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Renewed Purpose for Some Drugs

By Kevin Davies
Nov. 13, 2007 |  PHILADELPHIA — “The most fruitful basis for the discovery of a new drug is to start with an old drug,” the Scottish pharmacologist and Nobel laureate James Black once said. A number of speakers at CHI’s second annual Drug Repositioning Summit* quoted that phrase, which begged the question that Chris Lipinski, the former Pfizer chemist of “Rule-of-Five” fame, duly asked: “Why, then, has drug repositioning only become common in the past four or five years?”

Given the problems facing the pharma industry, it is curious that big pharma and more opportunistic biopharma brethren only seem to have grasped the potential of repositioning in the past few years. Companies such as Aspreva, Gene Logic, KineMed, Melior Discovery, NV Organon, and Sosei in Japan have all made drug repositioning a central tenet of their business plans and more companies are destined to emerge. 

In response to Lipinski’s rhetorical question, Donald Frail, head of Pfizer’s  Global Indications Discovery Unit in St. Louis, offered two reasonable answers: one, because the promise of the genomics revolution was oversold. The second was emergence of new “business realities” — in other words, the most important “omics” of all — economics.

Whatever the drivers, drug repositioning and repurposing are gaining momentum. Marcel van Duin, executive director with NV Organon, which is in the process of being acquired by Schering-Plough, called it “a shift from target-based discovery to compound-based discovery.” Organon is pursuing several repurposed drugs for new indications including contraceptives and anesthetics.

Lipinski noted some 80 or more ongoing repositioning projects, including some of the most high profile drugs on the market — Tamoxifen for bipolar disorder, Gleevec for rheumatoid arthritis, and Lipitor for Alzheimer’s disease and influenza. “One of the advantages of repurposing is that you’ve already invested so much,” said the veteran chemist.

Lipinski is now a scientific advisor to Melior Discovery, a biopharma in Exton, Pa. Melior uses a multiplexed in vivo screening platform called theraTRACE to screen compounds across more than 30 potential therapeutic indications. Melior’s co-founder and VP research, Michael Saporito, said the company’s approach works on most therapeutic areas, although one notable exception is oncology, “because in vivo models are not that predictive for use in the clinic.”

Saporito said the company has assessed more than 150 compounds so far. MLR-1023 — the company’s lead product — is a chemical that Lipinski originally synthesized at Pfizer in the 1970s. The compound withdrawn from phase III trials. The theraTRACE screen revealed a hit in the glucose tolerance test. Further studies showed it activates the Lyn kinase signaling pathway in vitro and could make a good combination therapy drug for diabetes.

A Biotech Within Pfizer
Pfizer is taking an even more radical approach towards drug repurposing. Under Frail, Pfizer has assembled a dedicated team of 50 scientists in St Louis to identify new indications for compounds — both failed and those still active in the clinic.

Frail said “indications discovery” was first used at Pfizer as far back as 1999, but a dedicated division was created in 2006. “Drug repositioning,” said Frail, referred to failed compounds, whereas the goal of “indications discovery” is to expand the indications for active and inactive compounds. “We do work on failed compounds,” he said, “we just don’t know which ones have failed yet!” Frail likened the new St. Louis center to “a biotech within Pfizer.”

The new group combines wet lab experimentation and in vivo models with a heavy dose of informatics and computational biology. Frail noted the early value of a text-mining tool called PharmaMatrix, as well as other tools for expression analysis, systems maps, and clinical informatics. He also praised Pfizer’s first-generation information system for compound data, which was recently deployed (See p. 34).

But Frail also issued a warning: “In our enthusiasm [for repositioning], let’s not forget it is all about Phase 2 success. Is there any reason to believe that a repositioned candidate will have less attrition due to lack of efficacy in Phase 2?”

Integrative Pharmacology
Tom Barnes, senior VP discovery at Gene Logic, said his firm is pursing “integrative pharmacology” with a host of partners including Pfizer, Roche, Organon, Lilly, Lundbeck, and Merck Serono. Gene Logic uses a variety of technology platforms, including in vivo imaging, multiplex bioanalytics, molecular and cellular pharmacology, and in silico biology. Its BioExpress database, for example, contains expression data on more than 20,000 samples and 400 disease states. A former Millennium Pharmaceuticals compound, GL1001, originally developed as an ACE2 inhibitor,  is being developed for pancreatitis.

Not surprisingly, a panel discussion on the topic of IP of drug repositioning featuring Richard Smith, a partner with Edwards Angell Palmer & Dodge, generated intense interest. Smith said that composition-of-matter patents on drugs are the strongest. On the other hand, methods-of-use patents are relatively weak, subject to off-label uses that erode protection. New court and patent office rules make it much easier to find “obviousness” and restrict lengthy presentations.

Judging from the stream of questions for Smith, there is new purpose among those pursuing repositioning strategies.
*CHI's Drug Repositioning Summit: Finding New Routes to Success. Oct. 10-11, 2007; Philadelphia, PA.

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