By retooling its R&D process, BMS increased development candidates entering the clinic from 50% to 80%
The last few years have not been easy for Bristol-Myers Squibb. Like other pharmaceutical companies, their pipeline was not delivering new drugs quickly enough, and competition from generics for its cancer drug Paraplatin (carboplatin) and the diabetes drug Glucophage (metformin hydrochloride) have continued to eat into revenues. And then there is the patent challenge to the anti-platelet medication Plavix (clopidogrel bisulfate), which was the company’s best-selling drug in 2003.
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(Source: Bristol-Myers Squibb)
Despite that gloomy catalog, researchers at the company feel they have turned a corner. BMS has had three new medicines approved in a 16-month span and has three new molecular entities, all of which were developed in-house, submitted to the US Food and Drug Administration for approval. That recent track record is no accident, the company says. Instead, it is the result of a focused effort to transform their research and development process.
“We are in the midst of one of this company’s most successful and productive periods of research and development,” says Elliott Sigal, MD, PhD, chief scientific officer and president of the company’s Pharmaceutical Research Institute. “We’re at the beginning of this and now we have the evidence of a real turnaround.” Sigal says the productivity is the result of a four-part R&D strategy:
• Focusing on 10 disease areas. These include Alzheimer’s; atherosclerosis/thrombosis; psychiatric disorders; HIV/AIDS; hepatitis; diabetes; obesity; oncology; rheumatoid arthritis and related diseases; and solid organ transplantation.
• Increasing development spending on late-stage assets and life-cycle priorities with co-development where appropriate.
• Complementing the company’s portfolio with in-licensing.
• Improving success rates.
The strategy appears to be delivering, but observers are taking a wait-and-see attitude. “I think they have certainly made significant strides in the past year, but obviously, nothing’s guaranteed,” says Sacha Baggili, senior research analyst at Global Insight, London. “Their medium-term outlook is certainly looking a lot more promising than it was a year or two ago.” While some large pharma companies are trying to make money by extending indications for established drugs, Baggili says BMS has been developing prospects for new molecular entities and proprietary products. “Their late-stage pipeline is looking quite healthy compared to some of the other companies.”
A Holistic Look
|Entecavir: Love at First Screen
Drug discovery researchers know that screening is usually a laborious slog occasionally interrupted by hits that can yield promising new molecules. Then there are drug candidates that emerge quickly due to a combination of hard work and serendipity. Such was the case with entecavir, an antiviral developed by Bristol-Myers Squibb (BMS) for the treatment of hepatitis B.
“There are some leads that you get when you first screen, those initial hits that just stand out above everything. They’re super potent and super selective,” says Richard Colonno, PhD, vice president, infectious diseases drug discovery, BMS, Wallingford, Conn. “You really know you have a winner when you start that way. Then as you try to use medicinal chemistry to improvise and try to make that compound and explore the possibilities of making that compound better, you realize that you really can’t do much better. That’s very rare in screening.”
Entecavir was developed in-house from a collection of nucleoside analogs. “This one started out pretty good right out of the gate. Therefore, the subsequent program was a little bit shorter because of it,” says Colonno, who has a long track record in developing antivirals at BMS. The FDA granted entecavir a priority review and it will be considered at an advisory panel meeting this month. Colonno says there are only two other approved nucleoside analogs, GlaxoSmithKline’s Zeffix (lamivudine) and Gilead Science’s Hespera (adefovir dipioxil).
Colonno says the intrinsic potency of entecavir is 300 to 500 times greater than that of Zeffix and Hespera, and it features superior viral load reduction, improvement in liver histology and improvement in liver biochemical tests. Renzo Canetta, MD, says entecavir works at three levels against the hepatitis B virus-priming, reverse transcription, and DNA synthesis. All drugs presently available for hepatitis B work only at one level, says Canetta, vice president, oncology global clinical research and development champion for entecavir. “It hits all the processes, and that is probably one of the reasons that we are seeing the results that we are.”
Colonno says his group used cell-based assays to isolate entecavir, the same approach they used to develop other drugs. “We’ve used it for hepatitis C, we’ve used it for HIV, and in both cases it has given us novel inhibitors, so that is a lesson learned.” Colonno says cell-based assays, which underline much of the research done at BMS, are useful tools because they get researchers past the barrier of getting into cells. They also have the advantage of meeting many targets that researchers may not be thinking of in terms of interactions between viral proteins and cellular proteins, or protein-protein interactions that can’t be reconstructed in a test tube. “I think that fundamental approach of using a cell-based screen gives you a far greater success rate in terms of pulling up things that are really worth pursuing.”
“I think the plan was a holistic look at where the company sat with its competitors,” says John Houston, PhD, vice president of applied biotechnology and head of biology at the company’s Wallingford, Conn., site. “I think it has made the company more competitive, I think it has positioned us more effectively to take leadership positions in key areas. It’s given a very clear direction for all the various project teams in the company, not just in research, but beyond that, to where they should put their major efforts and their major focus.”
Just a few years ago, research was ongoing in upwards of 35 disease areas, but the decision was made to focus R&D resources on 10 areas where there was an unmet need. Another part of the plan was to look for synergies between disease areas; for example, between obesity, diabetes and atherosclerosis. Finally, the company wanted to develop an R&D model that would allow them to use their resources more efficiently.
“There hasn’t been enormous survival pressure and I think there is now, and we’re all thinking of how we can do things more efficiently, particularly in drug discovery, which is often the first place that people look to find savings,” says Francis Cuss, MD, senior vice president for drug discovery. They used “lean thinking,” a management tool used by companies like Dell Computers and Toyota to decide how to make their products in the simplest, most direct manner, thereby eliminating waste. “It’s quite amazing when you start to apply this criteria to how we do drug discovery. You essentially see how inefficiently we do it.”
Those inefficiencies became clear when BMS performed a “rigorous” analysis of its drug discovery process, Houston said. This included tracking one compound through several steps of the process, including initial evaluation, the compound being made, how testing was done, how data was uploaded, and how other scientists used that data. “We actually did a root-and-branch analysis on every project that we had ongoing over the last year, tracked against the whole year, and we had this incredible display of data that showed us where our efficiency gaps were, where we could actually improve, how we could do our business,” Houston says. “We used this data to convince all of the scientists that change was actually needed. It was such an overwhelming set of data for them, and as scientists they love looking at data, so they looked at it and said, ‘Yes, you’re right, we could change here, we could improve there.’ “
Houston says they also demonstrated the release of resources that could be created by plugging robust, reproducible technologies in at various stages of the process. By doing that, activities being performed by eight to ten people could be put in an automated process or connected to another team that was doing similar work. “Those staff suddenly didn’t have to do this work. They could be released to do more in-depth biology or maybe higher value activities within the research project,” Houston says, something that resulted in “huge” efficiency gains. “This is a story that was well known within the screening and compound management community. It’s not necessarily a story that’s been used in lead optimization and early drug-safety assessment worlds, where it’s been very people intensive.”
Colleague to Colleague
Although BMS used consultants to initiate management changes in the past, they did not for this project. Houston says consultants lacked the intimate knowledge of how the company ran its business and presented data. “We used our best technology scientists who’ve been here for several years, who knew how to run technology systems and how to present data to scientists, we used them to do the analysis. So it was colleague talking to colleague using data and projects that they understood intimately, and that did a lot to convince them. People moved to the change much quicker than I thought because of it.”
Cuss said initiating such changes was easier at BMS than it might have been elsewhere due to what he calls the “Goldilocks” principle. “I think we’re just right in terms of size. We’re big enough to make the investments we need, but we’re small enough and geographically close enough to actually be more efficient.” BMS has 5,400 R&D employees and spent $2.3 billion on R&D in 2003, a figure that increased by 12% in 2004. Pfizer, by comparison, has 12,500 R&D employees with an R&D budget of $7.5 billion in 2004.
|Blocking Rheumatoid Arthritis at the T Cell Level
Abatacept, a first-in-class selective T cell co-stimulation modulator for rheumatoid arthritis, began its development life as a treatment for what is perhaps the prototypical autoimmune disease: psoriasis. The drug was discovered in the late 1980s, but it wasn’t until 1999 that Bristol-Myers Squibb decided to investigate its use in rheumatoid arthritis, a disease area the company believed was underserved.
“Its mechanism is unique,” says Michael Corbo, PhD, vice president and development champion for abatacept at BMS. Unlike other drugs that work downstream in the disease process, abatacept works by blocking T cell activation. It was discovered by Peter Linsley, PhD, and Jeffrey Ledbetter, PhD, two researchers who outlined the signaling needed for T cell co-stimulation in the late 1980s and early 1990s, Corbo says. Abatacept prevents T cell activation by preventing or interrupting the binding of CD28, a ligand, to CD80/86, the key ligand for the second co-stimulation signal, on the antigen presenting cell.
“You see activated T cells in the synovium of rheumatoid arthritis patients. Activated T cells also play a role in directing B cells what to do. They also talk to macrophages, and by doing that they really are the orchestraters of the immunoinflammatory cascade that you see in diseases like rheumatoid arthritis. The logic is, if you can prevent that T cell from becoming activated, potentially you can treat diseases like rheumatoid arthritis,” Corbo says. A great deal of research was done on abatacept using a variety of autoimmune models. “This included the collagen-induced arthritis model, where it showed activity, making us think it could have some activity in rheumatoid arthritis.”
Studies showed that abatacept is safe and effective, and the drug has shown particular promise in patients who respond inadequately to methotrexate and antitumor necrosis factor therapies, a population that currently has no other treatment options. The FDA accepted abatacept for its fast-track approval process, Corbo says. “One of the studies meets an unmet medical need, and I think that’s been recognized and that was part of the fast-track designation.”
Much of the increased R&D funding has been invested in technologies that allow researchers to perform investigative toxicology or predict safety early in the development process. “We have investigational toxicology and predictors of toxicology preclinically that help us select the right compound,” says Sigal. “We’ve learned what kind of assays can avoid problems of heart rhythm, which used to be a big reason that drugs would fall out in the clinic and even in the market. We have some assays that help us predict liver toxicity, although this isn’t a complete science as of yet. So we screen out compounds and we get our chemists to design compounds such that we have the fewest red flags as we move forward from the laboratory to the clinic.”
Some of the more recent technologies being used by BMS include high-throughput target identification using retinoblastoma synthetic lethal mutation. Targets are also validated using tissue gene expression, immunohistochemistry and knock down with siRNA. Targeted disease models were tested using biophotonic imaging that allows researchers to check the effects of candidate drugs in animals in real time. Cuss and Houston both say that while many of these are not necessarily bleeding-edge technologies, they had a key effect because of how they were used.
“We used technologies that we had proven and settled on in the screening organization,” Houston says, “and we were able to pass them out to the rest of the organization relatively easily. The key difference is integration, size of operation, (and using) robust technologies with proven track records.” By passing high-throughput screening technology onto lead optimization and safety profiling, chemists and biologists there were able to realize “huge” capacity increases, reduce the time for compound testing and improve integration, Houston says. “It’s an element of the size that we are, it’s an element of the fact that the management bought into the plan right up front and allowed it to happen, and the fact that we used robust technologies.”
Cuss says their use of biophotonic imaging to test oncology candidates is a prime example of putting a process together that is greater than the sum of its parts. “It’s applying that technology in the context of transgenic animals and putting it together in a package that will allow us to test partly the target validation, but also the therapeutic validation of our compounds.” Too often, pharmaceutical and biotech companies seem to be in love with technology for technology’s sake, and there is “a fairly long history of dry wells in the industry in terms of technology investment,” he says. “If you dance on the cutting edge, you can get cut. I think how we see it is that if you apply technology that is proven and robust, you can really make a difference in terms of your efficiency. You cut out much of the uncertainty that comes with technology that breaks down or you can’t quite make fit.”
Sigal says his company’s continuing efforts will be enhanced by state-of-the-art biomarker and pharmacogenomics tools. In the late 1990s, BMS built an applied genomics group and is now using that technology and methodology to determine the most effective patient populations for select programs in development. “I think one of the trends we’re going to see is more trials of enriched populations where you improve the signal to detect response of novel agents,” Sigal says. Presently, the research site in Wallingford is where much of the company’s high-throughput screening and compound management is done. But over the next six to 12 months, research labs in Princeton and Hopewell, N.J., will receive technology that will allow them to perform high-throughput lead optimization and safety assessment, says Houston. “This will release some of our high-value scientists to do basic research in a way that they haven’t had a chance to do because they were doing compound testing, so we should see the benefits of their basic research.”
The work done to retool the R&D process is already paying off, Sigal says. This year, the company completed 10 large phase III trials for three compounds, and all 10 met their primary endpoints. Then there are the three drugs recently approved and the other three being evaluated by the FDA. Sigal also notes that in 2001, only 50% of the company’s development candidates were entering human testing. In 2003, that rose to 80%. “It’s a very tangible measure of the quality of our compounds,” says Cuss. “I think what that 80% reflects is the kind of investment that we started to make three years ago. . . . There doesn’t seem to be any reason why any other company shouldn’t be able to do exactly the same thing if they choose to make the investment.”
[Refer to the February 2004 cover story to gain insights into how another pharmaceutical company made similar investments in their organization to ramp up R&D productivity.]
|A Kinder, Gentler PPAR Agonist
A new class of drugs called peroxisome proliferators activated receptor (PPAR) agonists have intrigued pharmaceutical companies because of their potential to treat type 2 diabetes, but they have also been a challenge to develop. Several companies have halted or delayed development of such compounds due to concerns over toxicity. Bristol-Myers Squibb (BMS), however, believes it has a keeper in muraglitazar, a PPAR agonist developed in-house.
“We see nice effects on the lipids and a very nice effect on the glucose levels,” says Rene Belder, PhD, vice president at BMS and development champion for the drug. Two-year carcinogenicity studies were started early and completed to address toxicity concerns; incidences of tumors found in rodents were investigated and found to be either species-specific or to occur at drug levels greater than 48 times human exposure.
PPARs are a group of receptors, including PPAR alpha and PPAR gamma, located in cell nuclei. Because they influence lipid and glucose metabolism, they are targets for research into controlling hyperglycemia and dyslipidemia associated with type 2 diabetes. Glitazars, the class of drugs to which muraglitazar belongs, can act on PPAR alpha and PPAR gamma receptors to improve dyslipidemia and restore insulin sensitivity. Two PPARs already on the market include Avandia (rosiglitazone) from GlaxoSmithKline and Actos (pioglitazone) from Takeda Pharmaceuticals North America.
Belder said the development of muraglitazar happened “very rapidly” for several reasons, including prospectively planning a “very aggressive and accelerated” carcinogenicity program. Traditionally, performing such studies and crunching the numbers takes three years, but BMS cut that time by about six months by using more resources. They also saved time by planning a 1,500-patient phase II trial with a very wide range of dosages; that allowed them to determine the optimal dosage for moving onto phase III trials. In clinical trials involving more than 4,500 patients, muraglitazar demonstrated significant glucose lowering and significant reductions in triglycerides. The company submitted an NDA for muraglitazar in December 2004.
Filed Under: Drug Discovery