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Oct 4, 2012

Accidental Blockbusters

Viagra made it big through serendipity, but it’s not the only drug that did.

Accidental Blockbusters

Researchers estimate that 347 drugs—that’s nearly one-quarter of all drugs on the market—have been aided during their discovery by a serendipitous event. [© Sergey Khamidulin - Fotolia.com]

  • When they synthesized compound UK-92,480 in 1989 at Pfizer’s research facility in Sandwich, Kent, Peter Dunn and Albert Wood envisioned a new drug that could fight angina as well as hypertension. Phase I trials, however, told a different story: The compound did little to fight chest pains, let alone high blood pressure—but did wonders for men seeking to maintain their erections.

    The rest is history: Pfizer repositioned its compound, sildenafil (Viagra™), as an erectile dysfunction drug, and brought it to market in 1998, when it became a blockbuster thanks to its higher-than-usual profile for a new drug—$102 million in ads (some featuring ex-Senator Bob Dole) accounting for 14% of the pharma giant’s total marketing budget that year—and millions of dollars more in free publicity as the punchline to late-night comedians’ jokes. In its first week after launch, 4.3 million prescriptions were written for Viagra, which last year generated nearly $2 billion in worldwide sales for Pfizer. Sales were up 3% from 2010—no small rise in a year where Pfizer’s total revenues from biopharmaceutical products dipped 1%.

    The story of Viagra is the sort of serendipity most drug developers can only dream of, but it has happened before and since. Dramamine is now sold as an over-the-counter travel sickness treatment, after entering the market as an antihistamine under its compound name dimenhydrinate.

  • Illuminating Research

    A research paper published earlier this year in the World Journal of Clinical Oncology sheds some light on the phenomenon. Using a 1999 study and three later-published books, a team of New Zealand researchers earlier this year found that 5.8% of all drugs on the market at publication—84 of 1,437 drugs—resulted from serendipity. Of that 84, indications for 53 were discovered in a clinical setting while indications for the other 31 were discovered in the laboratory.

    However, when the researchers expanded their definition to include additional drugs derived from the 84 (147 derivatives from the clinically discovered drugs, and 116 from the lab-discovered drugs) they concluded that 347 drugs had been aided during their discovery by a serendipitous event—nearly one-quarter (24.1%) of all drugs on the market.

    Categories of drugs seeing the most frequent instances of serendipitous development include central nervous system, accounting for 22 of the 84 serendipitous drugs (26.2%); cardiovascular (15 or 17.9%); and anticancer (13 or 15.5%). CNS drugs also had the highest percentage in clinical settings (17 of the 53 clinically discovered drugs, 32.1%): “This reflects the difficulty in developing drugs that need to pass the blood-brain barrier, and the dearth of biochemical assays modeling the diseases of the mind and pain,” the researchers reported.

    “This serves to highlight the unpredictability in drug research and the necessity to allow for and encourage freedom in research directions and promote the intellectual freedom of the scientists involved,” University of Auckland researchers Emily Hargrave-Thomas, Bo Yu, and Jóhannes Reynisson concluded.

    [The full study, “Serendipity in Anticancer Drug Discovery,” can be read here]

    The New Zealand researchers should be credited with attempting to quantify serendipity’s influence in drug discovery, and mostly succeeding. An anecdotal 2006 study published in Dialogues in Clinical Neuroscience by Thomas A. Ban, M.D., of Vanderbilt University noted a serendipitous drug omitted by the New Zealand study, the schizophrenia drug chlorpromazine.

    A 2009 essay by Sean B. Seymore, assistant professor of law at Washington & Lee University School of Law, observed a structural bias against accidental discoveries by the recently superseded U.S. patent law, since it required two separate acts—initial discovery, then reduction to practice—before inventors could pursue patent applications for inventions.

    Since then the Leahy-Smith America Invents Act (AIA), enacted last year, changed the awarding of patents from “first to invent” to “first inventor to file.” That key AIA provision, set to take effect March 16, 2013, removes the incentive for rivals to claim their inventions were conceived before the filing date. However, the new law allows first filers to reduce their inventions to practice after filing, requiring money and staff more typical of corporate giants than startups or the proverbial solo inventor in the garage.

    That aside, the chief obstacle to serendipity has less to do with patent law or intellectual freedom than with containing expenses. The cost of drug development can be anywhere from $1 billion (Tufts Center for the Study of Drug Development) to between $4 billion and $11 billion (InnoThink Center for Research In Biomedical Innovation), with both think tanks agreeing that it takes more than a decade to develop most new drugs. Biopharma giants have responded mostly by scrambling in recent years to cut R&D expenses through partnerships with smaller biotechs and university research labs.

    Biopharmas simply can’t wait as long as they used to for the lightning of chance or serendipity to strike in a bottle. That helps explain brisk interest in a recently launched federal agency-industry pilot program aimed at finding new therapeutic uses for shelved proprietary drug candidates.

  • NCATS Program

    As of September 28, about 160 pre-applications from researchers had been filed with NIH’s National Center for Advancing Translational Sciences (NCATS) to study any of 58 eligible compounds with a total 90 original indications, available under the pilot program, Discovering New Therapeutic Uses for Existing Molecules.

    Full applications are due in December. Following NIH peer review, NCATS will select investigators for cooperative agreement research grants to be awarded next year, perhaps sooner than the earlier announced date of July 1. “We hope to actually make the awards as early as late May or early June,” Christine Colvis, Ph.D., director of NCATS’ therapeutics discovery program, told GEN.

    The pilot program’s 58 compounds come from eight biopharma giants—Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson’s Janssen Pharmaceutical, Pfizer, and Sanofi.

    In announcing the program back in June, NIH director Francis S. Collins, M.D., Ph.D., said neurological disorders “would certainly be an area where we would hope there would be a lot of activity.” Fifteen of the NCATS program’s 58 compounds have neuro indications: five for depression, four for anxiety, three for cognitive impairment in schizophrenia, and one, CNS.

    Interestingly, the largest original indication category for the pilot program’s compounds is breathing disorders (16), followed closely by neurological (15), then pain (9) and obesity and diabetes (a combined 9). However, researchers will be able to pursue other indications.

    And as they do, it is not inconceivable that some will succeed more through chance than through their best laid plans. Perhaps the best insight on serendipity, shared by the New Zealand research team and others who have written on the topic, was the observation that while chance happens, it is up to sharp-minded people to take advantage of the resulting opportunities. That thought was crystallized by Louis Pasteur in 1854 when he was named dean of the science faculty at the Université Lille Nord de France into this oft-cited quote: “Dans les champs de l’observation, le hazard ne favorise que les esprits prepares.” In English, that translates to, “In the field of observation, chance favors only the prepared mind.”


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