*Angelo DePalma reports on how personalized medicine may further weaken the blockbuster model of drug development but open up lucrative new niche markets*
Angelo DePalma reports on how personalized medicine may further weaken the blockbuster model of drug development but open up lucrative new niche markets
Personalized medicine (PM) has been described as the right drug, for the right patient, at the right time, at the right dose.
National health systems and private payers would like to add at the right price, as well.
PM is based on pairing a treatment with a diagnostic to identify patients who will benefit most from treatment and who are least likely to suffer serious side effects.
Although PM has only recently become an industry buzzword, firms like GlaxoSmithKline began investigating treatment personalization more than a decade ago, before most omics techniques were available for diagnosing disease and monitoring treatment.
Critics say personalization will ruin big pharmas one-size-fits-all approach to drug development, but that strategy has been unraveling for some time anyway.
Boosters counter that, at worst, healthcare resources will be reallocated more equitably, and in the direction of patient benefit.
At best, the industry would recoup lost revenues through better compliance and higher prices, at least in some markets.
Today, most proponents predict a critical mass of personalized treatments in about a decade.
But Steven Burrill, head of biotech investment firm Burrill and Co., expects it will take as long as 20 years for PM to take off.
One thing is certain: Despite PMs universal embrace by regulators, large and small drug firms, and consultants and the media, its realization is a long way off.
Everyone recognizes personalized medicine as the Holy Grail, but its progressing at a snails pace, says Jim Datin, managing director at healthcare investment firm Safeguard Scientifics in Wayne, Pennsylvania.
Despite slow progress, though, PM successes are beginning to stream in. Herceptin is arguably the best-known example.
PM decreases the likelihood of drug fallout during late-stage testing (or even post-marketing) by identifying patients most likely to benefit and those least likely to suffer side effects.
This was recently seen with Elans biologic drug Tysabri for treating multiple sclerosis and Crohns disease.
Tysabri was withdrawn due to a high incidence of serious side effects, but was reinstated under TOUCH, a risk-mitigating, restricted-distribution program that monitors patients signs and symptoms.
PM could theoretically kick-start innovation at top-tier drug firms through the re-examination of the worlds pharmacopoeia, including molecules that have failed in human testing, for some value-adding personalization angle.
Such efforts could focus on the causes of failure, primarily toxicology, and efficacy, and seek to identify patient populations optimized for effectiveness, a low incidence of side effects, new indications, or a combination of all three.
Although not strictly an example of PM, the re-purposing of thalidomide illustrates how this might work.
Introduced as a sedative in the 1950s, thalidomide caused serious birth defects when taken during pregnancy.
Long after its withdrawal from the marketplace, the drug was re-discovered as a treatment for multiple myeloma, for which it was approved in the United States in 2006 under a strict program that controls its prescription and distribution.
Targeted therapies that disrupt specific pathways implicated in disease are considered PM because the drugs knock out narrow biological pathways that are not active in every patient with the disease.
Some effort has been expended into testing for specific pathways, but much more could be done.
Most of the emerging targeted therapies are oral drugs that disrupt one of several biological pathways implicated in cancer.
A 2008 study by Medco predicted a flurry of approvals of such drugs, which possess both novel structures and mechanisms of action.
The most prominent class of such agents is the vascular endothelial growth factor (VEGF) anti-angiogenesis agents, which block the growth of blood vessels that feed tumors.
Of these, GlaxoSmithKlines pazopanib has been approved for advanced kidney cancer.
Axitinib (Pfizer; thyroid, kidney cancers), alvocidib (Sanof-Aventis; leukemia, arthritis), motesanib (Amgen; breast, thyroid), and lonafarnib (Schering/Merck; breast) remain mired in late-stage human testing while clinical studies on Zactima (AstraZeneca; lung, breast cancers) have been halted.
Some worry that, despite its relative novelty, the VEGF class is already over-crowded.
Primo Lara, M.D., at the University of California, Davis, called pazopanib a me-too drug that provides none of the advantages (lower cost or greater safety or efficacy) expected of a top-line cancer agent.
Targeted oral cancer treatments cost up to $9,000 per month in the United States.
Their proper utilization has been a topic of concern.
Further personalizing these treatments by linking specific agents to genomic characteristics could help un-crowd the marketplace and provide greater value as well.
Another blow to the blockbuster model
Protestations from big pharma, governments, and consultants notwithstanding, personalization represents another blow to big pharmas beloved blockbuster model.
In the simplest sense, PM is bound to fragment markets and create winners and losers based on scientific pairing of patients and drugs.
The losers will be first-in-class or aggressively marketed products whose sales have nowhere to go but down.
Winners will be niche productsfor example, the fifth-most-prescribed drug in its therapeutic classprovided these drugs are paired successfully with a sufficiently supportive diagnostic.
Since PM depends on diagnostics as a point of differentiation from conventional therapeutics, its emergence depends on the co-evolution and conferring of equal status, at least scientifically, on both Rx and Dx.
Diagnostics technologies, hitherto distant step-relatives to drug-makers, will assume life-or-death significance for products developed under the PM paradigm.
Pairing drugs with tests will create endless upheaval, particularly within formularies, but nearly limitless niche opportunities for entrepreneurs to uncover valuable Rx-Dx relationships.
Clearly, future therapeutics and diagnostics will be aligned more closely than they are today, says Safeguards Datin.
Based on their ability to monitor drug effectiveness and disease progression, diagnostics will drive reimbursement.
Safeguard puts its venture money where its mouth is.
The firms 14-year involvement with Clarient, a cancer diagnostics firm, is illustrative.
Safeguard provides cutting-edge molecular tumor identification, staging, and grading that only recently had been the province of basic research.
Armed with that knowledge, the firm proposes a cocktail drug regimen to which a specific tumor is likely to respond.
Other firms provide similar services.
Some, like Clarient, use a statistical approach to match tissues with drugs; others, like Precision Therapeutics, employ a more empirical approach.
Precision cultures patients tumor cells and tests them against a panel of chemotherapy agents to determine drugs most likely to induce a positive response.
Theoretically, the personalization of cancer therapy could spare patients from unnecessary treatments and side effects, while streamlining the drug decision-tree and lowering costs for payers.
In practice, obtaining reimbursement for tests provided by firms like Clarient and Precision Therapeutics is uncertain.
Safeguard also invests in Avid Radiopharmaceuticals, which has a fluorine isotope technique for quantifying amyloid plaque for Alzheimers disease diagnosis.
The point is differentiating Alzheimers from Parkinsons disease, whose symptoms may overlap.
Eventually, after the approval of several of the more than 30 compounds in late-stage human testing for Alzheimers, the test should help pinpoint the right treatment.
The role of biomarkers
PM based on biomarkers (molecular tests, pathology, imaging) will remain a moving target, as the diagnostics industry has learned.
For years, critics noted that high cholesterol was a poor predictor of heart disease and that cholesterol-lowering agents appeared to work whether they lowered cholesterol or not.
A recent meta-study undertaken by genomics pioneer Celera and pharmacy benefits company Medco shed light on this conundrum.
Statin therapy, it turns out, is not uniformly effective in reducing primary cardiac events in all patents, only in the approximately 60% of the population carrying a genetic mutation at the KIF6 gene.
Celera markets a test, although not widely, to test for this genetic defect.
The number-needed-to-treat to prevent a health-related event, a measure of a therapys effectiveness (smaller is better), is 10 for those with the KIF6 mutation, and 125 for individuals who test negative.
This finding, if widely applied, would appear to slash markets for statins by 40%.
Not so, says H. Robert Superko, M.D., chief of medical affairs for Celera.
The test, he says, will guide optimization of statin therapy and perhaps bring unexpected benefits to drug companies.
If people know they carry the KIF6 mutation, in addition to having high cholesterol, they will know there is a genetic basis for taking the drug and will be more compliant, according to Superko.
About half of those taking statins stop taking them within a year after the first prescription.
Payers will benefit, too, as they save on costs associated with unnecessary drug therapy and in more favorable outcomes for individuals who are medicated appropriately. (For more on biomarkers, see Biomarkers and oncology forecasting: How to hit a moving target, Forecasting for complex diseases, and Different forecasting methods in the US and Europe.)
Intellectual property issues
PM raises interesting intellectual property, licensing, and royalty issues, particularly when tests and drugs are developed independently but combined into a single regulated entity (for example, Herceptin and her2neu tests).
The patentability of genes and other natural targets is under fire, says Timothy J. Shea, director at Sterne, Kessler, Goldstein & Fox PLLC, a Washington, DC intellectual property law firm.
Ongoing legal cases will very likely shape the personalized medicine industry for years to come, Shea says.
Shea cites the 2008 Bilski ruling in the US as a potential damper on innovation in PM.
A little-known case related to business method patents, Bilski substantially raised the bar for pairing patented tests with treatments.
In an even more recent case, Myriad, a US district court held that isolated or synthetic versions of naturally-occurring genes are not patentable.
Myriad has been appealed, and its eventual resolution will likely be one of the most important decisions in pharmaceutical patent law in the past 20 years.
With patent protection clouded in uncertainty, early-stage firms and universities, which rely on licensing revenue from diagnostics, are less likely to engage in risky gene hunting with the goal of pairing their inventions with therapeutics.
Unsurprisingly, pharmaceutical companies have generally held that diagnostic molecular targets (but not therapeutic ones) should not be patentable.
While these concerns are often couched in terms of protecting the public interest, Shea says, having to license these technologies increases the cost of drug development for big pharma, particularly in an environment where personalization becomes the only route to approval.
To learn more about personalized medicine, check out eyeforpharma's Personalised Medicine & Diagnostics Europe conference on March 9 and 10 in London.
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