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A companion in your corner (Part 1)
October 2012
by Randall C. Willis  |  Email the author


Dorothy didn't think much of the scrape in the beginning. In her 82 years, she'd had plenty of bumps and bruises, so she went about her business, preparing dinner. It wasn't until she turned around, however, and saw the droplets of blood trailing down her apartment hallway that she realized something was wrong.  
Dorothy had a history of atrial fibrillation, so her cardiologist had put her on warfarin to reduce her stroke risk. Unfortunately, the very thing that makes warfarin useful—its ability to prevent clots in a malfunctioning heart—is also the thing that can make it incredibly dangerous to someone like Dorothy, whose paper-thin skin breaks so easily. It can lead to uncontrolled bleeding.
Dorothy's cardiologist didn't make a mistake. Dorothy 's pharmacist didn't make a mistake. When the warfarin was prescribed, Dorothy was likely given the right dose. But so many factors can complicate the "right" dose of warfarin for any individual that it can sometimes feel like you're playing Russian roulette.  
Same old, same new
Dorothy 's case is not unique. Every year, millions of patients are given drugs or drug doses that may not suit their condition. In a now decade-old report, it was suggested that 40 to 75 percent of a patient population may not benefit from a particular drug for a given treatment, largely because community medical practice ultimately comes down to trial-and-error based on the best medical knowledge arising from highly controlled clinical trials and not highly variable real life.  
And despite advances in more targeted drug development and diagnostic technologies, things haven't necessarily improved over the last decade. In a recently published study, Eitan Emir and colleagues at Toronto's Princess Margaret Hospital showed that while several new anticancer drugs have demonstrated significant improvements in efficacy endpoints such as overall survival and progression-free survival over standard care, these efficacy improvements may have come at a significant price for patient safety and tolerance of treatment.
In a meta-analysis of 38 randomized clinical trials of solid tumor agents approved by the U.S. Food and Drug Administration (FDA) between 2000 and 2010, the researchers found that when compared to the control agents in each study, the odds of toxic death were 40 percent higher for patients receiving the new drug. Similarly, in patients on the new drug, the odds of treatment discontinuation increased by a third and the odds of a serious (Grade 3 or 4) adverse event increased by more than half.   The researchers were quick to point out that these results could have arisen for a variety of factors in the trial design, as well as because of the molecular activity of the drugs, but it did reinforce the importance for a solid understanding of any patient's baseline medical status when selecting a therapy.  
The need to more clearly define the connection of therapeutic decision-making to patient need and performance prompted organizations like the FDA to issue guidance about the development of companion diagnostics. In April 2005, the FDA released its draft preliminary discussion document, "Drug-Diagnostics Co-Development Concept Paper," to start the conversation.  
"Ideally, a new diagnostic intended to inform the use of a new drug will be studied in parallel with early drug development (Phase I or II trials), and diagnostic development will then have led to prespecification of all key analytical and clinical validation aspects for subsequent (Phase II and III) clinical studies," the report read.
The principle was—and is—sound. The execution has been more challenging.
Changing the approach  
According to specialists in the diagnostics industry, the first part of the challenge was convincing pharmaceutical companies it was a good idea.
"Companion diagnostics are obviously a great idea," says Stephen Little, vice president of Qiagen's personalized healthcare division in Hilden, Germany. "The physician benefits, the patients benefit and the payors benefit, but to move the field forward, pharma had to understand that it, too, would benefit from diagnostics co- development."  
The perfect example of this, Little continues, was in the early days of Vectibix and Iressa, "two drugs that were not on the market in Europe because they initially couldn't show enough efficacy [in broader patient populations]," Little says. "Once their efficacy could be linked to specific biomarkers and patients could be targeted, however, European regulators accepted their applications—clearly an example of a closed market that was opened through the development of diagnostics."  
The education was a two-way street, however, and Little adds, "I came from DxS, a small company that struggled to engender interest in the pharma industry to combine diagnostic tests with drugs, and we quickly discovered that if you don't bring pharma along, you're not going to get very far."  
By the same token, he continues, pharma initially assumed it knew how the diagnostics industry worked, but it didn't.  
"Diagnostics are not drugs. Pharma companies aren 't at all equipped to develop diagnostics, get them approved and manufacture them, so once they realized they could benefit from companion diagnostics, they began to adopt partnership models with diagnostics companies," says Little.  
Making inroads  
Even for traditional diagnostics companies, there has been a learning curve, according to Henrik Winther, vice president of corporate business development at Dako in Glostrup, Denmark.  
"The market-value drivers and the regulatory burdens are very different between routine diagnostic assays and companion diagnostic assays—prognostic and predictive assays—but at the same time, these assays are tightly interconnected through full diagnostic system solutions—hardware, software, reagents and analyzing tools—adapted to a standardized and optimized workflow of the diagnostic laboratory," he explains.
As Dako has shifted its focus more and more toward companion diagnostics development, it has seen its operating procedures and quality assurance significantly impacted. In addition, the company's commercial competencies have been challenged to expand the customer field from pathologists to also include oncologists and increase interactions with pharma companies.  
The education and early inroads proved vital to getting the market going. Improvements in biomarker identification and technical leaps in assay development have proven fruitful for the evolution of the companion diagnostics market, which generated sales of $1.3 billion in 2010 and will grow to almost $3.5 billion by 2015, according to an August 2011 report from visiongain.  
"The market for companion diagnostics has enjoyed strong growth in recent years, driven by adoption of marketed products and also due to the increase in the number of theranostics," says visiongain analyst Rupali Vadhera. "Over the course of the next decade, there will be greater demand for companion diagnostics as they improve the safety-efficacy profile of drugs and help reduce healthcare costs."  
Even the decision of how to develop a companion diagnostic can take two approaches. The first is a straight co-development project where throughout the drug development process, relevant biomarkers are identified, assays developed and validated and drug and diagnostic submitted for simultaneous regulatory approval.
The other form could be called a "catch-up companion," where a diagnostic assay already on the market is used to facilitate drug development. Winther describes this latter form as validation and registration agreements (VRAs), where commercialized companion diagnostics or regular diagnostics are used in clinical trials to select patients, and hence the company's task, in collaboration with pharma, is to validate and register the assay for the new indication or the new drug.  
The biggest differences between the two approaches, according to Winther? VRAs offer shorter timelines, lower risks and lower costs.
Valid idea  
Of course, simply having a test for a given biomarker or set of biomarkers isn't enough. The biomarker and test have to be validated to ensure that they actually help identify the right patient for treatment. And validation costs money.  
"Validation is one of the big challenges we face, which is why we work with pharma companies," says Qiagen's Little. "Let 's say you know you'll be reimbursed $200 to $300 per test and you have a good sense of the market size. When you compare that market value to the cost of putting the test through clinical trials, you quickly realize that it's not a very compelling investment case."
"That's why it's been so important for pharma to become involved," he adds. "Basically, pharma runs and pays for the clinical trial and the diagnostics company piggybacks on the trial."  
The decision to identify and validate a companion diagnostic adds entirely new layers of complexity, however, to an already complex clinical trials process.
When you develop a cancer drug targeted at a mutant form of a protein (e.g., EGFR, KRAS), it is obvious what you need to sample, says Little. But more often, you've discovered in your Phase II studies that your drug works on some patients and not on others, and you need to identify what biomarker is different between those two populations.  
"Ideally, we would love to develop and validate a test before a drug goes into Phase III but that isn't always possible," he adds. For this reason, Little feels it is essentially impossible to validate the biomarker and the drug in the same clinical trial.
In 2011, Cambridge, Mass.-based AVEO Pharmaceuticals initiated two such Phase II biomarker studies for its investigational drug tivozanib, a VEGF inhibitor currently in Phase III studies itself.  The first study was to evaluate biomarkers in blood and archived tissue samples and correlate them with clinical activity and/or drug-related toxicity from a trial of patients receiving tivozanib for renal cell carcinoma. The more recent randomized study, undertaken with Astellas Pharma, will look for biomarkers in patients with advanced metastatic colorectal cancer receiving mFOLFOX6 and either tivozanib or Roche's Avastin.  
"It is critical that we develop strategies that will enhance our understanding of patient populations that will best respond to specific therapeutic regimens, and I believe that BATON-CRC is a step forward on this front," says the study's lead investigator, Al Benson of Chicago's Northwestern University Feinberg School of Medicine. "I am excited to be involved in this trial and to learn more about how this treatment regimen with tivozanib may benefit patients living with colorectal cancer."
Qiagen's product line also highlights another challenge in validating diagnostic tests: regulatory variability.
"Unlike drug approvals where most regulatory agencies are looking for the same information, the regulatory process for diagnostics approval is quite variable around the world," Little says. "Things are much quicker in Europe, which is why we've marketed the KRAS-Erbitux test for several years in Europe, but it is new in the U.S."   
In July, Qiagen announced it had received FDA approval to market its Therascreen KRAS kit to provide guidance to physicians in the use of Erbitux for patients with metastatic colorectal cancer. Although it was Qiagen's first approval in the United States, the company has had this and tests for 30 other biomarkers approved throughout Europe, Asia and Japan.  
"The bar is set higher at the FDA, and you could have a whole discussion about whether it's too high or too low," Little says.  
Dako's Winther highlights the extra challenges afforded companion diagnostics, suggesting these tests hold the highest regulatory classification level, typically requiring investigational device exemptions (IDEs) and premarket approvals (PMAs). This is in contrast to routine diagnostics that only require "self-declaration" at the in-vitro diagnostic (IVD) Class I level.  
"The regulatory and clinical affair competences within Dako have therefore expanded dramatically within both expertise and capacity during the last five years," he says. "From a market-value driver point of view, there is no doubt that companion diagnostics require technologies that can provide quantitative results as well as innovative assay controls securing high-quality standardized and robust results, whereas the qualitative diagnostics are typically driven by parameters like turnaround time and workflow. These differences in value drivers are of course reflected in different demands towards our R&D functional area and those tools developed by the technology departments."
Cancer is key  
The one therapeutic area that has likely seen the most activity with companion diagnostics is oncology, where the ever-expanding repertoire of targeted therapeutics and efforts spent in preclinical and early clinical discovery and development have already pointed to the key biomarkers.
Little suggests the focus on oncology may revolve around smaller patient populations that one need study because of the nature of that link.
"It will be interesting to see what happens as we move into other therapeutic areas," he suggests.
When you move away from genetic biomarkers into areas such as metabolomics and proteomics, however, the water gets muddier and the required patient populations will likely rise significantly. The trick, he believes, will be in finding the most important biomarkers, not necessarily the most biomarkers.  
"We try to get a test we can use and that we know works, not necessarily the one with the most data. Just because you can measure 10,000 points, you don't have to. Ten points may be sufficient," Little says.
The growing activity in the oncology market is drawing the attention of not just diagnostics shops, but also of more traditionally supply-side companies looking to expand their markets and leverage their internal technology expertise. One such company is Life Technologies in Carlsbad, Calif., which in September announced it was partnering with Bristol- Myers Squibb Co. (BMS) to collaborate on companion diagnostics projects.  
"The pharmaceutical industry is increasingly turning its focus to discovering and delivering targeted personalized medications," said Life Technology's president of medical sciences, Ronnie Andrews. "For oncology alone, hundreds of agents are currently in clinical trials, and we see strong market opportunities in the robust expansion this will mean for the companion diagnostics space."  
For Life Technologies, it's about translating the company's success in technology platform development into the clinic and joining its knowledge of genomics and proteomics with BMS' expertise in clinical development to generate flexible, cost-effective diagnostic solutions.  
Similarly, Qiagen is looking to leverage its long-standing expertise in laboratory and research diagnostics into the companion diagnostics market, relying on technologies introduced from such acquisitions as DxS and most recently, Ipsogen. As Little suggests, these acquisitions give the company a solid presence in both solid tumors and blood cancers.  
The KRAS approval by the FDA is just the first step in the United States. Upwards of 40 percent of patients with metastatic colorectal cancer are unlikely to benefit from drugs like Erbitux and Vectibix because they carry a mutant form of the KRAS gene. For these populations, the test should allow physicians to put patients on other drugs that might have a better opportunity to provide benefit, thus reducing the loss of valuable treatment time.
Given that theirs is the only FDA-approved KRAS test on the U.S. market and that an estimated 110,000 colorectal cancer patients could be tested annually, Qiagen sees this test as a $20 million market. The company has 15 other such projects underway to co-develop and market companion diagnostics with major pharma and biotech companies. A quick survey of abstracts being presented at the European Society for Medical Oncology's (ESMO) 2012 meeting in Vienna would suggest that the pursuit of companion diagnostics in oncology is not showing any signs of slowing.
Ingrid CsToth and colleagues in the European Lung Cancer Working Party presented their findings of two microRNA biomarkers that offer significant predictive power in identifying which non-small cell lung cancer (NSCLC) patients will benefit most from treatment with a cisplatin-vinorelbine regimen.  
Similarly, Evelyn McKeegan and colleagues at Abbott present a retrospective analysis of four clinical trials of patients receiving the investigational drug linifanib for relapsed NSCLC. They found a signature of two tumor biomarkers was significantly associated with improved survival on linifanib but not with the other tested drugs, whether the drug was used first-line or later.
Pablo Maroto of Barcelona's Hospital de Sant Pau similarly noted links between c-Myc expression and renal cell carcinoma in patients receiving Sutent. Patients with c-Myc negative tumors experienced progression-free survival more than double that of their c-Myc positive counterparts.
As with Qiagen, Dako's expertise has largely been focused on oncology. In June, Dako announced FDA approval of two HER2 companion diagnostics for Genentech's new cancer drug Perjeta (pertuzumab) targeting HER2-positive breast cancer. And in February, the company signed a collaboration agreement with Amgen to develop a companion diagnostic for one of its investigational cancer drug candidates.  
"Dako's focus has been on oncology, primarily based on our history within cancer diagnostics and our technology offerings suited for the routine pathology lab," says Winther. "However, with Agilent's acquisition of Dako, the technology offerings have significantly expanded, and hence we now have the potential to both lead the innovations within oncology companion diagnostics, but also to plan for expanding into other therapeutic areas." 

STORY CONTINUES Click here for Part 2
Code: E101231



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