Despite the issues, there's a charisma to Dolan that's undeniable. It comes out in conversation, in the footage of Dolan cycling
next to Lance Armstrong, and in the stories of his travels through Africa. There's good reason to expect that it will be visible
in Dolan's role as the next chair of PhRMA. For BMS, it's also a good thing; a company facing a storm of patent and other
legal challenges needs a charismatic leader. But there's more than personal magnetism to Dolan's survival strategy for BMS.
The story of BMS today is one of a company remaking itself to focus on risk/benefit ratios at every level, from products to
markets to organizational structure. As Dolan moves the company out of overcrowded primary care markets, as he reworks the
organization so it can replace former blockbusters with new specialty drugs from its own pipeline, as he attempts to bring
BMS out of the storm and into a new period of prosperity, he's also testing a set of ideas, already embraced by FDA, that
promise to reshape the industry as a whole.
Elliott Sigal, MD, joined BMS in November 1997 as vice president of the newly created department of applied genomics. He quickly
rose through the ranks, his focus on genomics coloring the organization's broader goal of leveraging predictors of efficacy
or safety early in the pipeline or in the clinic. When BMS' beloved research chief James Palmer passed away suddenly in October
2004, Sigal was appointed chief scientific officer and president of the Pharmaceutical Research Institute, the company's R&D
Sigal never strayed very far from his roots. By the time Vioxx (rofecoxib) had other pharma companies scrambling to better
understand the idea of a drug's benefit/risk profile, Sigal and the rest of BMS were reaping the rewards of having reorganized
around the idea five years ago.
In the mid to late nineties, BMS launched an initiative to increase productivity in discovery. "By 2001, we almost tripled
our productivity," says Sigal. "But we were not satisfied with the quality in the middle part of the pipeline. So we instituted
procedures that would predict where we would run into problems downstream in terms of toxicology or safety or efficacy. And
we put into place departments that dealt with the quality of our drug discovery candidates, so we would not run into problems
in the clinic." Compounds that safely made it to humans rose from 50 to 80 percent.
"Unlike most industries where engineers design the product, in pharma, you are always learning about a drug's efficacy, utility,
and safety," says Sigal. "You unmask characteristics, not design them. The more you design and predict upfront, the more efficient
you can be—and that is what we've been doing.
"Investigational toxicology is a lot of old-fashioned biochemistry and the use of various chemical probes and biology applied
to studying something not everybody has spent a lot of time studying. We use gene expression arrays from genomic technology
to look for molecular signatures that might predict a response. In doing so, we can either redesign a compound or move forward
with the knowledge that whatever the issue, it is not relevant to humans."
BMS' use of investigational and predictive toxicology puts the company in good stead with FDA which, under its Critical Path
initiative, is pushing for toxicology packages that show a better understanding of a drug's risk profile. Sigal says BMS used
this approach when developing Baraclude (entecavir) for chronic hepatitis B. The drug was the first new molecular entity to
come before an advisory committee since Vioxx, and, says Sigal, "I wasn't sure which way it would go." But Baraclude received
a unanimous 18–0 vote from the committee and subsequently received FDA approval in March 2005.
BMS also applied that science in developing Pargluva (muraglitazar). The product has the potential to be a super drug: It
controls both blood glucose and lipids—part of the constellation of symptoms that characterize a patient with metabolic syndrome.
By some estimates, that population will reach 86 million US patients by 2025.
Several companies have already tried and failed to develop such a drug, or one like it. Industry observers are split over
whether FDA will approve Pargluva, whose application is currently being reviewed.