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A perfect match
It seems a logical enough extension of personalized medicine: pairing diagnostics with drug therapies to produce the best possible results, exactly matching patients whose genes predict they will be cured by a specific therapy. The field has been rapidly gaining traction, with new deals, mergers and acquisitions—both friendly and hostile—grabbing headlines.
Ever since the diagnostic and treatment combo Herceptin and its companion HercepTest was given the nod in 1998, the race has been on to match the two capabilities to patients and their needs exactly, with efficiency and cost-effectively.
"Molecular diagnostic markets are experiencing double-digit growth—and oncology, one of the key biomarker applications, remains a key investment area for in-vitro diagnostics companies and the healthcare industry overall," says Dr. Winny Tan, an analyst for business research and consulting firm Frost & Sullivan.
Although cancer is the headline-grabber, the field is seeing growth in applications for infectious diseases and in prenatal care, with a number of companies rapidly entering the field of non-invasive prenatal diagnostics. This rapidly growing market segment also relies upon molecular techniques like sequencing or arrays.
Using the companion diagnostic not only may improve therapeutic outcomes, but also may save patients and healthcare systems a significant amount of money since the newer classes of drugs can cost tens of thousands of dollars. By determining mutation status, doctors can potentially prescribe the relevant drugs only to patients who are expected to benefit from them.
Molecular diagnostics and arrays: A primer
Molecular diagnostics, or analysis of nucleic acids for guiding healthcare decisions, has the greatest level of integration into medical practice. There is increasing adoption of these tests as doctors are getting more familiar with and appreciate the improved sensitivity of these methods. This is the most mature segment of this diagnostic area, as the largest volume of test development from clinical laboratories and companies is occurring in this space. It seems as if new genetic tests are introduced every week, and the recent published development rates, such as those posted on the U.S. National Institutes of Health (NIH) website, www.ncbi.nlm.nih.gov/sites/GeneTests/, bear out that out.
Array-based diagnostics are maturing and continuing to have clinical applications, with an ever-increasing volume of clinical studies being published. More recently, clinical sequencing applications are coming to the fore, especially since next-generation sequencing (NGS) platform manufacturers are lowering the cost of sequencing the whole genome.
"A $1,000 genome is price-competitive with some of the genetic tests that are currently reimbursed," says Tan. "Even at the more basic techniques in molecular diagnostics, like PCR-based tests, will continue to grow due to infectious disease applications."
A small sandbox, with a lot of sand
According to a 2011 Frost & Sullivan report, more than 75 percent of the molecular diagnostics market is controlled by nine companies: Roche Diagnostics, QIAGEN, Gen-Probe, Abbott Diagnostics, Siemens, Becton Dickinson, Cepheid, bioMérieux and Beckman Coulter. Roche is the undisputed market leader with an almost 30 percent share and an unparalleled product portfolio, which includes molecular diagnostic tests for oncology, virology, microbiology and blood screening.
International diagnostics company QIAGEN's growth rate has outpaced competitors over the past three years, and the company has continued to announce and plan for new deals at the dawn of 2012. Emerging from primarily a sample-preparation technology and PCR reagent vendor, the company has aggressively expanded its business to the extent that approximately half of its sales now come from molecular diagnostics.
Similarly, Gen-Probe's growth rate has outpaced the industry average. The company is currently the global market leader in chlamydia and gonorrhea testing, and its innovative human papilloma virus test, which is CE-marked in Europe, is eagerly awaited in the United States.
Roche is the clear leader in the oncology segment. Roche has the capacity to design drugs and diagnostics, but it still does work with other companies. It recently made headlines as the company behind the hostile bid to take over Illumina. That deal would be critical as Illumina is known for its gene-mapping equipment, and is said to be on the verge of building a device that can map a sequence in a day, rather than in weeks or even months. Questions on that deal were referred to representatives of Genentech, another major player in the field, and part of the Roche family.
Dr. Bob Wasserman is a personalized healthcare strategy expert in oncology at Roche. He is responsible for the overarching personalized healthcare strategy and implementation across Roche's pRED oncology discovery and translational areas and the preclinical and clinical portfolio.
"Oncology is our biggest therapeutic area," Wasserman says, "and we have a full pipeline of new molecules to treat cancers. Everybody's aware of this need. Cancer's clearly moving toward a world where more drugs are approved with companion diagnostics. The key question to answer is, 'What is it about those cancers that makes them respond' to a particular therapy?"
Drilling down to the unique way a tumor behaves in a patient drives the way the field is integrating this double-barreled approach. Currently, at Roche, this has gone beyond the clinic into identifying patients and enrolling them in the appropriate studies—for them, and for their tumors.
"I can confirm that in 2011, we put three new antibodies into the clinic for which we enrolled patients based on them having tumors that expressed the protein that was the target or related to the target of the antibody therapy," says Wasserman. "We used a biomarker to select patients, and we did this starting from the very first dosing in humans. I think this may be unique for the industry."
What makes cancer the answer?
According to Tan, a large number of cancer biomarkers have been unsuccessful to date because of their non-specificity to the disease.
"Some biomarkers are generalized indicators of an immune response to the disease rather than the disease itself," she says. "Also, some blood markers are difficult to localize the disease when detected which is important in cancer for example. Understanding the mechanism of why the biomarker appears helps in determining specificity."
Tan says she thinks this is why disease signatures are getting more complex.
"The overly simple, single-biomarker test for a condition as complex as cancer is pretty unrealistic. The predictive value goes up when more markers are factored in," she says. "I think the reason why cancer biomarkers in research don't become successful diagnostic markers is that researchers aren't necessarily considering if a biomarker is useful or meets an unmet need for the doctor's decision-making as this is specific to patient management area. If they did, I think the publications would include proof of clinical utility in addition to just higher specificities and sensitivities."
The bottom line? If a biomarker can detect disease earlier or pre-disease, she offers, does that mean something can be done by the doctor or patient? If that answer is no, the test won't be ordered by the doctor.
Roche's Wasserman offers a similar opinion.
"Cancers are very complex," he says. "If we can't find the one thing that's driving it, it could be that the solution is made up of a group of biomarkers in the future."
Dr. Nicholas Kenny, executive vice president of oncology for contract research organization INC Research, has a good perspective on the state of the field, since his company has conducted more than 350 Phase I through IV oncology trials and investigated nearly 130 new and various anticancer therapies, including the introduction of more than 30 new chemical entities in first-in-man trials. Kenny says that lung cancer is a good example of how this approach works, and that combination diagnostics/drugs have come out the end of the pipeline.
"We're seeing this come up in the news all the time," Kenny says. "We're finally seeing targeting becoming a reality. A good example of this is in lung cancer. We came to early-phase trials in that area in a hurry. With chemotherapy, we treated everyone almost the same. What we are able to get out of a biopsy now, it's really remarkable."
Lung cancer duos gaining ground
As just one example of Kenny's point, in August of last year, the U.S. Food and Drug Administration (FDA) approved crizotinib (Xalkori) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) that express the abnormal anaplastic lymphoma kinase (ALK) gene. Xalkori is a Pfizer product.
Xalkori was approved with a companion diagnostic test that will help determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such targeted therapy approved by the FDA this year. The probe kit is a product of Abbott Molecular, approved under the priority treatment program, which allows for priority approval of drugs with special promise.
This ALK gene abnormality causes cancer development and growth. About 1 to 7 percent of those with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically non-smokers. Xalkori works by blocking certain proteins called kinases, including the protein produced by the abnormal ALK gene. At the point of approval, this was the second combination approved by the FDA last year.
Leaders of the pack
Another leader of the pack is diagnostics company QIAGEN, which has made several strategic moves of late. QIAGEN continues to build its international profile as a leading independent provider of molecular technologies for personalized healthcare, currently offering more than 30 assays that include tests for the biomarkers KRAS, BRAF and PI3K.
QIAGEN is expanding its presence in the personalized healthcare field through regulatory submissions, such as two completed in mid-2011 in the United States for the KRAS biomarker that are the result of an extensive range of research and development partnerships. It most recently announced a new assay, its therascreen EGFR Mutation Detection Kit RGQ in Japan. That tool detects genetic mutations to identify patients likely to experience a positive outcome with EGFR-inhibitor drugs targeting NSCLC. EGFR, the epidermal growth factor receptor, has been shown to play an important role in certain cancers and is the target of many new anticancer drugs.
QIAGEN's reps call this a milestone for the company's personalized healthcare strategy, as Japan is one of the world's largest markets for companion diagnostic tests. In April 2011, QIAGEN's therascreen KRAS Mutation Detection Kit was approved in Japan, targeting a different biomarker that is also used to guide cancer treatment decisions. The potential patient population alone in Japan for EGFR and KRAS testing is estimated at approximately 100,000 per year.
Next up for the company? QIAGEN also acquired the French diagnostics company Ipsogen last year, gaining rights to a portfolio of biomarkers including JAK2 and BCR-ABL that are believed to play a role in various blood cancers.
"Greater use of companion diagnostic tests such as our EGFR and KRAS assays may help overcome significant challenges by maximizing the efficacy and safety of therapies and improving patient outcomes," says Dr. Steve Little, vice president of global personalized healthcare at QIAGEN. "Japanese and other East Asian populations generally have a higher rate of EGFR mutations than other groups, and non-smoking East Asian women are the largest potential market for EGFR-inhibitor anticancer drugs. This approval allows QIAGEN to market our companion diagnostic along with major pharmaceutical companies offering certain EGFR-inhibitor drugs."
And let's not forget …
Another player of late has been Ventana Medical Systems Inc., a member of the Roche group, which recently launched a strategic collaboration agreement with Bayer Pharma AG for the development of a molecular companion diagnostic test that can help identify patients most likely to benefit from a novel Bayer antibody-drug conjugate (ADC). The deal accompanies other pacts that Ventana has inked with Pfizer and Sydndam Pharmaceuticals.
And in the lung cancer space, Ventana is also developing the first fully automated and standardized immunohistochemistry companion diagnostic test for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements. The test will identify NSCLC patients with ALK gene rearrangements who may benefit from Pfizer's Xalkori, the drug approved for use in the United States last August.
Where do we go from here?
Infectious disease testing is at least 60 percent of the molecular diagnostics market, says Tan, but the general diagnostics industry is undergoing a huge amount of change in regulatory, reimbursement, coding and healthcare areas. Overall, she adds, the general expectation is that reimbursement levels will continue to fall for all diagnostics, and that the molecular diagnostic segment isn't immune.
QIAGEN's Little says that what's significant is that it's difficult for a diagnostics company to do all the work themselves from a clinical perspective—that's why importation partnerships are key.
"The industry has begun to believe in using diagnostics to identify patient responders," he says. "After several years of slow movement, the pharmaceutical industry has begun to believe that. We are somewhat hampered by not doing clinical trials ourselves—ideally, an objective randomized clinical trial," he says. "With our global reach, QIAGEN has become a company of choice for drug companies."
Little concludes by adding that, while the bulk of his company's partnerships are in oncology, he says its next important area is in inflammatory disease. QIAGEN is also working in the neurology and psychiatry spaces.
Insurance reimbursements aside, Tan says the ability to stratify patients with companion diagnostics, no matter the disease, is driving the healthcare field closer to personalized medicine. Embracing the concept that people respond differently to potential therapies and that some of that response is tied to the genetic makeup of the individual is a huge stride.
Truly personalized medicine, she surmises, would be at the individual genome level. For that to happen, she opines that that would have to wait for NGS to get cheaper and for clinical researchers to be able to pull out the clinically relevant conclusions.
"We probably don't even want this granularity—we pretty much want clear conclusions to be able to make effective actions," she says. "I think the most important role of companion diagnostics in the industry today is to help change the low valuation of diagnostics in health management. What I mean by this is that people are generally willing to pay a lot of money for life-saving drugs, but the diagnostics are so cost-sensitive. Changing the cost-sensitive nature of in-vitro diagnostics is so critical as the current dynamics of the industry is leading to a decreasing trend in reimbursement for laboratory tests."
Over at Roche, Wasserman says the company 's development pipeline in the cancer space is full.
"There are currently 20 projects in oncology that have a diagnostic test component as part of their development," Wasserman says. "Although for some of these projects, we would likely use a test already available, and due to anticipated attrition in the pipeline, we would not expect all 20 projects to make it to the market."
INC Research's Kenny says progress in this area is "nothing short of remarkable."
"We're not curing people overnight, but if we can get more people to a stable condition more quickly, it's wonderful," he says.