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Illumina CDx Development Deal Shows Pharma Ready to Embrace New NGS Panel Testing Paradigm

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Originally published Aug. 26.

NEW YORK (GenomeWeb) – Recognizing that single-gene testing will soon be an untenable model for developing diagnostics accompanying personalized therapies, drugmakers are slowly moving toward advancing standardized, multi-gene platforms to identify best responders to their cancer treatments.

Last week, Illumina announced it was working with AstraZeneca, Sanofi, and Janssen Biotech to develop and bring to market a universal, next-generation sequencing-based companion diagnostic for drugs being developed by these pharma companies. Illumina plans to develop the CDx on its US Food and Drug Administration-cleared MiSeqDx platform.

"NGS at the moment is the only technology we've got that is able to rapidly characterize these variants in a panel. It's particularly applicable to genes that are complex where there are many thousands of variants or there are multiple genes that impact patients' response to drugs," Ruth March, VP of personalized healthcare and biomarkers at AstraZeneca, told PGx Reporter.

The hope of AstraZeneca and the other drug companies involved in this collaboration is to be able to do these different kinds of drug response-related genomic analyses with a single test. Janssen and Sanofi didn't respond to interview requests for additional details. AstraZeneca, meanwhile, is hoping to use such a test panel in the research setting, as well as part of a pivotal drug trial to prospectively select patients most likely to benefit from treatment.

"The Illumina partnership gives us an immediate opportunity to take the panel of genes that's able to look at all the known and unknown variants and take it through the regulatory pathway into one of our pivotal studies," March said, without revealing in which "key oncology" program AstraZeneca plans to test out the universal CDx panel.

Additionally, AstraZeneca hopes to apply the Illumina CDx panel to studies similar to the Lung Cancer Master Protocol (Lung-MAP), a trial in which multiple drug firms are using Foundation Medicine's NGS panel to stratify squamous cell lung cancer patients into various therapeutic arms in a Phase II/III study. The study, which launched in June, involves the National Cancer Institute, SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health (FNIH), Foundation Medicine, and five drug companies – Amgen, Genentech, Pfizer, AstraZeneca and 'its global biologics R&D arm, and MedImmune.

"It's this type of design that I think will be a step change in clinical trials and clinical trial designs," March said. Trials like Lung-MAP also signal a growing commitment on the part of drugmakers to explore new diagnostic frameworks that enable efficient use of the limited tissue samples available from cancer patients, and limit regulatory burdens. The rate at which researchers are uncovering new and rare genomic markers linked to cancer and drug response often makes single-gene companion tests obsolete by the time they garner regulatory approval and enter the market.

Moreover, the dearth of tumor tissue in certain types of cancers often makes it impossible for doctors to genomically analyze the sample more than once. As such, it would benefit patients, healthcare providers, and drugmakers alike if a single test of a patient's tumor sample revealed information on many clinically relevant markers at once, instead of whether patients have mutations in a single gene. This problem is particularly relevant in lung cancer, where mutations in genes such as ALK or ROS1 occur in less than 5 percent of patients.

"In these instances, even if there is a drug that targets that segment of the population, it is difficult to screen and identify patients eligible for that treatment," Anne-Marie Martin, who leads GSK's molecular medicine unit, previously told PGx Reporter. "It is becoming apparent that the marketplace is not going to be able to support five or six different FDA-approved assays for the same biomarker, particularly when they're not going to be used for the most part by the majority of labs because labs tend to use their own laboratory-developed tests."

Recognizing these challenges, more and more drug firms, among them Amgen, Clovis Oncology, BioMarin, and PharmaMar, have made public their intention to develop companion tests for their drugs on NGS platforms. This signals a significant shift in the drug industry's investment in developing personalized medicines, since it was not that long ago that most pharma and biotech firms considered NGS a tool that was unsuited for their commercial needs.

Meanwhile, any platform developed as part of this effort will need to be approved or cleared by the US Food and Drug Administration ahead of commercialization. The regulatory framework for such a test, however, will take time to iron out, given that an NGS-based, multi-gene CDx has yet to be taken through the agency.

Illumina is in the midst of readying its sequencing technologies for the clinical market, and toward this end it purchased regulatory and quality consulting firm Myraqa in July. "Illumina will be working closely with FDA on the regulatory challenges that will be encountered with this new approach to companion diagnostics," Mya Thomae, VP of regulatory affairs at Illumina, recently told PGx Reporter. "In discussions that have been held to date, FDA has been positive about our approach and appears to be committed to finding innovative regulatory solutions to ensure the best products for patients are reviewed and approved by FDA."

Thomae, former CEO of Myraqa, further elaborated that ideally the goal would be to take a universal NGS-based CDx through the FDA once, and then submit follow-up submissions to update the platform with additional intended uses and new markers. "The content of the panel will be driven by the needs of our pharma partners and their therapeutic pipelines," Naomi O'Grady, senior product manager within Illumina's Oncology business, told PGx Reporter. "Our inclusive approach is intended to reduce the need for downstream iteration."

In response to questions about Illumina's partnership to advance an NGS-based universal CDx, an FDA spokesperson said without elaborating that the agency "is considering several innovative approaches to sequencing panels," and intends to find "an efficient pathway" to bring a panel test for multiple therapies to market.

With its recent notice to the US Congress of its regulatory framework for lab-developed tests (LDTs) and finalization of the companion diagnostics guidance, the FDA has renewed emphasis on the fact that it considers tests that are essential to the safe and effective use of a drug to be high-risk devices requiring its approval or clearance. In bringing LDTs under its oversight, the FDA intends to turn its attention first to labs marketing tests with the same indication as FDA-approved companion diagnostics, screening tools meant to be used in asymptomatic patients, and high-risk diagnostics for infectious diseases. Then, the agency will bring into compliance LDTs with the same intended use as FDA-approved Class III devices and blood products.

However, separate from the LDT guidance, it seems that the topic of NGS-based panel testing in oncology will receive special attention from the agency. "FDA has put considerable thought into what the relevant requirements would be for oncology panels as companion diagnostics," the agency spokesperson said. "We intend to publish a draft guidance outlining our current thinking in the near future."

The agency has also held several public meetings to discuss the evolving regulatory framework for advanced sequencing-based diagnostics, and in it is slated to convene a workshop entitled "Next-Generation Sequencing Technology, Data Format Standardization and Promotion of Interoperability Protocols."

Moreover, the agency's 510(k) clearance last year of Illumina's MiSeqDx platform, associated reagents kit, and cystic fibrosis tests could offer some insights into the types of data that drug and test developers can expect to submit.

In discussing the review of MiSeqDx in the context of cystic fibrosis, FDA officials have previously said that the regulatory process was significantly helped by Johns Hopkins University's curated CFTR2 database, which allowed the agency to efficiently verify nearly 140 genes related to the disease. In this regard, the Pharmacogenomics Knowledgebase, or PharmGKB, is a curated database of gene markers associated with drug response, which could provide similar assistance to FDA officials reviewing a multi-gene NGS-based companion diagnostic.

Although the specific genes that will be included in Illumina's NGS CDx panel haven't yet been decided, March noted that the companies are considering a number on the order of 20 genes. "We've given Illumina information about the genes we would be interested in, and they will be getting similar information from other parties," she said.

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