Magazine Article | July 31, 2013

Sanofi Pharma R&D, The Case For Change Was Not Hard To Make

Source: Life Science Leader

By Cathy Yarbrough, Contributing Editor
Follow Me On Twitter @sciencematter

Sanofi will be the most productive and profitable R&D operation in the biopharmaceutical industry in 2015. That’s the vision of Elias Zerhouni, M.D., the company’s president of global R&D, and Sanofi CEO Chris Viehbacher, who persuaded Zerhouni, the former NIH director, to leave the world of academia where he had built a reputation as an innovative, successful, and charismatic leader.

Zerhouni, who joined Sanofi in 2011, said he viewed the position, his first in industry, as an opportunity to transform biopharmaceutical research and development from the inside. “Clearly we need to reinvent. We have to change the culture of the industry, which needs new ways of doing things,” he said.

Zerhouni has long been aware of the role biopharmaceutical companies play in combating disease and improving human health. His views about why pharmaceutical R&D has become sluggish and how it can be reinvigorated were shaped by his experiences at NIH and Johns Hopkins University School of Medicine. At the latter, he not only was a professor and chair of radiology and radiological science and executive vice-dean, he also founded and co-founded five start-ups.

But more than anything, at both places, Zerhouni was a change agent. During his six-year tenure at the federal agency, he initiated translational medicine, multidisciplinary research collaborations, and other programs, all to accelerate the progress of medical research. Although his campaign at NIH focused on the agency’s support of scientists at universities and government labs, Zerhouni said that he has long regarded academic and industry R&D as a highly interconnected and interdependent ecosystem.

Despite his ecosystem connections, Zerhouni’s ability to influence biopharmaceutical R&D was limited before 2011. The Sanofi position has enabled him to reinvent R&D from the inside of one of the major players in the biopharmaceutical industry. Under his leadership, Sanofi’s R&D now emphasizes the biology of disease, translational research, and open innovation.

Zerhouni felt that Sanofi leaders and scientists readily embraced his new initiatives. “The case for change was not hard to make,” he said. “In the industry, we fail a lot, and we fail really late.” Many failures in pharmaceutical development can be attributed to the lack of a deep understanding of disease biology during identification of drug targets, he added. “We don’t understand the language of biology as well as we should to effectively translate it into real innovation.”

“It’s The Biology, Stupid”
In a speech earlier this year on the future of genomic medicine, Zerhouni adapted the unofficial motto of President Bill Clinton’s first presidential campaign, “It’s the economy, stupid,” to underscore his comments about the real reason for failures in drug development. “It’s the biology, stupid,” he said.

Viehbacher recently echoed Zerhouni’s comments when asked by Bloomberg News to explain why Sanofi wasn’t investing resources in clinical studies on Alzheimer’s disease, in contrast to several of the company’s competitors. “I think we have to do a lot more basic science work to understand what’s going on,” said the Sanofi CEO. “We really, at best, partially understand the cause of the disease. It’s hard to come up with meaningful targets.”

Sanofi’s new commitment to the biology of disease does not signal the company’s evolution into a basic sciences company or elimination of internal research. “Instead, we are getting closer to the basic sciences in academia,” Zerhouni explained.

To get closer to academic basic sciences, Sanofi has been establishing an external innovation network of research partnerships with major academic institutions. “Our goal is to create synergies and intellectual collaboration that are of mutual benefit,” he said.

Sanofi’s external innovation network “is fundamentally different from what pharma companies have done in the past,” Zerhouni pointed out. Rather than paying the university for access to a particular lab’s research data and then walking away, the company is establishing “non-mercenary” collaborations between the “best and brightest scientists at Sanofi and the best and brightest in academia,” he said.

The company’s diabetes partnership with University of California at San Francisco (UCSF) is one example of Sanofi’s approach to external innovation. “This is a true partnership between scientists with very different strengths,” said Matthias Hebrok, Ph.D., director of the UCSF Diabetes Center. “UCSF is known for its deep understanding of the underlying biology of diabetes, while Sanofi has great expertise in screening compounds, identifying which molecules have potential, and moving them along to develop a new drug. Such an endeavor is almost impossible to accomplish in a single academic laboratory. Thus, both partners profit from the expertise of the other group.”

Partnerships with academic labs are not unique to Sanofi or the industry. In fact, they once were much more commonplace but vanished when the industry turned inward, adopting a culture of secrecy, Zerhouni said. “The secrecy came from an era when R&D was taken over by considerations such as intellectual property and the sense that biology would be understood in isolation,” he explained.

“R&D in pharma has been isolating itself for 20 years, thinking that animal models would be highly predictive,” he explained. In addition, the entire ecosystem, not just industry researchers, became arrogant as a result of the “phenomenal breakthroughs that occurred in the early 1990s,” he said. These breakthroughs “gave us the impression that we could cure human disease in animal models.”

Secrecy Now Sign of Weakness
Zerhouni stressed what many people in the industry have been saying recently — there needs to be more collaboration, partnerships, and open innovation throughout the industry. That secrecy he referenced earlier is now considered a sign of weakness because it impedes progress. “Times have changed, and it is no longer about who owns the data, but how to solve the problem faster,” he explained.

To eliminate the barrier of secrecy and stimulate open innovation, Zerhouni has hired several academic “stars” who bring their culture of open inquiry and their networks. Zerhouni and the other scientists whose reputations were made in academia tap their own professional networks to establish Sanofi’s innovation partnerships with government and university labs.

While the Sanofi scientists who have devoted their careers to pharmaceutical R&D are expected to replace secrecy with open inquiry, the academic researchers who have joined Sanofi must adapt to a corporate culture and learn the rigor of the translational process with their new colleagues. “It is an enormous challenge with a steep learning curve, but it can provide the joy of seeing the research ‘translated’ to a potential and even possibly an actual treatment,” he said.

Those researchers are not abandoning academia, he pointed out. “Sanofi scientists who left academia to join the company still have the opportunity to work with academic researchers as part of the company’s external partnerships,” he said.

Zerhouni said he does not regard Sanofi’s new approach to R&D as a model for the biopharmaceutical industry. “I don’t have the ambition to develop an R&D model to guide the whole industry. If what I do works at Sanofi, it will be adopted. If it doesn’t, it will be forgotten.”

Tips For Succeeding As A “Change Agent”

Although “change agent” has become an overused term, it aptly describes the career of Elias Zerhouni, M.D. Before joining Sanofi as president of global R&D, Zerhouni was a professor and chair of radiology and radiological sciences and executive vice-dean at Johns Hopkins School of Medicine and director of NIH. “I’ve had the opportunity to be put in the middle of circumstances in which things were not going well, and the organization’s leaders recognized that they had to find a new direction,” he said.

To reinvent Sanofi’s R&D culture, Zerhouni took advantage of his perspective as an outsider, a native of Algeria, and a newcomer to the executive suite of a major pharmaceutical company. He came to the U.S. from Algeria in 1975 for his residency in diagnostic radiology at Johns Hopkins.

“Being an outsider has been a huge benefit for me at Johns Hopkins, NIH, as well as Sanofi,” he said. An outsider is more willing to question an organization’s way of doing things. “Also being an immigrant has helped me to understand different points of view that exist in any complex organization, because today, all great institutions are multidisciplinary and multicultural by nature,” he said. “Part of my ability to succeed in the U.S. may be that I can bring a viewpoint that many people feel is sometimes surprisingly different and constructive in showing there is a different way.”

Believe In Your Vision
Zerhouni learned how to make things happen even when many of his colleagues thought it was impossible to do so or did not agree with his vision. For example, NIH leaders did not uniformly embrace his vision for the agency, outlined in the NIH Roadmap for Medical Research, published in 2003. Their attitude was, “Who is he to tell us what to do? What does he know?” recalled Zerhouni, whose first government job was the NIH director position.

The road map called for greater collaboration among the 27 institutes and centers of NIH, a substantial investment in translational research, and the awarding of research grants to support the high-risk innovative studies that, if successful, typically have the most significant impact on medicine. Because he believed these and other initiatives would strengthen not just NIH but the entire R&D ecosystem, Zerhouni turned to the U.S. Congress to enact legislation. The result was the NIH Reform Act of 2006.

“I wanted to make sure the change we implemented at NIH would be institutionalized,” he said. “When I set out to change the law governing NIH, due to the very partisan Congress, very few thought it would happen, and yet it did, despite great opposition, thanks to a lot of strategic preparation with the relevant senators and congressmen over the preceding three years.”

You Will Become Unpopular
A successful change agent must not be afraid of becoming unpopular. Because change is uncomfortable for some people, you will likely become unpopular. “Twenty percent [of the people you are working with] will be rabidly against you.” Zerhouni said.

However, if the change makes sense to them, most people will not oppose it even if it is unpopular. “Twenty percent will agree with you and will say, ‘He’s right, we need to move on to do things differently if we’re going to adapt.’ Sixty percent will be in the middle. Their attitude will be, ‘I want to see more. Let’s see how things go.’ They may not like the change, but will respect it.”

You Can’t Do It By Ordering People Around
In his past and current leadership positions, Zerhouni could have mandated that his vision be implemented. “But that would not have changed anything,” he explained. “You must understand that you can’t bring people to the same passion and vision that you have because of your position of authority. You can’t do it by ordering people around.”

Change agents should not compromise their vision to win the support of staff, he noted. “You must believe in your vision totally and have a deep understanding of what you want to accomplish and what makes you, as the leader, excited about it in a genuine way.”

Rather than order staff members to change, Zerhouni persuades them. “You first have to persuade others of the need for change, and then organize a fair, open process for all to participate in earnest and have the resilience and courage to implement what was agreed upon.”

Zerhouni also said that change agents should be transparent. “You can’t motivate others by not being genuine,” he said. “You want colleagues and staff to realize that you’re not initiating change for your own self-interest.”

Target Discovery To Phase 3: 10 Years

Soon after joining Sanofi as its president of global R&D in 2011, Elias Zerhouni, M.D., said he evaluated and then trimmed the company’s list of compounds under development to ensure that the company’s resources were being applied to the most promising projects with the highest likelihood of success. He also accelerated the pace of the company’s development of one of the most promising projects: the PCSK9 antibody, a cholesterol-lowering agent that he described as the prototype example of “terrific science leading to a terrific product.”

Because the project was accelerated, PCSK9’s development from target discovery to Phase 3 has required only 10 years. If proved safe and effective and approved by the FDA, the PCSK9 antibody, a fully human monoclonal antibody drug, will be a first-inclass therapeutic agent.

The antibody is based on the 2003 discovery of a physician-geneticist in France who studied the genetics of family members who died from cardiovascular disease at an early age. The physician linked the family’s high blood-cholesterol levels to a “gain-of-function” variant of the PCSK9 gene, which encodes a protein whose actions influence blood levels of low-density lipoprotein (LDL), the so-called “bad cholesterol.” Subsequently, a U.S. researcher identified a “loss-of-function” variant of the same gene in a subset of 300 African-Americans with very low levels of blood cholesterol.