At the beginning of this month the FDA released its much anticipated final guidance for companion diagnostics tests. It recognizes that those tests are evolving as essential components in order for new innovative therapies to be targeted to patients who will benefit the most. By and large, it contains no real surprises and lays out the definitions and approval processes that are needed to be followed to ensure the safety of the test designed to be used with a particular therapeutic. (See BioWorld Today, Aug. 4, 2014.)

Certainly since the original FDA draft paper was first issued three years ago, the importance of companion diagnostics has increased significantly thanks to the fact that they have proved their worth in a number of ways, including helping speed along the approval process of therapeutics. For example, melanoma drug Zelboraf (vemurafenib, Daiichi Sankyo Co. Ltd. and Roche AG) and lung cancer drug Xalkori (crizotinib, Pfizer Inc.) proved incorporating a companion diagnostic early in clinical development can save time and money: Both drugs advanced from phase I to FDA approval in just five years. In the case of Xalkori, Pfizer retained Abbott to develop a companion diagnostic when the drug was still in phase I. Zelboraf developer, Plexxikon Inc. (later acquired by Daiichi), meanwhile, approached Roche's diagnostics division before the drug had even entered the clinic, and the big pharma was so impressed that its therapeutics division jumped on board with a $706 million partnership. (See BioWorld Insight, Feb. 21, 2012.)

COLLABORATIONS INCREASING

It is not surprising that we are seeing partnerships between pharma and diagnostics companies being forged at an accelerating rate.

Astrazeneca plc is one firm that has been particularly active. At the end of July, the company said it had entered a collaboration with Roche AG to develop a plasma-based companion diagnostic test to support AZD9291, its investigational compound in development for non-small-cell lung cancer (NSCLC).

The test is designed to identify epidermal growth factor receptor (EGFR) mutations in both tumor tissue and plasma derived from patients with NSCLC, and to optimize the clinical development of AZD9291 for patients who are resistant to first-generation EGFR tyrosine kinase inhibitors (TKIs).

Mondher Mahjoubi, senior vice president of global product strategy for oncology at Astrazeneca, said the test will provide "an alternative method of identifying the T790M mutation because, currently, patients who have been treated with EGFR-TKIs in whom the disease has progressed have to undergo a repeat biopsy to assess whether they have a specific mutation."

NSCLC patients with the activating sensitizing EGFR mutation (EGFRm+) are particularly sensitive to treatment with currently available EGFR TKIs, which block the cell signaling pathways that drive the growth of tumor cells. However, tumor cells almost always develop resistance to treatment, leading to disease progression. In approximately half of patients, that resistance is caused by the secondary mutation known as T790M. In an ongoing phase I study, AZD9291 showed early evidence of activity as a once-daily monotherapy with clinical responses observed in an EGFRm+ population of patients with NSCLC who have previously failed on EGFR TKIs and also in patients with the T790M mutation.

Astrazeneca also is working with Qiagen NV, of Venlo, the Netherlands, to develop a non-invasive diagnostic test to identify NSCLC patients who are suitable for treatment with Iressa (gefitinib), an EGFR tyrosine kinase inhibitor that blocks the signals from the EGFR, which leads to tumor growth. Using the test, clinicians will be able to identify patients with the EGFR mutation, and therefore who might benefit most from treatment with the drug.

The two companies are seeking approval from the EMA for the test, as a companion diagnostic for Iressa.

Qiagen also is working with Eli Lilly and Co. on the co-development of companion diagnostics for targeting multiple cellular pathways involved in common cancer types. The agreement includes the development of tests that will be based on Qiagen's modaplex analysis platform, which can process multiple sample types and biomarkers in a single test.

In May, Cambridge, Mass.-based Idera Pharmaceuticals Inc. said it entered an agreement with Abbott for the development of an in vitro companion diagnostic test for use in clinical development programs to treat certain genetically defined forms of B-cell lymphoma with IMO-8400. At the American Association for Cancer Research Annual meeting in April, Idera presented preclinical data demonstrating the ability of IMO-8400 to inhibit the survival and proliferation of human B-cell lymphoma cells harboring the oncogenic MYD88 L265P genetic mutation.

Under the agreement, Abbott will develop a polymerase chain reaction test to identify the presence of the MYD88 L265P oncogenic mutation in tumor biopsy samples. That mutation, which can be identified in approximately 90 percent of patients with Waldenström's macroglobulinemia and approximately 30 percent of patients with the ABC subtype of diffuse large B-cell lymphoma, plays a key role in activating the Toll-like receptor pathways targeted by Idera's lead drug candidate, IMO-8400.

According to Lou Brenner, chief medical officer at Idera, "Research by Idera has established Toll-like receptor antagonism as a potentially promising approach for patients with B-cell malignancies harboring the MYD88 L265P mutation."

REGULATORY POLICIES STILL CLOUDY

Innovation in diagnostics, biomarkers and the evolving big data field all are having positive impacts on the development of personalized and precision medicine. However, Edward Abrahams, president of the Personalized Medicine Coalition (PMC), noted in order to encourage that innovation, clearer regulatory guidelines are needed. He participated in a recent House Energy and Commerce Committee workshop, as part of its ongoing 21st Century Cures Initiative, on the influence of evolving areas of genomic sequencing and diagnostic testing on product development. (See BioWorld Today, July 24, 2014.)

The uncertainty in regulatory policy prevailing today puts pressure on reimbursement of diagnostic tests that, in turn, sends negative signals to the investment community. "If products are not going to be reimbursed, they are not going to be developed as fast as we would like, especially for diagnostics," Abrahams said.

Washington-based PMC has drawn policy makers' attention to those issues in a recently released white paper, "The Future of Coverage and Payment for Personalized Medicine Diagnostics," which documents both the progress of personalized medicine and the ways in which some recent coverage and payment policies have discouraged its advancement.

PMC members said they believe that critical changes in payment and coverage policies will be needed to ensure innovation in the field continues to be encouraged. Although "over the past decade we've seen considerable growth in the scope and impact of personalized medicine, we have far to go," noted Amy Miller, executive vice president of PMC. "As the paper shows, we have the opportunity to impact change, thus ensuring higher quality care and potentially lowering systemic costs if the right treatments are targeted to the right patients."

The report points to the cloudy regulatory environment that exists today by contrasting the public positions of the two most important federal agencies for the entry of personalized medicine into the health care system: the FDA and the Centers for Medicare and Medicaid Services (CMS). The paper noted that last October the FDA released a cross-agency document, titled "Paving the Way for Personalized Medicine: FDA's Role in a New Era of Medical Product Development," which discusses its initiatives to advance personalized medicine. Conversely, CMS' main public documents in 2013 focused on the cost-cutting proposals discussed in PMC's white paper, without regard to either innovation or improving patient access to care.

Given the fact that the future of health care will be shaped in part by personalized medicine, industry stakeholders are hoping that the regulatory disconnect issues impacting the field will be addressed in the near future.