Does antisense make sense?
No-one doubts that the concept of antisense therapy is a good one. But what about the reality? Professor Kewal Jain, author of the recent Reuter's report on antisense therapies, assesses the potential impact of this novel approach to disease treatment.
Twenty years ago it all looked like science fiction: specially designed molecules to selectively knock out disease-causing genes. Over the past decade, through the persistent efforts of scientists and the financial assistance of investors, antisense oligonucleotides have proved themselves to be useful research tools. And now they are beginning to enter the therapeutic arena. Antisense will soon make sense.
Antisense oligonucleotides work by inhibiting the expression of disease-related genes. Yet their precise mechanism of action has only recently been elucidated. In the latest edition of Methods in Enzymology, a team of researchers from AVI BioPharma demonstrate that antisense compounds stop or slow the beginning phases of the gene-derived protein synthesis by inhibiting the gene's ability to scan the starting point. With this definition, researchers will quickly progress beyond the 'hit or miss' approach that has tended to dominate the field to date.
Indeed, antisense therapies represent a new paradigm in drug development, not simply a new mechanism of action. Experts believe that once the mechanism of action and toxicology profile have been satisfactorily understood and established, antisense products to many genes could be rapidly developed and approved. For instance, the first antisense drug, fomivirsen (marketed as Vitravene by Novartis and Isis) was approved by the FDA in 1998 for the treatment of cytomegalovirus infection. It took only nine years to develop - a much shorter time than that taken for the development of most traditional pharmaceuticals. The pressures for cutting development times to extend patent protection and reduce production costs are evident.
"The pluses of antisense technology are that it is a rapid and efficient tool to go directly from the gene to a pharmaceutical preparation that can inhibit the production of a gene product," says Dr Stanley Crooke, CEO and founder of Isis. This is not only a rational approach to drug development but also one which is likely to prove more economical than conventional approaches.
In the coming few years, approval is expected for a few more products, more than 20 of which are in clinical trials. They form a spectrum of technologies including ribozymes and antisense gene therapy, plus applications in molecular diagnostics and genomics-based drug discovery. There are 34 companies actively involved in antisense therapy development. Many of these have projects that are available for licensing and some are actively seeking corporate collaborations.
The track record of antisense has been good so far. There are fewer failures of companies and clinical trials compared with biotechnology companies in general. However, perhaps the most noteworthy disappointment recently was the failure in clinical trials of Isis Pharmaceuticals' ICAM-1 inhibitor, ISIS 2302, in Crohn's disease.
Despite such setbacks, antisense therapy against cancer and ribozyme therapy against HIV-1 infection look to be the most promising therapeutic areas over the next five years. "I think that cancer is really shifting to the non-toxics," said Andrews Grinstead, III, CEO of Hybridon, in a recent Wall Street Transcript interview. "I think we saw the first wave of that in the hormonal treatments. Now we've seen it with monoclonal antibodies. I think the next wave is going to be antisense compounds."
There are several innovative anticancer treatments in development, including gene therapy, and results of clinical trials in cancers of various organs are encouraging. Anticancer therapy is likely to enter the market by the year 2005 when it will be worth $600m. This value will increase to $1.8bn by the year 2010.
The next most promising area is HIV-1. Antisense therapy, if shown to be successful, can expect to capture $500m of the total anticipated world market for HIV-1/AIDS which is expected to be worth $2bn by the year 2005. Toxicity, as observed with older antisense oligonucleotides, will not be a problem with newer antisense oligonucleotides and ribozyme gene therapy.
In the cardiovascular system, prevention of restenosis after angioplasty is an important indication with no satisfactory treatment at present. There are several competing technologies including gene therapy using viral vectors. Antisense therapy is likely to be marketed by the year 2005 when the market will be worth $250m (a quarter of the total market). However, this market is unlikely to expand to more than $300m by the year 2010 because the need for coronary angioplasty may decrease due to preventive cardiology and complication of restenosis may be further decreased by refinement of procedures for angioplasty.
Other applications for antisense therapies will include viral infections and inflammatory diseases. Although the single Vitravene product is worth only $150m, combined with antisense molecular diagnostics and antisense drug discovery the market is currently worth $600m in total. Furthermore, the market value for all antisense technologies will jump from around $750m in the year 2000 to about $3.6bn in the year 2005 with a few products in the market and further development of other applications of antisense technologies. This will likely double in the following five years as more products become available, as existing products are coupled with better delivery and targeting technologies, and with increasing use of antisense approaches in genomics-based drug discovery and molecular diagnostics.
But if antisense technology represents a new therapeutic paradigm, how much will it penetrate current markets, especially with the growth of genomics-based medicine? Dr Richard Smith, analyst at Datamonitor, explains that the Human Genome Project and other genomics research may help antisense research to pick up again. "But it all depends on what arises from genomics research," he warns. "Effective antisense therapies will depend on identifying specific disease-associated RNAs."
The difficulty in predicting the antisense market lies partly in its own evolution. Nevertheless, in the longer term, some of the innovative antisense technologies such as locked nucleic acid (LNA) and peptide nucleic acid (PNA) have good prospects. LNA is a novel nucleic acid analog that displays a suite of properties that makes it highly attractive as an antisense drug. LNA combines the highest affinity ever reported for a DNA analogue for complementary DNA and RNA with a superb ability to discriminate between correct and incorrect target sequences. It has molecular diagnostic, as well as therapeutic, applications. Only one company, Exiqon in Denmark is working on this technology. Its subsidiary, Cureon, will offer target-specific, exclusive licenses to interested parties.
PNAs are DNA mimics and can be targeted to mRNA to block protein synthesis in an antisense strategy. PNA may be the breakthrough in the development of future antibacterial drugs for the treatment of various bacterial infections. Through various mechanisms, bacteria can acquire resistance against various antibiotics as rapidly as new antibiotics are developed by the pharmaceutical industry. In contrast, PNA is a complete new chemical entity not found in nature and no bacteria has developed inherent abilities to combat PNA. Furthermore, no known enzymes are able to degrade it. It is therefore highly unlikely that bacteria will readily be able to produce enzymes capable of cleaving PNA or develop resistance against it.
Only one company, Pantheco, also in Denmark, is developing applications for PNA. The technology was originally licensed by the University of Copenhagen to Isis Pharmaceuticals. Pantheco has now obtained a world-wide exclusive license from Isis for the use of PNA in the anti-infective area but Isis retains the rights for all other therapeutic areas.
Bacterial infections constitute a huge market, currently worth about $30bn, but no PNA product is expected to be in market in the next few years. It is possible that with accelerated development, a single product could reach the market in the year 2005 and might be worth $600m in a total antibiotic market of $40bn. With an additional product the market could increase to $900m by the year 2010.
But it is clear that investors are still tentative about antisense technologies. The approach still has to be convincingly proven at a general level. "I guess the real bottleneck now is going to be when do people get really enthusiastic about antisense?" says Mr Grinstead. "We think that's starting to happen."
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Professor K.K. Jain is a neurologist and neurosurgeon by training with extensive experience in the biotechnology and biopharmaceutical industries. He is the author of about 212 publications on important areas in biotechnology, neurology, biopharmaceuticals, and gene therapy. He is the author of a 1998 Textbook of Gene Therapy with a chapter on antisense therapy. Currently, he is a consultant at his own company, Jain PharmaBiotech, Basel, Switzerland.
The opinions, figures and forecasts in this article are solely those of the author, and not of QX Health.
2000-03-31 00:00:00
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