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Q&A: Genentech's Tim Behrens Discusses Recent WGS-focused Partnerships

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NEW YORK (GenomeWeb) – Just a few years ago, whole-genome sequencing wasn't something pharma companies discussed much in the context of their drug development efforts.

Sure, it may be a good discovery tool one day, drugmakers acknowledged, but WGS was still too expensive for broad application and using it yielded too much poorly understood data. But now that's changing.

Genentech recently inked two separate deals with 23andMe and Human Longevity through which the drug developer is planning to sequence thousands of genomes with the aim of improving its mechanistic understanding of diseases and informing therapeutic development. The 23andMe partnership is around Parkinson's disease, while the Human Longevity deal is more broad, spanning a number of diseases. But in both, Genentech is moving beyond genotypes and SNP data, and learning from whole-genome sequences.

In the cancer space, with drugs like Herceptin (trastuzumab), Tarceva (erlotinib), Kadcyla (ado-trastuzumab emtansine), Perjeta (pertuzumab), and Zelboraf (vemurafenib), Genentech has played a leading role in personalized medicine. And Roche, Genentech's parent firm, decided recently to take a majority stake in Foundation Medicine, a company that markets targeted sequencing-based cancer diagnostics. So it's no surprise that it is also among the first companies to move forward on integrating WGS data in a big way in its drug development work. These WGS-focused partnerships will help Genentech move its personalized medicine efforts beyond cancer, or at least, that's the aim.

Timothy Behrens, senior director of immunology, tissue growth and repair human genetics at Genentech, discussed with GenomeWeb the company's recent WGS-focused partnerships and its personalized medicine efforts in general. Below is an edited transcript of the interview.

How does Genentech plan to use the genome sequence information it will glean from the 23andMe partnership?

We have been very interested in the neuroscience therapeutic area for some time. We particularly have a strong area in neurodegeneration, which would include Alzheimer's disease, Parkinson's, Lou Gehrig's disease, and other neurodegenerative diseases. Parkinson's is a significant unmet medical need. There have been a number of genetic studies in recent years, which have provided some clues as to the pathways involved in the neuronal cell death that characterizes Parkinson's disease. So, that really sparked our interest.

23andMe has accumulated a very large collection of well-documented Parkinson's disease samples over the last several years. Perhaps it's the largest collection in the world. We've been in discussions with them for some time about their collection and about how we can best partner with them in discovery efforts for the disease.

23andMe already has a significant body of genotypic data. So, why move to whole-genome sequencing in this setting?

The data 23andme has generated is SNP data using high-density Illumina genotyping chips. These provide about a million or so genetic variants across the genome, all SNPs. We think the resolution to really understand this disease to the best extent possible does require understanding the sequences across the genome. There is quite a bit of evidence that Parkinson's disease can be caused by rare variants, sometimes [variants] that run in families. The SNP chips are potentially missing some of the important genetic factors contributing to the disease. So, by whole-genome sequencing we believe that we maximize our chances to identify rare genetic variants contributing to Parkinson's. We look forward to amassing quite a bit of data from the 23andMe collection.

In terms of the near-term impact of that collaboration, are there any drugs that are promising? Or if you can't talk about that, could you discuss any hypothesis you might have with regard to the rare marker you mentioned that might be important in Parkinson's?

There's quite a bit of published data on genetic factors contributing to Parkinson's. We're very interested in this therapeutic area and we think this partnership will allow us to identify new genetic factors contributing to the disease. The timelines are relatively long here in that we anticipate novel discoveries [about] new biology contributing to the disease. That's going to require follow-up studies here in our laboratories at Genentech and we hope that those kinds of experiments will lead to specific targets and new drugs. [Editor's Note: 23andMe highlighted that markers like LRRK2 will be further explored in the project that aims to sequence 3,000 Parkinson's patients and families from the 23andMe research community.]

You already have testing capabilities internally, as well as genomics expertise. Do you have whole-genome sequencing capabilities in house, and when do you decide when to partner externally?

We do have internal capability for whole-genome sequencing [using Illumina platforms]. We also have partnered outside for sequencing depending on the volume. But we have very good capability internally for data analysis, which is probably the more important thing for us at this point.

Moving on to the Human Longevity partnership, what is that project focused on? Do you have any specific goals you want to achieve or are there any specific disease areas you're focusing on?

HLI brings to the table significant expertise in high-throughput sequencing data analysis and have a proven track record for success in very large projects. The collaboration is really focused on our providing samples to HLI for sequencing. Many of these samples come from our clinical trials, but there are other additional sample sets that HLI will be sequencing for us. We will be doing joint data analysis with HLI. We have selected a number of [oncology and non-oncology] therapeutic areas for initial efforts and we expect those will expand over time.

You joined the LungMAP effort last year [which is a multi-drug, multi-arm, biomarker-driven clinical trial for patients with squamous cell carcinoma]. How is that project going and how is Genentech involved?

Regarding the status of the Lung Cancer Master Protocol trial with Genentech's taselisib, the trial is ongoing and enrolling patients. In December it was announced that now 400-plus sites were onboard recruiting.

From what you've published, it's clear that Genentech thinks there is a large role for precision medicine strategies in the immunotherapy space. Can you detail your efforts there?

As was reported in the Nature articles last year, we have been developing an anti-PD-L1 antibody for a variety of different tumor types. As was noted in those papers, the immunohistochemistry for the PD-L1 protein itself turns out to be an interesting biomarker for predicting those patients most likely to have good responses to anti-PD-L1 therapy. There are other efforts around the PD-L1 program trying to understand the baseline characteristics and the changes that occur in tumors after PD-L1 predict a good response. We're vigorously pursuing a number of those possibilities.

 

Last year Genentech published a paper describing a targeted sequencing method that the company's researchers had developed internally as a discovery tool. I believe it gauged markers within 88 cancer-related genes. Can you talk a bit about that platform? Have you made much use of it internally in biomarker discovery? When would you use this test over another targeted NGS panel that's been developed by an external partner?

I think it's fair to say that we and many others are interested in using sequencing and other genomic methods to understand the heterogeneity within human cancer. We have developed some of our own internal protocols. And we believe that these protocols have some promise in being applied to our clinical trials. We have also recently partnered with Foundation Medicine in a big way. Foundation Medicine has already developed sequencing-based diagnostic panels for cancer and we anticipate applying that platform to many of our clinical trials in the near future.

Other than the neurodegenerative space and cancer, are there any other indications where Genentech is working to advance molecularly informed or precision drugs?

I would just say that we're keeping a close eye on genetic discovery efforts in essentially all therapeutic areas, with the idea that these are very important fundamental experiments to identify pathways and potential new targets for disease, really across the board. Although there are areas where we have got a special emphasis with these outside collaborations, we have additional internal programs and partnerships that are all aimed at the same thing, and that is to better understand the genetic underpinnings of human disease.

As you know, President Obama has announced an initiative on precision medicine that will involve a broad range of stakeholders. Have you been asked to contribute to the effort or do you have an interest in participating?

It's fair to say that it's just too early in that effort for us to comment on how we might or might not contribute. But we applaud the president's initiative. This is an area that Genentech has been really developing data in, and for the last 15 years we've been pursuing the idea of targeting therapies to the right patients. So, we're supportive of the overall effort.

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