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ANP 3.8¢

Ready to run....interesting article

  1. howler

    280 posts.
    From a low of 10.5c a few weeks back, ANP has a massive market depth with buyers not wanting to sell in a hurry.

    Here is an interesting article from a couple of months back from Dr. Stanley Crooke. This stock could explode at any time, so don't say I didn't warn you. It is a bit of a read, but well worth it.

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    The Drug Designer Stanley Crooke is pursuing a completely new way of making medicine. But he has to convince the world it works

    Wall Street Journal - May 13, 2002
    David P. Hamilton


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    For 13 years, Stanley Crooke has struggled to convince skeptics that he and his company have mastered an entirely new way to make drugs.
    It's finally just about show time.

    Within the next year or so, Dr. Crooke's company, Isis Pharmaceuticals Inc. (www.isip.com1), is likely to have results from two late-stage human trials of drugs created using the new drug-development technology. Known as antisense, that technology theoretically could lead to a new class of drugs that can be quickly and easily targeted against cancer, inflammatory diseases and other conditions, with few side effects and potentially greater power than existing therapies.

    Antisense technology -- the name is a reference to one of the complementary double strands of DNA, known as sense and antisense -- aims to treat disease by blocking the activity of specific genes associated with a given condition. Many drugs, by contrast, are discovered essentially by chance, by testing various chemical configurations until one proves effective. As a result, the more clearly focused approach of antisense could speed the development process.

    While the concept is simple, getting antisense technology to work has been anything but easy. Years of inconsistent academic experiments have left many university researchers disappointed. An early major competitor of Isis, Gilead Sciences Inc., declared in the mid-1990s that the technology didn't work, and a few years later sold all of its antisense technology to Isis.

    Worst of all, several of Isis' drugs have failed during clinical trials, although in 1998 the company won regulatory approval of an antisense treatment for eye infections common in late-stage AIDS patients. Some critics remain unconvinced that antisense drugs work by blocking gene action, and think they might be acting more like conventional drugs. If true, that would deflate much of antisense's promise.

    None of that has fazed Dr. Crooke, a 57-year-old molecular biologist who in 1989 co-founded Isis, based in Carlsbad, Calif., after several years as head of research at SmithKline Beckman Corp., since absorbed by the company now known as GlaxoSmithKline PLC. Dr. Crooke insists that Isis has learned from its earlier setbacks, and that antisense technology is ready for broader use.

    "Like everything with antisense, the answer is more complicated than anyone would like," he says. "It's going to get there. I can say that today with as much confidence as anything I can say about drug discovery and development."

    Dr. Crooke argues that antisense technology is the answer to a number of problems facing the pharmaceutical industry -- in particular, its declining productivity. Despite billions of dollars lavished on pharmaceutical research, the pipelines of new products at many major drug companies are drying up.

    That problem, Dr. Crooke believes, stems in part from the industry's traditional reliance on screening vast libraries of small-molecule drugs -- aggregates of small chemical molecules -- against cell cultures to find likely candidates for effective treatments. "It's the same technology they were using in 1900," he says.

    The only other proven way to make drugs is with genetically engineered proteins such as antibodies, a more recent technology that is a specialty of biotechnology firms such as Genentech Inc. But such antibodies are tricky to make and must be injected rather than delivered in pill form, limiting their use outside of life-threatening diseases.

    Most microscopic activity in the body is regulated by an array of proteins -- long chains of organic molecules that do everything from giving structure to bones and cell walls to transporting oxygen to clearing the blood of harmful toxins and waste products. When small-molecule or protein-based drugs relieve symptoms or alter the course of a disease, it is largely because they have managed to gum up a tiny piece of protein machinery somewhere in the body.

    Small-molecule drugs rely on their chemical structure to wedge themselves into nooks and crannies of proteins, preventing them from latching onto other proteins and interrupting the chains of biochemical events that experts dub pathways. Pain relievers like aspirin or Merck & Co.'s Vioxx, for instance, work by blocking a protein enzyme called Cox-2, which normally promotes the production of hormone proteins called prostaglandins, which amplify nerve signals related to pain and cause tissue inflammation.

    Antibodies work much the same way but are far more specific, since they can be easily engineered to bind to specific proteins.

    Antisense drugs, by contrast, are stretches of DNA designed to silence the genes producing particular proteins. Normally, genes in cellular DNA transfer protein-building instructions from one DNA strand -- the "sense" strand -- to a molecule known as messenger RNA, which carries those codes to other molecular machines that assemble the protein.

    However, using a synthetic molecule that duplicates a snippet from the opposite DNA strand -- the "antisense" strand -- can disrupt that process.

    Carefully designed antisense molecules will bind to the messenger RNA in a way that attracts natural enzymes in the cell designed to cut up and recycle RNA molecules, preventing protein production. Since genetic defects that produce harmful mutant proteins are the source of conditions such as cancer, antisense technology seemed an ideal form of treatment.

    Dr. Crooke and his colleagues set up Isis in 1989 in temporary quarters at a warehouse, where the scientists used trash bags to seal off a portion of the space for a tissue-culture facility. Research teams set up four ventilating hoods in different parts of the space; if they ran them all at the same time, "we'd suck all the air out of the building," Dr. Crooke says.

    The Isis researchers set out to expand on earlier academic work in antisense, figuring they needed to thoroughly understand the chemistry of RNA, different ways in which antisense molecules could be designed and the way that such snippets of free-floating DNA would interact in the body.

    Even with the science at a relatively early stage, antisense had created such a buzz that Isis was able to sign three major research partnerships with pharmaceutical companies the next year, and went public the year after that.

    At about the same time, however, many academic researchers were starting to get frustrated with antisense. In some cases, scientists couldn't reliably duplicate seemingly successful antisense tests in the lab. In other experiments, antisense molecules would produce measurable changes in test cultures -- but so would other synthetic DNA molecules that lacked the specific coding to block the targeted protein production, suggesting that the antisense molecules weren't blocking the genes they were supposed to block.

    Something was clearly wrong. As disillusionment spread in the academic community, Isis scientists soldiered on, convinced that many university researchers weren't rigorous enough in their experiments. For instance, Isis researchers early on figured out that picking the right stretch of antisense DNA to test wasn't a straightforward process. Messenger RNA is a large molecule twisted around in a complex shape; think of it as a long strip of single-sided tape, twisted and balled up so that only portions of the sticky side are exposed. Antisense molecules, by contrast, are tiny and stick to only a small portion of the RNA. "If the RNA was the size of this room, you'd make an [antisense molecule] only about this big," Dr. Crooke says, holding up a hand to indicate the distance between his outstretched thumb and fingers.

    Because there wasn't any way to know in advance exactly which "sticky" parts of the RNA molecule would be available for an antisense molecule to stick to, Isis decided to test no fewer than 80 separate antisense probes against each RNA strand, and to select only those with the best binding behavior for further study.

    Synthesizing DNA molecules wasn't easy in those days, and many other researchers would often only test a single antisense sequence. "I told people, you're going to make a fool out of yourself" with such limited experiments, Dr. Crooke recalls. "That endeared me to them. But I was starting to get frustrated with how this field was going."

    The company occasionally had its own research setbacks. In one project, scientists sought to develop antisense drugs that would prevent HIV, the AIDS virus, from replicating. While one candidate seemed to show promise, further study showed that the antisense DNA wasn't blocking the gene it was aimed at. Instead, researchers found that several antisense molecules could lock together into a box-like shape that would bind to an HIV protein, preventing it from entering cells -- action more reminiscent of traditional drugs than antisense. Isis eventually dropped the project.

    What scientific progress the company did make didn't initially pay off in drug development. Isis' first stab at a product, an antisense molecule designed to treat genital herpes, bombed in animal tests. A second drug aimed at the papilloma virus that causes genital warts failed in midstage human trials.

    Regulatory approval in 1998 of Vitravene, an antisense treatment for cytomegalovirus infections of the eye, boosted spirits at the company. (Sales, however, have been lackluster, thanks to other AIDS treatments that reduced the incidence of CMV infection.) But it was followed just a year later by another failure, when a late-stage human test in patients with Crohn's disease, an inflammatory condition of the colon, showed virtually no effect. Isis shares plunged, and Dr. Crooke laid off 30% of the company's employees. "Those were dark days for all of us," he says.

    While the company had been quick to abandon other unsuccessful products, Dr. Crooke and his scientists remained convinced that the Crohn's drug should work, as earlier tests had suggested it would. They plunged into analysis of the test data and concluded that they had set too low a dosage. They revamped the study and launched it again; results are expected by early next year.

    Isis got a vote of confidence last year when Eli Lilly & Co. agreed to invest more than $200 million in Isis in exchange for rights to a promising lung-cancer drug now in late-stage trials. Isis shares hit a recent high last year on news of the Lilly deal and remain at historically high levels, as investors await results from the lung-cancer and Crohn's tests.

    Some academics, however, aren't convinced that even positive results would demonstrate that antisense works as promised. As Isis' own experience with the anti-HIV project showed, the antisense DNA molecules can stick to other proteins and interrupt important pathways much the way conventional drugs do. So even successful trials of the Isis drugs may not definitely prove whether they worked because they silenced the right genes or because they simply produced unanticipated, but beneficial, side effects.

    "I think we're still really looking for a proof of principle," says Cy Stein, a pharmacologist and antisense researcher at Columbia University. Dr. Stein, who serves as a scientific adviser to Isis competitor Genta Inc., adds that Isis has done "very good, first class" research in antisense. Nevertheless, he argues that no one has yet proved that antisense drugs work primarily by silencing gene activity.

    Dr. Crooke, who has sparred with Dr. Stein many times over the years, says such opinions reflect an "unsophisticated" view of drug development. He notes that figuring out exactly how any drug works is enormously complex, and argues that even if antisense drugs have other effects, there is plenty of evidence that their gene-silencing action works as expected.

    "I've never said that we've demonstrated that any particular drug mechanism is antisense and only antisense," he says. "What I have said is that we have enough evidence and experience to be certain that antisense mechanisms contribute substantially to the mechanism of these drugs, and that antisense works."

    -- Mr. Hamilton is a staff reporter in The Wall Street Journal's San Francisco bureau.

    Write to David P. Hamilton at [email protected]

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