Owing to the high clinical failure rates, genetically variable tumor characteristics, and skyrocketing drug development costs, the era of traditional blockbuster oncology agents has come to an end. With the advent of personalized medicine, we have entered the “niche-buster” era, defined as effective products delivered to identifiable patient segments. The good news is that all cancer stakeholders– oncologists, payers, drug manufacturers, and of utmost importance, the patients–benefit from delivering the right drug to the right person. Companion diagnostics, necessary for safe and effective use of targeted cancer therapies, are making a valuable contribution to patient outcomes as well as providing faster time to market and lower development cost for pharmaceutical companies.

With the success of targeted treatments such as Gleevec (imatinib mesylate; Novartis) and Herceptin (trastuzumab; Roche/Genentech) generating billion dollar sales revenue, the switch to personally-tailored medicine is a fait accompli. In this brave new world of personalized medicine, companion diagnostics have become the industry’s Rosetta Stone and allow researchers to decode which patients will best respond to specific treatments, conduct smaller clinical trials, improve efficacy, reduce side effects, lower development costs, and streamline regulatory approval.

It’s been 13 years since the FDA approved Herceptin with its eventual companion diagnostic Dako’s HercepTestâ„¢ for the treatment of HER2+ breast cancer. Since then, a groundswell of activity and regulatory support for the co-development of targeted therapies with companion diagnostics has only increased in recent years. Companion diagnostic testing predicts treatment response byidentifying alterations in genes such as the wild type 

 in colorectal cancer, anaplastic lymphoma kinase (

), in non-small cell lung cancer (NSCLC), and the mutation in the 

 gene associated with metastatic melanomas.

 gene may be a reliable predictor of treatment response to Erbitux (cetuximab; ImClone/Bristol-Myers Squibb/Eli Lilly)and Vectibix (panitumumab; Amgen) in colorectal cancer patients, the European Medicines Agency (EMA) recommends that the label indication for Erbitux be revised in the UK to focus on metastatic colorectal patients with the wild-type 

 gene. If clinical trials prove equally compelling, the FDA may follow suit and recommend that a companion diagnostic for 

 testing be included in the metastatic colorectal indication. A number of diagnostic companies have already announced plans to develop and market K-ras assays and in vitro diagnostic (IVD) test kits in anticipation of the future regulatory rulings.

-positive NSCLC using the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc) resulted in significantly better outcomes for patients with late-stage NSCLC. In the pivotal trial for crizotinib (Xalkori; Pfizor), 

-positive NSCLC patients treated with the ALK inhibitor resulted in an objective response rate of 50% to 61% in patients who would typically experience a 10% response rate to second- and third-line chemotherapies.

Recently, the FDA approved Tarceva (erlotinib) for first-line use in metastatic NSCLC patients who test positive for 

 mutations in exons using the cobasÂ® EGFR Mutation Test. Research demonstrated that 

-positive patients receiving Tarceva experienced 10.4 months progression-free survival versus 5.2 months with standard combination therapy. This test should prove valuable since 

 mutations are typically found in 10% to 30% of NSCLC patients. MolecularMD also has an exclusive patent for diagnostic technology that identifies patients with 

 mutations, which can predict which patients will be resistant to treatment with Tarceva or Iressa (gefitinib).

 mutation receiving Zelboraf (vemurafenib, Roche) experienced improved rates of overall and progression-free survival compared with standard therapy. In this case, the drug company partnered with the diagnostic company Plexxikon during preclinical development of Zelboraf, using the cobasÂ® 4800 

 Mutation Test, which resulted in accelerated approval of the drug. Whereas most agents take 10 to 15 years to reach the market, Zelboraf reached the market in less than six.

The FDA approved both Xalkori and Zelboraf in August 2011 with the requirement that the two targeted therapies be used in conjunction with their companion diagnostic tests.

Regulatory agencies such as FDA and EMA understand the profound implications companion diagnostics will have in ensuring the safe and effective delivery of molecularly targeted agents. In draft guidance issued on July 14, 2011, the FDA suggested that targeted oncology agents would only gain approval if reviewed in parallel with companion diagnostic tests, stating “the IVD companion diagnostic device will be essential for the safe and effective use of the therapeutic product, and its use will be stipulated in the labeling of the therapeutic product.”

To ensure that this “essential” component of targeted therapy be considered and pursued by pharmaceutical manufacturers, the FDA is determined to streamline the drug approval process by holding joint meetings with the Center for Drug Evaluation and Research, the Center for Biologics Evaluation (the centers responsible for drug products), and the Center for Devices and Radiological Health (the branch responsible for medical devices).

Kevin Hawkins, Director of Quality and Regulatory Affairs at MolecularMD, noted that drug companies are frequently informed they will need to develop a diagnostic in conjunction with a targeted therapy prior to submitting an investigational new drug (IND) application. As a result, many drug companies are partnering with experienced diagnostics companies early in the drug development process to successfully navigate the evolving regulatory landscape.

In addition, the FDA states that, “for a novel therapeutic product, an IVD companion diagnostic device should be developed and approved or cleared contemporaneously to support the therapeutic product’s safe and effective use.”

Co-development is central to the paradigm shift occurring in the regulatory field of targeted medicines, the ramifications of which will soon be felt in the European Union. In a 2011 White Paper, the EMA signaled its intention of regulating companion diagnostics by keeping these genetic tests under the IVD directive and giving them a class C rating, which indicates a high individual risk and/or moderate public risk.

According to Hawkins, the IVD directive is currently being rewritten as a regulation and will soon be passed into law. This will require the submission of premarket approval (PMA) applications similar to that required by the FDA; currently, the EMA only requires self-certification.

In the United States, the FDA has demonstrated its willingness to approve agents that closely hew to the agency’s draft guidance as evidenced by the rapid approvals of both Zelboraf and Xalkori. However, the FDA has also shown its willingness to reject targeted therapeutic oncologic agents because they lack a companion diagnostic. Such was the case in 2010, when the FDA rejected Omapro (omacetaxine mepesuccinate, ChemGenex) for the treatment of a subset of leukemia patients with the 

All of this makes it essential to partner with a cutting-edge companion diagnostic company with the skills to smoothly navigate today’s shifting regulatory terrain.

	MolecularMD Helping Navigate the Road Ahead

MolecularMD, located in Portland, Oregon, works closely with pharmaceutical companies throughout each stage of a drug’s clinical development program ensuring that the technology evolves with the drug, thus mitigating risk. By partnering with a company during the phase 1 stage of a drug’s development, MolecularMD can help evaluate the specific candidate biomarkers with a properly analytically validated test. During phase 2, MolecularMD fully implements the test in prospective trials so that the FDA will have a tailored therapy and an approved companion diagnostic available for phase 3 testing. In such a way, pharmaceutical manufacturers can be assured that the diagnostic will never delay approval of the drug and that MolecularMD can quickly adapt to new data as they evolve.

As the first and only diagnostic company to develop a standardized assay for the quantification of BCRABL levels, MolecularMD has proven its experience and success in the field. Part of that success is due to Brian J. Druker, MD, director of the Oregon Health & Science University (OHSU) Knight Cancer Institute, and the lead clinical investigator for Gleevec, the first molecularly targeted anticancer agent. His pioneering research in the field has facilitated the development of trailblazing BCR-ABL mutation testing, which has proved instrumental in getting FDA approval for the second-generation ABL kinase inhibitors dasatinib, (Sprycel; BMS) and nilotinib (Tasigna; Novartis), both indicated as first-line therapy for newly diagnosed Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase.

In 2011, MolecularMD partnered with ARIAD Pharmaceuticals to design a companion diagnostic test for the pan-BCR-ABL inhibitor ponatinib, an investigational agent for patients with resistant CML and Ph+ acute lymphoblastic leukemia (ALL). The test, which identifies patients with the T315I mutation, was developed and submitted to the FDA for approval within 18 months, proving that MolecularMD can achieve rapid turn-around times that help streamline clinical trials.

MolecularMD also works closely with OHSU, Dana- Farber Cancer Institute, and New York University Medical Center, all of whom give them firsthand access to genetic biomarker information that is of paramount importance in the development of cleareyed, cutting-edge diagnostic tools. The researchers at MolecularMD develop customized RNA-, DNA-, and IHC-based assay designs tailored to the oncology biomarker being evaluated.

By partnering with Kwok-Kin Wong, MD, at Dana- Farber Cancer Institute, MolecularMD has already developed assays to identify mutations in the liver kinase B1 (LKB1) tumor suppressor gene, which has been implicated in cancers of the lung, endometrium, skin, pancreas, colon, and breast. The assays were validated using both immunohistochemistry (IHC) and next-generation sequencing tests in 34 patient tumor samples, the results of which were presented at the American Association for Cancer Research Annual Conference, April 7-9, in Washington, DC.

Targeted therapy is fast coming into focus. Companion diagnostics offer exceptional benefits for physicians, regulatory agencies, insurance providers, and most importantly, patients. Expanding the capabilities of what cancer trials can accomplish will undoubtedly result in higher quality healthcare that is extremely cost-effective. Exciting commercial opportunities await those pharmaceutical companies who join forces with experienced diagnostic developers with the regulatory acumen and technological knowhow to navigate and conquer the emerging field of targeted oncology treatments. The increased clinical efficacy and fewer side effects associated with patient-stratified therapies may inevitably speed up approval times and lower clinical trial costs, making companion diagnostics a win-win for all involved.

			Shaw A. The crizotinib story: from target to FDA approval and beyond. InforMEDical. www.informedicalcme.com/lucatoday/ crizotinib-story-from-target-to-fda-approval. Accessed November 4, 2013.

			US Food and Drug Administration. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm268241.htm. Accessed November 4, 2013.

			Plexxicon. Melanoma and BRAF Mutant Cancer Program. www. plexxikon.com/file.cfm/13/docs/Plexxikon_Melanoma_v15%20 3%20final_080211.pdf. Accessed November 4, 2013.

			US Food and Drug Administration. Guidance for Industry and Food and Drug Administration Staff - In Vitro Companion Diagnostic Devices. www.fda.gov/medicaldevices/ deviceregulationandguidance/guidancedocuments/ucm262292. htm. Accessed November 4, 2013.

Articles

Owing to the high clinical failure rates, genetically variable tumor characteristics, and skyrocketing drug development costs, the era of traditional blockbuster oncology agents has come to an end.

Paul Watson

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Companion Diagnostics Are Driving Support in the Evolving Regulatory Landscape