Issue Date: February 22, 2010
Cracking The Tough Ones
In keeping track of the drug industry, it sometimes helps to monitor the ads. For example, Pfizer recently launched a print campaign about its dedication to research in Alzheimer’s disease, an area that has yet to produce a cure. GlaxoSmithKline beat Pfizer to the punch, however, with television spots featuring a GSK researcher explaining how her family history spurs her to find a cure for the disease. No hard feelings. In fact, the two companies recently teamed up in a joint venture called ViiV to develop drugs to treat another intractable disease: HIV/AIDS.
The ads and the partnership are evidence of change in both the science and the business of drug discovery and development. At GSK, research departments that were reorganized in recent years to focus on specific therapeutic areas are being broken down further to smaller, more aggressive teams. At Pfizer, an entrepreneurial approach to integrating biotech research continues even as the world’s largest drug company greatly expands centralized biopharma R&D with its acquisition of Wyeth. Traditional partnerships with academia and small biotech firms are becoming more collaborative. And Pfizer and GSK are not the only two major drug companies to forge what has long seemed unthinkable—research collaborations between major drug companies.
Changes are taking place amid high levels of frustration but also enthusiasm in the lab—and in reaction to extreme commercial and public demand for significant new cures. Drug researchers find themselves inundated by the data on human biology released in the decoding of the genome 10 years ago. At the same time, they have new tools, new organizations, and better integration of small- and large-molecule research. They have also come to realize that they can no longer approach untreated diseases on a proprietary basis.
Defining the areas where it is appropriate to work together, however, is tricky in an industry of monoliths. And in academia, the attitude is “learn-as-we-go,” as researchers adapt traditional scientific approaches to the research protocols and commercial realities of major drug companies. Much of the change is taking place under new leadership with a high level of cross-pollination. Former heads of research at big pharma, for example, have launched innovative academic research ventures.
These days, the answer to the decade-old question of whether new therapies will come from big pharma, biotech, or “other” is shaping up as an interesting variety of “all of the above.” And confidence is high in each sector.
“We have never sat on such a positive pipeline,” says Martin Mackay, president of global research and development at Pfizer. Two years into the job, Mackay has been involved in transforming Pfizer’s R&D, targeting an increase in biotech therapies. With the Wyeth merger, Mackay is now sharing top R&D functions with Mikael Dolsten, president of biotherapeutics research and development and former head of research at Wyeth. “We used to be three to one, small molecule to large,” Mackay says. “Now, we are 1.3 to one.” But success will come from covering many bases, he says, not just biotech. And it will require Pfizer to reach out.
“In Alzheimer’s disease we have small molecules, large molecules, and vaccines in the pipeline,” Mackay says. “But can any one company on its own do what needs to be done with something like Alzheimer’s disease?” he says. Partnerships focused on early-stage discovery will be crucial going forward, he says, noting that Wyeth brought with it a collaborative early-stage research venture with Janssen Alzheimer Immunotherapy Research & Development, a subsidiary of Johnson & Johnson.
Amgen, which recently received a 2009 Scrip Award from the drug industry publishing company for having the most innovative pipeline, is also focused on a range of small- and large-molecule projects with an emphasis on partnerships, according to Joseph Miletich, Amgen’s senior vice president of research and development. Partnerships will be a key component to drug discovery and development in an environment that is overwhelmingly complex, he says. “But the opportunities to actually gain insights into human biology and pathologies that rob us of quality and length of life have never been better,” he says.
Meanwhile, P. Jeffrey Conn, director of Vanderbilt University’s Drug Discovery Program, has established a laboratory designed to push academic research further downstream toward drug development. “In academic research, we are realizing that we have to be better at recognizing the value of what we bring to the table,” he says. This means moving away from the traditional model of handing over basic research and letting the industrial partner make of it what it will.
Academia’s new perspective on partnership, however, reflects big changes on the industrial side. “There is an industry-wide recognition that the old model for drug discovery and development is just not working,” says Conn, who is the former head of neuroscience at Merck’s West Point, Pa., research facility. “We don’t know what the industry will look like in five years, but we know it will look different than it did five years ago.” He acknowledges that recent big acquisitions, including Merck’s of Schering-Plough, indicate that the old strategy of responding to challenges by getting bigger is still in effect. “That’s been disappointing,” he says. “But the industry is still looking to try new things.”
Research is also leaning heavily toward genetics-based personalized medicine—therapies targeting individuals or groups of patients. A recent report by PricewaterhouseCoopers says the U.S. market for lab services, genetic tests, targeted medicines, and molecular diagnostics reached $27 billion in the U.S. last year, and it is projected to nearly double by 2015. In the consulting firm’s estimate, those figures are part of a total market ranging between $228 billion and $235 billion in 2009 and that includes health club memberships and nutritional therapy, illustrating not only the nebulous nature of personalized medicine, but also its general tendency toward preventive care and health maintenance.
“Everybody knows science is moving in this direction: the ability to make sure that our medicines get to the right patient,” Mackay says. A case in point is Pfizer’s c-MET/ALK program for small cell carcinoma. Phase I clinical trials indicate that a small cadre of patients respond favorably to the therapy, which employs a low-molecular-weight inhibitor. Pfizer has formed a collaboration with Abbott to look for diagnostics to test in later stage clinical trials in this program, which moved into Phase III trials in September.
“In the future, all of our oncology programs will look like this,” Mackay says. “In every discovery program we run now, we are trying to identify the patient population ahead of time.” Mackay says he and others in the industry previously estimated that it could take between five and 50 years for personalized medicine to have a major impact on large pharmaceutical companies. “Now, it looks a lot closer to five,” he says.
George Poste, who became R&D head at SmithKline & French in the early 1980s and held the position through two acquisitions of the company prior to its acquisition by Glaxo, agrees. He is now chief scientist at the Complex Adaptive Systems Initiative (CASI) at Arizona State University, a research effort focused on developing technologies for genetics-based drug discovery and development research. Large pharmaceutical companies will be key players in deploying those new technologies, he says.
“We have heard for almost three decades now that big pharma is a group of dinosaurs doomed in evolution to end with the scampering mammals of the biotech industry,” he says. “There are intrinsic advantages to scale that big pharma has,” he says. “It certainly comes with complications from the organizational standpoint. But the infrastructure needed to make a drug or vaccine is sufficiently formidable that you can’t discount the importance of scale.”
Part of CASI’s mission in studying the convergence of life science, engineering, and computing technologies in drug discovery is to change the role of the university. “We are trying to insert into the university the ability to translate basic research into a framework industry can assimilate,” he says.
An area in need of change is funding, Poste notes. Universities are still funded largely by the National Science Foundation and National Institutes of Health according to a siloed technology specialty framework, he says. “What we need is a much more cross-disciplinary research-funding mechanism,” he says. Getting funding is not the main problem, according to Poste, noting that President Barack Obama’s recent stimulus package allotted $8.2 billion to NIH for research. “The problem is in the way we are organized to use that funding,” he says.
Another area needing change, Poste points out, is the long-standing cultural divide between academic and industrial research, based on academia’s traditional insistence that pure and commercially applied science be kept separate. Many researchers would also “prefer sharing toothbrushes to sharing information,” Poste says. While this attitude affects both industry and academia, a key difference between the two camps hogties the academics, according to Poste. “In a company,” Poste says, “people want to solve problems—they recognize their welfare and reward is linked to problem solving. The biggest cultural challenge in academia is learning to say, ‘I don’t know.’ Industry has to say that constantly and then find out the answers.”
Vanderbilt’s Conn agrees. At Merck, he says, industry researchers focused on downstream projects and hadn’t the time to assess the usefulness of early-stage research coming from universities. “What they gave us was always half-baked from a drug discovery perspective,” he says. “We couldn’t sink our teeth into it and get to the next step.” At the same time, he says, academic researchers tended to overvalue their work.
Frustrated with the disconnect between academic and big pharma research, Conn considered moving to a smaller drug company but instead decided to attack the problem from a university research perspective. He found Vanderbilt’s technology-licensing office receptive to his notion that academia needs to get a better handle on what it brings to deals with big pharma.
Launched six years ago, Vanderbilt’s Drug Discovery Program opted for collaborative research funded by industry partners over traditional technology transfer and licensing (C&EN, April 20, 2009, page 25). The lab’s first success, Conn says, is a project with Amgen that used publicly available compound libraries to screen against two targets the effectiveness of allosteric modulators for G-protein-coupled receptors in neurology-related therapies.
“From there, we shared cell lines, shared data from screens, and let them see hits,” he says. “Nothing was proprietary. It would have cost Amgen $2 million to $3 million to do this. We did it at a fraction of the cost.” The project involved high-throughput screening and other pharmaceutical research technologies that are only now catching on at other universities.
More recently, Vanderbilt has become involved with full collaborative partnerships, including one with Johnson & Johnson on schizophrenia and one with Seaside Therapeutics on a therapy for fragile X syndrome, an inherited disease of the brain associated with autism.
Conn acknowledges the difficulty academic researchers have in sharing information, but he notes that the heads of research at Vanderbilt also have a lot of industry experience from companies such as Bristol-Myers Squibb, Eli Lilly & Co., and Merck. “We have a culture that is a remarkable blend between industry and academia,” he says.
Funding is also starting to move in a direction that may help translate basic research into new therapeutics, in Conn’s view. “NIH is under increasing pressure from Congress, and Congress from the public, to deliver on its investment,” he says. “It is becoming more proactive and aggressive in finding opportunities for research that leads to new therapeutics.”
In addition to the Vanderbilt collaboration, J&J is working in partnership on Alzheimer’s disease through Janssen Alzheimer Immunotherapy Research & Development. The subsidiary was established with J&J’s acquisition last year of Elan’s Alzheimer’s Immunotherapy Program, a portfolio of therapies Elan codeveloped with Wyeth. According to director Stef L. E. Heylen, Janssen is heavily focused on partnerships across the spectrum of commercial and academic research.
“Alzheimer’s is a very good example of where the old pharma model is clearly no longer sustainable,” Heylen says. “We have tapped into a broad network of innovation which is going on in academia and in biotech. The successful pharmaceutical companies will be those able to detect early, promising projects and pick them up and bring them forward. And innovation can come from anywhere.”
The Alzheimer’s Immunotherapy Program is a 50/50 alliance between Janssen and Pfizer focused on immunotherapeutic approaches to treatment of mild-to-moderate Alzheimer’s disease. Current programs include the monoclonal antibodies bapineuzumab IV and bapineuzumab Sub-Q and the vaccine vanutide cridificar. The companies split costs and potential revenue.
Meanwhile at Pfizer, Mackay is in the midst of assimilating a lot of new research from the Wyeth. Although the acquisition has been criticized as another megadeal to boost short-term profits, Mackay sees it as a coup for R&D. “From a parochial R&D perspective, I was very enthusiastic because the deal gave us potential leadership in biotherapeutics and also brought in technologies and compounds in key therapeutic areas, as well as vaccines,” he says.
Regarding Pfizer’s press on Alzheimer’s disease, Mackay says, “There are a number of approaches we have to cracking the disease, and I truly never felt more confidence that we have a chance of doing this.” But he admits there is a long way to go. “We don’t even know the cause of Alzheimer’s, so we need to work in as many mechanisms as possible to elucidate what is happening in that disease and come up with innovative medicines.” Drug candidates will emerge across a range of modalities, and small-molecule therapies will be important. This is true in other therapeutic areas as well.
Collaborative efforts between large pharmaceutical companies have been surprisingly effective so far, Mackay says. Describing a board meeting of ViiV, the company Pfizer launched with Glaxo to develop pooled discovery assets for HIV/AIDS, Mackay says there seemed little distinction among board members, including himself, from the two drug companies.
“Here I was, the head of Pfizer R&D sitting in the GlaxoSmithKline building with one other Pfizer colleague and the rest either Glaxo people or ViiV colleagues, all talking about how we are really going to have a go at cracking HIV,” Mackay says. “If you had said about three years ago that I would have been sitting in the Glaxo building, really collaborating as part of a joint venture, I don’t think it would have flown here.”
Pfizer is also involved in a partnership with Bristol-Myers Squibb to develop Apixaban, a highly selective factor X inhibitor to prevent and treat blood clots. “Again, I have been at meetings where both companies are represented, and it is very difficult to tell who comes from which company,” Mackay says. “But it’s easy to tell that we are trying to solve a problem in cardiovascular disease that has plagued us for many years.”
Coming from Wyeth, Dolsten, who now heads biotech research at Pfizer, sees the potential for powerful partnerships as a key advantage of the merger of the companies’ research engines. “We have a drug design technology base in small molecules, large molecules, antibodies, therapeutic proteins, peptides, and vaccines,” he says. “Before the acquisition, Wyeth had many attractive partners, but now we really hope to be perceived as one of the best partners because of the value we can add to the collaboration.”
In addition to collaboration with Janssen on Alzheimer’s, Wyeth brought other partnerships to Pfizer, including one with Catalyst Biosciences, which was launched in 2007 and focuses on engineered human proteins directed at metabolic disease and oncology targets, and another with Ablynx, a Belgian specialist in protein therapeutics based on single-domain antibody fragments targeting several disease areas.
Meanwhile, GSK is placing a greater emphasis on partnerships and reorganizing research into smaller research divisions, according to Patrick Vallance, head of drug discovery. The creation of Discovery Performance Units (DPUs), groups of 60 to 70 researchers, is a second wave of restructuring in the lab, following the creation of the firm’s Centers of Excellence in Drug Discovery (CEDD) program, which in 2001 set up research on the basis of therapeutic areas.
“The basic concept of the CEDD was right,” Vallance says. “But we didn’t go far enough in breaking it down to human-scale units. We had as many as 400 people in some CEDDs.” Now, he says, the CEDDs are umbrella organizations composed of DPUs.
With the new units has come a philosophy of expediting early-stage discovery through partnerships with academic researchers, he says. “There is a need for higher innovation at earlier stages of the pipeline,” he says. “The most innovative thing we do now is called the academic-DPU partnership, which puts the molecule in the hands of academic investigators to answer questions that need to be answered, putting them more in the driver’s seat.” The objective is to take back viable candidates for development by the DPU.
Vallance says GSK is currently more actively pursuing partnerships with biotech firms than with other major drug companies, but the latter will play an important role. In partnerships between major pharma firms, he points out, an important dynamic is the determination of “precompetitive” research space. The concept consists of know-how, technology, and intellectual property, once held highly proprietary, that can and should be shared to move collectively and quickly toward new therapies before collaborators take off and develop products individually.
Merck and AstraZeneca are currently recalibrating competitive boundaries in research on the combined effect of Merck’s MK-2206 and AstraZeneca’s AZD6244, compounds with preclinical evidence showing they have enhanced anticancer properties when used in combination.
“The purpose of the collaboration,” according to Reid Leonard, senior director of external research and licensing at Merck, “is for each company to cooperate in generating data on benefits of combining the two complementary mechanisms so that the data will be available to regulators ahead of time. In the old model, we would wait until one or the other company got on the market first before the combination studies would be done.”
Leonard and his peers at other major drug companies are particularly interested in early-stage partnerships aimed at pooling resources to develop shared research technologies. Novartis, Eli Lilly & Co., Merck, Pfizer, Johnson & Johnson, and Abbott Laboratories, for example, are partnering with Enlight Biosciences, a company established by PureTech Ventures to develop technologies for a better understanding of biology in early-stage drug discovery.
The partners are developing imaging and screening technologies, as well as new methods for discovering and validating biomarkers that would leverage advances in genomics and proteomics, and the aim is commercialized technologies, Leonard says. “One of the most positive signs I have seen in the last couple of years is a breakdown in the assumption that everything we do is highly proprietary,” he adds. “The challenge for Enlight’s leadership is to identify techs that are sufficiently interesting to all, but that no one member would want to own.”
Baruch Harris, vice president of strategy and operations for Enlight, says defining precompetitive space is a challenge but that the complexity of human biology revealed through genomics has made big drug companies more willing to take new risks in order to benefit as an industry. “We tend to look at technologies for early-stage discovery, things that help us understand complex biology better,” he says. “In an ideal world, a company would like to do everything itself, but there is the concept of a rising tide lifting all ships.”
Taking a similar focus is the Center for Imaging of Neurogenerative Diseases (CIND), at the Veterans Affairs Medical Center campus of the University of California, San Francisco. There, CIND’s director, Michael Weiner, also uses the rising-tide analogy in regard to early-stage research. The focus at CIND is development of biomarkers for a range of neurological disorders including Alzheimer’s disease, Parkinson’s disease, epilepsy, posttraumatic stress disorder, and depression.
The search for biomarker standards launched one of the longest-standing industry research huddles, the Alzheimer’s Disease Neuroimaging Initiative (ADNI). “Years ago, everyone realized in the industry that there was no standard for acquiring biomarkers or assessing which methods work best,” Weiner says. Initially, he says, no one company was willing to fund a project to develop a standard. But when the National Institutes on Aging, part of NIH, organized a meeting in 2002 between the heads of neurotherapy at major drug companies, nearly all attended.
From this meeting emerged ADNI, a pool of research organizations directed by Weiner that is working to define rates of progress in cognitive impairment, to develop improved methods for clinical trials in this area, and to establish a database aimed at improving the design of treatment trials. NIH provided $40 million in funding to the project, launched in 2004; the pharmaceutical industry provided $27 million.
“Clinical outcomes have a lot of variability, and companies want a validated surrogate,” Weiner says. “They want a biomarker. The precompetitive nature of it is a big deal.”
In Europe, government and industry have also invested in pharmaceutical research partnerships. The European Commission and the European Federation of Pharmaceutical Industries & Associations launched the Innovative Medicines Initiative (IMI) to facilitate collaborations. IMI emerged from a project called Innomed, launched in 2005, in which 16 drug companies and 14 universities took on projects in predictive toxicology and biomarker identification for Alzheimer’s disease. IMI went on to facilitate partnerships in areas such as diabetes and neurological disorders
The sheer complexity of human biology, the explosion of genetics data unleashed by the decoding of the human genome, and the push to develop personalized medicines are insurmountable pressures forcing drug companies to redefine their competitive boundaries in order to advance on intractable diseases, says Michel Goldman, executive director of IMI. He notes, however, that the foundation of greater sharing in partnerships dates back more than 10 years to efforts such as InnoCentive, an innovation consortium developed by Lilly.
Significant new drugs will emerge only from deep knowledge of disease processes, says Goldman. “Companies must have access to basic knowledge they cannot develop in-house,” he says. “But it is possible for them to work together for access to information. Knowledge is what needs to be precompetitive.”
Pfizer’s Mackay notes that major obstacles to delivering new drugs exist outside the laboratory. There are concerns about regulators keeping pace with new science and a whirlwind of questions about who will pay for new therapies in the debate on health care reform in the U.S.
“But I try to simplify things,” he says. “For me, as head of R&D, it comes down to choosing the right target to work on. The right molecule. But more importantly, it comes down to finding the right patient population.” If a company can get these three things right, he says, it will likely have a significant new medicine headed to the market. And regulators, seeing all three in place, will be more positive about bringing that compound along very quickly.
Ultimately, it will come down to the traditional competitive battlefield, he says. “The pipeline is the real proof of the pudding,” Mackay says. “I see a real renaissance. And in the next two or three years, we are going to show you something.”
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