Companies Create New Antisense Drugs As Clinical Trials Progress

Sidebar: Further Information - Companies Creating Antisense Drugs BROADENED FOCUS: Shaji George says an equal number of biologists and chemists make up Innovir Laboratories' research team. Embracing the idea that tomorrow's drugs will not merely treat symptoms, but also attack disease-causing genes, scores of biotechnology companies are developing compounds to intervene in the cell's genetic machinery. One focus of this activity is antisense therapeutics: the use of synthetic nucleic acids designed to bind messenger RNA and sometimes DNA-the "sense" molecules of protein production-to prevent the expression of specific genes involved in AIDS, cancer, and inflammatory disease, among other disorders. At first, researchers thought that antisense drugs would prove so specific there would be few side effects. But toxicity-related problems did arise in initial animal studies of antisense drugs in the early 1990s. Since then, companies are using these compounds cautiously. They are continuing to study new ways to make more effective, less toxic antisense therapeutics by changing their chemistries and formulations. About a dozen biotech companies "will live or die" based on the success of antisense technology, according to James Hawkins, an industry consultant and a founding editor of the journal Antisense and Nucleic Acid Drug Development. He and others think that that the antisense sector may be poised for expansion. "The market is large, and most manufacturing issues [such as how to produce large quantities of synthetic nucleic acids] have been solved," explains Peter Drake, executive vice president of Vector Securities International of Deerfield, Ill. So if the clinical benefit of compounds are clearly demonstrated, Drake continues, "you're going to see antisense drugs on the market." That's a big "if," however, since the Food and Drug Administration (FDA) has yet to approve the sale of an antisense compound. Several candidates are undergoing separate clinical trials for the treatment of cancer as well as viral and inflammatory diseases. It's too early in those trials to tell whether the whole class of antisense drugs will prove to be clinically effective. In the future, new antisense drug formulations -- as well as the next generation of chemically distinct antisense structures --may yield fundamentally different clinical results from those achieved with compounds now under review. Aronex Pharmaceuticals Inc.: http://www.aronex.com Genta Inc.: http://www.biospace.com/g/synd/__1bea46f6/exhib_script/exhibitors/GentaInc.html Gilead Sciences Inc.: http://www.biospace.com/g/synd/__fe1bc27a/exhib_script/exhibitors/GileadSciences.html Hybridon Inc.: http://www.hybridon.com Innovir Laboratories Inc.: http://www.biospace.com/g/synd/__abaabeee/exhib_script/exhibitors/InnovirLaboratoriesInc.html Isis Pharmaceuticals Inc: http://www.sddt.com/files/library/1corporateprofiles/corpstories/ISIS.html It also remains to be seen how antisense products will compare with other drugs, observers say. "The future of antisense therapeutics will be played out in terms of efficacy vs. cost," remarks Robert Rando, director of research for Aronex Pharmaceuticals Inc. of The Woodlands, Texas. On the other hand, he notes, antisense studies have led to the discovery of a variety of potentially valuable technologies and applications, such as procedures for efficient, large-scale synthesis of nucleic acids. These by-products of antisense research may take on productive lives of their own. Antisense technology is also gaining importance as a tool for the analysis of gene function and expression. "Antisense could find a home in gene therapy, as well as in genomics," or the study of multigenic interactions, Hawkins says. And because antisense drugs are intended to affect gene expression early in the development of disease, he continues, the molecules are also likely diagnostics. Hawkins anticipates that antisense therapeutics will eventually prove effective in treating a broad range of diseases. "As clinical trials progress and delivery issues get worked out, there's going to be a real scramble to find new targets [for antisense drugs]," he predicts. This rush will likely translate to jobs for molecular and cellular biologists. Beyond the core antisense companies he identifies, Hawkins estimates that an additional six or so biotech firms have invested heavily, though not exclusively, in developing antisense therapeutics. Pharmaceutical companies also participate in antisense research, though largely through partnerships with biotech companies and academic collaborations. POISED FOR EXPANSION: With manufacturing issues resolved, more antisense drugs will be on the market, predicts analyst Peter Drake. Some antisense firms have also raised capital through public stock offerings. Four companies -- San Diego-based Genta Inc.; Gilead Sciences Inc. in Foster City, Calif.; Hybridon Inc. of Worcester, Mass.; and Isis Pharmaceuticals Inc., headquartered in Carlsbad, Calif. --have accumulated a total of nearly $500 million from sales of stock, Drake reports. "That number may surprise many people," he notes, "because it represents a substantial financial commitment to an area that's yet to have a proven product." There are three basic types of antisense therapeutics, according to Hawkins. Classical antisense compounds are short, gene-specific sequences of nucleic acids, known as oligonucleotides, typically 15 to 25 bases in length. These molecules bind to complementary sequences on specific messenger RNAs and prevent them from being properly translated into protein. In addition, some antisense complexes are vulnerable to digestion by the enzyme RNase H, which may free an intact antisense molecule while destroying the target mRNA. Most antisense companies are developing at least some classical antisense compounds. Instead of relying on RNase H, the second type of antisense therapeutic takes advantage of ribozymes: enzymes made of RNA, not protein, that can be used to destroy mRNAs bound to antisense oligonucleotides. New York based Innovir Laboratories Inc. focuses exclusively on target-binding oligonucleotides called External Guide Sequences (EGSs) and delivery systems for targeting these oligonucleotides to specific organs in the body. EGSs recruit a cellular ribozyme, RNase P, that destroys the bound mRNA and releases the oligonucleotide for further search-and-destroy action. Other companies, including Hybridon, are pursuing an antisense oligonucleotide with a built-in ribozyme sequence. Some researchers in the field do not consider Hawkins's third antisense model, triple-helix DNA, to be antisense at all. Triple-helix oligonucleotides are designed to bind to target sequences in double-stranded DNA in order to block their transcription. Nevertheless, the chemical similarity between these and other antisense compounds means that they face similar challenges on the way to becoming viable drugs, including problems with stability, formulation and delivery, toxicity, and cost-effectiveness. Developers of triple-helix oligonucleotide therapeutics include Gilead Sciences and Aronex Pharmaceuticals. HIGH STAKES: The success of antisense technology is crucial for several biotech companies, notes industry observer James Hawkins. Promising though it has seemed to scientists and investors alike, antisense research has seen its share of challenges, Hawkins recalls. "First," he says, "the question was, does the theory work?" The first experimental antisense drugs were natural nucleic acids: short stretches of synthetic, single-stranded DNA designed to complement a stretch of messenger RNA in the target gene. These initial oligonucleotides were quickly digested by nucleases in target cells, so chemists modified the molecules to improve their stability. The replacement of a single non-bridging oxygen atom in the nucleic acid backbone with an atom of sulfur created more resilient phosphorothioate oligonucleotides. A variety of phosphorothioate antisense drug candidates emerged from these efforts around 1990. Several firms submitted investigational new drug (IND) applications to FDA for clinical trials of phosphorothioate compounds. Then, toxicity studies revealed decreased blood cell counts in rabbits and rats, and noted deadly hypotension in monkeys that received rapid intravenous infusions of oligonucleotide drugs. The problem seemed to lie with phosphorothioate chemistry itself, rather than the specific sequence of oligonucleotides. These findings indicated that antisense compounds, like many other experimental drugs, could cause unintended reactions (L.E. Black et al., Antisense Research and Development, 4:299-301, 1994). Antisense companies turned their attention to designing safer oligonucleotides and dosing regimens. Firms hired additional staff, including toxicologists and pharmacologists, to evaluate potential products. Pharmacological chemists were also enlisted to improve delivery technology. PROGRESS TO DATE: Isis Pharmaceuticals VP Frank Bennett says advances justify "continued exploration and optimization." Thanks to these efforts, about 10 different phosphorothioate oligonucleotides are now undergoing human trials. Moreover, according to a recent review by Stanley Crooke and C. Frank Bennett of Isis Pharmaceuticals (Annual Review of Toxicology, 36:107-29, 1996), careful experiments have also demonstrated that certain antisense oligonucleotides act as predicted to selectively inhibit gene expression. This mechanism had not actually been proved to act in early drug candidates. In fact, the authors report, antisense researchers have discovered several potentially useful oligonucleotides that work by binding proteins, rather than nucleic acids. "The long-term therapeutic potential of antisense oligonucleotides is not defined yet, and it is still possible that with a more sophisticated understanding of this technology, researchers will conclude that . . . [it] has an as-yet-unidentified fatal flaw," Crooke and Bennett write. "Nevertheless," they continue, "the progress to date provides justification for continued exploration and optimization." It's typical for emerging medical technologies to progress through several "waves" of challenges, according to Hawkins. "In the big picture, the antisense field is evolving as it should," he concludes. "The mechanism of action of a few potential drugs is understood, as well as some side effects. Now the emphasis is on getting the first prototype drugs to work." In the early years of antisense drug development, much of the research focused on chemistry. There was great demand for nucleic acid chemists to synthesize, modify, and optimize oligonucleotides for use as therapeutics. But as the field progresses to solving problems of drug delivery and toxicity, as well as identifying potential new targets, biologists and pharmaceutical scientists are being recruited to the sector in increasing numbers. At two of the oldest and most-established antisense companies, Hybridon and Isis --both of which have drug candidates in clinical trials -- biologists represent a substantial portion of the research staff, as well as of academic collaborators. Of Hybridon's total staff of 185 people, 33 are biologists, according to the company's director of strategic planning and technology assessment, Nevin M. Summers. These scientists work closely with collaborators in the pharmaceutical industry. Hybridon is also building ties with both public and private genome-sequencing efforts. "We're positioning ourselves to be the conduit from genomic discoveries to therapeutics," Summers explains. TIES THAT BIND: Hybridon’s Nevin Summers points out that his company is working with private and public genome sequencing efforts. "We have a strong need for biologists, but not necessarily for specialists," says Isis's Frank Bennett, who is vice president of biology at the company. "We look for people with broad training in several disciplines, who can apply knowledge to a specific problem and then move on to the next one." Because biologists at Isis often work with chemists, pharmaceutical scientists, and engineers, he adds, it's especially important that researchers "can appreciate what other disciplines can bring to solving problems." Ultimately, Bennett says, "publication is a major currency by which we judge job candidates, and by which we evaluate scientists within the company." While publishing papers isn't a high priority for most industrial scientists, presenting information in the public domain is crucial to Isis's efforts "to invent and validate a new technology," he explains. According to Richard Wagner, director of cell biology at Gilead Sciences, the firm devotes about a third of its research to classical antisense and triple helix technology. Gilead focuses its biological efforts on a few main areas. Cell cycle studies intended to identify and refine anti-cancer therapeutics are conducted largely by academic collaborators. Meanwhile, many of Gilead's in-house biologists attempt to surmount what Wagner calls "the single most important hurdle" for antisense at this point: how to get oligonucleotides into cells, in vivo. Eventually, Wagner says, "we may have to consider collaborating with people working on gene therapy, since we face a lot of the same problems." And because he expects that Gilead, like Hybridon, will form liaisons with genome sequencing companies, he's hired Ph.D.-level scientists with a broad knowledge of genetics. "Over time . . . antisense will become an important method for evaluating gene function," Wagner predicts. Even among the several smaller, more specialized companies researching oligonucleotide drugs, biologists play a prominent role in research. That's especially true at Innovir Laboratories, according to vice president for research Shaji George. Unlike most antisense firms, he explains, "we started out on the biological side but now have an equal number of biologists and chemists [on the research staff]." At the moment, he says, his company's strongest need is for nucleic acid chemists, biochemists, and cell biologists. George adds that Innovir has also forged academic collaborations with biologists and chemists. With a research staff of five chemists and four biologists, Columbia, Md.-based Dyad Pharmaceutical Corp. focuses its antisense research on developing topically applied treatments for dermatological diseases. But the same novel compounds the company has developed for RNA-specific hybridization may also prove to be useful diagnostics, notes Glenn Hoke, Dyad's vice president for research. These antisense molecules could be used as hybridization probes to measure disease-gene expression, he explains. Regarding opportunities for future expansion in the antisense sector, Hoke states, "At the moment, the market seems to be saying, 'wait and see.' Everybody is waiting for Hybridon, Isis, or another company to have success in the clinic. If they do, the field should take off-and I think there's a good potential for that happening." As an industry observer, Hawkins has a more cautious assessment: "The antisense field is at a crossroads." The first clinical assessment of antisense drugs "will lay the foundation for the field to move forward." Beyond that, he concludes, "future success in the field is a matter of separating phenomenology from good, quantitative science-and those in the forefront of antisense research are doing that." Alison Mack is a freelance science and medical writer based in Wilmington, Del.

Companies Create New Antisense Drugs As Clinical Trials Progress

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