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INTRODUCING THE ADVANCEBIO RP-MAB COLUMNagilent.com/chem/advancebio_RP

BIG NEWS FOR SCIENTISTS CHARACTERIZING mAbs

Weaving a Stronger Drug Safety Net

As modern techniques progress, more predic-tive assays may allow safety pharmacologists to perform better informed risk assessment.

A major reason for drug liability and with-drawal has been cardiovascular side-effects, pri-marily drug-induced Torsades de Pointes (TdP), a potentially fatal form of ventricular arrhythmia. The major preclinical assay required to gauge the risk of compounds for TdP is the hERG assay,

which is not sufficiently predictive because it tends to produce many false-positive results.

According to Yama Abassi, Ph.D., vice presi-dent of ACEA Biosciences, the hERG assay’s poor predictive value means that a number of good compounds in clinical development are being dis-continued. The industry urgently needs sufficiently predictive assays that can screen compounds in fairly see page 14

Advances in genomics, proteomics, and metabolomics are driving new biomarker development. Novel biomarkers promise to make precision medicine a clinical reality via early-detection markers, prognostic markers, and markers that more accurately predict treatment responses. Science Photo / Fotolia

A key hurdle slowing progress toward tai-lored therapeutics is developing appropriate biomarkers for diagnostics, prognostics, and prediction.

Despite much research, only a trickle of biomarkers has made it into clinical practice. Researchers, however, are pursuing novel avenues and making headway by dissecting the subtle architecture of normal versus can-cerous cells. New approaches include scru-tinizing aberrant glycans, microRNAs shed

from tumors, and epigenetic modifications, as well as mining and merging the vast stores of multi-omics data.

There are a number of key issues that must be considered prior to the successful development of a biomarker. “One of the most fundamental aspects that is too often overlooked is the specimen procurement process,” suggests Chad R. Borges, Ph.D, assistant professor, chem-istry and biochemistry,

Kathy Liszewski

Tailoring healthcare decisions based on biological infor-mation represents the promise of personalized medicine.

MaryAnn Labant

The issue of drug safety is as old as drug development itself. His-torically, animal models have been the cornerstone of preclinical drug development, resulting in mostly phenomenological observa-tions rather than providing a deeper mechanistic understanding of the side-effects of drugs or compounds in development.

see page 32

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November 15, 2014www.GENengnews.com

Traversing the Cancer Biomarker Labyrinth

A global network of off-targets for 1,200 FDA-approved drugs. Gold nodes are drugs; blue nodes are targets; gray edges are known links; and red edges are strong, new Similarity Ensemble Approach (SEA) predictions. According to SeaChange Pharmaceuticals, SEA—a chemoinformatic computational method—can predict drug side-effects and identify new therapeutic opportunities.

14 | NOVEMBER 15, 2014 | GENengnews.com | Genetic Engineering & Biotechnology News

Drug Safety Net Continued from page 1

DRUG DISCOVERY

high throughput and also provide mechanis-tic toxicity information.

The availability of human induced plu-ripotent stem cell (iPSC)-derived cardiomyo-cytes in scaleable quantities for screening purposes has generated excitement as a rel-evant and predictive model system. The chal-lenge is deriving pertinent information from these cells for risk-assessment purposes.

ACEA’s new xCELLigence® CardioECR system combines two cutting-edge technolo-gies, impedance and field potential elec-trodes, in the same platform. The impedance

electrodes allow for assessment of cardio-myocyte contractility and viability, while the field potential electrodes measure integrated ion channel activity.

The system conducts both readouts simul-taneously to capture and measure the events known as excitation-contraction coupling. The parameters and algorithms in the accom-panying software identify and analyze inter-esting aspects of cardiomyocyte response to compound treatment.

Furthermore, the FDA has begun to take notice of the importance of in vitro preclini-

cal assays for screening of proarrhythmic compounds. The agency is working to estab-lish the Comprehensive in vitro Proarrhyth-mia Assay (CiPA), a novel safety screening paradigm. Through the utilization of high-throughput, predictive, and mechanistic as-says, CiPA attempts to identify proarrhyth-mic compounds earlier in the drug discovery process.

Currently, the CiPA stakeholders are working together to design well-controlled validation studies to assess the reproducibility of the assays across different instruments and

different cells. A multisite study may be com-pleted as early as this month.

Liver Toxicity

A CiPA-like path is not yet in place to ad-dress the risk of rare or idiosyncratic drug-induced liver injury (DILI). Increasingly, expanded clinical studies are needed to rule out such risks. In general, today’s drugs will not cause a liver problem in animal studies, yet there are still liver problems in humans.

“People say we have to humanize pre-clinical testing. But even humans are not a good model for this rare toxicity. The aver-age human can take the drug entirely safe-ly,” discussed Paul Watkins, M.D., director, Hamner-University of North Carolina Insti-tute for Drug Safety Sciences.

“The chance that you are going to find liver cells to put into a mouse or to culture that are indicative of a rare event is low,” Dr. Watkins continued. “The problem is that liver cells available now are from ran-dom donors. If you could pick someone that actually had this rare event, and use iPSCs to make liver cells from that individual, you could at least begin to understand for that particular drug what is different in their liver cells from the average person.”

The University of North Carolina is the center for the Collaborative Cross, a popu-lation of inbred mice that have been mated according to a computer algorithm to arrive at the maximum genetic diversity. Forty-five strains are currently ready, and the complete

> Forendo Licenses U.S. Fispemifene Rights to Apricus for Up to $305M

Forendo Pharma, a Karolinska Development port-folio company, licensed to Apricus Biosciences the U.S. development and commercialization rights for the male urological conditions compound fispemifene, in a deal that could generate up to $305 million plus royalties for the licensor.

Fispemifene—the first selective estrogen receptor modulator designed only for men—is an oral once-daily, novel tissue-specific selective estrogen receptor modu-lator (SERM) indicated to treat secondary hypogonadism, chronic prostatitis, and lower urinary tract symptoms.

> Genentech, NewLink Launch $1.15B Cancer Collaboration

NewLink Genetics agreed to license its indoleamine-pyrrole 2,3-dioxygenase (IDO) pathway inhibitor NLG919 to Genentech and launch a research collaboration to discover next-generation compounds that combine IDO and tryptophan 2,3-dioxygenase therapies. It is estimat-ed that the deal could yield the licensor more than $1.15 billion.

The companies reason that IDO pathway inhibitors represent another breakthrough approach to cancer therapy as do recently-developed antibodies targeting CTLA-4, PD-1, and PD-L1.

The IDO pathway regulates immune response by suppressing T-cell activation, thereby enabling local tu-mor immune escape. NewLink said recent studies have demonstrated that the IDO pathway is active both with-in tumor cells as a direct defense against T-cell attack and within antigen-presenting cells in tumor-draining lymph nodes, where the pathway promotes peripheral tolerance to tumor-associated antigens.

> Astellas Ends Alzheimer’s Collaboration with CoMentis

Astellas Pharma terminated its six-year collaboration with CoMentis to develop and commercialize beta-secre-tase inhibitors for Alzheimer’s disease—a partnership that had been expected to generate up to $780 million for CoMentis.

Astellas said its decision came “based on the outcome of the research and development collaboration.” The phar-ma giant said it recognized impairment losses on other intangible assets of ¥8.1 billion (about $59.5 million) in the first three months of the company’s current fiscal year.

CoMentis’ website lists the status of the company’s lead product, identified only as “BACE inhibitor,” as “con-fidential.” That product, CTS-21166 (ASP1720), was re-ported to have shown promising results in two Phase I trials. Results showed a dose-dependent reduction of plasma beta-amyloid (Aβ) levels for an extended period

of time, with significant inhibition of plasma Aβ lasting more than 72 hours.

> Novartis Extends Deal to Use SomaLogic Proteomics Technology

Three years into a multiyear research agreement to use SomaLogic’s proteomics technology in its drug de-velopment efforts, Novartis has extended the deal and will take an equity position in the privately held life sci-ences tools and clinical diagnostics developer.

SomaLogic said the companies agreed to “enhance and expand” efforts undertaken as part of the collabo-ration. Under their previous agreement, the companies arranged to coordinate research at the Novartis Insti-tutes for BioMedical Research (NIBR) and SomaLogic to build an enhanced version of SomaLogic’s SOMAscan™ proteomics assay for NIBR, as well as develop specific SOMAmer® (Slow Off-rate Modified Aptamer) protein-binding reagents for multiple preclinical and clinical ap-plications in NIBR’s research and development portfolio.

SOMAmer reagents are designed to combine the best properties of both monoclonal antibodies and traditional aptamers. They can be applied in many cur-rent preclinical and clinical analytical assays, including quantitative high-content screening, targeted panels, flow cytometry, histochemistry, functional assays, and biophysical methods. n

News DISCOVERY & DEVELOPMENT

The xCELLigence RTCA CardioECR system from ACEA Biosciences combines impedance and multi-electrode array (MEA) technology with a pacing function. The system is designed to allow simultaneous real-time measurement of cardiomyocyte contractility by impedance, and electric activity by field potential measurement.

The Collaborative Cross addresses many shortcomings in available mouse strain resources, including small numbers of strains, limited genetic diversity, and a nonideal population structure. The breeding approach is designed to randomize the genetic makeup of each inbred line. Hamner Institutes / University of North Carolina See Drug Safety Net on page 16

16 | NOVEMBER 15, 2014 | GENengnews.com | Genetic Engineering & Biotechnology News

Drug Safety Net Continued from page 14

DNA sequence of every mouse is known. The mice can be used to screen drugs, and to be-gin to understand the genetic determinants.

Drugs that unexpectedly failed due to DILI have been shown to present toxicity in some strains of these heterogenetic mice pro-viding models for mechanistic studies.

The Hamner Institutes is also the seat for a major public/private partnership, the DILI-sim Initiative, which is developing a

computer based-model of mechanisms that underlie liver toxicity of drugs. DILIsym® software can create virtual patient popula-tions to predict rare liver-toxicity events, identify factors that place patient subpopu-lations at increased risk, and contribute to risk-management strategies.

In Silico Predictions

Inspired by the ligand-based organization

of targets in classical pharmacology, the Sim-ilarity Ensemble Approach (SEA) is a rapid, broad-scale, and model-free chemoinformat-ic computational method that operates on hundreds of thousands of ligands organized by their molecular targets.

“SEA allows us to ask and quantify wheth-er any given drug or drug-like molecule is more similar to a target’s ligands than would be expected by random chance alone. A strong

significance score is a prediction of possible off-target activity for that drug,” explained Michael Keiser, Ph.D., founder and chairman of SeaChange Pharmaceuticals and assistant professor at the University of California San Francisco School of Medicine.

“In collaboration with Novartis, we were able to determine that some off-targets were antitargets, which we found to be associated with adverse drug reactions (ADRs) via a guilt-by-association enrichment factor met-ric,” added Dr. Keiser. “Correspondingly, we were able to show that these antitargets were often better explanations of the drug’s known adverse reactions than any of its pre-viously reported targets.”

Off- and antitarget predictions are in-tended to prioritize, not to replace, the use of screening and experimental safety assays. Calculations are run rapidly on tens or hun-dreds of thousands of drug-like molecules to determine areas of potential liability for compounds.

Typical positive predictive values (PPVs) are 48–52%, even among known drugs, where one might have expected previously unreported antitargets to be sparse. These PPVs are approximately an order of mag-nitude better than those achieved in most virtual-screening campaigns.

The approach can be used for drugs and small molecules in development or on the market with known structures, and focuses on predicting ADRs that are mediated by specific antitargets.

The future goal is direct prediction of en-tire multitarget combinations. The increas-ing availability of big data may one day al-low linking a drug’s full on- and off-target profile with a patient’s unique genomic pro-file and electronic medical records for use in the emerging field of systems pharmacology.

Early Disease Detection

Many existing biomarkers are over 100 years old and lack the accuracy needed for

DRUG DISCOVERY

The University of Louisville (UofL) Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases bought In-stem’s Provantis® preclinical software solution as part of an expansion program. Provantis, a fully integrated Windows-based system with applications in nonclini-cal toxicology evaluation studies, will be used within the Regional Biocontainment Laboratory. This state-of-the-art facility provides scientific expertise and biosafety level-three laboratories for the discovery of therapeutics for serious pathogens and an infrastructure to meet pandemic or bioter-rorism emergency needs.

UofL funding for the expansion of its fa-cilities and the purchase of Provantis were awarded through a National Institutes of Health initiative to improve the nation’s top research facilities. n

Biocontainment Lab to Use Provantis Toxicology Software

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Genetic Engineering & Biotechnology News | GENengnews.com | NOVEMBER 15, 2014 | 17

timely detection of disease.Mechanistic biomarkers of drug safety al-

low informed decisions about a drug’s safety profile early in the development process. In collaboration with the Predictive Safety Test-ing Consortium, the Vaidya Laboratory was able to take the biomarker, kidney injury molecule-1 (KIM-1), forward from evalua-tion to confirmation, regulatory qualifica-tion, and point-of-care diagnostic testing for commercial utility.

Although seven biomarkers, including KIM-1, were qualified for preclinical toxic-ity in 2008, the clinical qualification of these biomarkers remains an uphill task. Early re-sults indicate that the list of kidney-disease biomarkers may need expansion given the heterogeneity and complexity of the patient population. MicroRNAs (miRNAs) have shown promise as potentially noninvasive and more stable biomarkers easily quantifi-able in biospecimens.

“We have generated miRNA profiles in human urine from patients with and without kidney injury to identify three to five miR-NAs to be early diagnostic, sensitive and spe-cific indicators of different forms of kidney disease,” stated Vishal Vaidya, Ph.D., head of systems toxicology in the Harvard Program in Therapeutic Sciences at Harvard Medical School and assistant professor of medicine and environmental health at Brigham and Women’s Hospital and Harvard School of Public Health.

These miRNAs provide mechanistic in-formation about the disease pathophysiology in the kidney. For example, miR-21, found to be significantly increased in patients with kidney injury, regulates metabolic alterations resulting in kidney damage. Because miR-21 is in the causal pathway of disease initiation and progression, measurement of miR-21 provides more mechanistic information.

The key is to now compare these emerg-ing miRNA biomarkers in the urine with the candidate protein biomarkers in a large number of patients, with and without kidney disease, over time to understand the tempo-ral profile and determine their effectiveness as early kidney-damage indicators as well as for their utility in patient stratification.

Quantitative Risk-Benefit Assessment

Quantitative risk-benefit assessment (RBA) requires a challenging combination of for-ward thinking and consistency of judgment. Standardized policies are required as well as industry agreement on the methodology for translation across organizations.

According to Israel Gutierrez, M.D., vice president of drug safety at Exelixis, profes-sionals familiar with a qualitative model may harbor doubts about the validity and poten-tial of the quantitative approach, impeding consensus. Exelixis performs quantitative RBA in an exploratory manner, on an ongo-ing basis, following methodology accepted by the European Medicines Agency (EMA) and the work processes put forward since 2010. The FDA is in the process of determin-ing its policies.

There are roughly 18 quantitative ap-

proaches to RBA. Out of all of the different methods, the medical application of mul-ticriteria decision and analysis (MCDA) is generating interest. Around since the 1970s, MCDA has been applied to drugs that have been approved, but historically it has not been easy to adopt or utilize.

New visual tools allow implementation of sensible and appealing methodologies, en-abling communication of findings and analy

ses to wider audiences without the need to delve into the statistical intricacies.

The assessment of benefit versus risk can change over time, as the understanding of drugs and population-specific characteristics evolves. It is now possible to project the con-tribution of the risk and benefit of those rela-tionships, and the impact of risk management on high-risk events, in circumstances that are considered important by companies and regu-

latory agencies.The EMA and others have already be-

gun to assess the benefit/risk profile of drugs in their portfolio and in develop-ment. Regardless of the method used, how one applies and weighs benefit/risk requires a methodology and a plan that is applied consistently a priori. Varying methodolo-gies can curtail and prevent progress of the analysis overall.

DRUG DISCOVERY