The lessons learned in developing companion diagnostics (CDx) for cancer – which accounts for all but one FDA-approved in vitro CDx device – are beginning to resonate in other fields, including autoimmune, cardiovascular (CVD), central nervous system and infectious diseases. But the peculiarities of cancer, where many causative genetic alterations are known, don't easily translate to complex indications such as Alzheimer's disease (AD), which doesn't yet have a defined culprit.

Still, the pace of discovery suggests that CDx may break out of the cancer space in a big way over the next several years, provided drug and diagnostic makers work together even more closely and find a way to pay for diagnostics in the face of ever-smaller target populations.

Oncology is a well-established and growing field for CDx, according to Rainer Metzger, vice president and head of precision diagnostics for Qiagen NV, of Venlo, the Netherlands. Virtually all big pharmas now have CDx programs in place for the cancer compounds in their pipeline, he said. But the main driver of that trend was the rapid advance in understanding the genetic underpinnings of different types of cancer, such as lung cancer, which has the highest known rate of genetic alterations linked to a particular cause when tobacco use is involved.

Tagrisso (osimertinib, Astrazeneca plc), Tarceva (erlotinib, Roche AG and Astellas Pharma Inc.), Iressa (gefitinib, Astrazeneca), Gilotrif (afatinib, Boehringer Ingelheim GmbH) and Xalkori (crizotinib, Pfizer Inc.) all were approved to treat lung cancer along with FDA-approved CDx devices designed to identify the appropriate patient population.

Although all diagnostics are developed to inform treatment, companion diagnostics are advanced "to decide whether a molecularly targeted medicine is appropriate for a patient," observed Anette Breindl, senior science editor of BioWorld Today.

That observation helps to explain why some cancer drugs have moved with astonishing speed, at least in comparison to so-called "normal" drug development timelines. Tagrisso, for example, gained accelerated approval from the FDA little more than 30 months after advancing into the clinic in March 2013. The once-daily oral therapy was approved to treat patients with metastatic EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) who progressed on or after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. (See BioWorld Today, Nov. 16, 2015.)

Gilotrif was another CDx win with its approval for advanced NSCLC patients whose tumors express the EGFR exon 19 deletions or exon 21 L858R substitution gene mutations. EGFR gene mutations are estimated to be found in only about 10 percent of NSCLC cases, and the majority express the EGFR exon 19 deletions or exon 21 L858R substitution. Qiagen's Therascreen EGFR RGQ PCR Kit was designed to identify patients with those mutations who would be likely responders to the tyrosine kinase inhibitor. (See BioWorld Today, July 15, 2013.)

'Think about the biology of the patient'

Companion diagnostics also have increased the breadth of treatment across multiple tumors. Tarceva, approved in 2004 in NSCLC, was accepted the following year as a first-line treatment in pancreatic cancer following a ringing endorsement from the agency's Oncologic Drugs Advisory Committee. In 2010, after a long battle to prove its value, the drug also was approved as a maintenance therapy in NSCLC. (See BioWorld Today, Nov. 22, 2004, Nov. 4, 2005, and April 20, 2010.)

But success with a companion diagnostic in one drug doesn't give the rest of a biopharma's pipeline a free pass. In 2014, Genentech, the Roche AG unit that developed Tarceva in collaboration with OSI Pharmaceuticals Inc., halted development of onartuzumab, another important drug in its lung cancer arsenal. A planned interim analysis of the phase III METLung study of onartuzumab, or Metmab, in combination with Tarceva in MET-positive, advanced NSCLC showed the drug did not meet its primary endpoint of overall survival. (See BioWorld Today, March 4, 2014.)

Nor does the availability of a CDx for one drug mean others cannot succeed. Last year, Genentech gained accelerated approval of Alecensa (alectinib), which had FDA breakthrough therapy designation, to treat anaplastic lymphoma kinase-positive NSCLC in patients who progressed or were intolerant to Xalkori. (See BioWorld Today, Dec. 14, 2015.)

The fact that most drugs continue to move to market without CDx represents something of a conundrum for CDx developers, whose customers include not just biopharmas but also payers, physicians and patients. Development of a CDx is not without cost, yet payers have been more reticent to reimburse diagnostics than drugs, despite interest from consumers in better understanding their genetic profile.

"Patients want to be given a drug that will work and that's safe," said Jerry Lanchbury, chief scientific officer of Myriad Genetics Inc., of Salt Lake City. "If a given drug isn't matched to the biology they have, they'll want to move on to another drug and, potentially, have their cancer halted or cured and their life saved."

A validated biomarker facilitates drug development by identifying the population with increased likelihood to respond to a given treatment, especially as cancer indications move in the direction of combination therapy. The availability of a CDx enables biopharmas to look for early signals during clinical trials, to halt development early if a drug isn't working and to conduct smaller, more focused trials that accrue more quickly and still meet regulatory scrutiny, Lanchbury said.

"Fundamentally, we think about patients and doctors," he said. "We really do think about the biology of the patient and getting a matched drug that really works in the biology of the tumor."

CDx could 'rescue' shelved drugs

In that regard, CDx also may identify new opportunities for drugs sitting on the shelf, Lanchbury added, citing Astrazeneca's Lynparza (olaparib) as a poster child. Approval of the first poly ADP-ribose polymerase (PARP) inhibitor in the U.S. and EU marked a remarkable turnaround after Astrazeneca initially said it was halting development of the product and the drug class fell out of favor following a high-profile phase III failure. (See BioWorld Today, Dec. 22, 2014.)

The European Commission authorized Lynparza for maintenance treatment of ovarian cancer patients with BRCA mutations who had complete partial response to platinum-based chemotherapy. The FDA approved Lynparza as a monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who were treated with three or more prior lines of chemotherapy.

The BRCA mutations, occurring in 15 percent of ovarian cancers, prevent homologous recombination, so PARP inhibition can kill tumor cells without affecting normal cells. Lynparza's approval came with the use of Myriad's BRACAnalysis CDx, intended for the detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes.

"The original studies in ovarian cancer actually failed," Lanchbury pointed out. "The drug wasn't efficacious enough. They didn't get the improvement in progression-free survival for which they had powered the study. It wasn't until we came along with our test for the germline – BRCA1 and BRCA2, the hereditary breast and ovarian cancer genes – and did a retrospective analysis of the phase III in ovarian cancer that we showed that, in fact, the drug was improving progression-free survival in the BRCA1 and BRCA2 mutation-positive class."

The outcome represented "a cornerstone" for Myriad in the CDx market, Lanchbury said.

"We worked with Astrazeneca to rescue olaparib," he told BioWorld Insight.

First CDx coming for drugs to treat chronic disease

Beyond lung cancer, Qiagen's Metzger cited hematological cancers such as leukemia and lymphoma as ripe targets for genetic mutations that lend themselves to CDx.

In cancer, CDx has moved so quickly, in fact, that the use of related technologies such as next-generation sequencing, multiplex (polymerase chain reaction) and liquid biopsy "are where the innovation is now emerging," Metzger told BioWorld Insight.

He predicted autoimmune diseases could be the next group of indications to make their presence felt across the CDx landscape, citing Crohn's disease, rheumatoid arthritis (RA) and multiple sclerosis as among "disease areas with genetic profiles that change as they progress," following a similar pattern of alterations that often emerges in cancer.

Autoimmune diseases also are notable for their association to the microbiome, "which is getting a lot more attention" from drug and CDx developers alike, Metzger said. In chronic indications such as Crohn's, diagnostics may play a beneficial role not only as tools to stratify patients for drug development but also as tools to monitor patients across time and assess the need for invasive procedures, such as colonoscopies.

"If we look at the tests that are under development, currently they're not as advanced as in cancer," Metzger pointed out. "But I think within the next 12 to 24 months we'll see the first tests emerge in the area of chronic treatment."

Myriad also is working on CDx for biologics in the autoimmune disease space, especially for patients with complex, severe and crippling conditions such as RA, psoriatic arthritis and ankylosing spondylitis who don't respond to methotrexate. Biologics already on the market to treat autoimmune conditions often cost up to $50,000 per patient per year, and most have response rates of only 40 percent to 50 percent, said Ralph McDade, president of Myriad's wholly owned subsidiary, Myriad RBM.

"Third-party payers have a lot of trouble just saying, 'OK, let's try this TNF-alpha inhibitor, and after 52 weeks we're going to assess the person by looking at their joints, if it's RA, and their general pain,'" he pointed out. "Our goal is to develop some really objective measurements where we can determine early on in the treatment – perhaps even before treatment begins – which type of biologic would be the most effective for a particular patient."

Challenges loom in rare and large indications

In terms of infectious diseases – a space that is ripe for CDx – the biggest challenge is the need to have approved tests available at the point of patient care to shorten the time between diagnosis and treatment. That, Metzger admitted, is a complex and expensive proposition for all but the largest clinical centers.

A similar issue applies to the development of CDx in rare diseases. Although in vitro diagnostics could help to pinpoint a rare diagnosis, "in an indication that might account for just 100 or 200 patients a year, it's too expensive for a pharma partner to co-develop such a test," he said. Instead, Metzger suggested that diagnostics companies could disseminate CDx for orphan indications to CLIA labs in various territories where patients could have ready access to them.

For larger indications such as CVD and central nervous system diseases, the challenges aren't any smaller.

"You're looking at very complex diseases that have multiple endophenotypes," McDade observed, pointing to big pharma's aversion to advancing CVD drugs due to the need to segment among patients who present with dyslipidemia, hypertension or general inflammation.

"I just don't see much interest in companion diagnostics" in the CVD space, he said.

AD, on the other hand, could be an ideal indication for CDx if researchers could agree on a target.

"A lot of people have been trying to correlate amyloid burden in the brain with Alzheimer's, using PET imaging," McDade said. "That's probably not the whole story. We don't know the whole story. There are many people who have plenty of amyloid at death, when you look at their brains, but they never had Alzheimer's. We don't quite understand the biology of Alzheimer's as well as we need to."

Myriad also is looking at the development of CDx, as well as additional diagnostics, for type 2 diabetes.

"We know there are biomarkers for cardiovascular risk – people who are going to have an event within a certain amount of time can be correlated to certain blood-based biomarkers," McDade said. But the two main sequelae – diabetic nephropathy and diabetic retinopathy – "are areas where we are seeing more interest" for CDx.

'Who's going to pay for it'

Part of the road forward for CDx could be linked to the evolution of drug development toward precision medicine. A diagnostic could become reclassified as a CDx over time if a molecularly targeted medicine were developed after the fact, BioWorld's Breindl pointed out, citing the BRCA testing for the PARP inhibitor, Lynparza, as an example.

Handling of those tests will need to accelerate dramatically, however, if they're to keep up with efforts to target drugs using a genomic approach. In the early 1990s, 5 percent of new drug approvals were for targeted therapies; in 2013, that percentage jumped to 45 percent. Approximately 80 percent of drugs approved by the FDA under the breakthrough designation have been for targeted therapies.

McDade said biopharmas are driving the decision to use a molecular diagnostic to survey a patient population or actually to inform drug development. From a diagnostics industry perspective, "if you can get a genomic marker or some kind of nucleic acid marker at the tumor that will tell you response rates, that's wonderful," he said. "But when we're dealing with pharma – and we do that a lot now in companion diagnostics programs – there's still a certain amount of trepidation."

Biopharma industry concerns are twofold. On the one hand, companies worry about what happens when a CDx doesn't play out as envisioned and appears to limit the market for a proposed drug. On the other, they fret about "who's going to pay for it," McDade told BioWorld Insight. Use of a CDx may add $50 million to $100 million or more to the tab for a new therapy, whose cost already averages $2.6 billion. (See BioWorld Today, Nov. 19, 2014.)

How those conversations play out – whether part of the cost is underwritten by a biopharma or third-party payer, for instance – often determines whether development of a proposed CDx moves forward. If a diagnostics company is on the hook for the entire development cost, it must also absorb all of the risk if the drug ultimately fails, McDade pointed out. The lessons learned in cancer drug development will apply equally to the development of CDx in other complex diseases, he predicted.

The diagnostics industry also is grappling with its own set of regulatory challenges. In 2014, the FDA issued a draft guidance on in vitro CDx devices. Following a report to Congress issued last year by the Patent and Trademark Office on the availability to patients of confirmatory genetic diagnostic testing and on the impacts of the patent system, cost and insurance on that availability, the FDA also issued a white paper earlier this year on advances in next-generation sequencing (NGS) systems in oncology testing that are changing the paradigm for CDx. But an FDA workshop in February made clear that the agency is just beginning to grapple with the nuances of regulating NGS and its effect on the development of CDx and drug development. (See BioWorld Today, Feb. 29, 2016.)

In the meantime, cancer still has room to run in CDx, Metzger said, noting that immuno-oncology is an area still begging for in vitro diagnostics, particularly as the number of combination therapies grows.

"It's important for payers to stratify patients, especially as we move more and more toward combination therapies," he said. "Immuno-oncology is a huge area and one that's not captured by companion diagnostics, but I think we will see movement in that direction before the end of 2016."