Biomarkers and companion diagnostics expand drug potential

Fig. 1. Biomarkers are a growing proportion of cancer testing. Source: Kalorama Information

The promise of personalized medicine (or, more recently, “precision” medicine) is becoming realized as more biomarkers and companion diagnostics roll out of clinical research and into commercial reality. For some new drugs, especially in oncology, the companion diagnostic is essential to approval. Payers, realizing that companion diagnostics can focus expensive drugs on appropriate patients (thereby avoiding reimbursement of the drug for others, and providing meaningful health benefit to members) are becoming more receptive to the tests. At the same time, some of the testing is becoming a tailored service from healthcare providers, whose labs have developed their own protocols for the testing.

Last June’s Supreme Court ruling, in APL vs. Myriad Genetics, that unaltered human DNA could not be patented, is expected to have mixed results in future biomarker commercialization. While voting unanimously that genes cannot be patented, the Court also gave approval for patenting complementary DNA (cDNA)—a synthetic step in Myriad’s (and others’) form of genetic testing. The ability to patent cDNA and other synthetic testing protocols will be the subject of future litigation (indeed, Myriad followed the Supreme Court decision with lawsuits against some out-of-the-gate competitors). But the consensus among industry commentators seems to be that some genetic testing will now be more readily commercialized, and the business overall will forge ahead.

Biomarkers for cancer

A biomarker is defined as a naturally occurring molecule, gene or characteristic that can be objectively measured and evaluated as an indicator of either normal biological or pathogenic processes, or pharmacological response to a therapeutic intervention. Typically, this involves genetic mutations, aberrant protein expression, or changing triglycerides levels. To date, the bulk of the biomarker work has been carried out in oncology, but interest and developmental efforts are underway in a wide array of non-oncology indications as well.

Fig. 2. How various biomarker tests affect therapy market.

Source: Kantar Health

Fig. 3. Companion diagnostics developed in-house or with collaborators. Source: Kantar Health

Today, the world market for in vitro diagnostic testing in oncology has reached $4.8 billion, and is expected to grow by 9%/year for the next few years to reach $7.3 billion by 2017, according to market researcher Kalorama Information (New York). Biomarker-based tests will outpace traditional testing like PAP smears, HPV and other assays, point-of-care tests of tumors or cancer cells and the like (Fig. 1). More than 200 companies are involved in some form of cancer-related testing, ranging from top-tier in vitro diagnostics giants Abbott, Novartis and Roche, to device makers such as Becton Dickinson and Siemens, to companies focused on molecular testing such as Gen-Probe and Bio-Rad, says Kalorama.

According to recent data from McKesson Specialty Health/USOncology Network (MSH), of the $18.5 billion in US drug sales related to anti-cancer drugs, nearly 60% were targeted therapies (as opposed to standard chemotherapy). And, of the 189 oncology therapies currently under development in the period 2012—2015, 105 agents (56% of the total) have an associated biomarker. By 2017, 34 of these pipeline therapies are expected to launch, and 20 of these will be targeted to biomarkers.

A separate study conducted by Kantar Health evaluates 69 agents that are currently in clinical development within the oncology pipeline. The study author, Stephanie Hawthorne, PhD, director, clinical and scientific assessment, Kantar Health (Foster City, CA) says: “Interestingly, the majority of the indications in which these 69 agents are being developed target rather small indications in terms of patient population size, with 60% of the ongoing pivotal trials being conducted in indications with a target population of less than 12,500 patients.”*

This represents a marked change from a decade ago, when much of the focus was on developing drugs that were targeted at the largest possible patient populations, such as breast cancer, non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Within this trend, she notes that some of the smaller indications represent tumors in which the incidence of disease is small overall, but others represent biomarker subsets of larger tumor types, such as Met+ NSCLC or NRAS mutant melanoma (Fig. 2).

However, despite the oncology community’s growing focus on personalized medicine, Hawthorne says that only 22% of the pipeline agents currently in pivotal trials are being developed in a biomarker-defined patient population (Fig. 4).

Oncology indications

“Unlike diseases such as hypertension or diabetes, which tend to be more limited in their manifestations and management, cancer is really a collection of hundreds if not thousands of unique diseases,” says Harish Dave, MD, MBA, a VP at Quintiles (Rockville, MD). With anti-cancer therapies being among the costliest and most toxic in the pharmaceutical arsenal, “The ability to avoid the unnecessary administration of expensive therapies—which can cost upwards of $10,000/month or more—that will provide no clinical benefit and may incur a lot of side effects (and even ER or hospital visits) provides tremendous opportunities for cost savings to plans and to the overall healthcare system, so there’s a lot of interest in this,” adds Michael Kolodziej, MD, FACP, national medical director for Oncology Strategies (Hartford, CT).

Fig. 4. Kantar Health projects that 30% of cancer patients will have a predictive biomarker by 2018.

From the physician and patient perspective, “The science has moved along fairly quickly in oncology because there is great sense of urgency and this is not a very forgiving disease category,” says Ed Pezalla, MD, national medical director for pharmacy policy at Aetna. “While you can comfortably experiment over several months with finding the right drug for controlling, say, high blood pressure, when it comes to tumor progression, you may lose a lot of ground with the trial-and-error approach and the resulting delays.”

Despite ongoing advances in genomic medicine, “Biomarkers still face multiple challenges going from bench to bedside,” says Meghan FitzGerald, president of Cardinal Health Specialty Solutions (Dublin, OH). “The industry is still grappling with how to cost-effectively integrate biomarkers into clinical care, but we believe as the science continues to advance and therapies become increasingly target-specific, biomarkers will become increasingly valuable and will ultimately play a bigger role in advancing cancer care.”

“If molecular diagnostic testing for cancer is inappropriately utilized, it could be expensive for the healthcare system and could lead to treatment recommendations that might not be fully evidence-based,” explains Marcus Neubauer, MD, medical director, oncology services for MSH. For instance, molecular diagnostic testing is often ordered when all “standard” therapy has been exhausted and patients are unlikely to benefit from further treatment regardless of which mutations are present.

“Identification of actionable DNA alternations is the best way to make advances in the overall treatment of cancer, and this can’t be ignored by payers,” he says. MSH is working on guidance to include molecular diagnostics in its network.

With regard to coverage decisions for any given biomarker-related test, Pezalla of Aetna notes that drug and test developers must demonstrate to payers that the following two key questions can be answered in the affirmative (and to support this with data, wherever possible):

• Does the test accurately and reliably measure what it’s supposed to measure?
• Are the test results able to impact patient outcomes, or physician decisionmaking regarding whether to use the medication or not?

“When it comes to deciding whether to reimburse a given test, we don’t have hard and fast rules with regard to specific outcome measures—we evaluate each test individually, but ultimately the question is ‘Has this test been shown to change patient outcomes or medical decisionmaking?’ That’s what we really need to know,” says Pezalla of Aetna.

For instance, test developers and drug makers must provide sound evidence that demonstrates improved outcomes. “If a target biomarker can help to stratify a patient group so that a $3,000 test can be shown to eliminate 60% of potential patients from taking a $10,000/month therapy, that provides a compelling cost-benefit analysis for the payer and hopefully leads to payer coverage of that test,” explains Kathy Lokay, president and CEO of Via Oncology, a D3 Oncology Solutions Co. (Pittsburgh).

Fig. 5. Frequency of approach in claims review by payers.

Source: Kantar Health

Fig. 6. Relative importance, for reimbursement decisions, of test factors.

Similarly, experts agree that efforts to attain proper coding for new biomarker-related diagnostic tests—in terms of designated National Drug Code (NDC) codes from FDA, and designated procedure and laboratory test codes from the American Medical Assn.—will expedite market uptake. “Expending the effort to establish dedicated codes for the test early on is preferable to forcing prescribers to rely on code stacking (that is, cobbling together an array of non-specific codes to roughly cover the individual lab procedures required for the test), says Pezalla of Aetna. “Private and government payers always prefer to see specific codes.”

The costs of these biomarker-related tests can vary widely, based on what is being tested and whether the physicians or pathology labs are free to use standard lab protocols or are required to use a particular “branded” test procedure. And to date, no consistent payment framework or infrastructure has evolved to systematize the reimbursement decisionmaking around these complex tests (Fig. 5, 6).

While experts agree that concurrent development of the diagnostic test is essential to supporting FDA approval and market uptake of a biomarker-targeted therapy, two options are available for getting it done: The drug company can partner with a company that specializes in diagnostic test development (as Pfizer did for Xalkori, partnering with Abbott Molecular), or can develop the test procedure itself using in-house capabilities (as Roche did for Zelboraf), and there are pros and cons associated with both approaches (Fig. 3). But in recent years, several biopharma giants, including Abbott, Johnson & Johnson and Roche, have successfully developed necessary companion diagnostic tests without the use of a third-party partner.

Successful examples of biomarker-targeted therapies include Herceptin (trastuzumab, Roche), which is approved for HER2+ breast cancer, Xalkori (crizotinib, Pfizer), which is approved for ALK+ non-small cell lung cancer (along with a companion diagnostic FISH assay), and Zelboraf (vemurafenib, Roche/Daiichi Sankyo), which is approved for BRAF V600E mutant melanoma.

“With these drugs, the manufacturers quickly recognized the activity of these agents in biomarker-selected patient populations and then directed development toward those groups—undeterred by the possibility of reducing market size potential. They have found that enrichment for patients who are highly likely to respond to their drugs can lead to faster product development times,” says Hawthorne of Kantar Health.

Both Xalkori and Zelboraf entered Phase I in 2006 and both received FDA approval in 2011—“an exceptionally short time to approval,” notes Mark Green, MD, chief medical officer at Xcenda (Charlotte, NC). Such rapid approval not only speeds time to market for patients, but helps the manufacturer to maximize exclusivity for that agent. And wisely, in both of these cases, the manufacturers began development of a companion diagnostic very early in the drug development and incorporated it into the pivotal trial design, “which was critical,” adds Hawthorne of Kantar Health.

While these examples refer to the development of biomarkers that can identify patients most likely to respond to a specific targeted agent, others can be used to identify patients who are unlikely to respond (thereby saving money for payers and reducing the patient’s unnecessary exposure to toxic therapies). One example, notes Hawthorne of Kantar Health, is the KRAS mutation test in colorectal cancer, which identifies patients with a KRAS mutation who are unlikely to benefit from an EGFR inhibitor such as Erbitux (cetuximab, Eli Lilly/Bristol-Myers Squibb/Merck Serono) or Vectibix (panitumumab, Amgen/Takeda). Still others, such as the prostate-specific antigen (PSA), are used to measure response to therapy in treated patients.

“It’s true that biomarkers will segment the patient population and likely reduce the number of patients eligible for treatment with a specific agent, but if a targeted agent is truly effective only in a biomarker-defined population, then development in an unselected population could dilute its apparent activity, and possibly lead to termination of development of the active agent,” says Hawthorne of Kantar Health. “Many believe that Herceptin probably would not have made it to market if development had not been honed toward the 25% of the breast cancer population that is HER2+.”

And, while some question the downside of patient-population segmentation that will inevitably limit the drug’s potential market reach, “the advantages include the potential to develop truly targeted therapies and creating a series of orphan indications (with favorable regulatory treatment) that can lead to the potential to have niche-buster indications,” says Dave of Quintiles.

An important pitfall for manufacturers to avoid is to bring a drug to market in a biomarker-defined patient population but without a validated companion diagnostic. “The FDA has taken a firm stand that it will not approve the drug if the test to identify the patients is not also available and approvable,” says Hawthorne of Kantar Health. “ChemGenex learned this lesson the hard way when it sought FDA approval of Omapro (omacetaxine; now called Synribo and owned by Cephalon/Teva) in T315I mutant chronic myeloid leukemia (CML) without a diagnostic assay to detect the mutation.” In its 2010 rejection of Omapro, FDA cited the lack of a companion diagnostic to identify the targeted patient population.

Notably, although an FDA-approved companion diagnostic is required for FDA approval of today’s biomarker-indicated therapies, “There is little regulation on which test actually needs to be performed in everyday clinical practice,” says Hawthorne of Kantar Health. “This has led to the development of alternative marketed tests or so-called home-brew assays that may be utilized at the lab or pathologists’s discretion.”

A key issue in this arena is that companion diagnostics approved at the time of drug approval are often priced much higher than a laboratory-developed test (LDT). “If the biomarker is novel, payers might insist—and labs might use—the branded companion diagnostic. However, over time, labs will often develop their own LDT at lower cost, thus payers will allow these LDTs to be used, too,” says Gordon Gochenauer, a director at Kantar Health. This commonly happens in hospitals first, since most have onsite pathology labs. “In this hospital case, payers do not see the exact test that is being used since the payers are billed as a DRG,” says Gochenauer. By comparison, he notes that in community practices, samples are often sent to central labs that might be contracted with payers to use a cheaper LDT.

In this regard, payers may have direct written policies in place to avoid the use of the novel (and likely more expensive) versions of biomarker tests. “A typical example is HER2 testing, where physicians are directed to use drugs like Kadcyla, Perjeta, Herceptin (all from Genentech/Roche) or Tykerb (GSK), says Gochenauer. There are two main categories of testing for HER2—immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Pathologists commonly use LDT versions on these tests but there are several branded versions, as well. “Some payers will have policies against using an LDT, but some might have contracts with labs to favor the use of LDTs rather than the FDA-approved tests, and these payers are likely the ones that will also have written policies against using the branded biomarker assays that use novel diagnostic techniques.”

“In general, payers are all over the board with their level of sophistication and level of interest in managing biomarkers,” Gochenauer adds.

Biomarkers for non-oncology indications

While the oncology sector has been leading the charge in efforts to develop targeted biomarkers and associated companion diagnostic tests, promising developments are underway in a variety of non-oncology disease categories, as well. Within this realm, efforts seem to be going down two distinct pathways—to exploit specific biomarkers that either are tied to a specific drug or tied to a specific disease (but not necessarily to any given therapeutic option within that category).

“Cancer is a group of diseases defined by gene mutations so identifying these driver mutations can lead to targeted therapy,” explains McKesson’s Neubauer. “This connection is less clear in non-oncologic diseases but there are some obvious examples, such as Gaucher’s disease, where targeted therapy can be used because it is a rare disease with an enzyme defect caused by a gene mutation.”

Disease-specific biomarkers and companion diagnostics

Rheumatoid arthritis is a chronic, debilitating disease driven by inflammation, significant bone and cartilage erosion, and structural damage, and has associated with it a range of co-morbidities (such as increased risk of cardiovascular disease, stroke and others). There are 1.5 million patients with RA in the US, and four million worldwide, and as many as 50% of RA patients are out of the workplace within five years of diagnosis, said Bill Hagstrom, CEO of Crescendo Bioscience (South San Francicso), a molecular diagnostics laboratory focused on rheumatology, in a July podcast hosted by Burrill Report.**

While the traditional method for evaluating RA patients involves an assessment of a few qualitative attributes (typically external signs and symptoms such as pain and swelling), Crescendo’s Vectra DA test establishes a unique signature for RA disease activity level and provides a quantitative assessment (on a scale of 1 to 100) of inflammatory burden, using 12 strategically selected immune, endothelial, bone, cartilage and metabolic biomarkers that reflect the underlying biology of RA at any point in time. “Hundreds and hundreds of potential biomarkers in RA were assessed to establish the most relevant 12,” says Hagstrom. Serum concentrations of the biomarkers are integrated into a proprietary algorithm, which generates a single score of 1 to 100 to classify disease activity as low, moderate or high. He notes that today, up to 40% of RA patents fail on the initial biologic—which can cost $25,000 per patient per year—and it typically takes a patient 12—18 months to dial in to the right drug at the right dosage to effectively manage their RA symptoms.

In the 2+ years since the Vectra DA test has been on the market, it has resonated well with physicians and payers alike, says Hagstrom. “Payers are in pain as it relates to RA, because it is a chronic, lifelong disease with serious co-morbidities and expensive therapy options,” he said.

Crescendo Bioscience uses the central lab model for this test, whereby the physician draws blood and sends the sample to the company, which guarantees three-day turnaround, using a highly automated lab. The centralized lab model has other benefits: “This approach has allowed us to collect aggregated, de-identified data to use for further ongoing studies,” says Hagstrom. The cost of the test (ranging from $500—$700 per test) is processed through the patient’s payer, and the test has up to 12 relevant reimbursement codes (associated with various immunoassay biomarkers and tests) to maximize private and government payer reimbursement.

Last year, Kalydeco (ivacaftor) from Vertex Pharmaceuticals (Cambridge, MA) received FDA approval for use only in patients who have a rare form of cystic fibrosis with a specific genetic mutation (aG551D mutation in the cystic fibrosis transmembrane regulator, or CFTR, gene). Cystic fibrosis affects about 30,000 people in the US, and is the most common fatal genetic disease in the Caucasian population. About 4% of those with CF, or roughly 1,200 people, are believed to have the G551D mutation, according to the company. FDA reviewed and approved Kalydeco as an orphan drug in approximately three months, under the agency’s priority review program, for drugs that may offer significant advances in treatment over available therapies. According to the Cystic Fibrosis Foundation, Kalydeco is the first drug available that targets the underlying cause of CF—a faulty gene and its protein product (CFTR).

In some cases, competing companion diagnostic tests exist for the same drug. Take Plavix (clopidogrel) or its generic equivalent, for example. Plavix must be properly metabolized to become active and block platelet aggregation. Two companion diagnostic test makers developed a test to track this key performance attribute. “One (the AmpliChip from Roche Diagnostics) determines the ability of the patient to metabolize Plavix, and the other (the VerifyNow P2Y12 Assay from Accumetrics) determines if someone already taking Plavix is getting the desired effect on platelet aggregation,” says Pezalla of Aetna, who notes that his company covers both tests. “Using these tests can help to improve clinical decisionmaking, although no randomized controlled trials have yet shown an impact on ultimate patient outcomes.”

Within the realm of immune disorders, Roche is developing a periostin ELISA companion diagnostic for its potential asthma treatment lebrikizumab (an anti-IL-13 MAb), which is in Phase III trials. Genentech’s rontalizumab (Phase II for systemic lupus erythematosus) and Roche’s RG7449 (Phase II for asthma) are also in development, with a companion diagnostic being developed by Roche.

For Alzheimer’s disease, there is a growing belief that the most effective treatments will be those that can be given before plaque/amolyoid buildup has produced irreversible damage to the brain. Thus, many researchers in the Alzheimer’s disease arena are developing tests that allow affected patients to be diagnosed long before traditional symptoms start to present themselves—and even before clinical markers related to cognitive function begin to change.

“The goal here is not to develop a genetic test that says ‘the patient might get it,’ but to develop a test that says ‘this patient has it but has no symptoms yet,’ as this will guide both drug usage and clinical trial development,” says Pezalla of Aetna.

Genentech, Roche’s US-based biotechnology unit, will try its experimental Alzheimer’s drug crenezumab (a humanized monoclonal antibody) on people with no signs of dementia—the first such trial to assess whether early intervention can prevent or slow the disease. HHS is backing the trial as part of the government’s National Alzheimer’s Plan. According to the company, the drug—which is designed to bind amyloid beta (Abeta), the main constituent of amyloid plaque in the brains of patients with Alzheimer’s disease—will be tested among 300 members of an extended family from Medellin, Colombia, who share rare genetic mutation that typically triggers Alzheimer’s symptoms around age 45.

Also within the realm of Alzheimer’s disease, Merck is collaborating with Luminex Corp. (Austin, TX) to develop a companion diagnostic device to help screen patients for recruitment into Merck’s clinical development program for MK-8931, Merck’s lead investigational candidate for Alzheimer’s disease. “Evaluation of biomarkers that may provide an indicator of disease onset and enable earlier diagnosis, which is an important goal toward facilitating early intervention and potentially improving the treatment of Alzheimer’s disease,” said Darryle Schoepp, PhD, SVP and head of neuroscience and opzhthalmology at Merck, when the collaboration was announced in March. Luminex will develop the candidate companion-diagnostic device to measure concentrations of two candidate biomarkers (Aβ42 and t-tau) in cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment.

Similarly, Takeda Pharmaceuticals (Osaka, Japan) and Zinfandel Pharmaceuticals (Durham, NC) have developed a genetics-based Alzheimer’s biomarker risk-assignment algorithm, which is now heading toward a Phase III trial. The algorithm is said to be able to gauge the risk of a patient developing Alzheimer’s disease within a 70%—80% accuracy range (comparing favorably with what is possible using imaging and cerebrospinal-fluid-based biomarkers). The formula involves using age and APOE status in addition to the biomarker TOMM40 to predict the risk of mild cognitive impairment due to Alzheimer’s disease within five years in older adults with normal cognition. Again, the goal is to enable earlier diagnosis so that therapy can help to slow the progression before too much damage and loss of cognitive function has occurred from plaque buildup.

Beyond Alzheimer’s disease, CSF and blood-based biomarkers and imaging biomarkers are also being pursued for such neurological disorders as Parkinson’s disease, Huntington’s disease, schizophrenia, frontotemporal dementia, depression, autism and more.