Fundamental knowledge of biology is what drives the pharmaceutical industry, James Sabry, Vice President of Partnering at Genentech and an ASCB Council member, told a Biomedical Research Caucus briefing on Capitol Hill Wednesday. And yet the kind of primary research that yields new insights into fundamental biological mechanisms is government-funded through agencies like the National Institutes of Health (NIH), Sabry said. "We can't get a grant from the NIH at Genentech. The money doesn't come to us directly. What comes to us is basic knowledge. Without that, our industry would come to a grinding halt in the United States."
Sabry warned, "If NIH funding continues to collapse at the rate at which it's predicted to, then science, the type that gives rise to these [innovative] drugs, will leave the United States." He continued, "With that will be the movement of pharmaceutical companies... away from this country."
Speaking to a packed congressional meeting room, Sabry offered the case of Zelboraf (remurafenib), a Genentech drug approved with a companion diagnostic test by the Food & Drug Administration (FDA), for treating metastatic melanoma as an example of a drug whose success was completely dependent on basic science discoveries made by NIH-funded researchers. Zelboraf targets a specific subset of metastatic melanomas linked to the BRAF V600E gene mutation in patients. By inhibiting the defective BRAF protein, Zelboraf has an exceptionally high response rate of 70-80% in patients with the mutation, Sabry said. Under a FDA "priority review" of drugs for diseases such as metastatic melanoma for which there are no adequate therapies, Zelboraf took only five years to go from research and development to launch (some drugs take ten years or more). Sabry attributed the success of Zelboraf to the earlier basic research that patiently elucidated the BRAF signaling pathways. "We used basic understanding of the [protein] structure that came not from Genentech, but from NIH basic research about signaling pathways in cells," Sabry explained. Once they had the target, Genentech scientists could deploy their expertise and resources to develop what became Zelboraf.
Sabry gave a current example, a new painkiller already in clinical trials that was developed by Xenon Pharmaceuticals in collaboration with Genentech. This drug has the potential to be "the best analgesic in the world. It wouldn't be addictive. It wouldn't have side effects. It would be highly specific," according to Sabry. Xenon discovered that congenital analgesia, a rare genetic disorder where a person is born unable to feel pain, is caused by a dysfunctional sodium channel, Nav1.7. Although Xenon made the connection, it was basic knowledge of Nav1.7 generated by NIH-funded research that allowed Xenon to develop the drug. "The work that found out about this channel's structure," Sabry explained, was done "in a fundamental neuroscience laboratory that was interested in ion channels and how they were signaling in nerve cells. As basic as basic science can get." Furthermore, much of the original research on Nav1.7 was done in yeast cells. Sabry said, "I know what you're thinking, 'What can a channel in yeast cells tell us about human disease?' And the answer is, 'At the time you don't know what it can tell you about the disease'." Here, basic work in a non-human model organism like yeast, Sabry said, helped scientists understand the function of the channel. Now industrial pharmacologists are testing what they hope will be a better, safer painkiller.
His third example was Herceptin (trastuzamab), the first targeted therapy for HER2-positive breast cancer. Herceptin is an antibody that binds to HER2 , shutting down cancer cell growth. Genentech has recently modified Herceptin by adding a toxic drug to the antibody and creating a combination that is highly effective at killing cancer cells while being less toxic than standard chemotherapy. The new product, Kadcyla (ado-trastuzumab emtasine), improves the lifespan of patients with metastatic breast cancer from about 14 months to 2 years. Sabry said, "The role of microtubules in mitosis was NIH funded and formed a foundation upon which many companies... could develop new anti-mitotic agents as anti-cancer agents." Many breast cancer survivors today would not be alive if it hadn't been for treatments like these that are derived from basic science research. Moreover, Kadcyla is being made in the U.S., Sabry said. "This is the kind of manufacturing that keeps jobs and innovation in the United States."
Sabry joined the pharmaceutical industry in 1997 when he co-founded Cytokinetics. He began his career with an MD from Queen's University in Kingston, Ontario, a residency in neurology at Harvard Medical School, a PhD in neuroscience at the University of California, San Francisco, and a postdoctoral research fellowship at Stanford University. In 2010, Sabry began his current position at Genentech, which employs 10,000 people and is considered one of the most successful biotech companies worldwide.
At Genentech, Sabry said, "If we understand basic science, our drugs make it to market. If we don't, the company dies." Roche, Genentech's parent company, spends more on research and development than any country in the world ($9.5 billion annually), according to Sabry. And yet Roche and all the leading pharmaceutical companies are dependent on basic science research that emerges almost exclusively from government-funded academic and other non profit research institutions, Sabry added. His appreance at the caucus was arranged in part by Representative Jackie Speier (D-CA).
On hand for the caucus briefing, Representative Steve Cohen (D-TN) echoed Sabry's endorsement of NIH funding and condemned the $1.6 billion in cuts forced on NIH by the sequester. Basic biomedical research is vital both to American industry and to American security, the Congressman contended. "The real Department of Defense is the National Institutes of Health," Cohen told the caucus. Telling the next generation of Americans that slashing basic biomedical research in the name of protecting them from debt is shortsighted, Cohen pointed out. "You [the next generation] are going to get the benefit [of NIH research], because the cures, the treatments, will affect you."