by Geeta Anand
John was the rare biotechnology executive who had lived in the terrifying world inhabited by the patients his company intended to treat—and still did. And he hated the disconnect he saw between the desperation of patients and the dispassion of clinical medicine.
Now that he was in charge, John wanted to infuse the science and business of drug development with patients’ life experience and their families’ sense of urgency, the same sense of urgency that drove him. He set about establishing such a corporate culture by inviting patients and their families every week to tell their stories to Novazyme’s employees—from the scientists to the secretaries—at what were called Lunch ’N Learns.
That first summer of 2000, Novazyme hosted about a dozen patients, some of whom John knew, others whom he’d never met. Greg Assink, John’s big supporter at the Children’s Pompe Foundation, showed up carrying pictures of his seven-year-old daughter Kelsey. John intentionally scheduled these Lunch ’N Learns when board members and company consultants were expected, hoping to draw them into his world. Almost everyone came away inspired to work harder. But what John hadn’t expected was how the visitors, and one young woman in particular, would affect him.
Her name was Lindsey Easton, and because she lived only an hour away, in Glenpool, a suburb of Tulsa, she was one of the first patients invited to visit. John had been introduced to her family by Dr. Slonim when he started the Children’s Pompe Foundation. The doctor had urged John to look up Lindsey’s family because she suffered from the same nonclassical infantile form of Pompe as Megan and Patrick. Slonim had seen Lindsey many years earlier, when she was a toddler, but hadn’t been in touch with her family for a long time. He didn’t even know if she was still alive. John tracked her down to find she had somehow outlived the life expectancy of five years for her disease type. She was, in fact, thirteen, but over the years, she’d lost almost all skeletal muscle strength, and she could—quite literally—move only her eyelids, mouth, and thumbs.1
The day Lindsey arrived, John showed up at the reception area, upbeat and smiling. “Hello Lindsey, how are you?” he asked cheerfully, beaming at the girl with big green eyes, long dark hair, and a chubby, expressionless face. She lay strapped in a wheelchair that reclined at about a thirty-degree angle. She responded with a series of grunts.
Lindsey’s mother, Laurie Easton, translated quickly: “How do you think I am?” Then Laurie laughed, mock-glaring at Lindsey, and said to her, “Could you please hold your wiseass comments in check for one afternoon?”
John chuckled, realizing that Lindsey, sick as she was, had the same feisty personality as his Megan. He led the young woman, accompanied by her extended family—parents, brothers, and grandparents—from the reception area down a hallway, pointing out Canfield’s office, his own, and others. Around the corner, they came to the main laboratory, peeking inside to see a dozen scientists measuring liquids and peering into test tubes. Circling through the empty half of the floor, they returned to the main conference room where the company’s thirty employees had gathered for lunch.
Laurie and Lindsey took questions from the audience—the mother sometimes speaking for herself, at other times interpreting for her daughter.
“What do you like to do best?” asked Hung Do, the most curious and extroverted of the scientists on Canfield’s team.
“She likes to read—she reads all the time,” Laurie answered for Lindsey. “She reads so fast I sometimes can’t get anything else done because I have to keep turning the pages. She read the Harry Potter book in three days. If I had invented an automatic page turner, I’d be a rich woman,” she finished, drawing chuckles from the crowd.
Hung followed up with question after question, and soon others joined in.
“If the enzyme works and you can move around again, what would you like to do?” Hung asked.
Again Lindsey made some noises and Laurie translated: “I’d like to kick my brother’s butt.” The room exploded in laughter.
“Are those tubes uncomfortable?” asked Tony McKinney, the head of drug development, on a more serious note.
“Do you receive any physiotherapy?” another employee ventured.
“Are you ever in pain?” Hung wanted to know.
Laurie Easton said her daughter’s stomach hurt sometimes when her digestive muscles didn’t work well, but that the tubes weren’t uncomfortable anymore because Lindsey had gotten so used to them. A physical therapist came over a couple times a week to move and stretch Lindsey’s arms and legs so they didn’t get stiff.
“It’s so wonderful to see all of you working on curing this disease,” Laurie said when the questions finally ceased. “For so long, we didn’t have hope. And now we learn that not only is there a company working on curing Pompe disease, but this company is right here in Oklahoma. Each and every one of you has brought us hope.”
Lindsey’s ventilator started beeping, picking up on an obstruction in airflow. Big tears raced down her motion-less face.
The room grew silent, choked with emotion. John, at the front of the room, looked red-faced and glassy-eyed. His voice breaking, his lips visibly trembling, John stood up to thank the visitors. “Laurie, Lindsey, thank you for coming here and sharing your stories with us. You, Lindsey, will inspire us to work harder than we ever imagined possible to help you and all other patients with Pompe disease.”
At the back of the room, Canfield held his breath, hoping John could maintain his composure. Canfield had been nervous about John’s plan to invite patients to speak to the staff each week. He told John that he agreed that it was important for the employees to understand the patient perspective, but he also believed scientists should be removed from the emotion so they were free to experiment without fear of failure. But John, as usual, had forged ahead regardless of his disapproval.2
Canfield followed John as he led the Eastons to the elevator, hugged each of them good-bye, and walked briskly to his office. Relieved that John had held himself together, Canfield retreated to his lab.
He didn’t see the scene that took place moments later in John’s office, down the hall from the lab. John stood with his back against the door, letting tears flow freely. Hearing a doctor talk about the progression of the disease was one thing—coming face to face with it in actuality was quite another. He felt so sorry for Lindsey. He felt so scared for Megan and Patrick. He would work longer, harder, faster. He could not—he simply would not—let Novazyme fail.
15
Cowboys
Fall–Winter 2000
Oklahoma City, Oklahoma; Horscham, Pennsylvania;
San Francisco, California
Years later, John would concede there was one place he never should have ventured: the laboratory. The time, the precision, and the meticulousness required in truly great science didn’t play to his strengths. Science could be funded, could be encouraged, and could be inspired, but it could not be rushed. In late 2000, John, who had absolutely no scientific training, crossed the line into making scientific decisions that almost ruined Canfield’s reputation, and made Neose believe for a time that his company was a fraud. It compromised his ultimate goal—helping his children—and John never forgot the lesson.
It began with the two scientific problems Canfield had to solve to make his version of the enzyme deficient in Pompe patients, acid alpha-glucosidase. Before adding the two processing enzymes, Canfield needed to make the Pompe enzyme with the right sugar chains attached. To do this, he used an obscure chemical inhibitor called deoxymannojirimycin, or DMJ, which had been discovered years earlier in Japanese fungi. But there wasn’t nearly enough DMJ available anywhere in the world to make the kilograms of Pompe enzyme he needed for animal and eventually human testing. He needed to either find a way of procuring more DMJ or find a viable substitute.
Next, and perhaps even more challenging, Canfield had to find a way to make a human version of phosphotransferase, or PTase, the longer and more complicated of the two processing enzymes he used in the next stages
of production. PTase was needed to convert the Pompe enzyme into the highly phosphorylated form necessary to be taken into the correct region of the cell. For his lab work, Canfield had extracted the PTase out of cow udders, but as Neose’s Roth had so assertively noted, the FDA was unlikely to approve a product made using animal ingredients. So Canfield set about trying to decode and produce one of the most complex proteins known to man. It proved more difficult than Canfield had ever imagined.1
Subtly, but steadily, the time pressure John imposed on the company began to affect its science. To be sure, John’s sense of urgency did inspire Canfield and his team to work faster than any of them had believed possible. But John didn’t quite know when to stop.
To push the science, John relied on the man Canfield had hired to be chief of drug development, the genial Tony McKinney. In his first meeting with McKinney, John outlined his timeline for the development of Canfield’s science. Novazyme was to finish animal studies by December 2000 and enter human trials in September 2001.
“Your job is to make this happen. I don’t want to hear it isn’t possible because it’s never been done before. We’re doing things differently here,” John said, testing out the sentence that would become his refrain. “We’re not doing things on the regular drug development timeline. We’re doing things on Novazyme time.”2
“Sure, Chief,” said McKinney, even though he had spent more than a decade in the drug industry in sales and new product development, and knew John’s timeline would be very difficult to achieve. But McKinney adopted it anyway, moved and inspired by John’s sense of urgency and the desperation of the patients he met. McKinney had been at the company only a few weeks when a couple showed up in the lobby, having read about Novazyme and driven from Kansas in the hope of bringing home a treatment to save their baby who was dying of Pompe disease. One of the hardest things he’d ever done was to explain to the parents just how many more tests and experiments were needed to be completed before Novazyme would have a treatment to offer their baby.3
McKinney set about immediately developing the design for the animal studies testing Canfield’s enzyme in mice, the generally accepted prelude to human clinical trials. The animal tests needed to be persuasive enough for the FDA to approve moving to human testing, the next step in drug development. McKinney sought expert advice from Dr. Nina Raben, the NIH biochemist who had bred a colony of mice with Pompe disease, and Dr. Barry Byrne, the pediatric cardiologist and gene therapy researcher at the University of Florida. Not only did Raben help design the animal studies, but she was so impressed and excited by Canfield’s science that she agreed to send a shipment of mice with Pompe disease, which she had recently generated. These mice were in extremely short supply, and were desperately sought by Genzyme and others researching the disease.4
By the end of the summer of 2000, McKinney had twenty-four mice with Pompe disease waiting at the animal facility at the University of Oklahoma for Canfield’s animal experiments to begin. He also had in place a draft plan to test Canfield’s enzyme in mice. Prodded by John, McKinney began to push Canfield to provide some of his experimental enzyme for animal testing.
“I need the stuff—when are you going to give me the stuff?” he said.
“Two weeks,” Canfield would reply, in a question-answer pattern that repeated endlessly.5
As the weeks flew by and summer turned into fall, it became clear that Canfield was struggling more than he would admit. Not only had he been unable to find enough DMJ for his needs, but he also couldn’t even find anyone able to produce it. He had signed a contract with a firm in New Zealand to make the inhibitor, and five chemists were working on the project every day. But each week, the company sent a report of a new snag. Finally, Canfield canceled the contract and assigned two of his own scientists to find an alternative inhibitor, something more widely available.
For many weeks, two Novazyme scientists scoured scientific journals for similar inhibitors. They found several with a comparable chemical structure, ordered them, and began to test them one by one, trying to determine whether any were close enough to DMJ to be substitutable. One inhibitor called kifunensin seemed to produce a similar result—and there was a plentiful supply in the world. Canfield didn’t have time for certainty. With McKinney breathing down his neck, Canfield ordered a few laboratory tests validating equivalence, bought eight grams of the chemical, and shifted his attention to the next looming obstacle—making PTase. “I feel like we’re building an airplane as we’re flying it,” he muttered, standing at the whiteboard with his science team, writing out one equation after another. To those outside the science group, he said only, “We’re working on it.”6
Meanwhile, he was beginning to worry that it might not be possible to clone PTase, at least not any time soon. Nobody had ever sequenced the gene that makes the enzyme, much less attempted to produce it, so he had to figure out everything from scratch. Most enzymes were made by one gene, but Canfield thought this one might be produced by two. He knew the identity of one of the genes, but not the other. To find it, he spent days scanning a new computer database of large genes identified in the federally funded Human Genome Project, which attempted to identify all of the genes in the human body. He pulled out a piece of one gene that resembled PTase. Using this segment, he guessed at the structure of the rest of the gene. Then, in a test tube, he put the two genes together with a lipid reagent known to coax genes to make proteins, hoping the product that emerged would be PTase.7
The product passed the first test, and an elated Canfield waited in his office for his scientists to perform a confirmatory test. They added the test substance they hoped was PTase to the Pompe enzyme. If it turned into the highly phosphorylated form, they would know the substance they had made was PTase.
But a few hours later, Canfield’s scientists reported back that the product they had produced didn’t phosphorylate the Pompe enzyme. It was past midnight, but Canfield didn’t call it a night. He crossed his arms, a sign that he was upset, and ordered everyone on the science team to report to the conference room.
“Back to the drawing board,” he said dejectedly.
The next day, McKinney was in Canfield’s office, saying, “We’ve told our investors that we would have animal results by the end of the year. Bill, when are you going to give us some of the stuff?”8
“You can’t put science on a timeline,” Dr. Canfield said, rubbing his eyes in exhaustion. “These timelines are guides, Tony. We do our best to meet them, but these are not some deadlines to be met at all costs.” John, who had been at the company for seven months now, watching Canfield struggle, privately told McKinney to develop a backup plan.
At the next management meeting, McKinney proposed his backup. “Bill, your guys are still picking up cow udders each week at the stockyards, right? And using it to make PTase for laboratory work?”
“Right,” confirmed Canfield, his voice barely audible.
“Well, at last count, I calculated we have one hundred kilograms of cow udders in six different freezers here. If the human PTase is going to take longer to produce, why don’t we use the bovine enzyme for our first drug candidate? It’s similar to the human version. We can produce a second-generation drug using human PTase.”
“Extracting enzyme from cow udders is impractical,” Canfield said loudly, uncrossing and crossing his arms angrily. “It takes a 20-kilogram cow udder to produce enough PTase to make half a milligram of the treatment. That’s only a single dose of medicine. Imagine how many cow udders would be needed to supply patients for a year-long clinical trial, let alone the Pompe patient population for life. Not to mention that—as we’ve been over many times before—the FDA will never approve a medicine made using bovine enzyme.”
John sat back and let McKinney do the arguing.
“But Bill, what about heparin?” McKinney asked, referencing a blood thinner made from pig intestines that the FDA had approved. “It’s not impossible for the FDA to agree, however reluctantly, to use
an animal enzyme, isn’t that right?”
“That’s voodoo science!” Canfield burst out, shaking his head.
McKinney looked stunned for a moment and then, sounding a little hurt, said, “You know, Dr. Canfield, with you the glass is not only always half empty, it’s a little dirty, too.”
John guffawed, breaking the tension, and soon everyone including Canfield was chuckling. McKinney had a folksy way of making observations that others couldn’t quite put into words.
Canfield continued to dismiss McKinney’s idea, but John, who had helped conceive it, privately assigned McKinney to the task of finding a herd of cows that might be acceptable to the FDA as the source of PTase. To satisfy the FDA, the two men believed, they needed a herd with records of everything the cows had eaten since they were born. Maybe then the regulators would be convinced the animals had no communicable diseases.
“You find the herd,” John told McKinney. “I’ll deal with Bill.”
A month later, with Canfield still working on human PTase and McKinney still searching for a herd, John came up with his own Plan B. He had spent most of the $8.3 million faster than he had believed possible. Not only had he paid $2.5 million to have a small, three-thousand-square-foot manufacturing plant built directly across from the Novazyme research labs, but he and Canfield had also hired fifty new staff members, from scientists to regulatory experts to manufacturing gurus. They would need more money early next year, and he didn’t have what he needed to raise the next stage of venture capital funding—scientific data showing the enzyme worked in animals. McKinney had the plan and the mice, but Canfield was still trying to make his medicine.
Novazyme’s partnership agreement with Neose said that the company would invest another $562,000 within three months of Novazyme’s successful performance of “proof of concept” experiments, or animal studies demonstrating the efficacy of Canfield’s enzyme. After that, Neose would also bear half of the costs of drug development—which would slow John’s expenditures considerably.