A diagnosis of AIDS was a death sentence until the advent of drug cocktails in the 1990s allowed patients to suppress the disease indefinitely. Now scientists say a similar combination strategy may change the course of cancer treatment.
That's the bet being made at Roche Holding, AstraZeneca (AZN), and Sanofi-Aventis (SNY), whose latest efforts to develop a new generation of combination treatments are prompting the U.S. Food & Drug Administration to rewrite the rules for drug research. The FDA guidelines, not yet public but expected this year, may shave five years off development time lines and lead to dramatically better drugs, says Ira Mellman, head of cancer research at Roche's Genentech unit.
For more than a decade, cancer researchers have been crafting drugs to disrupt the precise cellular processes that fuel cancer, creating a $51 billion market in 2009. So far, the survival benefits have been measured in months, not years. That's because cancer, like the virus that causes AIDS, evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, researchers are developing new, targeted combinations that work in tandem to block cancer.
"We're looking to see a radical change in terms of stopping the disease in its tracks," says Tal Zaks, head of global oncology drug development at Sanofi in Paris. "The return on investment here is not going to be just evolutionary; it has the potential to be revolutionary."
Cocktails of experimental drugs wouldn't have been possible just five years ago, when FDA rules required that the merit of each active ingredient be proved before it could be added to a combination. The FDA worried about approving a combination in which one part was useless, or worse, harmful.
Today, after 20 years of work on the human genome, scientists have new insights into the cellular and genetic links between different disease pathways. As a result, the FDA is ready to allow testing of drug cocktails designed to hit cancers at multiple points, says Richard Pazdur, the FDA's top cancer regulator. "This is an era of a greater understanding of the disease," Pazdur says.
Savings for drugmakers could be substantial if the FDA, as expected, sets up a path to allow companies to forgo differentiating the drugs during the last and most expensive trials needed for regulatory approval. Those studies, pivotal phase III trials, can cost hundreds of millions of dollars and take years to complete.
Companies are taking different approaches to combination treatments. Pfizer (PFE), the world's biggest drugmaker, and Roche, the world's largest maker of cancer medicines, are developing the needed parts in their labs. Roche's leading combination began safety tests in patients this year, and Pfizer has four combinations in early human trials.
A second group of companies is looking outside to acquire components. Novartis (NVS) and GlaxoSmithKline (GSK) started two studies this year combining an experimental drug from each company. AstraZeneca and Merck also began a collaborative trial. Meanwhile, Sanofi has licensed a molecule that inhibits a cancer-related enzyme from Exelixis (EXEL) and an antibody against a separate protein target from Merrimack Pharmaceuticals. It will combine the two into a new drug based on a recipe concocted by its own scientists. Such collaborations and acquisitions are likely to increase as FDA regulations are clarified, Zaks says.
Combining drugs is not new. Doctors began mixing chemotherapies more than 40 years ago to reduce side effects and improve outcomes. Compared with targeted therapies, though, chemo can be a blunt instrument that wipes out a wide swath of cells, including healthy ones.
Cancer begins when a gene mutation triggers some cells to divide faster than normal. Aberrant cells multiply to form tumors with billions of units competing for blood nutrients. The competition and rapid reproduction yield additional mutations that help the cancer grow and eventually take root in new organs. Through similar adaptations, cancer develops resistance to medicines.
The first studies of targeted cocktails better able to prevent cancer from escaping will be released in 2012, says Harish Dave, global head of hematology and oncology at clinical trial firm Quintiles, which had a role in 48 of the 50 best-selling cancer drugs. "We may see something very interesting come out," he says. However, the risk of the therapy "is that you could be shutting down so many activities in the cell that it could be toxic."
Cancer drugs aren't cheap. Dendreon's (DNDN) Provenge treatment for prostate cancer, for instance, sells for $93,000 for the one-month, three-dose cycle. Total sales of cancer drugs have risen 10 percent to 20 percent a year for a decade, according to research firm IMS Health. And combinations of cutting-edge targeted drugs will likely drive costs for patients and insurers even higher, since each component is so expensive.
"Five years ago, you couldn't get companies to agree to combine their agents," says John J. Wright, a senior investigator at the National Cancer Institute's drug evaluation program. That led the NCI to broker a legal framework—assuring each company maintains rights to its components during cocktail trials—that's leading companies to collaborate.
The first combinations available to patients will be mash-ups of existing treatments, such as Roche's Avastin and Bayer's Nexavar. Yet Roche's Mellman says combinations of pre-approved treatments are "old school," and that the real potential for drugmakers will be in the next generation of targeted cocktails, "driven by scientific discovery that starts in the laboratory."
The bottom line: Taking a cue from the cocktails of drugs that have made AIDS survivable, drugmakers are pursuing combination therapies against cancer.