Promises and Pitfalls - Drug Discovery and Development

Combine years of ever-shrinking development pipelines, revenue erosion from generic drugs, and growing price resistance from Medicare and private payers and it looks like Big Pharma’s model of relying on billion-dollar “blockbuster” drugs is becoming obsolete.

But what can replace it? For many, the answer lies in personalized medicine. “The pharmaceutical industry can and will be a big driver of personalized medicine. Without them, I don’t think it will happen,” said Edward Abrahams, PhD, executive director of the Personalized Medicine Coalition, a nonprofit consortium of about 160 academic, pharmaceutical, biotech, diagnostic, patient advocacy, and insurance companies in Washington, DC.

In the past, the drug industry felt that serving segmented markets couldn’t justify the cost of developing highly targeted drugs, Abrahams said. But “without this changed paradigm, they now believe they are dead in the water because the blockbuster model looks more or less done,” he added.

To be sure, there are many pitfalls before the potential of personalized medicine can be achieved. Some of these include reducing the cost and increasing the speed of next-generation sequencing technologies; convincing Medicare and private insurers to reimburse costs of pharmacogenetic testing; encouraging average-size drug companies to integrate biomarker information into development and early-stage clinical trials; and facilitating the creation and use of companion diagnostics.

“Biomedical research will not result in opportunities for cures unless they are married to advances in regulatory science,” Food and Drug Administration Commissioner Margaret Hamburg, MD told the Personalized Medicine Coalition in February. The agency, she added, hopes to issue draft regulatory guidance on companion diagnostics by the end of the year, a date she acknowledged as “probably not fast enough for all of you.” Despite its vagueness, her announcement of a timetable was heartening because it was the first time the agency had issued any such pronouncement for the nascent field.

Also promising are developments in sequencing technologies, which must become faster and cheaper if researchers are to uncover physiological pathways of diseases, validate drug targets, and develop diagnostics to tailor prevention regimes and personalize therapies. “By and large, the study of common genetic variation for common disease didn’t definitively give us much of that,” said David B. Goldstein, PhD, director of the Center for Human Genome Variation at Duke University’s Institute for Genome Sciences and Policy.

Over the past 20 years, more than 100 genome-wide association studies have been conducted for more than 40 diseases, leading to identification of hundreds of risk-inducing polymorphisms. But while regions have been associated with risks for certain diseases, identifying which gene in those regions is responsible has proved daunting. What’s now needed, Goldstein said, is to look comprehensively at genetic variation in very well-characterized patients, something that will be enabled by next-generation sequencing. “From that, we will start seeing the sequencing of genomes for all common diseases, and that will lead to identification of disease genes,” he said.

Indeed, recent advances in second- and third-generation DNA sequencing machines promise to bring down the cost of a full human genome scan to less than $3,000 and eventually to the Holy Grail of $1,000. Sequencing system manufacturers Illumina Inc. (San Diego), Applied Biosystems, Life Technologies Corp. (Carlsbad, Calif.), Pacific Biosciences (Menlo Park, Calif.) and Oxford Nanopore Technologies Ltd. (Oxford, U.K.) are among those that have unveiled new platforms during the past few months.

H1N1 Overstock
About one third of the 229 million H1N1 vaccine doses purchased by the US government may have to be discarded if they are not used before they expire, according to a Washington Post report.

Between 81 million and 91 million doses of the swine flu vaccine were administered via injection or nasal spray. Approximately 60 million doses were donated to developing countries or saved for future use. An estimated 71.5 million doses from the $1.6 billion program could expire before administered. The H1N1 vaccine was developed quickly, but production problems delayed delivery until after the second wave of infections peaked. The World Health Organization disputes charges that it overreacted to the pandemic and has launched an internal review of its response.

Across the Atlantic, the British government has announced it is cancelling more than a third of the 60 million doses ordered from GlaxoSmithKline. Initially ordering 90 million doses, it cancelled an order for 30 million from Baxter Healthcare earlier in the year. In total, less than 5 million British citizens have been innoculated to date.

Illumina has produced a second-generation system capable of sequencing a whole human genome for less than $10,000. The system generates 2 billion paired-end reads in a single run.

Life Technologies presented early results of a third-generation single-molecule sequencing technology that uses nanometer-sized semiconductor crystals attached to DNA polymerase molecules to detect individual protein molecules. In a presentation at the Advances in Genome Biology and Technology meeting in February, the company said its Invitrogen “Qdot” technology generates signals 100 times greater than conventional fluorescence detection, producing faster and more accurate continuous readouts of DNA.

But the more serious challenge to developing personalized medicine may be economic rather than scientific, according to a report from McKinsey & Co. Medicare and private insurance payers are moving slowly (at best) to support pharmacogenetic testing.

While industry executives believe that personalized medicine may eventually reduce costs, they remain unsure whether it is or could be cost-effective.

While most Big Pharmas have biomarkers and companion diagnostics programs in place for their compounds under development, the average drug company is developing biomarkers for only 30% to 50% of its compounds and companion diagnostics for fewer than 10%, McKinsey said. Company executives are worried that the FDA will require larger Phase 2 trials incorporating companion diagnostics and might also require them to include marker-negative patients in Phase 3 trials out of concern for off-label usage—actions that they fear will increase costs and force development delays.

On the positive side, Medco Health Solutions and CVS Caremark, two the nation’s largest pharmacy benefit managers, will begin offering their client companies genetic testing services this year in an effort to save costs and improve health outcomes. “Making such tests the standard of care can significantly reduce waste, improve patient care, and raise the safety profile for powerful new medications,” says Felix Frueh, PhD, Medco’s vice president for personalized medicine R&D.

Unfortunately, the U.S. government’s support for comparative effectiveness research has the potential to sabotage personalized medicine, said Francis Collins, MD, PhD director of the National Institutes of Health. “There is a potential collision, here,” Dr. Collins told a forum last year. Personalized medicine is “going to get lost in the wash by considering everyone equivalent, which we know they are not,” he predicted.

About the Author
Contributing editor Ted Agres, MBA, is a veteran science writer in Washington, DC. He writes frequently about the policy, politics, and business aspects of life sciences.

This article was published in Drug Discovery & Development magazine: Vol. 13, No. 3, April 2010, p. 6.