In 1991, the Children's Hospital of Philadelphia (CHOP) and the Wistar Institute teamed up with Merck to develop a rotavirus vaccine to combat the illness that affects thousands of children every year. This partnership of an international pioneer in pediatric medicine, an independent biomedical research institute, and a giant pharmaceutical company produced the oral vaccine RotaTeq. Since its approval in February 2006, about 8 million doses have been distributed worldwide, immunizing an estimated three to five million children.
Rotavirus causes fever, vomiting, and diarrhea, and affects "most everyone" by age five, says Paul Offit, chief of Infectious Diseases at CHOP. "In the US, it causes about 70,000 hospitalizations and 60 deaths a year. In the developing world, it kills about 2,000 children a day. In the late 1980s, we felt we had a strategy for preventing the disease by vaccination. So we went to four pharmaceutical companies, and eventually began collaborating with Merck," Offit says.
Offit and Fred Clark, a PhD in Offit's division, spent 10 years working on rotavirus before hitting on a strategy against it. Stanley Plotkin, an emeritus professor at the University of Pennsylvania School of Medicine, and also with CHOP, first launched the program in his laboratory at Wistar and worked on it in the early years. (All three - Plotkin, Offit, and Clark - were at Wistar and CHOP at various times in different capacities during the rotavirus endeavor.) "It involved a complex web of institutional relationships," says Offit.
To develop the science, the researchers did "what everyone does when they make a vaccine," says Offit. "You try to figure out the part of the virus that makes you sick, the part that induces an immune response that is protective, and separate the two so that you have a weakened virus that can still induce a protective immune response."
All species on earth have their own unique type of rotavirus, says Offit. "But calf rotavirus doesn't cause disease in people, and human rotavirus doesn't cause disease in calves. So we combined the two viruses so we had the weakened disease characteristics of the cow strain but also included the human genes that invoked the immune response - so you have the best of both worlds." It took 10 years.
Finding a vaccine was not enough. "Developing a product is roughly a one billion dollar project, not to mention what it requires to scale up at manufacturing level," Offit says. "The definitive Phase III clinical trial alone is a $350 million undertaking. When we thought we had a vaccine, we went to a company because only a company has the resources and expertise to develop a product."
The world's four top vaccine makers "just all happened to be in the area - GlaxoSmith Kline, Wyeth, SanofiPasteur, and Merck," says Offit. "We went to all of them, and were most drawn to the Merck scientists."
Merck liked the science and believed there was a medical need, recalls Offit. "People were dying of rotavirus, and although it doesn't kill many people in this country, it causes a lot of suffering, and 60 children dying of it is not trivial. It was an unmet medical need." Michelle Goveia, a medical director for pediatric vaccines at Merck, remembers, "It seemed like a very good idea with solid research behind it, so Merck thought it would be a very promising venture."
Clark, Offit, and Plotkin patented the vaccine in the 1990s, and CHOP and Wistar licensed the patent to Merck. The company's policy is not to disclose the terms of its licensing arrangements, but as Jennifer Allen, public affairs director for Merck's vaccine division, says, "They lasted throughout the partnership; that's part of what allows you to move forward."
The original researchers and Merck scientists then worked together to develop the vaccine further, and Merck worked on the clinical development plan as well, according to Goveia. Typically researchers bring data to Merck, and if the company takes on the project, the researchers "pass the baton" to the company while it starts clinical development and manufacture, explains Goveia. "So you start with a proof-of-concept study showing the vaccine is well-tolerated and efficacious; then you look for an appropriate dose, and once you get further into development, Merck starts playing a bigger and bigger role."
The company developed the protocol for the first study in humans in 1993, and Offit and Clark worked as investigators for the study. In all, eight studies involving the vaccine led to the development of RotaTeq.
"It's hard to make a vaccine," Offit says. "We had the strains in the late 1980s, and it took almost 20 years to develop the vaccine. And because the regulatory hurdles are high, it took a four-year, 70,000-child trial in 11 countries to show that it was effective and safe."
Conducted from 2001 through 2004, that four-year study was one of the largest clinical trials that industry ever conducted, says Goveia. "A large study of 70,000 children - only industry could take on. Throughout the development, it was a very collaborative effort even though Merck was running the program. Typically, we run that [kind of] trial in consultation with those [the original] scientists."
The FDA approved the oral vaccine in February 2006 for use in infants, in three doses at two, four, and six months of age. The FDA also recommended the vaccine for routine use by the Centers for Disease Control and the American Academy of Pediatrics.
Offit, Clark, Goveia, and other investigators coauthored the January 2006 RotaTeq study published in the New England Journal of Medicine. The Lancet named it the best medical research of 2006. "It was a great honor," says Goveia.
Merck, which has licensure in over 60 countries, is committed to distributing the vaccine to children in the developing world "because that's where the significant mortality is," Allen says. In partnership with the Nicaraguan government, the company has made a $75 million commitment to donate RotaTeq to vaccinate the entire population of Nicaraguan children for three years. The goal is to create a model for developing countries to immunize their children, Allen says.
Merck is also conducting studies of the oral vaccine in sub-Saharan Africa and Southeast Asia to make sure it works in the developing world, where more children are malnourished and have intestinal bugs, Allen explains. "Because of the differences between industrial countries and the developing world, we want to ensure that this vaccine is efficacious and safe in the developing world because it's an oral vaccine."
Offit says the vaccine has saved thousands of hospitalizations in this country, and will "no doubt" begin to save thousands of lives worldwide. Does he find that satisfying? "Yes, although the satisfaction came earlier, with the realization that it could be done."
What has made the partnership work? "I think our science is good and ended up being right, and what they [Merck] did was the science of development. That's not well appreciated," Offit says. When the vaccine was licensed in 2006, some news accounts said that Merck was marketing it. "It was far more than that. They did the research to develop it, and did it well."
Goveia, meanwhile, says saving lives is what spurs her on. "It's the reason I work in pediatric vaccines. It's what keeps me motivated."
Sometimes a pharmaceutical giant teams up with a smaller company to make even bigger things happen. AstraZeneca Pharmaceuticals, a global developer of medicines in areas ranging from oncology to infection with US headquarters in Wilmington, Del., has about 65,000 employees. Still, it reached outside the Philadelphia region to collaborate with Targacept of Winston-Salem, NC, a company with just 102 employees, to develop medicines to treat Alzheimer's disease and to improve cognition in schizophrenics.
William Caldwell, one of Targacept's founders and its vice president of drug discovery and development, says the basic research on neuronal nicotinic receptors (NNRs) evolved since the 1980s when the early program focusing on nicotinic receptors started at R.J. Reynolds. This continued after Targacept became a wholly owned subsidiary of R.J. Reynolds in 1997 and was later spun off in 2000. "That basic understanding led to several clinical programs, and ... a proprietary system ... we use to design new molecules," says Caldwell. By 2004, Targacept had developed a promising new molecule that sought out these receptors, part of a class of drugs known as NNR Therapeutics.
Meanwhile, AstraZeneca was doing its own research in the psychiatric field. A decade ago, its Wilmington Del., discovery unit created Seroquel, approved by the FDA for the treatment of patients suffering from the depressive episodes and the acute manic episodes in bipolar disorder and to treat schizophrenia.
Neurology is a priority for AstraZeneca, says Johan Hoegstedt, the company's vice president for planning and business development, neuroscience. Hoegstedt explains. "The molecule Targacept was working on was a clear medical breakthrough in attention and cognition. We'd looked at Targacept for several years because we thought they were into very interesting things. We were looking for key breakthroughs, and we felt it was time to get the two companies together."
John Reid, director of global alliance management at AstraZeneca, then met Jeffrey Brennan, Targacept's vice president for business and commercial development. Reid says, "Jeff and I met at BIO in 2004, and we both recognized a good strategic fit for both companies for this molecule."
One year later in 2005, the two companies struck a research and licensing deal to collaborate on AZD3480 (which Targacept previously referred to as TC-1734), a compound targeting Alzheimer's disease, cognitive deficits in schizophrenics, and more. The science developed from there.
Cognitive impairments prevent three-quarters of schizophrenics from leading normal lives, and research has shown that nine of 10 schizophrenics smoke, notes J. Donald deBethizy, president and chief executive officer of Targacept. "One explanation for this high rate of smoking is that schizophrenic patients may be self-medicating with nicotine in order to address the cognitive impairment associated with the disease and thus function better." Unlike nicotine, which acts nonselectively throughout the central and peripheral nervous system, AZD3480 targets specific neuronal nicotinic receptors (NNRs) that play a role in cognition to improve it.
The AstraZeneca/Targacept Collaboration Research and License Agreement covers the licensing of AZD3480 for clinical development and commercialization to treat Alzheimer's disease, cognitive deficits in schizophrenia, and other cognitive disorders, and a research collaboration to discover additional drug candidates that act on NNRs.
Using its different assets, the partnership's goal is to break new ground and find new ways to treat neurologic disorders. Hoegstedt says, "What they have is strong science in terms of nicotinic receptors, and we add sales and marketing expertise, development, and clinical, regulatory, and manufacturing experience as well."
AstraZeneca's workforce dwarfs Targacept's, so the partnership's challenges have included very different corporate cultures in terms of size, complexity, location, language, experience, and other issues. Mutual respect, tolerance, and professionalism make it work, according to Hoegstedt.
Good team building helped from the start. To manage this complex relationship and to keep it healthy and productive, alliance managers on both sides facilitate three joint teams working the clinical and preclinical phases. In practice this means a joint research team of a dozen scientists from both companies meets in Wilmington and Winston-Salem at least every two months, according to Caldwell. "There's a lot of cross-fertilization of ideas. That's where the creativity, resource management, and joint decision-making about research happen."
The bulk of preclinical drug-discovery work occurs at Targacept's labs. A global product team at AstraZeneca handles products in clinical development. "It's very cross-functional," says Hoegstedt.
Brennan and Reid attend quarterly development team and research team meetings representing alliance management, a role set up to balance the benefit of collaboration versus the benefit of each individual. "We resolve disputes," Brennan says. "We're challenged by not having our company hats on but having our collaborative hats on, as opposed to project management, which is an internal function. It's a subtle difference."
In 2007 the parties announced the launch of two Phase IIb clinical trials of AZD3480. "Because the product kept moving successfully through different stages of development, the team focused on AZD3480 has been assigned a dedicated global product director," Hoegstedt explains.
To date, AZD3480 has been studied in a dozen clinical trials. The current study in mild to moderate Alzheimer's disease involves about 525 patients, randomly treated with one of three doses of AZD3480, an active comparator or placebo for 12 weeks. The current study in cognitive deficits in schizophrenia involves about 400 patients on antipsychotic drugs, randomly treated with one of three doses of AZD3480 or placebo, also for 12 weeks. Each study is due for completion by the end of 2008."We are enthusiastic about the cognitive effects of AZD3480 and its potential for treating cognitive deficits in schizophrenia and Alzheimer's disease," says Hoegstedt - "two areas where the unmet medical need is very high."