by Geeta Anand
From the back of the room where he had been sitting, nervous at the prospect of patients being present, Landy jumped up as soon as the meeting ended. Inspired by the hope he heard in the voices of patients and their families, he forgot about how uncomfortable he had been at the very idea of the meeting. He rushed from one patient family to the next, introducing himself and thanking them for coming. Like most of the Genzyme staff there, he had never before met patients with Pompe.10
As Landy mingled, he saw a bioreactor operator named Patrick embrace John and say, “I’ve got a daughter, too, and I can’t imagine what you go through. Your daughter is beautiful. I want you to know I will not let you down.”
Landy, agreeing with Patrick, but not given to emotional declarations himself, simply shook John’s hand and nodded, biting his lip.
* * *
John flew home to Princeton on a private jet that evening with Megan, Aileen, and Sharon, talking nonstop and excitedly. He was still coming down from the nervous state he’d hyped himself into in the days before the big summit.
“In just five months, I’ve formulated a strategic plan to move Genzyme’s largest ever drug development program forward,” he said. “It’s been such hard work. I never would have thought it possible. Did you see how inspired people were at the end?”
“They sure were, John,” Aileen said, leaning back in her seat and closing her eyes. She, Sharon, and Megan had flown up that morning for the luncheon, and it had been an exhausting day.
“We built a consensus around the plan and, with the meeting today, we’ve begun to create a sense of urgency within the company to move quickly into clinical trials,” he said. “I bet we can have Megan and Patrick treated by the summer,” he added, with his customary confidence, and really believing it himself.
“You really think so, Mister John?” Sharon interjected.
“I’m trying my damnedest,” he said.
“You sure are,” Sharon said, growing tearful. “I just can’t wait for the day, Mister John. I am so proud of you.”
Megan, who had been looking out the window, jumped into the conversation. “Daddy, when did you say Special Medicine will be ready?”
“It’s almost ready,” John said. “Just a few more months, honey.”
“I don’t want it to be blue anymore—I want it to be pink,” she said.
He nodded and said, “Okay, honey, we can make it pink.”
“Will I be able to walk?”
To walk? When he had first told Megan a year and a half ago about a medicine he was making for her—then, as now, calling it Special Medicine—one of her first questions had been whether she would be able to walk. At the time, there had been reason to believe it was possible. Now, two years later, she and Patrick were so weak that the muscles in their legs and torsos were possibly too damaged to repair themselves.
Today, he would consider it a victory if the children’s hearts were made healthy by the drug—and there was still a good chance that would happen. That alone would pull them back from the danger of heart failure, which was a risk the family now faced every day. He had to hold on to what might be, John told himself, not what could have been. If only he could help their hearts, he thought again, he would be happy.
“Daddy, will I be able to walk?” Megan asked again, interrupting his thoughts.
“I hope so, Megan,” he said, haltingly. “But we don’t know. I don’t think it will happen right away. Special Medicine isn’t magic, you know. You’re going to have to work really, really hard to get stronger. Will you do that?”
She nodded, but possessed of her father’s persistence, she pressed again: “But will I walk?”
It was a sensitive thing he was trying to do, resetting her expectations without taking away her hope. Hope, as he knew, was perhaps second only to love, the most powerful motivator in the world.
“I think you’re going to get a whole lot stronger. I know your heart is going to get a whole lot stronger,” he said. “I don’t think you’ll walk right away, Megan. But if you try really, really hard, you never know what can happen.”
24
The Sibling Study
Spring–Summer 2002
Framingham, Massachusetts; Cambridge,
Massachusetts; Princeton, New Jersey; Ocean City,
New Jersey
At long last, the Pompe leadership team turned its attention to discussing the clinical trials on which Genzyme hoped to win FDA approval. At the group’s meeting in the Framingham science building, Landy took the floor and used a flip chart to present his plan. It called for a single clinical trial in twelve patients who would all be less than a year old.1
John, stunned that Landy was conceiving of a trial that by design could not include his children, lobbed the first question. “Why are we testing in infants first?”
“There are several reasons,” Landy said smoothly. “The main reason is that the life expectancy of infants is so short that we can demonstrate in less than a year that our therapy extends their lives. That’s the gold standard for the FDA to approve a therapy,” he finished matter-of-factly.
It was the same argument John had heard for four years from researchers at Pharming and Duke. That argument was why he had formed the Children’s Pompe Foundation in the first place—to fund clinical trials in his kids’ age group, which nobody else was planning to do. If now, at Genzyme, the first major trial of the treatment he’d been so desperately pursuing did not include his children, then the past four years had in many ways been an enormous waste of his time.
“Dr. Alfred Slonim has always recommended a new treatment be tested first in slightly older kids,” John pressed. “Testing in infants first doesn’t make sense because these kids are usually the sickest. You may have the perfect drug, but these kids may be too sick to ever be rescued.”
“What you’re recommending is Novazyme’s strategy,” Landy said.
“Call it what you want—the reality is this,” John asserted. “These infants probably make no enzyme at all, so you may have the greatest drug and still not get clinical benefit because of the body’s immune response.”
“John, we may only include babies who are crim positive, and in case you don’t know, that’s medical terminology for a patient who naturally produces a small amount of active enzyme,” Landy said, enunciating every word, his voice louder. “We have many factors to consider here in trial design, including the fact that we may be working with a very limited supply of enzyme and babies need the least amount of drug.”
As he spoke, Landy grew steadily more red-faced and breathless. “Testing in infants is the fastest way to get the drug approved,” he repeated. “You’re proposing the Novazyme plan.”
“That’s because the Novazyme plan is the best goddamn plan I’ve seen,” John retorted, refusing to back down. His hard-won credibility as head of the Pompe program depended on being seen as able to rise above his own needs as a father—to be coolly, serenely objective. After all this time, he wasn’t always able to remember that.
In the quiet of his office after the meeting, Landy calmed. His anger at the challenge to his authority as medical director in front of the science team had caused him to lose any ability to sympathize with John. Now, mentally reviewing the meeting, Landy realized what had occurred almost immediately to everyone else—that though John didn’t mention Megan and Patrick, he was arguing against a clinical trial plan that excluded them.2
Surely, Landy thought, there could be a compromise. He pulled the binder with the enzyme production and supply plans from his desk, and silently scrutinized the spreadsheets that predicted future drug supply. After a moment, he pulled a legal notebook from another desk drawer and began scribbling notes. Half an hour later, he opened a document on the computer and began typing, rewriting the clinical trial plan to include two trials—one in sixteen infants and another in sixteen young children.
It was asking a lot of the manufacturing team. Neither trial could begin until Genzyme had ma
de enough of the enzyme—a little over a kilogram—to last a full year. It wasn’t prudent to take the risk of running out, he believed, while the big, new bioreactors in Allston were still being built and the trial enzyme was going to come from three older ones at Genzyme’s plant in Framingham. For Landy’s new plan to work, four of the next five runs in the bioreactors needed to come out clean.
Still, he thought, it could work. It could be a way to help John’s kids.
Unfortunately, almost everything went wrong during the next few weeks on the manufacturing front. The yield from the first run was less than the Pompe leadership team had predicted, in part because the portion of drug that needed to be set aside for testing to validate the new system had not been subtracted out of the supply calculation. Then several bioreactor runs failed. The final blow came in April when some glass vials in which Pharming’s enzyme was stored cracked. A senior official recommended throwing out all the Pharming vials. John pushed van Heek to broker a compromise in which Genzyme would throw out only vials that were part of the production runs in which others had cracked. Still, it cost dearly. A third of the Pharming drug was lost. The first Genzyme drug made by the Framingham bioreactors had to be siphoned off to supply some of the Pharming patients who would need to be transitioned to the Genzyme therapy a year ahead of plan.
When the Pompe leadership team assembled three months later in May to finalize the clinical trial design, there was only half as much enzyme available as everyone had hoped. Red pen in hand, Landy stood before the group saying he needed to change the trial design to reflect the shorter supply. He wanted to keep the infant trial at sixteen patients because he thought that was the bare minimum needed to convince the FDA that the experimental drug worked. Most drugs were approved on the basis of testing in hundreds of patients.
John held his breath as Landy paused and turned the page of his flip chart. Had he canceled the second trial?
To John’s relief, he saw that Landy still planned a second trial. But the relief dissolved in dismay as John saw how Landy had done it. He had limited participation to children younger than three years old, who would need less enzyme because they were smaller. Megan, five, and Patrick, four, would not qualify.
What could he say? What Landy had done was perfectly reasonable from a clinical and corporate perspective—and in the overall interest of speeding a treatment to market for all patients. As director of the Pompe program, John couldn’t think of one single rational argument to make against it. But as a father, he longed to put up his hand and say, “What about Megan and Patrick?” The whole room knew his kids were dying. How could they put forward a plan that wouldn’t include them?
Rage surged within him as Landy painstakingly described the dose levels for the trial and the clinical endpoints he would measure. But John reminded himself that he had sold himself to Genzyme as someone who could be objective and rise above his children’s desperate need to run a program to benefit all patients. Landy was only doing his job.
Megan and Patrick were not part of his job description.
A few days later, with McKinney at the wheel, he and John rode to Genzyme’s headquarters. McKinney tried to make small-talk, but John didn’t engage, staring silently out the window ahead. McKinney was one of the few people at work with whom John spoke candidly about his fears for his children. McKinney knew that John found it excruciating to maintain his objectivity as leader of the Pompe program when his children’s lives depended on its decisions, and often marveled privately to his wife that he didn’t know how John carried it off.
When John finally spoke, his voice was dark and distant. McKinney was used to the young program director’s quick wit and humor, his exasperation and impatience. He was ready for him to complain about Landy’s insensitivity, but he didn’t in any way expect to hear what John said next.
“You know, Tony, sometimes you get awfully tempted,” John said, his face unreadable. “There’s drug sitting there. You wonder if anyone would notice if some of it went missing.”
John was actually suggesting stealing some of the drug and giving it to his children!
“I’m sure you think about it, John, but that’s a dangerous road to start down,” McKinney said, haltingly. “I’m sure we can find a better way.”
“Of course,” John said, sounding utterly exhausted. He leaned back and stared out the window again.
“I’m sorry, John,” McKinney said softly. “I’m so sorry.”
The two men were quiet for the rest of the ride. John’s mind kept turning over the shock of Landy’s announcements—and the thought of those bottles of enzyme, just sitting there. He’d thought about it before. His coworkers and his investors would be shocked if they knew how many times he’d thought of it before. What if he took several vials of drug? How would he give it to the kids? It had to be infused in their veins in a hospital every two weeks. The children needed to have an operation to have a tube installed so large volumes of enzyme could be safely infused. Should he take the drugs and fly the kids to Mexico?
It wasn’t that simple. Nothing ever was. The children needed to be monitored by doctors who knew about the disease. What if they built up antibodies to fight the enzyme? He would never know if the right doctors weren’t doing the right tests.
All the plans ended in failure. With a sigh, he turned back to face the road. He couldn’t just take off with a few vials; he had always known that. He would have to find another way.
Back in his office, John pulled out the reports from the manufacturing team and a calculator and began to go over the drug supply numbers. He looked at Landy’s latest plan and added up the amount of drug each patient needed. Landy’s calculations were based on his assumption that the clinical trials couldn’t begin until Genzyme had a year’s supply of enzyme on hand. Maybe, John thought, he could persuade Landy to go with a nine-month supply instead. That way they could include bigger kids like Megan and Patrick.
Late that afternoon, John showed up at Landy’s door. It was open a crack and he could see Landy seated at his desk, his sleeves rolled up, the knot of his tie loosened. Papers were spread all across the desktop. John recognized the same drug supply lists that he himself was clutching. He knocked and sat down at his small conference table, pulling out the legal pad on which he’d recalculated the supply.3
“Hal, I wanted to show you how, if we keep a nine-month supply of drug, we can include bigger kids in the trial,” John said.
“I’m not comfortable with that,” Landy said immediately. “You have to be conservative. Every time we turn around, there’s less drug. It would be an absolute disaster if patients were left without drug in the middle of the trial.”
“But Hal, that’s a risk many parents would take,” John said, still not mentioning the names that burned on his tongue. “What’s the alternative for the patients? Many of them will die if they have to wait longer.”
The two men argued back and forth, until it became clear to John he was not making any inroads. Defeated, he picked up his papers to leave. He was starting to stand up when Landy said quietly, “John, I want to let you know I also want to treat Megan and Patrick.”
The words stopped John cold. In the nine months they had worked together, Landy had never said the names of John’s two sick children before. He had been longing to hear Landy’s exact words for four long years, and now they had just been uttered in a quiet, matter-of-fact tone.
“What—what are your thoughts?” John said, struggling to maintain his composure.
Landy described a plan for John’s kids that he had been putting together for several days, ever since he realized he would have to revise the trial in a way that would exclude them. He hadn’t wanted to share it with John until it was all set. He told John that he preferred not to petition the FDA to give his kids the drug on a compassionate-use basis—a provision the federal agency sometimes approved to make experimental treatments available to patients who will otherwise die—because the company might face accus
ations of favoritism. Parents of children with Pompe called almost daily, begging for some of the enzyme. They had their senators and congressmen lobby Henri on their behalf.
To get around any possible nepotism charge, Landy had devised a scientific rationale for a tiny third clinical trial, calling it the Sibling Study. He would argue that it was necessary to help Genzyme understand not only why Pompe disease manifested differently in patients, but also why the enzyme treatment’s effectiveness varied widely. Megan and Patrick had the exact same defect in the gene that coded the Pompe enzyme, and yet they had very different forms of the disease, Megan being much stronger than Patrick. Landy said he would argue that the Crowley siblings were ideal for an experiment aimed at finding the causes for the varying clinical manifestations of the disease and effectiveness of the treatment.
“When could we begin?” John asked, breathless.
“We can begin as soon as we’ve written a protocol, probably in about two months. Where would you like us to conduct the trial, John?”
“CHOP is close to our home and has the best doctors,” John said immediately, using the acronym for the Children’s Hospital of Philadelphia.
“Then I’ll begin a dialogue with the hospital’s clinical trial review board,” Landy said. “As soon as they approve the trial, we can begin.”
John sprinted back to his office and called Aileen. “Hal just told me they want to treat the kids,” he blurted out as soon as she was on the line.
“What are you saying?” she asked. “When will it happen?” He could tell she was excited, but not quite believing what he was telling her.
He repeated everything he had heard from Landy. He thought they could get the children treated in two or three months.
“Two or three months,” Aileen repeated, in a tone of wonderment and joy.
The next afternoon, John pulled up at the home his family had moved into only a month earlier. As the limousine drove away, John paused for a moment, staring up at the enormous white brick house with three turrets. He and his daughter both thought it looked like a castle, which was half the reason Megan loved it. It was a beautiful spring day, with a peaceful blue sky framed by tall trees. He stepped into the foyer from which two staircases rose gracefully on either side of the doorway leading to the great room. Megan, in her electric wheelchair, sped through that doorway and pulled up an inch from his feet.
