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In Blockbuster Deathwatch, PGx Plays Larger Role

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Is the blockbuster model dying?

A Novartis official thinks so, and has put a 10-year life expectancy on pharma’s bread-and-butter drug-development model. The belief, echoed by other drug makers, has increased the amount of pharmacogenomics-based R&D performed by big pharma.

“It’s our current position that the blockbuster approach … is not sustainable,” Robert Schmouder, executive director of translational medicine at Novartis, said during a Cambridge Healthtech Institute conference. “We expect that at most it will be 10 more years for that paradigm, and then either companies will evolve into more focused approaches or fail based on that.”

“It is, I think, a fairly bleak view right now,” he added.

Industry observers have often viewed biomarkers and pharmacogenomics as a death sentence for the blockbuster model. However, with drug-development costs soaring above $800 million for a single product and recent high-profile failures of investigational drugs, such as Pfizer’s cardiovascular therapy torcetrapib, the industry is facing increasing pressure from investors, the public, and health authorities to embrace alternative R&D strategies to improve its record.

That Novartis has taken this prognosis seriously is evident in the fact that the pharmaceutical giant is in the midst of shifting its entire drug-development approach from a system structured to yield drugs that are efficacious for broad populations, to a process designed to target early and quickly the specific subset of people that will most likely benefit from a drug.

At the meeting, Schmouder said the company has altered the traditional three-phase drug-development model for a “learn and confirm”-type protocol that will allow for earlier proof-of-concept studies in humans.

Although this new model is not a guarantee that all investigational candidates will garner approval from the US Food and Drug Administration, it “is moving the probability in our favor,” Schmouder said.

Turna Ray

Promise, Hurdles with Cell-Based RNAi Screens

Pharmaceutical firms are finding cell-based RNAi screens to be a valuable drug-discovery tool, but are learning that the approach still has a number of limitations that need to be taken into account, according to speakers at Cambridge Healthtech Institute’s Molecular Medicine Tri-Conference held in late February.

Several speakers at the conference noted a number of advantages of cell-based RNAi screens over small-molecule screening for target identification. The reasons include the fact that most cell types are amenable to RNAi, it’s relatively easy to knock down any gene of interest, and the resulting data is extremely informative.

The approach still has some limitations, however; most notably, RNAi’s well-known tendency to produce off-target effects. In addition, several speakers discussed challenges related to the cells themselves.

For example, John Reidhaar-Olson, research leader in the department of research informatics for genetics and genomics at F. Hoffman-La Roche, noted that cell-based RNAi assays are particularly prone to edge effects because the cells in the outer wells of the plates grow at a different rate than the cells in the inner wells. As a result, his group usually ignores the outer wells in most studies, he said.

Steven Haney, group leader in oncology genomics in the department of biological technologies at Wyeth Research, said that his lab has had problems with the “penetrance” of some RNAi screens, in which the level of GFP in the cells is heterogeneous, making it difficult to interpret.

After further study, Haney said his team found that the expression levels of several proteins varied significantly within cells grown in culture, meaning that the problem is not heterogeneity of the siRNA knockdown, but heterogeneity of protein expression. The issue is an “artifact of the cell culture itself,” Haney said, perhaps due to the fact that cells proliferate faster in culture than they would under normal biological conditions.

Bernadette Toner

Short Reads

The US Food and Drug Administration will review the Roche Diagnostics cobas TaqScreen MPX test designed to diagnose HIV and hepatitis infections in donated blood and plasma. The test is a real-time PCR-based single-multiplex assay that, if approved, would be used to detect HIV types 1 and 2 and hepatitis viruses C and B. Also, FDA will review for clearance a pair of Roche’s genotyping-based tests that detect and strain-type human papillomavirus.

CombiMatrix’s molecular diagnostics unit will create an array-based test using biomarkers linked to autism that were developed by the Center for Applied Genomics. The company will use the markers through a partnership with TCAG in a constitutional genetic array test that will be used to screen for autism and “more than
50 disorders.”

Thanks to a renewed and expanded partnership and licensing agreement, Biosite will have access to more of Compugen’s diagnostic and immunoassay biomarkers. The new agreement covers cardiovascular and oncology indications through which Compugen will earn milestone payments and royalties.

VisEn Medical and Merck will develop and apply fluorescence agents to image disease-related biomarkers in vivo. VisEn says the program will use proprietary and literature-derived biomarkers linked to cardiovascular disease together with VisEn’s fluorescence agents and fluorescence molecular tomography imaging systems.

XDx will in-license IP from the University of Minnesota that will enable the company to use gene expression technology to assess the status of systemic lupus erythematosus in patients. In a separate agreement, the company gets access to SLE patient samples taken from an NIH-funded study of biomarkers for autoimmune diseases via a partnership with Minnesota and Feinstein Institute for Medical Research in New York.

A unit of Kaiser Permanente, the nation’s biggest managed-care company, plans to create a large repository of genetic material to examine the genetic and environmental factors affecting disease and patient response to medications. Kaiser plans to build a large database of biological samples, drawing on its base of 2 million members in the northern California region.

Third Wave Technologies has countersued Digene after the company sued Third Wave in January for allegedly infringing its human papillomavirus IP. In its suit, Third Wave claims Digene has “abused its monopoly power to thwart competition” in the HPV diagnostics market.

The Van Andel Institute and Spectrum Health started a molecular technologies lab to study genomics and proteomics for application in cancer, heart disease, mental illness, and other diseases. The Center for Molecular Medicine, located in Grand Rapids, Mich., has $6 million in funding.

Patents

US Patent 7,191,068. Proteomic analysis of biological fluids. Inventors: Ron Rosenfeld, Sri Nagalla, and Mike Gravett. Assignee: Proteogenix. Issued: March 13, 2007.

This patent relates to the “identification of proteomes of biological fluids and their use in determining the state of maternal/fetal conditions, including maternal conditions of fetal origin, chromosomal aneuploidies, and fetal diseases associated with fetal growth and maturation. In particular, the invention concerns the identification of the proteome of amniotic fluid (multiple proteins representing the composition of amniotic fluid) and the correlation of characteristic changes in the normal proteome with various pathologic maternal/fetal conditions, such as intra-amniotic infection, or chromosomal defects.”

US Patent 7,184,893. Method for selecting an optimally diverse library of small molecules based on validated molecular structural descriptors. Inventors: Richard Cramer and Robert Clark. Assignee: Tripos. Issued: February 27, 2007.

The patent covers “a unique validation method” that can be used to ascertain the “relative usefulness/validity of individual metrics” related to biological screening projects of a “large combinatorially accessible chemical universe.”

US Patent 7,177,767. Systems and methods for the detection of short and long samples. Inventors: Vladimir Ostoich, Kenneth Aron, and Dennis Bleile. Assignee: Abaxis. Issued: February 13, 2007.

According to the abstract, this patent includes systems “for detecting the accidental use of short and long samples in the clinical analysis of a sample, specimen, or assay. The systems can include a clinical analyzer for determining one or more values for one or more measurable characteristics of a sample.”

US Patent 7,189,825. Cancerous disease modifying antibodies. Inventors: David Young, Susan Hahn, and Helen Findlay. Assignee: Arius Research. Issued: March 13, 2007.

This patent covers “a method for producing patient cancerous disease modifying antibodies using a novel paradigm of screening. By segregating the anti-cancer antibodies using cancer cell cytotoxicity as an end point, the process makes possible the production of anti-cancer antibodies for therapeutic and diagnostic purposes. The antibodies can be used in aid of staging and diagnosis of a cancer, and can be used to treat primary tumors and tumor metastases.”

Data Points

$100 Million

The Broad Institute will use a $100 million donation from the Stanley Medical Research Institute to establish a new center to study the genomics and chemical biology of psychiatric disorders.

$2.8 Million

Uppsala Bio, a Swedish biodevelopment organization, will fund a new project to the tune of $2.8 million and has put out a call for applications. The project should involve diagnostic tools, predictive medicine, or drug discovery research.

The Scan

WHO Seeks Booster Pause

According to CNN, the World Health Organization is calling for a moratorium on administering SARS-CoV-2 vaccine boosters until more of the world has received initial doses.

For Those Long Legs

With its genome sequence and subsequent RNAi analyses, researchers have examined the genes that give long legs to daddy longlegs, New Scientist says.

September Plans

The New York Times reports that the US Food and Drug Administration is aiming for early September for full approval of the Pfizer-BioNTech SARS-CoV-2 vaccine.

Nucleic Acids Research Papers on Targeting DNA Damage Response, TSMiner, VarSAn

In Nucleic Acids Research this week: genetic changes affecting DNA damage response inhibitor response, "time-series miner" approach, and more.