With targets aplenty, precision medicine seeks precise path forward

With trailblazer 23andme Inc. re-emerging in the personal genomics space with a $115 million series E to reinvigorate its direct-to-consumer efforts and the price point for whole genome analysis falling below the important $1,000-per-person barrier, precision medicine (PM) has made its way into the everyday vernacular.

Now what?

As a panel at the 2015 BIO Investor Forum made abundantly clear, the opportunity to expand drug development into ever more specialized subgroups has galvanized investigators around the globe, fueled by the 100,000 Genomes Project conducted by the UK's National Health Service, the growing whole genome sequence database of Icelanders amassed by Amgen Inc. subsidiary Decode Genetics Inc. and the million-person cohort envisioned in the NIH's ambitious Precision Medicine Initiative (PMI). (See BioWorld Today, Aug. 1, 2014, March 26, 2015, Feb. 2, 2015, and Sept. 21, 2015.)

But faced with an almost unlimited number of targets and many compelling needs, efforts to marshal those data also could face a tug of war over whether to go bigger or smaller.

Esteban Burchard, professor of medicine and bioengineering and therapeutic sciences at the University of California, San Francisco, and a member of the PMI panel of experts, pointed out that, to date, 95 percent of NIH-funded research has focused on populations of European origin.

"We're mining genes only looking at 5 percent of what's available," Burchard said.

In one example of the dangers of that narrow perspective in the application of drug development, Burchard cited the now-generic drug Plavix (clopidogrel bisulfate), which he noted is not well metabolized by some 65 percent of individuals in some Asian communities due to genetic polymorphisms associated with clopidogrel resistance. Thus, the blockbuster drug, prescribed almost routinely in hospitals to prevent blood clots after a heart attack or stroke, was completely unreliable for that group of patients.

"That's a missed scientific opportunity to get it right," Burchard said.

'ON THE CUSP OF A REAL REVOLUTION'

Precision medicine hopes to reduce such shortcomings. But unlocking the genetic secrets of millions of individuals across diverse, global populations and discovering biomarkers that could help scientists to tune drug development with pinpoint accuracy is a monumental task. Aside from government initiatives, gaining access to large-scale, highly integrated multi-omic data and linking that with highly characterized phenotypic information is challenging for researchers, said Tyler Wish, co-founder and CEO of Canadian PM firm Sequence Bio, because most health systems are not designed to collect, manage and manipulate such information, let alone use it collaboratively to drive innovation.

Sequence Bio, based in Newfoundland and Labrador, is leading a large-scale PM initiative to capture integrated multi-omic and phenotypic data on 100,000 people in the region, which was settled 400 years ago by immigrants of English and Irish descent and largely self-propagated. Descendants of those settlers – who live mostly in small communities that for centuries were connected only by boat – offer a unique opportunity to capture a mother lode of data from a genetically isolated population across various socioeconomic strata.

Newfoundland is associated with the world's highest incidence of certain rare diseases, Wish said, including the world's largest percentage of residents with epilepsy. Because residents of the region access Canada's publicly funded health care system through a single tertiary center in St. John's, the database includes historic information – 10 years of "fairly rich phenotypic information," Wish said – that can be studied longitudinally to understand disease etiologies and progression. Additionally, the population includes many large family pedigrees, "which can be very beneficial in this type of work," he observed.

The ultimate goal of the collaborative effort is to mine the data and identify patient subpopulations, therapeutic targets and biomarkers that could lead to the discovery of drugs that would benefit not only patients in the region but also more broadly.

"Our company is very bullish about the paradigm of precision medicine," Wish said. "We believe we're on the cusp of a real revolution for making better and safer drugs, quicker and cheaper."

PATIENT-TO-PATIENT VARIABILITY TRUMPS OTHER VARIABLES

Matthew Scholz, CEO of Seattle-based Immusoft Corp., said his preclinical gene therapy company and others like it are the clinical beneficiaries of early PM work, despite the perennial lag in translating discoveries into therapies. Immusoft's immune system programming platform produces long-lived, biologic-producing plasma cells from a patient's resting B cells, which are harvested from a simple blood draw, are genetically modified and differentiated in vitro and then re-injected into the patient, where they home to the bone marrow, take up survival niches and produce the intended therapeutic. (See BioWorld Today, Aug. 20, 2012.)

"For us, everything about dosing and production is per patient," Scholz told the BIO Investor audience. "If you take certain cells from two people, modify them both and grow them in a dish, they produce different levels of a therapeutic and they'll engraft at different rates. For us, understanding diversity and the range of behavior of people's cells is critically important."

As Immusoft has scaled up, the company has discovered that "patient-to-patient variability actually trumps most other variables," he added. "As we go forward, paying attention to these things is quite important to us. This is where medicine is going."

But some researchers want precision medicine to go much bigger, aiming for disorders that cut across very large patient populations.

Pamela Sklar, chief of the division of psychiatric genomics at the Icahn School of Medicine at Mt. Sinai, for example, wants to bring new drugs to common but complex psychiatric indications such as schizophrenia – a disorder, she maintained, in which PM principles still apply.

"The work we've been doing is largely focused on the most successful aspect of genetics over the last 20 years or so, which is the ability of large consortia to work together," Sklar said. "Everything we've learned about common complex diseases requires these types of public-private partnerships. Many of these things are a numbers game."

Sklar also emphasized that the study of genes isn't an end unto itself.

"The DNA sequence doesn't tell you what the biology is, and it's critical to make that move," she said, citing efforts that are further along in areas such as cardiovascular disease and cancer. "We need to produce the kind of data that will let us get a much more integrated or holistic view of gene expression and epigenetics and understand how the genome and biological pathways interact."

Andrew May, chief scientific officer of Berkeley, Calif.-based Caribou Biosciences Inc., which is seeking to advance new applications for CRISPR-based technologies, agreed that a fundamental need in PM efforts "is not just the accumulation of the underlying sequence data but a systematic attempt to try to characterize and validate the information that comes out of those studies."

Another area that May called "underserved" in PM is an examination of populations at the level of microbial variation, which could have important implications for clinical variation within biosystems.

"Anything we're looking at from a core population genome perspective is going to be missing layers of information based on these changes," May said.

To translate PM discoveries into therapies, Scholz added, "it's important to focus on how these populations age – not just the symptoms they develop but the underlying etiology. It's hard to find a better corollary for all of these malfunctions in life than age itself. If you want to get serious about investing in human health, you have to treat the underlying problems of age."

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