The Best American Science and Nature Writing 2011 (29 page)

It was entirely possible that elesclomol would work in low-LDH patients and not in high-LDH patients, or in high-LDH patients and not in low-LDH ones. It might work well against the melanoma that confined itself to the skin and not against the kind that invaded the liver and other secondary organs; it might work in the early stages of metastasis and not in the later stages. Then there was the prior-treatment question. Because tumors quickly become resistant to drugs, new treatments sometimes work better on "naive" patients—those who haven't been treated with other forms of chemotherapy. So elesclomol might work on chemo-naive patients and not on prior-chemo patients. And in any of these situations, elesclomol might work better or worse depending on which other drug or drugs it was combined with. There was no end to the possible combinations of patient populations and drugs that Synta could have explored.

At the same time, Synta had to make sure that whatever trial it ran was as big as possible. With a disease as variable as melanoma, there was always the risk in a small study that what you thought was a positive result was really a matter of spontaneous remissions, and that a negative result was just the bad luck of having patients with an unusually recalcitrant form of the disease. John Kirkwood, a melanoma specialist at the University of Pittsburgh, had done the math: in order to guard against some lucky or unlucky artifact, the treatment arm of a Phase 2 trial should have at least seventy patients.

Synta was faced with a dilemma. Given melanoma's variability, the company would ideally have done half a dozen or more versions of its Phase 2 trial: low-LDH, high-LDH, early-stage, late-stage, prior-chemo, chemo-naive, multidrug, single-drug. There was no way, though, that they could afford to do that many trials with seventy patients in each treatment arm. The American biotech industry is made up of lots of companies like Synta, because small start-ups are believed to be more innovative and adventurous than big pharmaceutical houses. But not even big firms can do multiple Phase 2 trials on a single disease—not when trials cost more than $100,000 per patient and not when, in pursuit of serendipity, they are simultaneously testing that same experimental drug on two or three other kinds of cancer. So Synta compromised. The company settled on one melanoma trial: fifty-three patients were given elesclomol plus paclitaxel, and twenty-eight, in the control group, were given paclitaxel alone, representing every sort of LDH level, stage of disease, and prior-treatment status. That's a long way from half a dozen trials of seventy each.

Synta then went to Phase 3: 651 chemo-naive patients, drawn from 150 hospitals in fifteen countries. The trial was dubbed SYMMETRY. It was funded by the pharmaceutical giant Glaxo Smith Kline. Glaxo agreed to underwrite the cost of the next round of clinical trials and—should the drug be approved by the Food and Drug Administration—to split the revenues with Synta.

But was this the perfect trial? Not really. In the Phase 2 trial, elesclomol had been mixed with an organic solvent called Cremophore and then spun around in a sonicator, which is like a mini washing machine. Elesclomol, which is rock-hard in its crystalline form, needed to be completely dissolved if it was going to work as a drug. For SYMMETRY, though, sonicators couldn't be used. "Many countries said that it would be difficult, and some hospitals even said, 'We don't allow sonication in the preparation room,'" Chen explained. "We got all kinds of unbelievable feedback. In the end we came up with something that, after mixing, you use your hand to shake it." Would hand shaking be a problem? No one knew.

Then a Synta chemist, Mitsunori Ono, figured out how to make a water-soluble version of elesclomol. When the head of Synta's chemistry team presented the results, he "sang a Japanese drinking song," Chen said, permitting himself a small smile at the eccentricities of the Japanese. "He was very happy." It was a great accomplishment. The water-soluble version could be given in higher doses. Should they stop SYMMETRY and start again with elesclomol 2.0? They couldn't. A new trial would cost many millions of dollars more and set the whole effort back two or three years. So they went ahead with a drug that didn't dissolve easily against a difficult target, with an assortment of patients who may or may not have been ideal—and crossed their fingers.

SYMMETRY began in late 2007. It was a double-blind, randomized trial. No one had any idea who was getting elesclomol and who wasn't, and no one would have any idea how well the patients on elesclomol were doing until the trial data were unblinded. Day-to-day management of the study was shared with a third-party contractor. The trial itself was supervised by an outside group, known as a data-monitoring committee. "We send them all the data in some database format, and they plug that into their software package, and then they type in the code and press 'Enter,'" Bahcall said. "And then this line"—he pointed at the Kaplan-Meier in front of him—"will, hopefully, separate into two lines. They will find out in thirty seconds. It's, literally, those guys press a button and for the next five years, ten years, the life of the drug, that's really the only bit of evidence that matters." It was January 2009, and the last of the 651 patients were scheduled to be enrolled in the trial in the next few weeks. According to protocol, when the results began to come in, the data-monitoring committee would call Jacobson, and Jacobson would call Bahcall. "ASCO starts May 29," Bahcall said. "If we get our data by early May, we could present at ASCO this year."

 

In the course of the SYMMETRY trial, Bahcall's dining-room-table talks grew more reflective. He drew Kaplan-Meiers on the back of napkins. He talked about the twists and turns that other biotech companies had encountered on the road to the marketplace. He told wry stories about Lan Bo Chen, the Jewish mother and Jewish father rolled into one—and, over and over, he brought up the name of Judah Folkman. Folkman died in 2008, and he was a legend. He was the father of angiogenesis—a wholly new way of attacking cancer tumors. Avastin, the drug that everyone cheered at ASCO seven years ago, was the result of Folkman's work.

Folkman's great breakthrough had come while he was working with mouse melanoma cells at the National Naval Medical Center: when the tumors couldn't set up a network of blood vessels to feed themselves, they would stop growing. Folkman realized that the body must have its own system for promoting and halting blood-vessel formation, and that if he could find a substance that prevented vessels from being formed he would have a potentially powerful cancer drug. One of the researchers in Folkman's laboratory, Michael O'Reilly, found what seemed to be a potent inhibitor: angiostatin. O'Reilly then assembled a group of mice with an aggressive lung cancer and treated half with a saline solution and half with angiostatin. In the book
Dr. Folkman's War
(2001), Robert Cooke describes the climactic moment when the results of the experiment came in:

With a horde of excited researchers jampacked into a small laboratory room, Folkman euthanized all fifteen mice, then began handing them one by one to O'Reilly to dissect. O'Reilly took the first mouse, made an incision in its chest, and removed the lung. The organ was overwhelmed by cancer. Folkman checked a notebook to see which group the mouse had been in. It was one of those that had gotten only saline. O'Reilly cut into the next mouse and removed its lung. It was perfect. What treatment had it gotten? The notebook revealed it was angiostatin.

It wasn't Folkman's triumph that Bahcall kept coming back to, however. It was his struggle. Folkman's great insight at the Naval Medical Center occurred in 1960. O'Reilly's breakthrough experiment occurred in 1994. In the intervening years, Folkman's work was dismissed and attacked and confronted with every obstacle.

At times Bahcall tried to convince himself that elesclomol's path might be different. Synta had those exciting Phase 2 results and the endorsement of the Glaxo deal. "For the results not to be real, you'd have to believe that it was just a statistical fluke that the patients who got drugs are getting better," Bahcall said, in one of those dining-room-table moments. "You'd have to believe that the fact that there were more responses in the treatment group was also a statistical fluke, along with the fact that we've seen these signs of activity in Phase 1, and the fact that the underlying biology strongly says that we have an extremely active anticancer agent."

But then he would remember Folkman. Angiostatin and a companion agent also identified by Folkman's laboratory, endostatin, were licensed by a biotech company called EntreMed. And EntreMed never made a dime off either drug. The two drugs failed to show any clinical effects in both Phase 1 and Phase 2. Avastin was a completely different anti-angiogenesis agent, discovered and developed by another team entirely and brought to market a decade after O'Reilly's experiment. What's more, Avastin's colorectal-cancer trial—the one that received a standing ovation at ASCO—was the drug's second round. A previous Phase 3 trial for breast cancer had been a crushing failure. Even Folkman's beautifully elaborated theory about angiogenesis may not fully explain the way Avastin works. In addition to cutting off the flow of blood vessels to the tumor, Avastin seems also to work by repairing some of the blood vessels feeding the tumor, so that the drugs administered in combination with Avastin can get to the tumor more efficiently.

Bahcall followed the fortunes of other biotech companies the way a teenage boy follows baseball statistics, and he knew that nothing ever went smoothly. He could list, one by one, all the breakthrough drugs that had failed their first Phase 3 or had failed multiple Phase 2s or that turned out not to work the way they were supposed to work. In the world of serendipity and of trial and error, failure was a condition of discovery, because, when something was new and worked in ways that no one quite understood, every bit of knowledge had to be learned, one experiment at a time. You ended up with VAMP, which worked, but only after you compared daily 6-MP and daily methotrexate with daily 6-MP and methotrexate every four days, and so on, through a great many iterations, none of which worked very well at all. You had results that looked "boinking good," but only after a trial with a hundred compromises.

Chen had the same combination of realism and idealism that Bahcall did. He was the in-house skeptic at Synta. He was the one who worried the most about the hand shaking of the drugs in the SYMMETRY trial. He had never been comfortable with the big push behind melanoma. "Everyone at Dana-Farber"—the cancer hospital at Harvard—"told me, 'Don't touch melanoma,'" Chen said. "'It is so hard. Maybe you save it as the last, after you have already treated and tried everything else.'" The scientists at Synta were getting better and better at understanding just what it was that elesclomol did when it confronted a cancer cell. But he knew that there was always a gap between what could be learned in the laboratory and what happened in the clinic. "We just don't know what happens in vivo," he said. "That's why drug development is still so hard and so expensive, because the human body is such a black box. We are totally shooting in the dark." He shrugged. "You have to have good science, sure. But once you shoot the drug in humans you go home and pray."

Chen was sitting in the room at Synta where Eric Jacobson had revealed the "boinking good" news about elesclomol's Phase 2 melanoma study. Down the hall was a huge walk-in freezer, filled with thousands of chemicals from the Russian haul. In another room was the Rube Goldberg drug-screening machine, bought with Milken's money. Chen began to talk about elesclomol's earliest days, when he was still scavenging through the libraries of chemical companies for leads and Bahcall was still an ex-physicist looking to start a biotech company. "I could not convince anyone that elesclomol had potential," Chen went on. "Everyone around me tried to stop it, including my research partner, who is a Nobel laureate. He just hated it." At one point Chen was working with Fujifilm. The people there hated elesclomol. He worked for a while for the Japanese chemical company Shionogi. The Japanese hated it. "But you know who I found who believed in it?" Chen's eyes lit up: "Safi!"

 

Last year, on February 25, Bahcall and Chen were at a Synta board meeting in midtown Manhattan. It was five-thirty in the afternoon. As the meeting was breaking up, Bahcall got a call on his cell phone. "I have to take this," he said to Chen. He ducked into a nearby conference room, and Chen waited for him with the company's chairman, Keith Gollust. Fifteen minutes passed, then twenty. "I tell Keith it must be the data-monitoring committee," Chen recalls. "He says, 'No way. Too soon. How could the DMC have any news just yet?' I said, 'It has to be.' So he stays with me and we wait. Another twenty minutes. Finally Safi comes out, and I looked at him and I knew. He didn't have to say anything. It was the color of his face."

The call had been from Eric Jacobson. He had just come back from Florida, where he had met with the DMC on the SYMMETRY trial. The results of the trial had been unblinded. Jacobson had spent the last several days going over the data, trying to answer every question and double-check every conclusion. "I have some really bad news," he told Bahcall. The trial would have to be halted: more people were dying in the treatment arm than in the control arm. "It took me about a half hour to come out of primary shock," Bahcall said. "I didn't go home. I just grabbed my bag, got into a cab, went straight to LaGuardia, took the next flight to Logan, drove straight to the office. The chief medical officer, the clinical guys, statistical guys, operational team were all there, and we essentially spent the rest of the night, until about one or two in the morning, reviewing the data." It looked as if patients with high-LDH tumors were the problem: elesclomol seemed to fail them completely. It was heartbreaking. Glaxo, Bahcall knew, was certain to pull out of the deal. There would have to be many layoffs.

The next day Bahcall called a meeting of the management team. They met in the Synta conference room. "Eric has some news," Bahcall said. Jacobson stood up and began. But before he got very far he had to stop, because he was overcome with emotion, and soon everyone else in the room was, too.