Chris Anderson

The single marker, single therapeutic model is still valid, but some diagnostics focus on multidrug therapies.

Since the development of the first companion diagnostic for Herceptin was introduced more than 10 years ago, the development paths for these tests have followed the same formula: stratify patients by
identifying a single marker that can predict the likelihood that a single therapeutic will or won’t be an effective form of treatment.

From a clinical standpoint, a companion diagnostic (CDx) seeks to close the gap between a “one size fits all” approach to using a drug and a tailored approach to using the drug in an individual patient. The bulk of the companion diagnostics available for clinicians target oncology drugs and have been developed as researchers have come to better understand the mechanisms, pathways, and manifestations of cancer, all helping to answer the age-old conundrum of why certain patients respond to therapy while others show no improvement.

In short, a companion diagnostic helps clinicians determine the safest and most effective use of a drug for only those patients who stand to benefit from it. On the flip side, it also helps avoid unnecessary treatment for patients who won’t respond, which allows doctors to seek alternate treatment routes right away—an especially important consideration for oncologists to avoid wasting time on ineffective treatment. A CDx test can also help identify patients that may have a significant adverse reaction to a drug.

Earlier this year, the FDA released guidance for drug and diagnostic companies involved in the development of in vitro companion diagnostics. The guidance is intended to help pharmaceutical and diagnostics companies understand how to work in collaboration with the FDA to gain approval not only for the new therapy, but also the accompanying diagnostic. It also encourages collaboration between drug makers and diagnostics companies as early in the drug development process as possible.

“The goal is to stimulate early collaborations that will result in faster access to promising new treatments for patients with serious and life-threatening diseases,” the FDA noted in its July consumer update, “Personalized Medicine and Companion Diagnostics Go Hand-in-Hand.”

CDx Tests in Drug Development, Clinical Trials

When it comes to the development of companion diagnostics, pharmaceutical companies have largely held the upper hand in collaborations with diagnostics makers. “In my view, companion diagnostics has not been a good business historically for most diagnostics companies,” said Brad Gray, CEO of Seattle-based NanoString Technologies. “The vast majority of the spoils for getting a drug approved
has always gone to the drug company, with the companion diagnostics manufacturer getting only a small fraction of the economics—as well as very marginal uptake, [particularly when] laboratory-developed tests have worked around whatever approach was used in the FDA-cleared test.”

Still, the prospects for diagnostics company may improve, say industry experts, as pharmaceutical companies are beginning to see the benefits of companion diagnostics. Not only are companion diagnostics improving drug targeting, identifying the patients most likely to benefit from the pharmaceutical companies’ therapies, they are also guiding clinical trials and generating the kind of data that can secure regulatory approvals.

Much of this shift comes from the understanding that the days of the blockbuster drug are gone. “It wasn’t that long ago when pharmaceutical companies were hoping their drugs would be the wonder pill serving millions and million of people,” said Peter Krein, Ph.D., Director of Medical Affairs with Qiagen. “I think the industry has changed dramatically, with [pharmaceutical companies realizing that they must target population subgroups], both for efficacy in their trial work—to get drugs approved—as well as having the benefits for payers—to get [reimbursements] approved.”

While some drug makers may be more open to collaboration with diagnostics companies, this openness is not universal, noted Laura Housman, Chief Commercial Officer with German diagnostics company MolecularHealth. In many instances, pharmaceutical companies want to control all aspects of the drug development process.

“There has been a duality of thought among pharma companies: ‘Do we just buy it, or do we develop it ourselves?’ [The split is hard for pharma companies to avoid because diagnostic development] is not their core competency,” noted Housman, who previously worked in Novartis’ molecular diagnostics group. “If a pharma company develops its own diagnostic, it can control everything from start to finish,
particularly as it relates to the diagnostic in the trial. [Alternatively, a pharma company can] find ways to [work] with diagnostics companies that are meaningful and won’t hold the trial hostage.”

Housman credits companies such as NanoString that have invested in getting their diagnostics products approved by the FDA. These companies not only foster closer collaboration with pharma, they also negotiate better financial terms for CDx development. If a diagnostics company has “invested the time, energy, and capital resources to have a diagnostic that has been FDA cleared, has clinical utility, has been documented in a lot of peer-reviewed publications, and has strong usability within a core market, it removes barriers to the adoption of therapies,” she said. “When you make those investments, you have a stronger position in terms of calling the shots in a deal.”

Bastiaan van der Baan, Vice President of Clinical Affairs at Agendia, believes drug companies will favor collaborations with CDx developers as they look to develop more highly targeted therapies. “A big change is that five years ago it wasn’t that common to do a biomarker-drug development combination,” he observed. “Nowadays, especially in oncology, most drugs are developed in combination with some kind of companion diagnostic, or the program contains at least the attempt to find relevant biomarkers.”

In addition, companion diagnostics play a vital role in patient stratification and recruitment for clinical trials, while also generating efficacy and safety data. For this reason, the diagnostics companies interviewed for this story indicate that they prefer to become involved in a drug development program as early as possible, whether it is for a new chemical entity or an existing drug that has already gained clearance for one indication and has the potential to be repurposed.

“We would love to be preclinical, in the earliest stage of target identification as possible, and then continue to translate and evolve that both in the translation and biomarker development phases as well as the drug development phases,” Housman said.

Krein agreed. “We want to get involved very early on. Traditionally, pharmaceutical companies had their own process in place for biomarker discovery, and they typically started involving diagnostic companies in Phase III. That is a bit late from our perspective.”

Peter Krein, Ph.D., (left) is Director of Medical Affairs with Qiagen. Laura Housman (right) is Chief Commercial Officer with German diagnostics company MolecularHealth.

Evolving the CDx Model

For now, companion diagnostics continues to focus on single genetic markers that suggest a single therapeutic. Nonetheless, a changing paradigm for cancer treatment is leading to a new generation of diagnostics. With next-generation sequencing becoming more sophisticated and less expensive, some diagnostics will begin to focus on multiple genetic abnormalities known to contribute to a specific cancer.

“Being able to subtype patients is vital to the treatment of [specific cancers] in the future, and we think every drug should benefit in terms of using subtype-guided therapies,” said NanoString’s Gray. To do that, the diagnostics will need to query not just one targeted gene, but tens, dozens, or even hundreds of genes in order to develop as precise a picture of each patient’s cancer as possible.

Broader panels, whole-genome and whole-exome sequencing, and powerful informatics capabilities are what will help drive this multiple marker approach, according to Molecular Health’s Housman. It is an approach that the company embraces.

“Kudos to Foundation Medicine and other companies that have been working hard to drive the approach for pancancer-level sequencing panels,” she declared. “When you start clinical trials, you have an idea clearly of what you want to do, but there is so much that can be undiscovered and unknown. And when you are using a single gene approach or even a smaller panel approach, you are not going to see everything along the pathway. You are never going to find the things you didn’t know existed.”

As researchers learn more about specific cancer pathways and more therapeutics are approved as effective against known pathways, combinations of these therapies are showing greater treatment efficacy. Since cancers are often active on multiple pathways at once, diagnostics attuned to such polyphony should gain favor. This approach will certainly push the traditional concept of a companion diagnostic, but it also holds significant promise.

“Breadth and depth [are essential], whether sequencing [encompasses] the whole genome, the exome, or even just a broad, targeted panel,” Housman continued. “[You need to see more than] the hotspot—the single marker. [You must see] the whole array of what is going on in the tumor [to have] the best shot at making the best suggestions for treatment.

“There is a tremendous sea-change opportunity here. The half-life of these innovations is far shorter than it has ever been. Companies aren’t waiting a couple of years to see how this plays out. There are a lot of different players, and it is the most exciting and innovative time I’ve seen in the industry.” 

Chris Anderson is the former Chief Editor of Drug Discovery News, which he helped launch in 2005. ([email protected])

This article was originally published in the November 19 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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