May 17, 2010
Annals of Innovation
Why is it so difficult to develop drugs for cancer?
In the world of cancer research, there is something called a Kaplan-Meier curve, which tracks the health of patients in the trial of an experimental drug. In its simplest version, it consists of two lines. The first follows the patients in the "control arm," the second thepatients in the "treatment arm." In most cases, those two lines are virtually identical. That is the sad fact of cancer research: nine times out of ten, there is no difference in survival between those who were given the new drug and those who were not. But every now and again—after millions of dollars have been spent, and tens of thousands of pages of data collected, and patients followed, andtoxicological issues examined, and safety issues resolved, and manufacturing processes fine-tuned—the patients in the treatment arm will live longer than the patients in the control arm, and the two lines on the Kaplan-Meier will start to diverge.
Seven years ago, for example, a team from Genentech presented the results of a colorectal-cancer drug trial at the annual meeting of the AmericanSociety of Clinical Oncology—a conference attended by virtually every major cancer researcher in the world. The lead Genentech researcher took the audience through one slide after another—click, click, click—laying out the design and scope of the study, until he came to the crucial moment: the Kaplan-Meier. At that point, what he said became irrelevant. The members of the audience saw daylight betweenthe two lines, for a patient population in which that almost never happened, and they leaped to their feet and gave him an ovation. Every drug researcher in the world dreams of standing in front of thousands of people at ASCO and clicking on a Kaplan-Meier like that. "It is why we are in this business," Safi Bahcall says. Once he thought that this dream would come true for him. It was in the latesummer of 2006, and is among the greatest moments of his life.
Bahcall is the C.E.O. of Synta Pharmaceuticals, a small biotechnology company. It occupies a one-story brick nineteen-seventies building outside Boston, just off Route 128, where many of the region's high-tech companies have congregated, and that summer Synta had two compounds in development. One was a cancer drug called elesclomol.The other was an immune modulator called apilimod. Experimental drugs must pass through three phases of testing before they can be considered for government approval. Phase 1 is a small trial to determine at what dose the drug can be taken safely. Phase 2 is a larger trial to figure out if it has therapeutic potential, and Phase 3 is a definitive trial to see if it actually works, usually incomparison with standard treatments. Elesclomol had progressed to Phase 2 for soft-tissue sarcomas and for lung cancer, and had come up short in both cases. A Phase 2 trial for metastatic melanoma—a deadly form of skin cancer—was also under way. But that was a long shot: nothing ever worked well for melanoma. In the previous thirty-five years, there had been something like seventy large-scale Phase 2trials for metastatic-melanoma drugs, and if you plotted all the results on a single Kaplan-Meier there wouldn't be much more than a razor's edge of difference between any two of the lines.
That left apilimod. In animal studies and early clinical trials for autoimmune disorders, it seemed promising. But when Synta went to Phase 2 with a trial for psoriasis, the results were underwhelming. "Itwas ugly," Bahcall says. "We had lung cancer fail, sarcoma next, and then psoriasis. We had one more trial left, which was for Crohn's disease. I remember my biostats guy coming into my office, saying, 'I've got some good news and some bad news. The good news is that apilimod is safe. We have the data. No toxicity. The bad news is that it's not effective.' It was heartbreaking."
Bahcall is a...