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Leading by Example

By By Kevin Davies

March 12, 2007 | Delray Beach, FL — At Cambridge Healthtech Institute’s annual Pharmaceutical and Biotech Leader’s Summit*, held on Florida’s sun-splashed Gold Coast, drug industry executives provided fascinating accounts of the profound organizational and technological changes that are helping organizations overcome industry-wide challenges.

Representatives from Merck, the Novartis Institute for Biomedical Research,  Decode Genetics, and others shared their companies’ experiences adapting to the shifting market, and focusing on innovation not only in the lab, but also in their corporate communities.

2001 and All That
Kathleen Metters has spent 19 years rising up the ranks at Merck, from postdoc to senior VP and head of basic research. Metters said three major events in 2001 had a big impact — the hiring of Peter Kim (now President of Merck Research Laboratories); the purchase of Rosetta Inpharmatics; and a redesigned business process. Indeed, Merck’s drug pipeline has doubled in the past five years.

Metters said key changes within the company positively impacted people and process. “Merck [previously] ignored culture,” she said. “Merck has always had extremely strong functional expertise, but lacked a real understanding of disease therapeutic areas.” Merck’s reorganization reflects a renewed desire to rebuild the company’s scientific strength.

Merck created six therapeutic franchises with responsibilities from target to Phase IIb. Staff can now think as physician scientists, asking how products can be brought forward. “Without that strategy, we don’t believe we can accurately estimate the probability of success and thus the level of investment needed for each product,” Metters said.

Merck has shifted considerable resources into biomarkers and imaging, as well as building a new department of experimental medicine. It is investing heavily in the industrialization of research, notably high-throughput screening and RNA interference (RNAi). Merck now has online access to libraries of 2.2 million compounds. Robotics systems are generating more than 60 million assay results per year. And 600,000 RNAi wells were screened last year to identify new targets

Those technologies are assessing candidate molecules early in the discovery cycle. “Now, an entity needs to be fit for its purpose... there has to be explicit design of that molecule in order to answer questions you’re trying to ask,” said Metters.

Prior to last year’s acquisition of Sirna, Merck’s biggest investment came with the purchase of Rosetta Inpharmatics. “We thought we were buying a gene expression company,” said Metters, “but it’s developed into a genetics and informatics company that informs much of the strategy within R&D.”

In addition to helping identify targets, Rosetta’s informatics technology has been instrumental in introducing genome-scale RNAi, network and pathway reconstruction, and helping Merck to be “much more predictive about intervention.” Rosetta was “more than an acquisition, it became an attitude!” said Metters. “Innovative thinking really produced a sea change within the company, particularly within early discovery.”

NIBR Alliances
Jeremy Levin
, global head of strategic alliances at the Novartis Institute of Biomedical Research (NIBR), said like all big pharmas, Novartis faces rising costs, compound attrition, and a dearth of novel drug targets. There is no single solution to overcome these problems, Levin said: “I haven’t heard a coherent answer.”

Levin reckons that the big pharmas reshaping R&D “are the companies that are going to win.” A major part of NIBR’s strategy is licensing deals worth $13.5 billion last year, increasingly for early-stage compounds. Levin’s alliance team speaks a total of 15 languages, which comes in handy as the quest for new chemical technologies pushes into eastern Europe. Levin too is bullish about RNAi, believing that Novartis’ partnership with Alnylam would produce new therapeutics.

Internally, the main research goal is to build a new ‘grammar’ for organizing the genetic and chemical universes towards drug discovery. The company is forging new ways to discover and validate targets, using siRNA, antibodies, proteins, predictive animal models, and better ways to stratify patients. But newly identified targets must be placed in context of molecular pathways, Levin said. Fittingly, the former CEO of Physiome (see “A Virtual Pharmacopeia,” Bio•IT World, Nov.  2002) said Novartis maintains “a rich interest in in silico biology.” Indeed, several former Physiome modelers have joined NIBR, which is also collaborating with Entelos.

Decoding Drug Development
Smaller biopharmas, which obviously lack the luxury of massive alliance programs or industrializing their research pipelines, must find novel routes to enhancing efficiency. Mark Gurney said Iceland’s Decode Genetics has high hopes for a pair of cardiovascular disease inhibitors, DG-031 and DG-051, which target the leukotriene pathway. The goal, says Gurney, is to find a successor to DG-031 in just two years.

Gurney ticked off a dozen or so factors that helped speed the development of DG-051 including the need for urgency,  forming the right multidisciplinary team, and communicating the vision. Outsourcing was fine, so long as it complemented the team’s in-house capabilities. Software called GeneComposer  facilitated gene synthesis design. Small changes in codon usage produced dramatic changes in microbial expression, while tweaking surface residues had a major impact on crystallization. Aided by Emerald Biosystems, Gurney said, the DG-051 target protein was crystallized in weeks.

By contrast, the synthesis of a chemical candidate took 12 months. For this, Decode utilized a chemical library of high-binding energy chemicals, dubbed the Fragments of Life. Fragment screening was used for lead identification and chemotype switching, which has now resulted in a commercial product.

Among other notable speakers were Vertex Pharmaceuticals’ Mark Murcko, the FDA’s Larry Lesko, and Genentech’s Paul Fielder.

*The Pharmaceutical and Biotech Leaders' Summit; Delray Beach, Florida, January 16-28, 2007.

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