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James A. Geraghty, a board director of five NASDAQ-listed biotech companies and author, joins a conversation with Paul Hastings, CEO of Nkarta Therapeutics and Chair of the BIO Board of Directors for a Fireside Chat at the BIO International Convention on Monday, June 13 at 1 pm PT.
Geraghty’s new book, “Inside the Orphan Drug Revolution: The Promise of Patient-Centered Biotechnology,” explores the origin of the Orphan Drug Act and the impact nearly 40 years later. These biotech leaders will discuss the importance of the legislation to scientists, advocates, and entrepreneurs, BIO’s advocacy for this policy and subsequent developments, and the challenges facing orphan drugs today.
The following is an excerpt from the Foreword of Inside the Orphan Drug Revolution: The Promise of Patient-Centered Biotechnology by James A. Geraghty:
Like any expectant mother, Abbey Meyers hoped above all to have a healthy child.
Neither she nor her husband Jerry, then a military officer, had any family history of genetic diseases or any reason to expect anything unusual.
And when their son David was born in 1968, everything seemed fine. Around the time David turned two, however, he started to show some odd symptoms, like stuttering, rapid blinking, and uncontrollable movements of his arms, legs, or head.
Her pediatrician called them “tics” and said, “Don’t worry. He’ll outgrow it.”
But Abbey’s concerns grew as David’s disruptive behaviors worsened year by year. He experienced repetitive muscle tics, uncontrollable head shaking, wildly flailing arms and legs, involuntary noises, hyperactivity, and other behaviors that made daily life very difficult. In nursery school, his teacher wouldn’t tolerate his behavior.
His pediatrician still had no answers, and his disease remained undiagnosed.
Finally, one day when David was eight, Abbey was reading a Sunday newspaper magazine when she came across an article about a teenager with a strange neurological disease.
The article described a boy with a disease called Tourette’s syndrome. A neurological disorder first described in a paper by Georges de la Tourette in France in 1885, it was characterized by an onset in childhood, frequent tics, uncontrollable movements, and compulsive behaviors—and was often misdiagnosed as a psychiatric disorder.
Abbey Meyers vividly recounts the exchange that followed with her husband in her memoir, Orphan Drugs: A Global Crusade, “I sat in my chair mesmerized. I could not believe what I was reading…‘Jerry,’ I screamed. ‘Come here, I found out what’s wrong.’ Jerry rushed into the room and picked up the article. He started reading. ‘This is beyond belief,’ he said. ‘Whoever heard of a diagnosis made possible by a Sunday magazine?’ But he agreed; the article listed David’s symptoms. What to do now?”
Her answer to that question would trigger the start of the orphan drug revolution.
Abbey first took the article to her pediatrician, who agreed she might be right and referred her to a specialist, Dr. Arthur Shapiro, at New York’s Mount Sinai Hospital.
Dr. Shapiro was studying Tourette’s and, after examining David, confirmed the diagnosis. He prescribed Haldol, a powerful tranquilizer used for schizophrenia. But as another Tourette’s parent had bleakly put it, Haldol “makes a zombie out of people,” and the Meyers quickly had to take David off it.
When David turned nine, Dr. Shapiro found a way to get him a drug called pimozide that blocked dopamine receptors in the brain and appeared to help other Tourette’s patients. It was approved for sale in Europe but not yet approved in the United States; however, Dr. Shapiro was participating in a clinical trial for Tourette’s patients, and the Meyers were able to enroll David and he did well on the drug, and at school, with hardly any side effects.
The drug was being tested by McNeil Laboratories, a division of Johnson & Johnson—the giant healthcare company with an image of caring for babies and families.
But McNeil was developing the drug primarily for conditions like schizophrenia, with millions of potential customers, and executives there saw Tourette’s only as an addon. When they decided to discontinue developing trials for schizophrenia—in 1979, just a year after David began taking it—McNeil also ordered pimozide stopped in Tourette’s.
Despite desperate pleas, David and other Tourette’s patients could no longer get any.
As Abbey Meyers summarized the situation, “The pharmaceutical industry simply ignored orphan drugs. Even when an academic scientist had already discovered a treatment for a rare disease, no pharmaceutical company would manufacture it.”
“My journey in the orphan disease world began not because my son was sick, not because he had a rare disorder, but rather because the medication that eliminated his symptoms and gave him a chance to live a ‘normal’ life was suddenly unavailable to him—discontinued by the manufacturer because it was deemed not profitable enough due to the small potential number of patients who would buy the medication.”
Meyers wrote that companies then viewed rare disease patients as “disposable, like a paper plate that is relegated to a garbage bag after the picnic is completed”—a view sadly borne out when results later confirmed that pimozide worked in Tourette’s disease.
To redress that wrong, Abbey Meyers set out to build a coalition.
“By working together, ordinary people were able to plug an enormous hole in the healthcare system when the ‘free market’ did not address their needs. To accomplish this, they needed to attract to their cause other patients, physicians, politicians, business leaders, government employees, and millions of others throughout the world.”
This is their story, and the story of those who have joined them in plugging that hole.
Why should people care?
Most people know the names of just a handful of rare genetic diseases that have somehow been given extraordinary publicity by celebrity entertainers or athletes.
Muscular dystrophies became familiar to Americans in the 1950s through comedian Jerry Lewis’s popular telethons—and to Europeans through similar television appeals, continuing successfully in France and Italy today. ALS, amyotrophic lateral sclerosis, became famous first as Lou Gehrig’s disease when it cut horribly short the life of the legendary baseball player, and again in 2014 when a fundraising “ice bucket challenge,” championed by popular college baseball star Pete Frates, went viral. Cystic fibrosis is known to many through the work of NFL star Boomer Esiason and his son Gunnar.
But the great majority of genetic diseases are very little known. To most people they remain arcane, hard to understand, a little scary, and often better ignored.
Even their names can be intimidating. Many invoke an obscure, long-dead discoverer, like the nineteenth century doctors Gaucher, Fabry, or Duchenne. Others reflect nearly unpronounceable pathologies, from mucopolysaccharidosis (MPS) and familial hypercholesterolemia (FH) to metachromatic leukodystrophy (MLD) and facioscapulohumeral dystrophy (FSHD). In total they cover the alphabet comprehensively, from Aagenaes syndrome to Zuska’s disease.
Rare diseases are also called “orphan diseases,” so named because they were long abandoned (or orphaned) by a profit-driven pharmaceutical industry. Officially these are defined by laws as diseases affecting up to a certain number of patients: in the United States 200,000; in the European Union one in 2,000; and comparable numbers in other countries.
And most people think if there’s no family history of a disease, there’s no need to worry.
So why a book about orphan drugs, which by definition treat only rare diseases? Did they really trigger a revolution important enough to care about? And if so, why is that so little known?
In fact, orphan drugs have revolutionized society, for reasons ranging from the deeply personal to the broadly cultural and political.
Rare diseases deserve our attention because they’re merciless, causing families often far worse human suffering than common diseases.
And unlike many common diseases, few can be prevented or treated by a good diet or exercise.
Perhaps most importantly, a rare genetic disease could someday strike any family—and an orphan drug become of utmost urgency to anyone with a child or grandchild, niece or nephew.
Most genetic diseases are monogenic, resulting from a defective mutation in a single gene. And although they can of course “run in families,” one can equally have no prior family history.
The reason lies in the ways genetic diseases are inherited.
We each carry two copies of any gene. Someone who has one mutated copy of a gene is a carrier. When two parents each carry a mutation in one of those two copies for a recessive condition, neither shows symptoms of the disease, but each of their children has a 25% chance of inheriting the disease and a 50% chance of becoming a carrier. If one parent carries a mutation for an autosomal dominant disorder, each child of that parent has a 50% chance of inheriting the mutated gene and suffering from the condition.
In autosomal dominant diseases, such as Huntington’s or polycystic kidney diseases (PKD), a single copy of a disease-causing mutation is sufficient to cause the disease. Although a parent with that mutation usually shows symptoms of the disease, many are asymptomatic until long after having children, and a new variant mutation can sometimes occur in births with no family history of the disorder.
Autosomal recessive diseases, such as cystic fibrosis and sickle cell disease, are transmitted through recessive or “masked” genes. They are “sleeping killers,” in which two copies of a gene must be mutated to cause a disease; their effects are usually hidden in two asymptomatic carrier parents.
Finally, X-linked disorders, like hemophilia, Duchenne muscular dystrophy, and Rett syndrome, are caused by genetic defects on the X chromosome, one of the two sex chromosomes. Because women have two X chromosomes, most mothers are, again, usually disease-free carriers.
So, it is not at all uncommon for a baby to be born with a genetic disease to two parents with no family history of it.
And by the nature of genetic variability, all of us likely carry one or more mutations that can cause a genetic disease. Because we rarely know in advance when both parents carry the same defect, many devastating genetic diseases are no more predictable than, as Phil Reilly put it in Orphan: The Quest to Save Children with Rare Genetic Disorders, “an unlucky roll of the genetic dice,” which could strike any family at any birth.
In fact, according to recent estimates, we each carry an average of one to two mutations that can cause severe genetic disorders. We all know how badly we’d hope for a therapy if our family was affected.
A few of these diseases can develop unexpectedly in adulthood—one example above is FSHD —but most do strike at birth or within the first months of life. Without a swift therapeutic intervention many can lead to an early death, lifetime incapacity, or an inexorably worsening disability. About one in every three children affected by a genetic disease dies before reaching their fifth birthday.
Moreover, these diseases collectively affect far more families than most people imagine. A recent article in the American Journal of Human Genetics summarized their collective toll:
In aggregate, clinically recognized (single gene diseases) compose a substantial fraction … of known human diseases … ∼8% of live births have a genetic disorder … eight million children born worldwide each year with a … condition that is life threatening or has the potential to result in disability. In the US alone, Mendelian disorders collectively affect more than 25 million people …. Each year, more than three million children under the age of 5 years die from a birth defect, and a similar number survive with substantial morbidity. (And) each child with a genetic disorder has been estimated to cost the healthcare system a total of $5,000,000 during their lifetime.
In some cases, the costs can be even higher. Approved hemophilia therapies can cost up to $600,000 per year for an adult in the United States, or more than $20 million over the course of a lifetime.
More than 6,000 distinct monogenic diseases have now been identified, and recent analyses estimate the ultimate total to top 10,000. Although each is rare, together they afflict an estimated 25 to 30 million Americans, almost one in 10. Around the world genetic diseases collectively are thought to afflict around 300 to 350 million people, comparable to the population of the entire United States.
But despite those staggering burdens, genetic diseases are routinely misdiagnosed for years.
One recent analysis found that only 11% of children with rare genetic diseases were accurately diagnosed at first. The “diagnostic odyssey” is often excruciatingly prolonged; in a European survey of how long it took to diagnose eight rare diseases, 25% of families waited between five and 30 years for a correct diagnosis, and the initial diagnosis was incorrect in 40% of all cases.
And today, 40 years into the orphan drug revolution, an estimated 95% still lack a therapy.
So, we all have a primary stake—self interest—in seeing the orphan drug revolution flourish.
But people should also care for other important reasons.
First, orphan drugs have already transformed life for hundreds of thousands of people in the United States and around the world. Others now in development show promise to treat millions more.
Since the Orphan Drug Act’s passage in 1983, drugs have been approved by the U.S. Federal Drug Administration (FDA) for more than 900 orphan conditions versus fewer than 10 in the ten years earlier. These drugs can collectively treat more than a million people in the United States alone—keeping children alive, out of hospitals, off ventilators, and out of wheelchairs, and sparing families the hardships of 24-hour care.
By helping patients live healthier lives, these therapies have also enabled both them and their extended families to contribute productively to society economically and in many other ways.
Per the long-established principle in medicine to “treasure your exceptions,” the orphan drug revolution has also taught us much about non-rare diseases—larger indications, as they’re often called—and has had an important, and still growing, impact on finding ways to treat them.
Parkinson’s disease, Alzheimer’s disease, high cholesterol, and many other conditions that afflict millions of people are being revealed to have individual monogenic, or single-gene, subtypes, opening doors to treating more genetically complex forms afflicting millions of people.
Insights from rare disease studies are also enabling more effective use of common medicines, allowing them to be tailored to individuals who will actually benefit from them and furthering the long-sought goal of “personalized medicine.”
As the authors of one recent survey of “lessons learned from the field of rare diseases” concluded: “A large percentage of medicines do not work for the patient populations they are intended to treat. Increased knowledge regarding genomics (can help identify) groups of likely responders and non-responders.”
Technologies honed in pursuit of orphan drugs have also had much broader applications—an impact shown vividly when RNA technologies developed in treating rare diseases allowed the creation of COVID-19 vaccines with unprecedented speed. As Walter Isaacson wrote in his study of gene editing, The Code Breaker, “I began … thinking that biotechnology was the next great scientific revolution. (Seeing COVID-19) made me realize that I was understating the case.”
The orphan drug revolution has also transformed the culture of medical science.
Academic scientists who 40 years ago would never have dreamed of going “into industry” now routinely join start-ups or cofound companies. In parallel, industry-sponsored research, which was long oriented narrowly toward the development of individual drugs, has helped illuminate basic scientific principles applicable across broad fields of medical research.
Young scientists and physicians considering such paths may take special interest in the stories of others taking research not only from bench to bedside but all the way to regulatory approval.
The final reason we should care is that sustaining this revolution requires our active support.
Every year sees new laws that greatly impact both the number of new drugs developed and the number of patients able to get the ones they need. Policies supporting innovation and access can expand both, whereas misguided policies aimed at the wrong problems can constrain both.
The Orphan Drug Act came into being only because patients and families fought for it. The last section of this book explores what people who care can do to ensure it remains vibrant today.
