Going for multiple shots on goal

Drugmakers seek more than one application for compounds in early phase of development

Kimberely Sirk
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As the first part of this series began with the single word,"Viagra," this installment begins by invoking another blockbuster drug:Lipitor. The Pfizer giant, introduced in 1996, quickly eclipsed othercholesterol-lowering medications produced by competitors.
But the world hasn't seen a drug with similar impact,introduced and marketed at a sweet spot in pharmaceutical history. And theindustry might not see another.
According to an article that appeared on Forbes' website on November 30, 2011—theday that Lipitor went off patent—a number of disparate factors contributed toLipitor's success. 
"There may never be another drug like it," says Forbes' Matthew Herper. "That's becauseof fundamental shifts in our understanding of biology, because of demands madeby patients, doctors and society on new drugs and because new drugs now have tocompete with super-cheap generic versions of every medicine ever invented.Already, eight of 10 prescriptions are for generics, and the drug industry isfocusing on higher-priced, specialty products for patients who are not helpedby existing options. Good luck creating a new cholesterol drug as potent, safefor most people and widely tested as Lipitor." 
To put the vast reach of the drug in perspective, Herperadds that the drug has lowered the cholesterol of tens of millions of peoplesince its launch, and has racked up more money in annual sales than MajorLeague Baseball.
Lipitor launched an era where it seemed that there could oneday be a pill for every concern. However, that era brought with it massiveadvertising buys and equally massive drug scandals where side effects broughtdown blockbusters such as Vioxx.
The edge of the cliff
Michael Keech, senior vice president in the GlobalLifescience Practice at Celerant Consulting, explains that the approachingpatent cliff has significantly impacted what he sees as the three stages ofdrug development.
He says those three phases—discovery, preclinical andclinical development—proscribed drug development until recently. Bigmoneymakers coming off patent challenge this paradigm and threaten to upendmultibillion dollar businesses.
"Between now and perhaps 2015 to 2016, about $170 billion to$200 billion in drugs are due to come off patent," Keech says. "That's forcedorganizations to think about how to reposition their drugs."
He says, too, that companies are increasingly looking atmore than one application for various compounds in the beginning ofdevelopment, or to take "multiple shots on goal."
"There are a few reasons to repurpose for practicalreasons," he adds. "If a drug is already on the market, there is an existingsafety profile. If we have that safety and efficacy information on a drug thatperhaps did not meet its clinical trial endpoints, we save money becausereformulation is still cheaper than starting over."
From a business standpoint, too, shareholders are receptiveto the idea that companies are looking back into their own pipelines to bringto market new drugs, or new indications for old drugs.
"Shareholders like the idea of the company spending lessmoney in development," Keech says.
The biggest companies, or those with the most foresight andresources, have dedicated business units to just this purpose. Called somethingakin to a "new indication discovery unit," Keech mentions household names suchas Pfizer, Novartis, Bayer, Lilly and GlaxoSmithKline (GSK) as those who devoteminds and fund to this purpose.
Generic drugs only stand to gain in this environment.
Given the flurry of acquisitions and mergers in recentyears, it's clear that big drug companies have an insatiable appetite forsmaller ones.
Keech says that smart companies will begin to implement aproactive business plan 48 to 72 months before a big-grossing drug goes offpatent. Clearly, he says, a number of players have taken a deep dive into thegenerics business within the past several years. He mentions big players suchas AstraZeneca, GSK and Sanofi, which are working the generic business and alsopursuing joint ventures in increasing numbers. Teva and EndoPharma are alsoaggressive in this space.
"Companies are seeking to backfill these projected losses inthe next four or so years by acquiring smaller companies and novel products,"Keech concludes. "All of what you'd consider the top 10 drug companies have astrategy in place that makes them well positioned to weather this with newstrategies."
He gives the example of Lipitor as a hard-to-replaceblockbuster.
What, then, should drug companies be doing to ensure a softlanding?
Keech says the companies should plan for the loss of patentprotection years in advance of the actual event. They should, as part of thisstrategy, work closely with companies that manufacture authorized genericversions of their compounds.
As Pfizer did with Lipitor, the company entrenched itselfwith marketing and within the hearts and minds of patients to keep as muchbranded product flowing as possible.
However, with price pressures from current healthcare reformefforts, generics will increasingly become the preferred drugs for prescribersand health insurance plans alike. As the population ages and prescription druguse increased, the pressure for generic versions of blockbuster compounds willcontinue to increase.
Neither Pfizer nor Roche responded to several requests forinterviews for this story.
Keech also says the environment is ripe for companies thathave new technologies which might not necessarily involve lab benches andbeakers. Great minds in the space are now also meeting at events that have astheir focus the discussion of drug repurposing. 
Cecelia E. Cauwenberghe of business research and consultingfirm Frost & Sullivan said much the same in this space last month—that inthe past five years, rapid innovation in the biopharmaceutical space has helpedto temper the effects of rising development costs and stagnant product output. Companies always need new projects to fill pipelines and keep investorscontent, and to pick up the slack when candidates have not met their benchmarksin clinical trials.
The development stakes are high for drug companies.Recently, Targacept announced it will slash almost half of its workforce due toa recent failure of a compound in Phase III trials. The compound, TC-5214,which was being developed in partnership with AstraZeneca, repeatedly failed toprove that it was better than a placebo in treating depression. TheWinston-Salem, N.C.-based Targacept has no U.S. Food and Drug Administration(FDA)-approved drugs to its credit yet, but is working with AstraZeneca on acompound targeted to Alzheimer's disease. But for the near-term, that promisedoesn't help the 65 people who'll be packing their desks at Targacept.
According to the experts, the new plan of attack must be tomaximize technology. And numerous businesses—not merely pharma companies andresearch organizations—are looking to do just that.
On the other hand, as a step forward, the pharma industry isfocused on exploring the full potential of a broad spectrum of compounds andpro-drugs at earlier stages—that is, those in preclinical development—with theaim to provide additional opportunities and diminish risk.
As mentioned last month, Translational Life Sciences isworking on a crowdsourcing model to develop the blood pressure medicinelisinopril for multiple sclerosis. The model, which was introduced in beta formon Jan. 31, seeks to enlist collaborators to design Phase II trials of thisindication. Founder Dr. Tomas Sablinski, a transplant surgeon by training,calls the idea for his company "a Linux of drug development, in a sense."
Biovista, also mentioned last month, is well known in drugdevelopment and the repositioning space.
Another interesting opportunity to use existing informationin a new way is taking shape at a company known as Cellworks. Founded byexperts in software and semiconductors, the company seeks to develop models tomine vast repositories of known information about drugs, protein interactionsand genetics to predict what will work in humans.
Cellworks is a private, venture-backed biopharmaceuticaltherapeutic design and development company based on platform predictingclinical outcomes. The model will offer the pharmaceutical community innovativebest-in-class therapies that are substantially de-risked, yet have adramatically increased probability of success.
Founders Pradeep Fernandes and Taher Abbasi base their workon the notion that it takes an average of 12 years and $1.2 billion for a drugto travel from the research lab to the patient. These astronomical and risingcosts are, they say, in part due to the high failure rate inherent in drugdiscovery—less than 10 percent of drugs that begin preclinical testing evermake it to human testing, they say. From there, the funnel to the patientnarrows even further with only one in five drugs that enters human testingachieving  approval for treatment.
"Our model takes molecularly targeted therapies and measurestheir impact on specific diseases," says Fernandes. "We can also theoreticallymix and combine doses in computer models."
For new medicines to continue to reach patients, today'sdrug developers must find new avenues that increase the likelihood a drug willmake it from discovery to approval, and in a perfect world, predict clinicaloutcomes upfront.
The company has a pipeline of preclinical programs targetingautoimmune disorders and epithelial-based tumors. Its lead compound, CWG952, isready for clinical development for the treatment of rheumatoid arthritis. Italso seeks to enter the oncology space in the near future.
Cellworks was founded in 2005 with a novel approach ofdesigning therapies based on technology emulating human physiology andpredicting clinical outcomes. In 2009, Cellworks closed a $7.5 million Series Afinancing. The company has facilities in both California and India.
The company's founders say their strategy was to beginslowly, growing collaborations and broadening and deepening their experience indemonstrating that their algorithms could accurately crunch massive amount ofdata to spit out likely compounds for success in treatments. Since then, theysay they've pursued roughly 40 collaborations with partners both large andsmall, running a range of academic medical centers and researchers across thecountry, but will seek a few commercial partnerships on the horizon.
The speed at which their model works is noteworthy, giventhe notion that traditional drug development can take more than a decade. Somedata sets can be processed in less than an hour, rather than months. In thearthritis work the company has done, the founders say that more than a million in-vivo equivalency studies werecrunched to produce results in days. They were able to evaluate three drugs notused before in that indication, combined them in sub-therapeutic levels andfound success in animal tests. All three drugs were previously FDA-approved.
"We have the building blocks," says Abbasi. "We can nowexpand these compounds into other areas, with fewer side effects."
Sanford-Burnham Medical Research Institute at Lake Nona in Orlando is alsoworking on the library concept.
Using a comprehensive listing of clinically approved drugsthat was made available through recent efforts by the National Institutes ofHealth as a starting point, the organization is creating the Sanford-BurnhamDrug Repurposing Collection, which can be leveraged against the group'sstrengths in stem-cell biology, phenotypic cell-based screening andhigh-throughput chemical biology.
The library will be made available to local nonprofitresearch institutions such as the Salk Institute, the Scripps ResearchInstitute, the University of California at San Diego and its affiliatedchildren's hospital, Rady, as a resource to further advance translationalmedicine for rare diseases.
Dr. Layton Smith, the director of drug discovery atSanford-Burnham, points out that this private, independent research group is100-percent focused on basic sciences, not on education or patient care. Smithestimates that the group will have, by summer's end, a library of about 2,000to 3,000 small molecules and stem cells ready for researchers to use to provethe efficacy of their compounds and move on to FDA approval. Many will have notonly FDA approval, but also the nod of European and Japanese authorities.
If a molecule is patented, the group looks for vendors towork with, or synthesizes a version of the molecule themselves to complete theinventory. As with Cellworks, the group promises to compress the time needed torun screens from molecules in the library.
Smith also points out that the setup of the center for pureresearch for this purpose gives it a "boutique" capability, cutting time anddrawing together the technology and talent to make this approach to drugdiscovery happen.
"We hope people get excited about this approach," he says.

Sanford-Burnham Research 
National Institutes of Health 
Salk InstituteScripps Research InstituteUniversity of California at San DiegoRady Children's Hospital

Kimberely Sirk

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