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LSF Magazine: Fall 2012

Biotech Benificence


The story of John Crowley’s heroic efforts to save his children from a rare, fatal illness has been the subject of a front-page article in the Wall Street Journal, a book by journalist Geeta Anand, and a Hollywood movie starring Harrison Ford. There was no treatment for the disease. Crowley embarked on a quest to find one. He soon found himself running a startup biotechnology company – quite unexpectedly, because he had no prior experience in the field.

As the company struggled to develop a medicine, Crowley’s children grew weaker. On more than one occasion, desperation led him to push envelopes in science and business development. His personal and professional stakes in the work did not always coexist harmoniously. Examining Crowley’s unusual predicament yields insights into the practical moral foundations of biotechnology as a scientific, commercial, and human enterprise.

WE PLAN, GOD LAUGHS

The son of a New Jersey police officer who died on duty when he was seven years old, John Crowley graduated from the Harvard Business School in 1997 and prepared to move his young family – wife Aileen, two-year old son, John, and one-year old daughter, Megan – from the East Coast to Walnut Creek, California. He was set to begin a promising career in management consulting with the highly-regarded San Francisco firm, Marakon Associates. Financial security was on the horizon. Aileen was expecting the couple’s third child. Life was good, the future seemed bright. “We were on top of the world,” says Crowley.

Suddenly, the world came apart. At fifteen months, Megan had not taken her first steps (although she otherwise appeared normal and healthy). In March 1998, a week after Aileen gave birth to a second son, Patrick, a series of tests led to a rare diagnosis – Megan had Pompe disease. Neither John nor Aileen had ever heard of it. Doctors informed them that their daughter would become progressively weaker. Her heart would begin to fail. She would struggle to breathe, and probably not live beyond five years of age. There was no treatment. The Crowleys were instructed to go home and prepare for the inevitable.

There was a 25 percent chance that Patrick was also afflicted. Pompe – named for the Dutch pathologist who first characterized the illness in 1932 – is a genetic disease that occurs when a child receives a defective copy of a recessive gene from both parents. The gene implicated in Pompe disease codes for an enzyme called acid alpha-glucosidase (GAA). GAA plays a critical role in the conversion of glycogen to energy. Mutations in the gene reduce the molecule’s biological efficacy, resulting in an enzyme deficiency. In the absence of sufficient functional GAA, glycogen accumulates in cells. Lysosomes – cytoplasmic organelles that break down cellular waste and debris – are overwhelmed. Cells become clogged; organ function declines; muscles atrophy. Patients become immobile. Eventually, they die.

For John and Aileen, the diagnosis was shattering. The couple’s dreams were wiped out in an instant, replaced by anxiety and dread. They put off testing Patrick for a time, since he appeared robust. They felt ill-prepared at that moment to face more devastating news. When John Crowley looks back on this period of his life, he reflects on an old Yiddish proverb: “We plan, God laughs.”

TAKING ACTION

John found that passive acceptance of his daughter’s plight was impossible. Compelled to act, he went online to educate himself about Pompe disease and the current state of biomedical research on the condition. He discovered a small, dispersed, and underfunded community of physicians and endocrinologists working to improve care for patients with Pompe and other rare lysosomal storage disorders (LSDs). He also found a ray of hope.

Crowley learned of two research groups that were planning clinical trials of experimental enzyme replacement therapies (ERTs). Geneticist Yuan-Tsong Chen of Duke University was making recombinant GAA in Chinese hamster ovary (CHO) cells, with assistance from a Taiwanese company called Synpac. In Manhasset, New York, on Long Island, Pompe expert Dr. Alfred Slonim was working with a Dutch company called Pharming that had bred thousands of transgenic rabbits carrying the gene for human GAA. Pharming scientists were purifying a supply of the enzyme from rabbit milk.

The Crowleys returned to New Jersey, where John and Aileen had both grown up, to be closer to top medical specialists, and to the couple’s support network of friends and family. John resigned from Marakon Associates and accepted a position in sales and marketing at Bristol-Myers Squibb in Princeton. It was nearby, the pay was good, the health insurance was excellent, and the regular hours enabled him to devote considerable time and energy to pursuing a cure for Megan.

As the Crowleys adapted to their new reality, the burden of Pompe on the family grew heavier – test results showed that Patrick, too, had the disease. John hit on the idea of starting a private foundation to raise money for research. He established the Children’s Pompe Foundation and sought funds to support a clinical trial in which his children could be enrolled. He worked with the Muscular Dystrophy Association to increase awareness of the disease among philanthropists, and over the next two years, collected more than $1 million to support the work of Chen, Slonim, and others.

In November 1998, Crowley attended a medical conference on Pompe at the National Institutes of Health in Bethesda, Maryland. He listened to Dr. William Canfield of the University of Oklahoma Health Sciences Center describe preliminary efforts to develop a chemically modified version of GAA that would significantly increase uptake of the enzyme by affected cells. Canfield claimed that the Duke and Pharming enzymes were inferior and would have to be administered at very high doses in order to achieve therapeutic effects.

The claim was disconcerting because Crowley knew the Duke and Pharming teams were struggling to deliver enough GAA for clinical trials. Chen’s group had lost a batch of precious enzyme when its CHO cells became contaminated by a virus, and the Pharming team had reported disappointing yields from the rabbit milk purification method. If the supply problems weren’t solved, the first trials would enroll only infants because clinical efficacy could be established with less enzyme. The Crowley children might not qualify to receive the treatment.

NOVAZYME

A year passed. The Duke and Pharming programs stalled. Megan and Patrick grew progressively weaker. Both needed ventilators to help them breathe. Crowley was tired of waiting. In January 2000, he contacted Canfield, who had resigned his position at the University of Oklahoma to start a private firm called Targeted Therapies. The company, located in Oklahoma City, was grossly undercapitalized. Crowley offered to help raise the first $250,000 in capital for the business.

Canfield needed an experienced CEO to raise money. Crowley helped him conduct a search, in vain. They couldn’t find a suitable candidate willing to move to Oklahoma. Acutely aware of the ticking clock, Crowley nominated himself for the job. Given the lack of alternatives, Canfield took the proposal seriously.

Aileen was taken aback by it. John was doing well at BMS, and earning an annual salary of over $100,000 . His position provided the family with a measure of security and – importantly – health insurance. On the other hand, jumping to Canfield’s startup was a way for John to become directly involved in finding a cure for Megan and Patrick, and others like them. Aileen didn’t stand in his way. “We were so desperate to take control of the situation,” says John, “that we were willing to do almost anything to drive toward a treatment for our kids.”

The family remained in New Jersey; John commuted to Oklahoma City as needed. He and Canfield courted angel investors, and collected a total of $1.2 million. Then Canfield persuaded a Pennsylvania-based biologics company called Neose Technologies that his chemistry could improve replacement therapies for a wide range of enzyme deficiency disorders. Neose agreed to partner on the Pompe project, and put in another $500,000. The Neose commitment was an important validation of Canfield’s science. Suddenly, venture capitalists were willing to invest. Crowley changed the name of the company to Novazyme, and sold portions of it to Perseus-Soros, Catalyst, and HealthCare Ventures. Novazyme closed its Series A financing round with over $8 million in the bank.

The fundraising went well, but Crowley’s lack of experience soon became an issue. A few executive miscalculations prompted members of the Novazyme board of directors to question whether they had the right CEO in place. They were concerned that Crowley’s desire to obtain a medicine for his children at any cost was encouraging recklessness, and impairing his judgment regarding the best interests of the company and investors. At one point, an overenthusiastic spin on preliminary data from a less than rigorous experiment prompted a board member to question seriously whether the enterprise was even legitimate. John acknowledges mistakes, but believes that his passion and sense of urgency were essential ingredients in the company’s success: “If I had done things the conventional way at Novazyme, I don’t think we would have moved as quickly as we did.”

By mid-2001, Novazyme had grown impressively. The payroll had expanded from a handful of employees to over a hundred. Canfield had completed animal studies of the modified enzyme, and the company had built a small pilot manufacturing plant in anticipation of a clinical trial in human beings. The next infusion of venture capital, however, was tied to a benchmark – a treatment in the clinic by September. Crowley knew the timetable was nearly impossible to meet.

In order to move forward, the small firm needed to tackle a series of daunting technical and organizational challenges with which it had no prior experience. Novazyme would have to design and conduct a Phase III clinical trial that would deliver unequivocal evidence of the safety and efficacy of the company’s medicine to the FDA. If successful, the firm would need to begin manufacturing substantial quantities of the product – again according to stringent regulatory standards – and to distribute it to physicians treating Pompe patients all around the world.

Given the magnitude and complexity of the looming tasks, Crowley was reluctant to take them on without assistance. He concluded that the best way to deliver appropriate returns to investors, guarantee survival of the GAA research program, and speed the production of an ERT for Pompe patients, including his own children, was to solicit aid from a larger corporate partner. He sent out invitations to an open house.

Two big biotech companies stopped in to visit. Genentech in South San Francisco, California proposed a partnership to help bring Canfield’s enzyme to market, an arrangement in which Novazyme would retain substantial control of the project. Boston-based Genzyme was also interested. Making orphan drugs for lysosomal storage disorders had become the company’s biggest business. By 2001, Genzyme had marketed two highly successful treatments for Gaucher disease, completed a Phase III study of an ERT for Fabry disease, and set its sights on Pompe. Genzyme wanted to discuss a full acquisition of Novazyme.

The choice between Genentech and Genzyme was difficult, and later became the subject of a Harvard Business School case study (“Novazyme: A Father’s Love”). Crowley reasoned that Novazyme’s Pompe program would be one among many projects at Genentech, and could get lost in the shuffle. At Genzyme, in contrast, it would likely become a top priority. Genzyme had already made a serious investment in the area – it had taken over Pharming’s assets and purchased rights to Chen’s enzyme from Duke University. It had also initiated its own internal research program. Crowley imagined that work on a treatment for Pompe disease “would keep the Genzyme board up at night knowing that it had to succeed.”

He saw that pricing Novazyme would likely become a major obstacle. Investors were encouraged by the firm’s performance. They hoped to compete with Genzyme, not join it. Moving a product into clinical testing would set the stage for a lucrative public offering. Crowley needed to secure a valuation on the order of that potential return. He was not optimistic, but managed to negotiate a deal in which the Bostonians gave up $137.5 million, with additional payments contingent on the future performance of Canfield’s technology.

It was enough. Novazyme became a wholly-owned subsidiary of Genzyme, and Crowley became a Senior Vice-President with responsibility for Genzyme’s Pompe program – the largest and most expensive R&D project in the company’s history. Crowley had put together a wonderfully cohesive organization at Novazyme by stressing patient advocacy as a core element of the company’s mission. Genzyme CEO Henri Termeer wanted to encourage the same spirit in Genzyme’s Pompe work. He later told the Wall Street Journal, “I wanted John to come in here, make a lot of noise, shake every corner of the company, and get things moving.”

THE MOTHER OF ALL EXPERIMENTS

Genzyme was prepared to spend unprecedented sums on Pompe, but it could not afford to take four independent research programs forward. From the enzymes under development at Duke, Pharming, Novazyme, and Genzyme, the company needed to select one on which to concentrate its efforts. Crowley drew up a plan to conduct a rigorous test in mice in 2002. The trial was so important that it became known in Genzyme lore as the “Mother of All Experiments.” Managing the competition between the project teams required a good deal of diplomatic skill.

Each of the four therapies was at a different stage of development. Canfield’s modified enzyme was promising, but less advanced, and still not ready for a trial with human beings. It was a longshot. The process was blinded. Enzyme supplies were color-coded and stripped of all other identifiers. Only two people at Genzyme knew which was which. The result was a virtual tie between two of the candidates. The final selection was based on manufacturing yield because very high doses were required to produce therapeutic effects – twentyfold higher than replacement therapies for other LSDs. The ultimate winner of the contest was an enzyme that had been developed in-house at Genzyme with a high-producing CHO cell line.

The next step was a global clinical trial, a colossal undertaking. As the experimental therapy moved closer to the medical marketplace, Crowley entered what he calls the most difficult period of his career. Scaling up enzyme production remained difficult. There was not enough GAA to conduct a meaningful clinical trial with older children or adults. The trial was designed for infants and children up to three years old. Megan and Patrick did not qualify. John Crowley was shipping medicine to patients all over the world, but time was running out for his own children. Doctors estimated that they had less than a year to live.

Genzyme’s physicians sought a scientific rationale for treating Megan and Patrick. A sibling trial was proposed, a comparative study of the same therapy administered to patients carrying the same mutations in the GAA gene, but presenting with different clinical manifestations. Megan was stronger than Patrick. A study of how each responded to the drug could provide the company and regulators with important information regarding how to prescribe and administer it. Genzyme approached the Children’s Hospital of Philadelphia about serving as a trial site. The institution was uncomfortable with the appearance of enrollment bias and declined.

The Crowleys were crushed by the news. John cast about for an alternative means of getting medicine to his children. He dreamed one night of simply taking enzyme from the company to treat Megan and Patrick himself. He knew better than to do that, but then, without consulting his colleagues, arranged for a sibling trial to be conducted at the University of Florida. Company officials were incensed by the maverick gambit, and problems in the trial design forced them to cancel it. CEO Henri Termeer commented, “You can’t blame the guy for trying, but in the end, we had the systems in place to rein him in.”

Genzyme made another attempt to set up a sibling trial, this time at St. Peter’s University Hospital in New Brunswick, New Jersey. Crowley resigned from Genzyme in order to eliminate any potential conflict of interest. The protocol was approved. In January of 2003, John pressed a button at St. Peter’s to begin the infusion therapy for Megan and Patrick. The Genzyme ERT saved their lives.

Today, Megan and Patrick are both in public high school in Princeton, NJ, a sophomore and freshman, respectively. Their muscles remain weak and they are still dependent on ventilators, wheelchairs, back-up batteries, and nurses, but they are stable and healthier. Their hearts, once dangerously enlarged, have returned to normal size. In April 2006, the FDA concluded its review of clinical evidence on the safety and efficacy of Genzye’s enzyme replacement therapy for Pompe disease, and approved sales of the product under the trade name Myozyme®. When Megan Crowley was diagnosed with Pompe disease in 1998, her parents were told, ‘There is no treatment.’ Now, thanks in part to John Crowley’s determined efforts, many families dealing with diagnoses of rare genetic disorders are told, ‘Here is what we have for you…’

AMICUS THERAPEUTICS

Crowley’s short but pressurized stints at Novazyme and Genzyme supplied him with valuable experience as a biotech executive. He felt equipped to do more in the field. For a time, he worked in the Princeton office of the venture capital firm, Domain Associates, evaluating life science investment opportunities. He also remained active in rare disease advocacy. In the summer of 2004, Crowley was offered the CEO post at Amicus Therapeutics, a newly-seeded startup that planned to develop ‘next-generation’ therapies for LSDs. He declined, but agreed to serve on the company’s board of directors.

Amicus was operating in an incubator space in New Jersey with a handful of employees. The firm made steady progress in animal studies over the course of the year. By December 2004, Crowley was ready to join. He had become convinced that the company’s technology represented the next best chance to improve health and quality of life for patients with Pompe disease and other rare disorders. Myozyme was a life-saving therapy, but not a perfect drug, and not a cure. Amicus had a chance to elevate the field once more. Its R&D teams were working to extend pioneering research conducted by company co-founders Robert J. Desnick and Jian-Qiang Fan, geneticists and leading authorities on LSDs at New York University’s Mount Sinai School of Medicine.

In many LSDs, the central problem is the manufacture of misfolded, dysfunctional enzymes. Amicus is developing orally-administered small molecule ‘chaperones’ that target, bind, and stabilize misshapen proteins, and facilitate proper folding. The goal is to restore rather than substitute, in order to circumvent delivery and immunogenicity problems that continue to plague many ERTs. Chaperone molecules can be employed in conjunction with ERTs, but also as independent monotherapies. Amicus and development partner GlaxoSmithKline are currently testing a chaperone for Fabry disease (migalastat HCl) as a monotherapy in a pivotal Phase III clinical trial. Preliminary results are expected later this year. A chaperone-ERT combination product for Pompe disease is in Phase II testing, and the company is investigating applications for Gaucher and other orphan diseases as well.

Crowley’s work at Amicus is no longer driven by the desperation and intense emotion that motivated his entry into the field at Novazyme and his direction of the Pompe disease program at Genzyme. He remains unapologetic, however, about occasionally subordinating objectivity to passion and sentiment in organizational leadership and strategic decision-making. To recreate the patient-centered culture that he established at Novazyme, Crowley supplements standard mission statement ideals (teamwork, communication, and excellence, for example -- organizational habits or characteristics that contribute directly to the efficient execution of operational objectives) with others that are unique to Amicus. In the articulation of core values for Amicus, he unabashedly affirms compassion and humanitarian service, virtues not routinely viewed as assets in the competitive worlds of science and business, and sometimes regarded as liabilities.

In practice, Amicus works closely with patients and rare disease advocacy organizations. The company disseminates information on disease management, treatment options, access to experimental therapies, and clinical trial enrollments. It connects patients and families with support services and resources that can help them interact productively with medical professionals, negotiate insurance and reimbursement mazes, and effectively manage various daily coping challenges. The company is also engaged in broader forms of outreach including public education, public policy formation, and community-building among rare disease advocacy groups. In organizing these various functions, Amicus draws on the practical wisdom of its chief executive, the father of two children suffering from a severely disabling lysosomal storage disorder.

THE ORPHAN DRUG ACT

The conflicts of interest and commitment that Crowley wrestles with in his professional life are reproduced on broader scales in political frictions and moral dilemmas that rare diseases generate in society at large. Drug development is an enormously expensive undertaking. In economic terms, attending to the medical needs of small patient populations is wasteful and unsustainable. In moral terms, from a purely utilitarian point of view, it is unfair and unjust.

To allocate scarce healthcare resources for the treatment of rare diseases is to resolve – provisionally – essential tensions between equality, justice, and individual rights as social values. It favors rights. Individuals, organizations, and states treat rare diseases despite the high cost because failing to do so would constitute abandonment. The story of the Crowley family has moved mass audiences because it resonates with a broadly shared and deeply ingrained sentiment – abandonment is tragic and ethically unsettling.

The commitment of the American people to beneficence, charity, and medical rights was expressed materially in the Orphan Drug Act (ODA) of 1983. The ODA apportions grants to support research on new treatments for rare ailments and tax credits for offset the costs of clinical testing. Manufacturers of orphan drugs do not have to pay FDA user fees, and orphan products are usually given expedited reviews; regulatory delays have been minimized. The clinching incentive furnished by the Act is the provision of seven years of exclusive marketing rights to manufacturers of orphan drugs. Without the ODA, it would be economically infeasible for biotech and pharmaceutical companies to develop new treatments for rare diseases. Thanks to this piece of legislation, there are more than 350 FDA-approved orphan drugs on the market in the United States, products that ease pain and suffering and frequently save lives in previously neglected patient populations.

John Crowley has been a vocal champion and defender of the ODA. In 2010, he testified on behalf of the Biotechnology Industry Organization (BIO) before the Senate Committee on Health, Education, Labor and Pensions. He reminded the august body that the Orphan Drug Act has effectively stimulated innovative R&D projects, improved the lives of millions of patients and families, and helped to launch a new industry. Crowley went on argue that if these benefits are to be maintained in increasingly challenging economic conditions, and in the era of genomics – in which the identification of ‘ultra-rare’ diseases will almost certainly accelerate – the incentives offered by the Orphan Drug Act need to be updated. Our beneficence will be tested again.

 

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