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J&J Tests WGS of Rheumatoid Arthritis Patients to ID Markers of Drug Response, Predisposition Genes

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As a first step into whole-genome sequencing, a division of Johnson & Johnson is sequencing 450 rheumatoid arthritis patients from a clinical trial of its approved drug Simponi (golimumab) with the goal of identifying disease predisposition genes and markers that correlate with drug response.

The study is the first large-scale next-generation sequencing study conducted by the pharmaceutical giant, but Mark Curran, the vice president of systems pharmacology and biomarkers in the immunology therapeutic area of J&J's Janssen, told Clinical Sequencing News that it will likely not be its last.

If this first study goes well, he said, the division will apply the technology to other autoimmune and inflammatory conditions.

Janssen outsourced the sequencing to BGI but is doing all of the analysis in-house, Curran explained. This strategy makes sense for the firm, he said, because its primary function is to develop drugs, so it does not have the infrastructure to do large-scale whole-genome sequencing.

Nevertheless, the company does have internal sequencing capabilities for "small projects and internal validation of experimental results for outsourced projects," Curran explained. In-house, the company has Illumina's HiSeq, Roche's 454 GS FLX, and Life Technologies' SOLiD, which reside in different groups throughout the company, he said.

Because the sequencing is being done in the context of a clinical trial, Curran said that there are strict standards in terms of privacy and quality that must be adhered to, and that BGI meets those standards.

For its study, the group sequenced the whole genomes of 450 individuals who had enrolled in a clinical trial for Simponi.

One major key to the project, said Curran, is having a well-phenotyped cohort. That will enable the researchers to "ask questions about differences between disease and non-disease, rheumatoid arthritis, and other inflammatory disorders," as well as the "genetics of response to treatment."

To do the analysis, Curran said the researchers would first take a "candidate gene approach," and look at pathway genes and loci that have been previously implicated in autoimmune diseases. Next, they will look across the entire genome for other correlations with predisposition to disease, although he acknowledged that the study may be a bit underpowered for this approach to turn up anything.

Additionally, he said, because this is the first large-scale sequencing study for the company, they plan to examine the results from a technical point of view in terms of determining the best ways to assemble genomes and call variants. There are two aspects to the study, Curran said. "There's the disease question, and there's the 'how do you analyze genomes?' question," he said.

Curran said that while the study is mainly a scientific one to better understand the disease, one area that he hopes it will have an immediate impact on is understanding the genetics of response to Simponi. "We're hoping this data will inform on new mechanisms and pathways," he said.

Other pharmaceutical companies have been reluctant to embrace next-generation sequencing within clinical trials because of the added complexity and cost, which could end up prolonging the approval process for a drug, diminishing a company's return on investment in the drug's revenues (see CSN 6/21/2011).

However, Curran said that the study of Simponi was slightly different since the drug is already approved. Additionally, while others have said that pharma may be reluctant to do sequencing studies in combination with drug trials because the studies could ultimately limit the population of patients eligible for the drug, Curran said that he did not think that was a major issue.

"It's an interesting question," he said, and "it's certainly true that in the past that has been a debate within the industry." However, "we don't want our drugs used where they're not going to be efficacious or safe."

Also, because so little is known about the genetics of rheumatoid arthritis, the study could potentially uncover new drug targets. "The primary concern is scientific," he said, and "what we can understand better about the disease so we can come up with the next and better therapy."

Nevertheless, he said pharmaceutical companies still face challenges in justifying the use of sequencing, the main one of which is simply "being convinced that there's value," he said.

"The understanding of the genetics of complex disease hasn't been particularly useful, so there's resistance to doing more of the same," he said. "The lessons from Mendelian disease have not translated well to complex diseases."

However, he said that next-generation sequencing is fundamentally different from whole-genome scans and genome-wide association studies. And, if this first study yields promising results, he said it is very likely that the company will continue to do more sequencing studies.

"We've positioned this project as the lead, and we'll develop capabilities around analysis and understanding, and if we find value with this approach we'll quickly follow up with psoriasis, [inflammatory bowel disease], and other indications," related to autoimmune and inflammatory conditions, he said.

"It's not beyond the possibility that within the next few years, we'll have thousands of genomes sequenced for these different conditions," he said.

Curran also indicated that the firm will continue to outsource the majority of its sequencing work to BGI and other sequencing firms, at least in the near term. "The value proposition is better for us to acquire that resource externally when we need it," he said. "For our needs, we have not invested significantly in building a sequencing platform internally."

Analysis, however, is different. "We do that internally and collaborate with individuals that are aligned to certain diseases and bring certain technical pieces to the experimental design." Having in-house analysis capabilities is "critical," he said.

Going forward, he anticipated that desktop sequencers would enable individual researchers in pharmaceutical companies or academic labs to do "small experiments rapidly and well." Those small experiments would inform larger ones with hundreds or thousands of genomes that would then be outsourced. "The larger companies have a cost-efficiency and speed advantage," he said.

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