOD's relevance to the lungs is enormous," says Freeman. He says that "aggressive research" is under way in the U.S., Europe, and Japan, adding that several major Japanese pharmaceutical companies have extensive research efforts that remain cloaked in secrecy. Officials at Sterling Drug also are enthusiastic about the enzyme's potential. Sterling modifies its SOD with polyethelene glycol to increase its half-life to more than five days. The company is now conducting human trials to examine the enzyme's ability to help patients with reperfusion or closed head injuries, as well as those who have undergone cardiac surgery. "This is an extremely interesting project, both clinically and technically," says Carolyn Kruse, assistant director of project planning for Sterling. "We have many, many small indicators that this stuff works," says Kruse. At the same time, Kruse says that her company doesn't expect to find a bonanza around the corner. "Antioxidants are unchartered territory," she says, "and we are just trying to figure out how to use them." DDI scientists are now researching second- and third-generation SOD products, including a recombinant human enzyme. These improved drugs would be longer-acting, and would avoid the potential for immunological reactions. Saifer believes that their findings will vindicate the company's faith in the value of antioxidants. "Before, no one was convinced that SOD would work," says Saifer. "Now the feeling is about 50 percent positive, and growing." He adds, with a laugh, "I guess that we've become mainstream." Renee Twombly is a freelance science writer based in Durham, N.C.

Biotech Firms Forge On In Race To Unearth Profits From SOD

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