Ever since the diagnostic and treatment combo Herceptin andits companion HercepTest was given the nod in 1998, the race has been on tomatch the two capabilities to patients and their needs exactly, with efficiencyand cost-effectively.
"Molecular diagnostic markets are experiencing double-digitgrowth—and oncology, one of the key biomarker applications, remains a keyinvestment area for in-vitrodiagnostics 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 seeinggrowth in applications for infectious diseases and in prenatal care, with anumber of companies rapidly entering the field of non-invasive prenataldiagnostics. This rapidly growing market segment also relies upon moleculartechniques like sequencing or arrays.
Using the companion diagnostic not only may improvetherapeutic outcomes, but also may save patients and healthcare systems asignificant amount of money since the newer classes of drugs can cost tens ofthousands of dollars. By determining mutation status, doctors can potentiallyprescribe the relevant drugs only to patients who are expected to benefit fromthem.
Molecular diagnosticsand arrays: A primer
Molecular diagnostics, or analysis of nucleic acids forguiding healthcare decisions, has the greatest level of integration intomedical practice. There is increasing adoption of these tests as doctors aregetting more familiar with and appreciate the improved sensitivity of thesemethods. This is the most mature segment of this diagnostic area, as thelargest volume of test development from clinical laboratories and companies isoccurring in this space. It seems as if new genetic tests are introduced everyweek, and the recent published development rates, such as those posted on theU.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 haveclinical applications, with an ever-increasing volume of clinical studies beingpublished. More recently, clinical sequencing applications are coming to thefore, especially since next-generation sequencing (NGS) platform manufacturersare lowering the cost of sequencing the whole genome.
"A $1,000 genome is price-competitive with some of thegenetic tests that are currently reimbursed," says Tan. "Even at the more basictechniques in molecular diagnostics, like PCR-based tests, will continue togrow due to infectious disease applications."
A small sandbox, witha lot of sand
According to a 2011 Frost & Sullivan report, more than75 percent of the molecular diagnostics market is controlled by nine companies:Roche Diagnostics, QIAGEN, Gen-Probe, Abbott Diagnostics, Siemens, BectonDickinson, Cepheid, bioMérieux and Beckman Coulter. Roche is the undisputedmarket leader with an almost 30 percent share and an unparalleled productportfolio, which includes molecular diagnostic tests for oncology, virology,microbiology and blood screening.
International diagnostics company QIAGEN's growth rate hasoutpaced competitors over the past three years, and the company has continuedto announce and plan for new deals at the dawn of 2012. Emerging from primarilya sample-preparation technology and PCR reagent vendor, the company hasaggressively expanded its business to the extent that approximately half of itssales now come from molecular diagnostics.
Similarly, Gen-Probe's growth rate has outpaced the industryaverage. The company is currently the global market leader in chlamydia andgonorrhea testing, and its innovative human papilloma virus test, which isCE-marked in Europe, is eagerly awaited in the United States.
Roche is the clear leader in the oncology segment. Roche hasthe capacity to design drugs and diagnostics, but it still does work with othercompanies. It recently made headlines as the company behind the hostile bid totake over Illumina. That deal would be critical as Illumina is known for itsgene-mapping equipment, and is said to be on the verge of building a devicethat can map a sequence in a day, rather than in weeks or even months.Questions on that deal were referred to representatives of Genentech, anothermajor player in the field, and part of the Roche family.
Dr. Bob Wasserman is a personalized healthcare strategyexpert in oncology at Roche. He isresponsible for the overarching personalized healthcare strategy andimplementation across Roche's pRED oncology discovery and translational areasand 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'saware of this need. Cancer's clearly moving toward a world where more drugs areapproved with companion diagnostics. The key question to answer is, 'What is itabout those cancers that makes them respond' to a particular therapy?"
Drilling down to the unique way a tumor behaves in a patientdrives the way the field is integrating this double-barreled approach.Currently, at Roche, this has gone beyond the clinic into identifying patientsand enrolling them in the appropriate studies—for them, and for their tumors.
"I can confirm that in 2011, we put three new antibodiesinto the clinic for which we enrolled patients based on them having tumors thatexpressed the protein that was the target or related to the target of theantibody therapy," says Wasserman. "We used a biomarker to select patients, andwe did this starting from the very first dosing in humans. I think this may beunique for the industry."
What makes cancer theanswer?
According to Tan, a large number of cancer biomarkers havebeen unsuccessful to date because of their non-specificity to the disease.
"Some biomarkers are generalized indicators of an immuneresponse to the disease rather than the disease itself," she says. "Also, someblood markers are difficult to localize the disease when detected which isimportant in cancer for example. Understanding the mechanism of why thebiomarker appears helps in determining specificity."
Tan says she thinks this is why disease signatures aregetting more complex.
"The overly simple, single-biomarker test for a condition ascomplex as cancer is pretty unrealistic. The predictive value goes up when moremarkers are factored in," she says. "I think the reason why cancer biomarkersin research don't become successful diagnostic markers is that researchersaren't necessarily considering if a biomarker is useful or meets an unmet needfor the doctor's decision-making as this is specific to patient managementarea. If they did, I think the publications would include proof of clinicalutility in addition to just higher specificities and sensitivities."
The bottom line? If a biomarker can detect disease earlieror pre-disease, she offers, does that mean something can be done by the doctoror 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 theone thing that's driving it, it could be that the solution is made up of agroup of biomarkers in the future."
Dr. Nicholas Kenny, executive vice president of oncology forcontract research organization INC Research, has a good perspective on thestate of the field, since his company has conducted more than 350 Phase Ithrough IV oncology trials and investigated nearly 130 new and variousanticancer therapies, including the introduction of more than 30 new chemicalentities in first-in-man trials. Kenny says that lung cancer is a good exampleof how this approach works, and that combination diagnostics/drugs have comeout the end of the pipeline.
"We're seeing this come up in the news all the time," Kennysays. "We're finally seeing targeting becoming a reality. A good example of thisis in lung cancer. We came to early-phase trials in that area in a hurry. Withchemotherapy, we treated everyone almost the same. What we are able to get outof a biopsy now, it's really remarkable."
Lung cancer duosgaining ground
As just one example of Kenny's point, in August of lastyear, 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 anaplasticlymphoma kinase (ALK) gene. Xalkori is a Pfizer product.
Xalkori was approved with a companion diagnostic test thatwill help determine if a patient has the abnormal ALK gene, a first-of-a-kindgenetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the secondsuch targeted therapy approved by the FDA this year. The probe kit is a productof Abbott Molecular, approved under the priority treatment program, whichallows for priority approval of drugs with special promise.
This ALK gene abnormality causes cancer development andgrowth. 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 worksby blocking certain proteins called kinases, including the protein produced bythe abnormal ALK gene. At the point of approval, this was the secondcombination 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 itsinternational profile as a leading independent provider of moleculartechnologies for personalized healthcare, currently offering more than 30assays that include tests for the biomarkers KRAS, BRAF and PI3K.
QIAGEN is expanding its presence in the personalizedhealthcare field through regulatory submissions, such as two completed inmid-2011 in the United States for the KRAS biomarker that are the result of anextensive range of research and development partnerships. It most recentlyannounced a new assay, its therascreen EGFR Mutation Detection Kit RGQ inJapan. That tool detects genetic mutations to identify patients likely toexperience 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 targetof many new anticancer drugs.
QIAGEN's reps call this a milestone for the company'spersonalized healthcare strategy, as Japan is one of the world's largestmarkets for companion diagnostic tests. In April 2011, QIAGEN's therascreenKRAS Mutation Detection Kit was approved in Japan, targeting a differentbiomarker that is also used to guide cancer treatment decisions. The potentialpatient population alone in Japan for EGFR and KRAS testing is estimated atapproximately 100,000 per year.
Next up for the company? QIAGEN also acquired the Frenchdiagnostics company Ipsogen last year, gaining rights to a portfolio ofbiomarkers including JAK2 and BCR-ABL that are believed to play a role invarious blood cancers.
"Greater use of companion diagnostic tests such as our EGFRand KRAS assays may help overcome significant challenges by maximizing theefficacy 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 EGFRmutations than other groups, and non-smoking East Asian women are the largestpotential market for EGFR-inhibitor anticancer drugs. This approval allowsQIAGEN to market our companion diagnostic along with major pharmaceuticalcompanies offering certain EGFR-inhibitor drugs."
And let's not forget…
Another player of late has been Ventana Medical SystemsInc., a member of the Roche group, which recently launched a strategiccollaboration agreement with Bayer Pharma AG for the development of a molecularcompanion diagnostic test that can help identify patients most likely tobenefit from a novel Bayer antibody-drug conjugate (ADC). The deal accompaniesother pacts that Ventana has inked with Pfizer and Sydndam Pharmaceuticals.
And in the lung cancer space, Ventana is also developing thefirst fully automated and standardized immunohistochemistry companiondiagnostic test for anaplastic lymphoma receptor tyrosine kinase (ALK) generearrangements. The test will identify NSCLC patients with ALK generearrangements who may benefit from Pfizer's Xalkori, the drug approved for usein the United States last August.
Where do we go fromhere?
Infectious disease testing is at least 60 percent of themolecular diagnostics market, says Tan, but the general diagnostics industry isundergoing a huge amount of change in regulatory, reimbursement, coding andhealthcare areas. Overall, she adds, the general expectation is thatreimbursement levels will continue to fall for all diagnostics, and that themolecular diagnostic segment isn't immune.
QIAGEN's Little says that what's significant is that it'sdifficult for a diagnostics company to do all the work themselves from aclinical perspective—that's why importation partnerships are key.
"The industry has begun to believe in using diagnostics toidentify patient responders," he says. "After several years of slow movement, thepharmaceutical industry has begun to believe that. We are somewhat hampered bynot doing clinical trials ourselves—ideally, an objective randomized clinicaltrial," he says. "With our global reach, QIAGEN has become a company of choicefor drug companies."
Little concludes by adding that, while the bulk of hiscompany's partnerships are in oncology, he says its next important area is ininflammatory disease. QIAGEN is also working in the neurology and psychiatryspaces.
Insurance reimbursements aside, Tan says the ability tostratify patients with companion diagnostics, no matter the disease, is drivingthe healthcare field closer to personalized medicine. Embracing the conceptthat people respond differently to potential therapies and that some of that responseis tied to the genetic makeup of the individual is a huge stride.
Truly personalized medicine, she surmises, would be at theindividual genome level. For that to happen, she opines that that would have towait for NGS to get cheaper and for clinical researchers to be able to pull outthe clinically relevant conclusions.
"We probably don't even want this granularity—we pretty muchwant clear conclusions to be able to make effective actions," she says. "Ithink the most important role of companion diagnostics in the industry today isto help change the low valuation of diagnostics in health management. What Imean by this is that people are generally willing to pay a lot of money forlife-saving drugs, but the diagnostics are so cost-sensitive. Changing thecost-sensitive nature of in-vitrodiagnostics is so critical as the current dynamics of the industry is leadingto a decreasing trend in reimbursement for laboratory tests."
Over at Roche, Wasserman says the company's developmentpipeline in the cancer space is full.
"There are currently 20 projects in oncology that have adiagnostic test component as part of their development," Wasserman says."Although for some of these projects, we would likely use a test alreadyavailable, and due to anticipated attrition in the pipeline, we would notexpect all 20 projects to make it to the market."
INC Research's Kenny says progress in this area is "nothingshort of remarkable."
"We're not curing people overnight, but if we can get morepeople to a stable condition more quickly, it's wonderful," he says.