DECODE
COVE R STORY
ALMOST THERE
Kilogram-scale production is near the end of the long journey of drug discovery.
PHARMA OUTSOURCING Pharmaceutical companies look for outsourcing partners all along the DRUG DEVELOPMENT PIPELINE
EVERY INNOVATIVE pharmaceutical on
the market today got there only after an expensive trip through what people in the drug industry call the pipeline. It’s a trip that takes years if not decades to complete. At the start of the journey is a target: a cell, protein, or molecule that scientists believe is implicated in a disease. In smallmolecule drug discovery, chemists typically bombard the target with one molecule after another, looking for a chemical that acts on it in a medically useful way. After chemists hit on a promising molecule, they turn to developing a process with which they can make it at a reasonable cost. Numerous synthetic routes, catalysts, and reaction conditions are considered. Once they have a process—and the molecule has passed successfully through a battery of efficacy and safety trials—the chemists and their engineering colleagues are ready to manufacture the molecule so it can emerge from the pipeline as an approved drug. There was a time when drug companies
would undertake these steps—discovery, process development, and manufacturing—on their own. These days, however, most firms engage an outside partner to help with at least one of them. In the pages that follow, C&EN presents three case studies of outsourcing relationships along the drug development pipeline. In the first case, a Belgian drug company enlists the aid of a Midwest contract research firm that has a novel technique for discovering potential drug molecules. In the second case, one of the bestknown U.S. drugmakers partners with a California company that uses gene manipulation to create new biocatalysts. Together, they develop an environmentally friendly reaction step that yields a critical drug intermediate. And in the third case, a French biotech company turns to a Dutch fine chemicals maker for help with a potentially dangerous manufacturing route. Thanks to a pioneering microreactor-based technique, the WWW.CEN-ONLINE.ORG
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Dutch company wins a contract to make a drug that could become a blockbuster arthritis medication. As these case studies show, all kinds of outsourcing is done along the drug pipeline by pharmaceutical companies big and small. But the three stories have one thing in common: More than being just a helping hand, the outsourcing partners all contribute something unique that the drug companies couldn’t have done on their own.
CONTENTS ADDITIVE APPROACH, 12 The desire for a collaborative relationship is behind a contract research deal. GREATEST HITS, 14 A big drugmaker and a small biotech firm make biocatalytic music together. HANDLE WITH CARE, 17 A biotech firm rewards a new approach to making a dangerous compound.
DECODE
COVE R STORY
ADDITIVE APPROACH CASE STUDY #1: UCB taps deCode for
structure-based drug discovery
UCB AND DECODE GENETICS’ chemistry
and biostructures division aren’t saying much about the drugs they are working on in a collaboration announced last month—only that deCode will work with the Belgian company on structure-based discovery of small-molecule modulators of “undisclosed cytokine targets” in the area of inflammation. But the companies are discussing how the partnership advances their strategies to, in deCode’s case, further a fragment-based lead discovery technique and, in UCB’s, to boost its pipeline. The collaboration comes as UCB is working to better coordinate its in-house chemistry and biology capabilities, says Graham Warrellow, vice president of chemistry at UCB’s U.K.-based operation. “The time is right to catalyze on what we know about the biologicals world in terms of the types of targets researchers go for and to try to find a way to target these
pathways using small molecules,” he says. Not that making chemistry and biology work together efficiently is an easy trick— many have tried and failed. “But I believe the reason people have failed in the past is because they have not used the right assays or approach,” Warrellow says. It is also difficult for any one company, he says, even one with sizable biology and chemistry research organizations, to pull this off on its own. That’s where UCB’s year-old NewMedicines drug discovery group comes in. Since launching NewMedicines, UCB has forged deals with biotech firms, including deCode, Proteros Biostructures, and SAI Advantium, and has started an alliance with King’s College London. “We’ve tried to create something like an open innovation platform,” Warrellow says, “where we access people in industry and academia in stitching together a network.” UCB found an ideal partner for its cy-
“Science is science and drug discovery is risky, and anything can happen. But we plan for risk and not failure.”
tokine inflammation project in deCode’s U.S.-based chemistry and biostructures division, Warrellow says. Specializing in protein-protein interactions, the division recently made an initial new drug (IND) filing with the Food & Drug Administration for modulators of the protein phosphodiesterase 4D (PDE4D), which it discovered through a structural biology investigation using molecular fragments to modulate protein-protein interactions. DeCode has already put three compounds into the clinic and now is looking for a partner to develop the PDE4D modulator as a treatment for cognitive deficiency associated with Alzheimer’s disease and other disorders, according to Lance Stewart, pres-
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TANDEM DeCode
Genetics pairs structural biology and chemistry in its discovery techniques.
ident of the biostructures division, located in Bainbridge Island, Wash. The firm is also promoting its discovery technique, called Fragments of Life, to third parties such as UCB. Fragment-based drug discovery has been gaining attention recently (C&EN, July 21, 2008, page 15). DeCode’s approach focuses on a unique application of chemistry to biology, claims Alex Kiselyov, president of the company’s chemistry division in Woodridge, Ill. “Instead of using high-throughput screening or cell-based screening, we use highthroughput crystallography and chemistry in tandem,” he says. Nuclear magnetic resonance and surface plasmon resonance are also applied to gain insights into how molecule fragments bind to targets, he adds. “THE IDEA is to understand where the
molecule binds and what it does, exactly, to the active site, to the allosteric site, or to an interface of the protein-protein interaction,” Kiselyov says. “Chemists digest this information, evolve the particular molecule into a lead candidate, and feed it back to structural biology. Structural biology reiterates its round of crystallography and feeds this information to chemists, and on and on we go.” UCB’s Warrellow sees a distinct advantage to fragment-based discovery over the more widely used high-throughput approaches that vet complex, high-molecular-weight compounds. “In the days of the combinatorial library, you would generally be picking up high-affinity interaction, but efficiency was often quite low,” he says. “It is quite interesting that the output from the industry during that period went into a kind of decline.” The additive process of building up fragments is more logical than the reductive one of determining what part of a larger molecule binds to a target, Warrellow argues. “Having a crystal structure of a fragment binding with the protein demonstrates to the chemist how that small piece
of the molecule interacts with the target,” he says. “It clues the medicinal chemists in on how to alter the structure and where to add functional groups to molecules in order to increase the binding.” DeCode’s Fragments of Life library complements the compounds and fragments in UCB’s own collection, Warrellow says. Just as important, deCode researchers will serve as an extension of UCB’s in-house R&D team. “Now we are treating collaborators as collaborators, not service providers,” he adds. “This is a change for us.” UCB is also gaining access to expertise in protein-protein interactions. “The reason we went to deCode is that we just believe they are one of the best structural biology groups in the world,” Warrellow says. “They have a very strong capability to clone, express, and purify proteins and then take them further into structural studies.” UCB also considered deCode’s pharmaceutical chemical production capabilities, which can produce Phase III quantities, a plus, Warrellow says, but there is no guarantee that the partnership will go that far. In fact, the deal is open-ended as to how far it will proceed; it will continue as long as it adds value to what UCB can do on its own to find small molecules that modulate protein interactions, he says. DeCode’s Stewart agrees the end-point of the collaboration will be determined by performance. “We have managed to put together a collaborative program where the goal is an IND. And there is a commitment to achieving that goal from both sides,” he says. “Science is science and drug discovery is risky, and anything can happen. But we plan for risk and not failure.” Both companies agree that the collaborative nature of the relationship is likely to prolong it, and both see a long-term partnership as ideal. Warrellow also sees it in the context of a trend toward collaborative work between commercial drug research enterprises. “It is the only way forward for the drug industry,” Warrellow says, noting that UCB has a similar working arrangement with the other contract research organizations and has other deals it has not announced. “The issues that we deal with in discovering new drugs are so complex that even in the very large organizations, it is difficult to provide the right balance of all the skill sets. I am excited about the future; having a more open innovation approach is a much more invigorating way to work,” he says.—RICK MULLIN WWW.CEN-ONLINE.ORG
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COVE R STORY
GREATEST HITS CASE STUDY #2: Merck advances process development
by tuning up biocatalysts with Codexis
JUST AS AN ORCHESTRA needs instru-
ments, Merck & Co.’s process development group needs synthesis tools. For several years, biocatalyst developer Codexis has focused on fine-tuning such tools. Together, Merck and Codexis believe they can make music through biocatalysis. Although the companies each have expertise, like string and brass sections they see themselves as complementary, not overlapping. Codexis’ strengths are in enzyme optimization and manufacturing, whereas Merck specializes in synthesis and process development. As partners they extend each other’s reach. Moreover, in coming months, when they present results of their process development work together, they expect to dispel any lingering doubts about the utility of
biocatalysis for making pharmaceuticals. Biocatalytic syntheses are appealing because they can be run in standard equipment under mild conditions with less solvent while giving high enantioselectivity and yield. But they have been plagued by what Merck and Codexis managers say are misconceptions about inconsistent catalyst quality, high cost, long development times, and an inability to adapt to different reaction conditions. Customized enzymes can be extremely competitive with other catalytic approaches, contends Greg Hughes, an associate director in Merck’s process research department. Typically, he notes, “a process that is more environmentally friendly also tends to be much more economically attractive.” Codexis’ enzymatic approach to
catalysis meshes well with Merck’s desire to develop environmentally benign syntheses, Hughes says. Merck’s process research group strives to be “green by design” while implementing the best solutions across all stages of drug development and manufacturing, he explains. “It’s our philosophy that we should be able to do green chemistry well because we do chemistry well,” Hughes says. “Our hope was that this collaboration would give
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CODEXIS
sues of turnaround and scale-up are really nonexistent,” Hughes says. “We can turn around results very quickly and really be assured that 99 times out of 100 we are going to have success.” Success is tied in large part to the statistical protein sequence-activity relationship (ProSAR) technique that Codexis uses to optimize enzymes (Nat. Biotechnol. 2007, 25,
OPTIMUM ENZYMES rise to a number of A Codexis biocatalysis-based researcher monitors approaches.” a series of 1-kg The partnership capacity fermenters. has its roots in 2006 discussions of Codexis’ idea for putting its biocatalysts in process chemists’ hands. Historically, says Gjalt Huisman, vice president for pharmaceuticals R&D at Codexis, the firm had kept its enzymes inhouse and conducted the screening and optimization work for others. After Codexis launched its Codex biocatalyst panels in early 2007, Merck signed on as the first subscriber. Each 96-well panel represents an enzyme class. Available chemistries include ene reductases, ketoreductases, transaminases, acylases, and halohydrin dehalogenases for making pharmaceutically relevant compounds such as chiral alcohols and chiral amines. “The ability to address different enantioselective transformations is very efficient,” Hughes says. To begin with, the enzymes in the panels have been engineered to be easy to manufacture at large scale, Huisman explains. They are also robust across a range of process conditions including solvent concentration, temperature, and pH. Compatibility between a biocatalyst and a substrate molecule can be improved via directed evolution of the enzyme. After a substrate is screened against a panel for initial activity and selectivity, Codexis uses gene sequence and function information to transform hits into process-specific biocatalysts. Following this approach, Merck began testing the panels and reporting results back to Codexis. Communication between the companies includes discussions of further optimization and scale-up. “In our experience over the past few years, the is-
338). As a result, the speed at which enzymes can be developed and delivered in kilogram quantities has risen dramatically, Huisman says, often taking only two to three months from inquiry to commercial biocatalyst. Work with Merck got off to an even faster start with the first panel, a ketoreductase collection. “Very quickly, the panel gave Merck an enzyme it could use to reduce a
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specific chloroketone and manufacture the desired alcohol,” Huisman says. Compared with the biocatalytic process previously used to make this pharmaceutical intermediate, the enzyme operated at three times the substrate loading and at a 60-timeshigher substrate-to-enzyme ratio, and it gave higher yield. Through these and other results, the col-
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laborators say, they have been learning a lot from each other. Weekly interactions help sustain what the companies call a highly collaborative and scientifically satisfying relationship. “Both sides really appreciate the efficiency with which this level of collaboration allows each of us to advance our programs,” Hughes adds. Although Merck’s process chemists are no novices, the collaboration with Codexis is their first involving biocatalysts. “The use of biocatalyst-based process research at Merck has undergone a dramatic increase over the past few years that we have been involved in this partnership,” Hughes says. “The barriers to using this technology have been significantly lowered.” ACCESS TO A VARIETY of readily avail-
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able catalysts for screening is a key factor, Hughes says. Being able to then rapidly move from screening hits into larger scale execution with minimal development has helped increase the efficiency with which Merck can employ this chemistry. “For large-scale ketone reductions, the use of ketoreductases has become the methodology of first choice within Merck,” Hughes adds. Merck has reported that these enzymes can be screened and scaled up as rapidly as their chemocatalytic counterparts, and their environmental impact and cost of use at large scale is lower (Acc. Chem. Res. 2007, 40, 1412). “Biocatalysis can exceed other chemical capabilities in terms of its flexibility and adaptability,” Hughes says. “In addition to being able to solve any one particular problem effectively, you can also solve problems across a broad scope of substrates very easily. “As a result of this collaboration and our history with biocatalysis, tremendous progress has been made in addressing some of the issues with earlier forms of this technology,” Hughes adds. “We’ve come a really long way in unlocking the tremendous potential that enzymes offer in the development and production of pharmaceuticals.”—ANN THAYER
DSM
COVE R STORY
HANDLE WITH CARE CASE STUDY #3: In a manufacturing pact, DSM has the
right reactor for the right product from NicOx
SMALL PHARMACEUTICAL companies
almost always need to hire a chemical manufacturer to get a new drug to market, and in that regard, NicOx’s contract with DSM is business as usual. The details of the collaboration, though, are anything but. In two industry firsts, the partners will use a microreactor-based process to make an arthritis drug that is the first in a new class of cyclooxygenase-inhibiting nitric oxide donators. The drug, naproxcinod, is the nitroxybutyl-substituted form of naproxen, the well-known nonsteroidal anti-inflammatory drug. Containing a nitrate group, the substituted compound is difficult to make. But once ingested, it provides the expected analgesic effect and also slowly releases NO to act as a messenger molecule in the
body. NicOx, based in France, expects to file for regulatory approval by midyear. Microreactors installed at DSM’s site in Linz, Austria, will enable the safe and cost-efficient production of large quantities of a nitrated intermediate. Nitration reactions must be handled carefully because they generate products that can violently decompose. Strict control of reaction conditions is needed to make the nitration selective and to allow extraction and neutralization of the desired nitrated product. In a traditional batch-manufacturing process, these constraints would call for highly dilute and biphasic conditions in specialized safety equipment. Occurring instead in a continuous flow through millimeter-sized channels, the microreactor
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process transfers heat efficiently and limits the residence times of unstable materials. Working with glass specialist Corning, DSM designed a microreactor system that combines three key process steps—the nitration reaction, neutralization, and workup—and ultimately generates a few hundred tons of product per year. Within a “few inches” after the starting materials are mixed, the process is already in a safe mode, explains Michael Hartmann, senior vice president for new business development at DSM Pharma Chemicals. “It’s very controlled, and you never have a lot of dangerous material around in the first place,” he says. “It also is very fast and therefore cleaner, and the yields are better, which contributes to productivity without huge amounts of equipment.” When NicOx sought a manufacturing partner, it wasn’t looking for a high-tech answer but rather a supplier that could manage the difficulties of making nitrated products, says Gavin M. Spencer, the French firm’s vice president for business development. “Our decision was driven by DSM’s capability, flexibility, and ability to meet NicOx’s needs.” DSM was O OCH3 willing to take –O on the project O + O N and deliver on the timeline O Naproxcinod NicOx required, Spencer notes. “They also demonstrated that they had the knowledge and skills in manufacturing to take the process from the small scale we had already developed to the scale we’ll need when naproxcinod is on the market.” Moreover, Spencer believes DSM understood NicOx’s needs as a small firm preparing to launch its first product. “We don’t have unlimited funding and are not able to do everything that a big pharmaceutical firm can do,” he says. “DSM has been very responsive and accommodating in dealing with questions and issues as they arise and in progressively structuring our work with them to allow us to achieve what we need.” Hartmann agrees that transparency between the collaborators was important, especially when it came to developing new technology around a new product. The project started with running a traditional small-scale batch process to produce a few kilograms of material. “There definitely were issues with scalability and cost-effectiveness,” Hartmann says. “At the very beginning, we saw an opportunity to use microreactors and actively developed a process in the lab.”
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and some feasibility work in late 2007, DSM proposed using microreactor technology, at least as a second-generation process, Hartmann says. Along with the safety and processing advantages, he says, NicOx appreciated how quickly large amounts of material could be made available. When scaling up a microreactor-based process, scientists “number up,” or add more identical parallel reactors, rather than reengineering the process to work in larger vessels, Hartmann explains. As a result, “the development efforts and investment are much less,” he says. After about six months’ work, DSM had a pilot-scale process that could supply hundreds of kilograms. In November 2008, NicOx reported positive Phase III trial results for treating osteoarthritis with naproxcinod. A week later, DSM and NicOx signed a long-term manufacturing agreement for
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COVE R STORY
the active pharmaceutical ingredient. To conserve resources, NicOx ended a supply contract with fine chemicals maker Archimica, which had met its obligations at its Springfield, Mo., site. DSM will now supply commercial quantities of naproxcinod to support product launch. EXECUTIVES at NicOx and DSM say their
close relationship on both technical and business levels helped them move from feasibility studies to large-scale production in about 18 months. “DSM is turning out to be a very strong partner in addressing the challenges that we come up against as we work toward filing for regulatory approval,” Spencer says. “Obviously they are heavily implicated in this work over the next few months to complete the chemistry parts of the dossier and having their site ready for inspection.” DSM’s work with microreactors dates back at least a decade, and the company has used them for manufacturing fine chemicals. But DSM believes that the system developed with Corning for naproxcinod will be the first industrial-scale use of microreactors for making a pharmaceutical under current Good Manufacturing Practices. The Food & Drug Administration should soon get its first look at the new production technology. Hartmann believes the approach will be consistent with agency initiatives encouraging “quality by design” because the precise control of reaction processes translates into control over product quality. Meanwhile, NicOx is looking for a large drug company partner to help commercialize a drug that has blockbuster potential. The market research firm Datamonitor suggests that the launch of naproxcinod, expected in 2010, will help the market for osteoarthritis drugs grow more than 3% per year to reach $5.5 billion by 2017. Just six years ago, naproxcinod’s future was in doubt. In 2003, NicOx’s partner, AstraZeneca, returned the product to NicOx when, despite good safety and efficacy profiles in Phase II trials, it failed to show a desired gastrointestinal benefit compared with existing cyclooxygenase-2 (COX-2) inhibitors, such as Merck & Co.’s Vioxx. Within about a year, however, Vioxx was withdrawn over concerns about blood pressure and cardiovascular safety. Pfizer’s Bextra was taken off the market in 2005. These events were a boon for naproxcinod because the NO it releases
helps maintain normal blood pressure and reduce vascular inflammation. If approved, naproxcinod could end up as the only brand name drug to compete with Pfizer’s Celebrex, which had sales of about $2.5 billion in 2008. NicOx’s drug development platform involves taking known drugs and grafting NO-donating groups onto them via chemi-
cal linkers. This process creates patentable entities that it hopes have improved safety, efficacy, or activity. Among its 10 programs, NicOx is working on NO-donating antihypertensives with Merck and ophthalmology drugs with Pfizer. Naproxcinod may be only the first such drug to emerge, along with a new technology to make it.—ANN THAYER
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