The Cure

by Geeta Anand

  But perhaps the best gift that their new wealth had brought John and Aileen was the end of their constant worries about money. Where John had complained since the day they were married about all the bills and financial obligations—the mortgages, the student loans, the support for his grandparents, and, of course, the medical bills of late—now Aileen watched in disbelief as he wrote out check after check without saying a word. “It sure helps to have a gazillion dollars,” she giggled.

  As Aileen finished dinner, John began to throw out one extravagant idea after another for Megan’s birthday—clowns, ponies, cakes the size of houses. “Okay, okay, I have it now,” he said, finally. “I’m going to talk to Megan tomorrow and see what she thinks.”

  * * *

  At Genzyme, John was painstakingly establishing his leadership of the Pompe program, but there was one reality no amount of doggedness was going to change: money. By selling to Genzyme, John had clearly guaranteed millions of dollars more for Pompe drug development than he ever could have wrung out of his jittery venture capitalists at Novazyme. But even Genzyme wasn’t in the business of overspending on drugs that might never work.

  To prepare for next year’s budget, John calculated the cost of continuing the development of all four of the company’s potential treatments for Pompe: $80 million in the coming year. Henri was prepared to spend more money on Pompe than any other drug development program at his company, but $80 million was out of the question. He gave John a budget of $50 million, still by far the largest development budget at the company, and said, “It’s time to rationalize your costs.”2

  It was a euphemism for one of the toughest decisions in the drug industry, aside from the fact that his children’s lives could depend on the right answer. In the next two months, John needed to pick the one enzyme with the greatest potential, throw all of Genzyme’s money and staff at it, and shut the other enzymes down.

  Having been indoctrinated in more than a year of daily conversations with Canfield about the importance of having the right sugar chains attached to the enzyme, John was certain that his approach was best. John also had every reason personally to want Canfield’s enzyme to succeed. If it were chosen as Genzyme’s single, $50 million enzyme, John would almost certainly control the clinical trials since he was the president and general manager of Novazyme—now a Genzyme subsidiary, under the terms of the merger. If he were in charge, he would somehow make sure Megan and Patrick were in the first clinical trials. That was, in large part, why he had pressed to be made director of all the Pompe programs.

  John would have made a strong pitch to go with Novazyme’s enzyme except for one caveat—Canfield was still struggling in the lab. He had made many different versions of the Pompe enzyme using the new ingredients of human PTase and kifunensin, and none seemed to work nearly as well as the earlier bovine-based versions in mouse experiments. In their due diligence before the acquisition, Genzyme scientists using Canfield’s enzyme made with the new ingredients had also been unable to replicate the stunning early results he and John had presented months earlier.

  Henri had gone forward with the deal anyway, believing in Canfield’s approach, and concluding from his scientists’ complaints that it needed some tweaking to work right. Failure at one point in time didn’t mean failure forever, as far as Henri was concerned. He’d gone forward with a Gaucher disease drug that had failed in the first trial, overruling almost everyone around him who urged restraint. It turned out that most patients in this trial were given too low a dose, and that the drug produced dramatic results at higher doses. That drug, Cerezyme, had become one of the most successful in biotechnology history.3

  Canfield was working obsessively through nights and weekends to find and fix the problem with his enzyme, but John knew it was anybody’s guess how long it might take. The Novazyme enzyme was not the right choice for his children and other Pompe patients who might die if they didn’t get a treatment within the next six months. For them, it would be better to choose one of the other enzymes, even though they apparently lacked the right sugar chains to get to the lysosomes of muscle cells in large numbers. Genzyme could return to Canfield’s enzyme as a second-generation treatment once he’d worked out the kinks.

  But which one of the others would be the best pick?

  At night in the Charles Hotel, John read over volumes of scientific documents describing what was known so far about the three other potential enzyme therapies. Now that he was inside Genzyme, John had access to far more data about animal studies and clinical trials than had ever been published.

  His thoughts first turned to Chen’s enzyme—perhaps that would be the best choice. John would never forget the sight of baby John Koncel sitting up in his mother’s lap, lifting his arms and smiling, after only a few weeks of infusions. But John would also never forget the sight that followed two or three months later. The child was no longer sitting up, he was breathing with difficulty—slowly, he was regressing.

  John read that baby John’s parents had taken him home to Illinois, where he was still alive but very weak, needing a ventilator to breathe and battling almost constant infections. A second child on the same enzyme, after initially improving, had also lost almost all the gains the drug had won for him. But there was still some hope. A third infant had done so well on the Chen enzyme—without any regression—that he was walking and about as strong as the average twoyear-old.4

  The child with the stunning improvements was the only one of the three whose body naturally made a minute amount of the enzyme correctly. It appeared that as a result, his body did not treat the infused enzyme as foreign, and thus didn’t create antibodies to fight it. Like this child, Megan and Patrick also made a tiny amount of enzyme—less than 1 percent—which was why they hadn’t died as babies. If Chen’s drug were chosen, John felt certain his children would respond well to the medicine. Chen’s protégée, a passionate young doctor named Priya Kishnani, was now running a small second trial with eight babies for Genzyme, designed to include only infants six months old or younger who could breathe on their own and made small amounts of enzyme themselves.5

  Yet, first Chen and now Genzyme had struggled to manufacture enough of the enzyme even to run these tiny trials. The second trial now under way had been delayed repeatedly because the contract manufacturer couldn’t make enough of the medicine and one batch after another failed to pass inspection. John didn’t know how long it would take to find a better way to make the drug, if it was even possible.

  The third potential drug candidate was the Pharming enzyme, the rights to which Genzyme now owned. Over room service pasta dinners, John pored over all the records of the tiny clinical trial that Pharming had conducted in 1999. Four infants had been infused with Pharming’s rabbit enzyme in its first trial, and one had responded so well that he was now as strong as an average two-year-old. The other three infants had seen their hearts grow dramatically stronger, but they had had variable gains in strength in the rest of their bodies. Two of these three babies had regressed after a time; the third continued to gain strength, but very slowly.6

  As John read on, he saw the Dutch researchers had drawn very different conclusions from Drs. Chen and Kishnani about the patients’ varied responses. The baby who responded the best did, indeed, make a tiny amount of enzyme himself, but the one who improved next best produced absolutely no enzyme. Both of these two top responders were the babies who had received the therapy when they were very young—three months old and two and a half months old, respectively—and not yet severely affected by the disease. The Dutch researchers believed that patients treated when they were very young, before they had lost a significant amount of muscle strength, had the best prognosis.

  In addition to four babies who were treated, John discovered five other Pompe patients who had also received the Pharming therapy. Three of them were juveniles or adults when they received the treatment, and included Tiffany, Randall House’s daughter. They gained some strength, not in any way comparable to
the babies, but still meaningful.7

  Tiffany, for one, felt energetic enough for the first time in several years to go to school after starting treatment and having an operation to correct severe scoliosis of the spine. She hadn’t been able to attend high school because of fatigue and respiratory infections, relying instead on a tutor at home. But a year ago, she had enrolled as a freshman at the University of Texas in San Antonio. She was still in a wheelchair and needed support from a breathing machine at night, but even the modest gains in strength and endurance had measurably changed her life.8

  But as John read on, he saw that Pharming’s manufacturing problems also made it an imperfect candidate. The enzyme was still being purified out of the milk of transgenic rabbits. Not only were the rabbits difficult to milk, requiring sedation to calm them down, but over time they made less and less enzyme. Pharming had also raised a herd of cows with their genes altered to produce the human Pompe enzyme in their milk. But to the great disappointment of scientists at both Pharming and Genzyme, the cows’ milk contained so little enzyme that it was almost impossible to purify it out.9

  If Genzyme were to put its efforts behind the Pharming drug, John learned, it would mean maintaining a supply of tens of thousands of the rabbits, which John viewed as almost comically impossible. It would not only be a logistical nightmare, but growing medicines in live animals posed a substantial threat of contamination.10

  And what if it ended up being John’s decision to shut down the Pharming treatment? The Dutch researchers who had developed it and the patients still on the medicine were passionate proponents of its benefits, and had already expressed fear that it would be discontinued. If the drug was not chosen and the rabbit enzyme was discontinued, these patients, including Tiffany, would have to be switched to the chosen drug candidate. What if they didn’t do as well on the new medicine? Who would they blame?11

  The final option was the one Genzyme scientists had developed internally to try to get around the manufacturing problems with the Chen and Pharming products. Genzyme already had extensive experience growing enzymes in Chinese hamster ovary (CHO) cells, the method Chen had used; the company’s Gaucher treatment, Cerezyme, was made this way, in enormous, temperature-controlled bioreactors in a big manufacturing plant in Allston, a section of Boston across the river from Genzyme.

  Where the type of CHO cell that Chen had chosen produced a very low yield of Pompe enzyme, scientist Bob Mattaliano’s team began with a cell line known for its high productivity. They injected the gene that made the human Pompe enzyme into the cells and added different chemicals to coax them into producing it. After substantial trial and error, they thought they had a good sample and tested it by injecting it into mice. It seemed to work—not nearly as well as Canfield’s had appeared to in Novazyme’s early results, but it still held promise. And this enzyme was so easy to make that Genzyme could produce oceans of it.

  Should Genzyme throw $50 million a year at this approach that showed some modest improvement in mice but hadn’t been tested in humans? What if it didn’t even work as well in human beings as the Chen or Pharming enzymes?

  The more John thought about the choices, the more he realized that there was no way to know, for sure, which way to go. This level of playing God appalled him. It seemed almost inconceivable to think that his children’s futures and the hopes of all Pompe patients in the world rested on a choice he would make based on incomplete information. And yet in the business world—as he had learned at Harvard and preached at Novazyme—choices were always made based on incomplete information. For all the talk of patients, management’s allegiance to shareholders was paramount. Resources, businessmen would say, must be conserved to make sure the company continues to make money, which in turn allows it to continue to make medicine.

  On that scale, painful as it was, stopping production of three of the four Pompe enzymes was the lesser of the evils that John faced.

  A solution emerged from the science side. Soon everyone, including John, decided that the only way to know how to proceed was to conduct a massive comparative study of the four enzymes against each other. But it couldn’t be done in humans, which was the optimal way to test a potential new medicine. Novazyme’s and Genzyme’s internally developed enzymes needed much more animal testing before the FDA would allow them anywhere near a human being. So the comparative study would have to be done in the next best medium—mice. It was a risky proposition given that everyone knew that drugs worked differently in mice than in humans, but at least there would be some uniform basis for comparing the four competing enzymes.

  John agreed on the need for the study. But privately he worried that the level of acrimony of the internal debate over the merits of the different enzymes might spill over into the experiments. Genzyme’s scientists thought so little of Novazyme’s science that they had resisted even doing the Novazyme deal. Would they set up the experiments so that the Novazyme enzyme was likely to fail? If they did, John was certain he would never know. He was out of his league at this level of science, and he knew it.

  There was only one person John knew and trusted at the company who had the scientific credentials to go toe to toe with Genzyme’s scientists: Bill Canfield.

  “I need you, Bill,” John said, cradling his office phone between his ear and shoulder. “Will you join the Pompe leadership team?”

  “So now you need me,” Canfield said bitterly. He had not even begun to forgive John for leaving him off the leadership team. It had taken John multiple attempts, and days of leaving voice mails and messages with Canfield’s secretary, to get him on the line at all.

  Eager to get Canfield immersed in the scientific aspects of the debate, John quickly dove into an explanation about the test tube and mouse experiments planned to compare the four enzymes.

  “It’s a waste of time,” Canfield scoffed. He believed that the Pompe enzyme was best taken up by the lysosomes of muscle cells if the right sugar chains were attached with phosphate molecules at the ends. He’d processed his enzyme so each of the seven sugar chains finished with two phosphate molecules. The other three enzymes weren’t processed after they were made in the CHO cells or rabbit milk. They had some differing amounts of naturally occurring sugar chains, but not nearly enough of the right kind, according to Canfield. The only one that had a prayer of reaching the lysosome at some level was Chen’s, which had two phosphate molecules at the tip of one sugar chain. On Genzyme’s internally developed enzyme, only one of the sugar chains had a phosphate molecule at the tip. The Pharming enzyme had sugar chains with varying amounts of phosphate molecules, but they were blocked by other molecules.12

  “Bill, the experiment is going to happen with or without you,” John said, stuttering a little as he tried to appeal to Canfield’s rationality over his injured dignity. “You’re the only one I trust to make sure it’s done properly, that our enzyme has a fair shot.”13

  John knew from others at Novazyme that Canfield was still nursing hurt feelings about being sidelined. John didn’t doubt his decision, but he felt ashamed of how he had handled it. He ought to have flown to Oklahoma and explained it face to face, he thought to himself, rather than in a brief, awkward telephone conversation. Expediency had overridden sensitivity in the sprint to save his children’s lives, and he had deeply hurt his former partner. John took a couple of shallow breaths, waiting for Canfield to answer.

  As stubborn and moody as Canfield could be, he was—as John had always known—also supremely rational. And he wasn’t about to miss an opportunity to be involved in a decision that could define the future of his life’s work.

  “When do you need me in Cambridge?” he asked gruffly.

  23

  The Mother of All Experiments

  Winter 2001–Spring 2002

  Princeton, New Jersey; New York, New York;

  Cambridge, Massachusetts; Framingham,

  Massachusetts

  Megan’s fifth birthday was, as John had planned, a page out of a princ
ess story. Both he and Aileen conceded that it was way over the top for a five-year-old, but they wanted it that way. Now that they had, as Aileen joked, “a gazillion dollars,” they wanted to use it to celebrate their joy that Megan was still alive on the birthday that one doctor after another had said she would never live to see. Each knew the other was also wondering how many more birthdays Megan would have.

  At around 11 A.M. on Sunday, December 16, a white stretch Lincoln Navigator SUV limo pulled up to the Crowley house. Megan, prim and pretty in a black velvet dress, surrounded by six girlfriends, had been waiting in her wheelchair at the upstairs window as her mother took hot rollers out of her hair. “Mommy, the limo’s here. Let’s go,” Megan shouted, wrenching two hot rollers out of her hair.

  “Geez, Megan, you’re going to burn yourself,” Aileen admonished. “This is just going to take five seconds.”

  And true to her word, Aileen had Megan ready seconds later. Her shoulder-length brown hair hung in graceful curls around her. Megan looked in the mirror, eyes smiling for the cheeks that couldn’t move.

  “You look beautiful, honey,” Aileen said. She put a pink birthday hat on her daughter’s head and carried her down the stairs, Sharon following with her ventilator. A throng of relatives waiting in the den and kitchen shouted “Happy Birthday” as Megan appeared, luminous. John plucked Megan out of Aileen’s arms and carried her outside to the limo, sparkling bright white in the sunlight of the 50-degree winter day.

  “Where do you want to sit, Princess Megan?” he asked.

  “I want to be right in the middle!” she said excitedly.

  John strapped her into a car seat in the center of the backseat and plopped down beside her.