BIO 2014: Antisense and Disruptive Technologies for Drug Discovery


Editor’s note: The BIO 2014 convention begins today in San Diego. Stanley Crooke is among the speakers at a breakout session Wednesday titled Blazing New Trails in Disruptive Innovation: Stem Cells, RNA and Epigenetics-Based Therapeutics. —BVB

For the past 25 years I, with my colleagues at Isis Pharmaceuticals, have persevered in the creation and validation of a genuinely disruptive drug discovery platform, antisense technology. To advance from a blank canvas to a mature technology, now proven by the marketing approval of mipomersen (Kynamro) and encouraging clinical data from a number of Isis’ later-stage drugs, has required two decades of innovation and commitment to the science and patients—and, yes, money.

For all the time, effort, and capital, you might well ask, “Was it worth it?” or even, “Why pursue a disruptive technology for drug discovery?”

Part of the answer is obvious: the well-documented decline in the productivity of our industry’s drug discovery processes. A couple years ago, Sanford Bernstein’s Jack Scannell and colleagues showed that from roughly 1950 to 2010, the number of new drugs per billion dollars of R&D spending has declined from more than 30 to less than one. This trend manifests in increasing prices charged for new drugs, as well as industry’s greater reliance on a few blockbusters for profits. Successive pharmaceutical mergers to resolve this bottleneck through increased scale have had no effect in improving this lop-sided ratio.

The major cause for this productivity decline, however, is our industry’s failure to successfully invest in disruptive innovation through more efficient research technologies, prolonging reliance on the century-old platform of small molecule drug discovery. That this approach continues to generate drug candidates is both a blessing—because there is some ROI—and a curse, because the predictability of getting some products to market reduces the incentive to make high-cost, high-risk, high-reward research investments.

Meanwhile, there has been a quiet revolution in the “redefinition” of diseases. This realization was critical in my decision to pursue antisense technology; i.e., designing pharmaceuticals that will functionally “silence” a gene mutation; or activate a gene to compensate for an underlying genetic defect.

Unlike classic medical definitions, which rely primarily on the symptoms observed in the later stages of disease progression, modern definitions of disease now focus on the molecular and pathological factors that cause or maintain disease—not the symptoms or outcomes. Importantly, molecular pathological definitions are actionable, and bring focus to causes of disease. This relatively new definition has resulted in a deeper understanding of disease processes and identifies the patient subpopulations most likely to respond to a molecularly targeted therapeutic—a perfect opportunity for antisense therapeutics.

When I surveyed the tools for drug discovery in the 1980s, antisense technology was by far the most interesting. Antisense offered a dramatic increase in the specificity of drug action—essential for a genuine leap in drug discovery technology. Another “disruptive” attribute was the potential for antisense to enhance development efficiency. Once the mechanism of action for antisense technology could be established, intra-class predictability of antisense drugs dramatically reduced the failure rate of drug development. Conversely, the early failure rate of small molecule drugs is around 90 percent. With antisense, basic investments can be amortized across all chemically similar molecules. Efficiency improvements occur due to improved success rates and processes shared by an entire pipeline.

When I founded Isis, very little was known about antisense technology. I predicted at that time that 20 years and $2 billion would be needed to determine its viability. The magnitude of the medical and commercial opportunity, however, compelled investors and major pharmaceutical companies to support us, even when the industry consensus about antisense was pessimistic. The key to re-energizing the Isis team at moments of great disappointment has always been the scale and quality of the opportunity in our sights.

Sincere commitment to the data has been critical to the success of something as disruptive as antisense. Zealotry has no place in the business of science. At every bottleneck, the Isis team has critically reviewed the data to chart the best way forward—if possible. Accepting what the data teach is essential to data-driven decision-making.

As Isis and antisense matured, we looked for new ways to extend the therapeutic potential of this platform.

Our strategy at Isis has always focused on maximizing long-term value. The success of this strategy hinged on using antisense technology to create a drug discovery and development platform. This concept was easily conceived, but it was extraordinarily challenging to execute.

To create antisense technology we needed to create a new medicinal chemistry—antisense chemistry. This meant taking a relatively traditional approach to medicinal chemistry, i.e. make and test many analogs, and apply it to the novel challenge of creating a chemical toolbox for antisense drug discovery. We have succeeded in creating multiple generations of antisense chemistries with substantially enhanced drug properties. Compared to first-generation antisense drugs, drug potency has now improved more than a hundred fold, potentially reducing healthcare costs. In our clinical studies with newer second-generation and generation 2.5 drugs, we have observed improved tolerability, which suggests these newer chemistries could lead to significant increases in patient compliance.

We control the platform through more than 1,200 issued patents world wide—ownership that will extend for many years due to an “evergreen” effect from an additional 600 pending patent applications.

To better exploit the commercial and technological potential of antisense, Isis has granted licenses to associated companies—Alnylam, Regulus, and others. This has yielded more, and varied, antisense drugs than we could otherwise afford to develop on our own; and has created both a future royalty stream and current income for Isis operations.

The disruptive impact of antisense has been amplified by Isis’ early decision NOT to become a “fully integrated” pharmaceutical company, a typical ambition of many biotechnology companies. Isis’ low experimental product failure rate and relatively low-cost, faster-paced research has yielded a product pipeline that grows annually by up to five candidates. Isis now has 32 drugs in development, of which six are expected to be marketed in the next few years, and which will join our portfolio of three therapeutics that are now commercially available.

Isis’ business strategy, coupled with the growing opportunities for antisense and its efficiencies in drug development, provide a unique potential for this exciting new disruptive technology.

Stanley Crooke, MD, PhD, is the founder, Chairman and CEO of Isis Pharmaceuticals Follow @

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