By Wayne Koberstein, Executive Editor, Life Science Leader magazine
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A recent report by the United Kingdom consultancy Diaceutics stirred up a great deal of media coverage and public discussion about personalized medicine (PM) in the pharma industry. Diaceutics ranked the industry’s top companies by their “readiness” for PM, mainly by linking drugs with “companion diagnostics” or other measures to identify narrowly defined groups of patients most likely to benefit from the drug treatment. The concept, stated simply, is elegant and enormously appealing, but the details would make the devil proud.
Diaceutics sliced and diced a set of criteria to yield a “snapshot in time” of the companies’ relative positions, a hierarchy arranged into three categories with the provocative names of “disruptor” (top), “breakaway” (middle), and “follower” (lowest). Roche and Novartis are the sole disruptors, meaning that they have taken the lead in PM by extraordinarily disrupting their normal ways of operating and doing business. Breakaway companies — AstraZeneca, Eli Lilly and Company, Bristol-Myers Squibb, and Pfizer — may have extensive PM plans and activities but presumably have yet to show major change visible to outsiders. Followers — GlaxoSmithKline, Sanofi, Amgen, and Merck — no doubt cringe at that distinction, but supposedly demonstrate even less commitment to PM as a primary R&D or business model.
One important caveat of the Diaceutics report is omission of key criteria: planning and intent. Have companies that launched themselves furthest into PM done so from an a priori belief in the concept or because they were reacting to untoward developments — such as efficacy and safety problems emerging for products already on the market?
“We shied away from judging whether a company has arrived at their personalized medicine status because they had to or because they had the opportunity,” explains Peter Keeling, president and CEO of Diaceutics. “What we can say is that, directly or indirectly, one company is more predisposed to understanding the key factors in commercializing diagnostics than another.” Keeling points to BMS, which he believes has probably “internalized” lessons from Medco’s use of PM to guide prescribing of Plavix.
Jamie Dananberg, VP of translational medicine and tailored therapeutics at Lilly, has an answer to the “snapshot” approach, and specifically why his company, despite its 2008 pledge to become a “targeted therapeutics” company, captured only a midtier rating from Diaceutics: “Independent of how we get labeled by some subjective set of semiquantitative measures to assess where we are in business, every change we make relative to the portfolio takes a lot of time and would not be apparent to anyone for many years,” he says.
Way Beyond Biomarkers
Roche has a long history with diagnostics, and it helped pioneer PM with Herceptin, though it is still seeking a PM solution with Avastin after its limitations surfaced on the market. The Avastin search is “a huge scientific challenge,” says Thorsten Gutjahr, head of biomarkers at Roche Diagnostics. “As anti-angiogenesis, there are not only tumor factors but patient factors involved.” Novartis was also ushered into the PM arena when it chose to develop and launch Gleevec for a targeted disease population. Roche has torn down barriers between its traditional Dx (diagnostic) and Rx (pharma) organizations. Novartis has built a new molecular Dx unit within the Rx division. Both companies have used licensing, partnering, and acquisition extensively to bring in new technology platforms, knowledge, and skills from small companies and universities.
The Disruptors have also moved ahead from the days when their lead PM products were the same ones that put them in the game: Novartis with Tasigna (nilotinib) and Roche with Tarceva (erlotinib), plus others among their products and pipelines. Still, few people outside the industry likely see the companies as leaders in the field. Previous hype about using the genome map to predict and cure diseases in individuals has soured public expectations. But also, the activities of even the largest pharma companies are still small compared to the entire healthcare system, where widespread support for PM is vital.
But, the isolated successes with targeted medicines are the exceptions that prove the rule: PM works. Now, if you define success as improved outcomes for the set of patients most likely to have improved outcomes, it would seem you are rigging the odds. Here is the rub, though: to identify that magic patient set, you must beat some of the highest odds in medical research, and even then development is a long road ahead, as Michael Nohaile, head of molecular diagnostics at Novartis, attests. “The biomarker is not enough. It’s the first, and in many ways, the most critical step, but you also have to have a very high-quality, reproducible testing system that allows it to work, and that is actually quite hard,” Nohaile says. “And, having a good test is not enough to ensure that it is being used to the patient’s benefit and system savings. You also have to deliver that information in ways that are actionable for clinicians and doctors.”
Reason may temper expectation for biomarkers but it hasn’t slowed their proliferation. Genomics is now only one of many biomarker sources, among proteomics, metabolomics, and other “omics” constantly emerging. Bioinformatics is critical — not just to analyze existing data but to guide design of biomarker experiments. Consolidation of diagnostic testing in certain disease areas is inevitable, as in cancer, where Source Bioscience, Illumina, and Barts Cancer Institute are collaborating on an “integrated genetic test for characterizing cancer tumors at the molecular level.” PM may also apply to multiple drugs or entire drug classes. Companies want to use adaptive trial designs, maximize sample collection, diversify stratification data, and of course, integrate Dx and Rx development.
Roche, Novartis, and others have stepped up basic research collaborations to find and sift through still newer biomarkers. Roche’s acquired subsidiary, Ventana, gives it broad access to tissue samples for biomarker screening. In June, Roche agreed to provide UCLA with research tools and researchers in exchange for some access to university discoveries in cancer and stem cells. The deal also highlighted another, below-the-radar strength of Roche in PM: the company makes and sells the widely used tools it will supply to UCLA for high-throughput screening, genetic expression profiling, and exome sequencing.
Medium-size pharma companies are also investing in PM, if only now at the clinical research level. Merck KGaA is using tests by MDxHealth in its Phase 3 trials for cilengitide in glioblastoma, though so far with no obvious commitment to commercializing the drug/test combo. Trials have always stratified patients according to diagnosis. One difference with PM is the scale of resolution in defining patient groups with molecular markers rather than symptoms or histories.
Patient stratification in a clinical trial is one thing, but quite another in medical care. In practice, will physicians deny treatment for the “outliers,” patients who test negative for the favored pathway, gene, etc.? Will enough of the outliers receive treatment to skew the results in the treated population? If the answers are no and yes, respectively, and to a sufficient degree, the benefits of PM could be lost.
Commercial targeted therapies could also be seriously limited by how quickly patients relapse due to resistance that develops during treatment. But drug resistance is not a problem peculiar to PM; in fact, it may help overcome the problem.
Nohaile says, “Companion diagnostics are intrinsically developed to factor drug resistance into the equation. Companion tests enable physicians to make the best drug choice for their patients, and this may include switching to a different therapy as appropriate. In turn, companion diagnostics can actually help us learn more about what leads to resistance, and hopefully, to develop treatments which may benefit those patients.” Others we interviewed echo his points.
Of Mice And Goliaths
All the activity by Pharma is both good news and bad for small Dx and lifescience research companies looking to do business in PM. Most diagnostics are small and tailored to a traditional business that sells to labs and purchasing agents. They have few options in commercializing a molecular companion diagnostic: go it alone, find a partner, or give up their technology in licensing or acquisition. Most large pharma companies seem unwilling to invest in unproven Dx technologies or integrate Dx and Rx strategies as the leaders have.
Small companies are also at a disadvantage in addressing regulatory and reimbursement issues — no small hurdles even for the big players. Payers and regulators will follow grass-roots demand. The very audiences with whom small Dx companies lack contact are critical to driving payer and regulator buy-in.
That is what the large companies are apparently counting on — a groundswell of public acceptance of the PM approach based on a simple formula as expressed by Gutjahr: “It is essential to recognize what value a companion diagnostic is giving to the payers and society. What payers want is the best use of their resources that is available, they want patients to have a good chance to respond to the therapy, and they want a good cost-benefit.”
Arguably, large companies are better equipped to defend premium pricing of Dx/Rx products, using the powerful tool of clinical data. “From their perspective, payers are already paying premium prices and often getting not much for the premium,” says Howard Tag of Tag & Associates. “Targeted therapies give payers something very important to them — an evidence-based mechanism to identify the right cases for the treatment and avoid those where money would be wasted.”
Perhaps PM will become a cost-saving alternative to steep co-pays, which now keep many U.S. cancer patients and others from even filling their prescriptions. But co-pays are just one example of the many structural impediments to PM that persist despite all progress. A 2010 report by Health Advances/BIO does a good job of outlining all the barriers, from insurance coding confusion to disconnects between Dx and Rx regulation, that need reforms for PM to succeed overall.
It may be that the large companies, at least those now in the lead, are not all that eager for the overall infrastructure to change. Aside from wanting payers and regulators to “recognize the value” of targeted medicines, the leaders may prefer the uneven status quo versus a more level playing field where barriers are removed and their advantage is possibly lost or diminished.
A large company has sufficient resources to develop a targeted drug for a limited population, ride out the initial marketing difficulties, then reap the rewards of premium pricing on a new scale. But add competition and a universal set of therapeutic/economic expectations to the formula, and the returns may be less stellar.
Personalized medicine has the potential of transforming drug therapy into something much safer and more effective than we have ever experienced. Might it also alter the landscape to the point that the new standard becomes business as usual? Only a moving picture, not a snapshot, will tell.
Hubs Of Reform
Personalized medicine hinges on public and private reforms. As the largest U.S. payer, CMS is both a leader and follower in practical changes to reimbursement. New CMS billing codes can be created through National Coverage Determination proceedings (www.cms.gov/DeterminationProcess), usually initiated by companies or other interests, or a request process (www.cms.gov/medhcpcsgeninfo/01_overview.asp). Current codes are owned and maintained by the AMA. CMS has a mandate from the Affordable Care Act to facilitate PM and is meeting this July “on setting payment rates for new laboratory tests,” a spokesperson says. The FDA is circulating a draft guidance on review and approval of drugs with companion diagnostics. And private payers, like Medco, are even leading the PM charge — but on their own terms.