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Friday, July 12, 2024

The Aftermath of a 'Miracle Cure' for a Rare Cancer

You really can't understand all the excitement surrounding personalized medicine without knowing a little bit about Gleevec. And once you know the full story of Gleevec, you really can’t help but see much of that excitement as wild and even dangerous exaggeration.

Personalized medicine (sometimes it’s also called “precision medicine”) works by tailoring health care to our genomes. Traditional, one-size-fits-all medicine, the criticism goes, treats us all as if we’re the same, but personalized medicine tracks the molecular-genetic differences between us to deliver the right treatment, to the right patient, at the right time. The approach has gotten its most purchase in the management of cancers and rare diseases, but champions foresee a future where it spreads out across all facets of health care, revolutionizing the treatment of everything from diabetes and cardiovascular disease to asthma and rheumatoid arthritis. A big part of the enthusiasm is economic in nature. Rather than sending patients off on costly and frustrating trial-and-error odysseys, advocates of precision medicine see its ability to find the right gene-treatment matches from the beginning of care as a way to reel in the skyrocketing costs of modern health care.

The poster child for this personalized medicine revolution is Gleevec. The US Food and Drug Administration (FDA) approved Gleevec in 2001 for the treatment of chronic myelogenous leukemia. It’s a rare blood cancer that arises when a person’s bone marrow produces excessive white blood cells, which eventually overwhelm their body, leading to infections, an enlarged spleen, uncontrolled bleeding, oxygen starvation, heart failure. Treatments existed prior to 2001, but they were risky, incredibly uncomfortable, and didn’t always work. For the 5,000 to 10,000 people in the United States diagnosed each year, life expectancy was less than five years.

Biomedical researchers had known since the 1950s that patients with chronic myelogenous leukemia had an unusual, small chromosome, which came to be called the “Philadelphia chromosome” as a reference to the city where the discovery was made. Subsequent research revealed that patients wound up with the Philadelphia chromosome as a result of a rare translocation event wherein chromosome 9 and chromosome 22 mistakenly swapped segments during cell division. That insight directed attention to the place where chromosomes 9 and 22 joined up, revealing the molecular source of the problem. The segment of chromosome 9 latched on to 22 in such a way that a gene carried along for the ride was set in overdrive, producing an enzyme that stimulated uncontrolled cell growth in the bone marrow.

The discovery of Gleevec is the stuff of legends. Brian Druker, an oncologist at Oregon Health & Science University in the 1990s, was eager to develop a treatment for his patients with chronic myelogenous leukemia, and his research showed that the drug giant Novartis had a chemical compound—STI-571—which looked promising because of its ability to target the rogue enzyme and stop the cancerous cascade that followed. Novartis executives weren’t enthusiastic about investing in a drug that would treat so few people, but Druker eventually convinced them to let him test it on humans. The first clinical trial started in 1998, when STI-571 was administered to about 30 people who were coming to the end of their battle with chronic myelogenous leukemia. The results that came in just months later were like nothing that oncologists had ever seen. Every participant responded positively to the drug, with only moderate side effects. Over the next two years, the drug was given to thousands of patients, the vast majority of whom saw their white blood cell counts return to normal.

Novartis submitted its application to the FDA in early 2001 and 10 weeks later—record time—Gleevec was approved. Gleevec was hailed in the press as a “smart bomb” and a “miracle cure.” The tiny pills appeared on the cover of Time magazine under the line, “There is new ammunition in the war against cancer. These are the bullets.” It inspired episodes of prime-time dramas Law & Order and The West Wing.

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Gleevec was approved just as the Human Genome Project was wrapping up, and it served as Exhibit A for those who were looking for evidence that the era of gene-guided health care had arrived. Francis Collins, director of the Human Genome Project, spotlighted Gleevec at the project’s celebratory conclusion. Gleevec was remarkable, but it was not exceptional; rather, Collins predicted a future where any disease you could name had its own Gleevec.

Two decades later, Gleevec retains its vaunted status. “Before Gleevec” and “after Gleevec” has come to mark the moment when personalized medicine shifted from aspiration to reality. Patients from Druker’s early trials who are still alive serve as powerful reminders of how Gleevec “changed everything.” The president and CEO of the Leukemia & Lymphoma Society marked the 20-year anniversary of Gleevec’s FDA approval, noting, “It was the birth of precision medicine: the right drug to the right patient at the right time.”

That's the short version anyway. A closer look at what followed after the FDA approval, on the other hand, paints a different picture.

There were warning signs right away. The article in Time, after conveying the enthusiasm, concluded by pointing out that the drug sold for well over $2,000 a month. That translated into an annual cost of between $25,000 and $30,000. The Novartis CEO admitted the price was steep, but there was good reason, he countered. The existing therapies for chronic myelogenous leukemia were priced similarly. Moreover, the market for Gleevec was small, and Novartis invested $600 to 800 million in the research and development of a new drug. The higher-than-usual price tag was necessary to offset the company’s financial commitment to the lifesaving treatment; Novartis might not even make much of a profit on its new drug. The price, the CEO said, could even come down if the population of patients who took the drug expanded.

The price of Gleevec stayed in the $25,000-to-$30,000-a-year range for some time. Then something strange happened. Around 2006, the price began climbing. The market for Gleevec had indeed expanded after its release because it changed a deadly blood cancer into something that could be managed like a chronic disease, which by the Novartis CEO’s own reasoning should have brought the price down. Around the same time several other drugs that worked similarly, called “tyrosine kinase inhibitors” based on the proteins that they shut down, also came out alongside Gleevec. One, in fact, was Novartis’ own Tasigna. Economics 101 would suggest the arrival of competitors drives down prices, but the exact opposite happened. The newcomers were priced even higher than Gleevec, in the $5,000-to-7,000-a-month range. And the listed price of Gleevec gravitated up toward that of the new arrivals. Starting late in the first decade of the 21st century, the price of Gleevec steadily rose, 5 percent one year, 8 percent another, then nearly 20 percent. Patients who paid $2,200 a month in 2001 were paying triple that amount a decade later. By 2011, Novartis was making more than $4 billion annually.

The chronic myelogenous leukemia community, appalled by what was unfolding, eventually cried foul. In 2012, patients and loved ones of those with the disease posted a petition to Change.org asking members of Congress to intervene on Novartis’ price hikes. One patient who was in Druker’s original trial of STI-571 complained, “It is borderline criminal to force people to make the choice between life (being able to afford the Gleevec) and death (being financially unable to buy the drug that will save their lives).” Another supporter of the petition simply pleaded, “My grandma needs this medicine.”

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Druker and more than 100 chronic myelogenous leukemia physicians and researchers also took to the fight, penning an article for the premier hematological journal Blood in 2013 that sounded an alarm about the “unsustainable prices of cancer drugs.” Gleevec, they warned, was setting a dangerous precedent that other cancer drugs were chasing, which was normalizing profiteering in the drug industry and driving up the costs of health care.

The rising price of Gleevec was what garnered most of the critical scrutiny, but Novartis was also employing other tactics to protect and even extend its monopoly on the drug. The patent was set to expire in 2013, but the company filed for a series of extensions which moved that deadline to 2015. Then, when the patent was up, Novartis utilized a pay-for-delay strategy, the details of which were hidden behind the veil of a confidentiality settlement, paying off the manufacturer of the first approved generic to withhold distributing its version for seven months, thereby delaying its arrival until 2016.

All the while, Novartis marketing gradually directed attention toward Tasigna, saying it was even better than Gleevec, which would encourage oncologists to switch patients to a Novartis product that had years left on its patent protection.

The normal rules of economics no longer applied. That troublesome picture only became clearer when the generic version of Gleevec was released in 2016. With conventional drug markets, the arrival of generics led to significant price drops because competition drove them down. Generic Gleevec, however, arrived in the United States with a list price of about $5,000 a month, far more than what Gleevec had first fetched in 2001.

It wasn’t until 2019, when a number of generic versions became available, that the price of the lifesaving treatment for chronic myelogenous leukemia finally dropped to a reasonable rate. Novartis, by that point, had made roughly $50 billion in global sales off Gleevec. Meanwhile, the cost of treating chronic myelogenous leukemia had plateaued around 2015–2016 when the Gleevec patent expired and the first generic version came online. Physicians had indeed moved their patients over to one of the newer tyrosine kinase inhibitors like Tasigna. Chronic myelogenous leukemia, as a result, continues to be an extremely pricey diagnosis 20 years after Gleevec appeared on the market, driven in large part by the steady arrival of shockingly expensive drugs that follow the financial example set by Novartis and its magic bullet.

Druker and the other chronic myelogenous leukemia experts warned in 2013 that Gleevec was setting an unsustainable example in health care. They were right. In the two decades that followed the arrival of Gleevec, the costs of oncological therapies increased significantly. New precision medicines in oncology have a median price of $150,000 a year, the same annual price that Gleevec reached before its first generic arrived. A recent survey of oncologists found that more than two-thirds of them predicted the expanding reliance on precision medicines meant higher costs for the future of cancer care.

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All this has led to a new term in oncology: financial toxicity. Oncologists have started warning their patients about the economic implications of their care. One study found that more than 40 percent of cancer patients exhaust their entire life’s assets within two years of diagnosis. The diagnosis also makes somebody more than two and a half times more likely to go bankrupt. Right when a person needs to focus their energy on staying healthy and battling cancer, they’re hit with the additional anxiety associated with trying to stay financially afloat.

When we shift from cancers to rare diseases—the other domain where precision medicine has made therapeutic advances in the past 20 years—the numbers are even more outrageous. Zolgensma offsets the degeneration of nerve cells in children with spinal muscular atrophy. Zokinvy halts the rapid aging associated with Hutchinson-Gilford progeria syndrome. Zynteglo combats insufficient levels of hemoglobin in the blood of patients with severe beta-thalassemia. These are conditions which, like chronic myelogenous leukemia, arise from a very basic genetic mechanism, which allows for developing pharmaceutical interventions that can target those aberrant systems. But they come with a cost. Each of these drugs are listed at between $1 and 3 million dollars.

And those are the economic stakes facing patients for whom drugs like Gleevec or Zolgensma do exist for their disease. For most patients with most diseases, there simply isn’t a personalized medicine treatment available. That’s not because they just need to wait a little while longer for their Gleevec to get FDA approval. It’s because 20 years of genetic research has made it clear that most diseases don’t lend themselves to a Gleevec existing at all. Most common, complex diseases like diabetes, cardiovascular disease, asthma, and rheumatoid arthritis are not caused by a simple genetic mechanism. There are no Philadelphia chromosomes awaiting discovery for those diseases. If they existed, they would have been found already.

Let's be clear: The discovery of Gleevec is a tremendous story. The initial identification of the Philadelphia chromosome, the subsequent work to elucidate the molecular mechanism responsible for the unique blood cancer, Druker’s effort to find and test STI-571—these were heroic works of scientific genius. Patients diagnosed with chronic myelogenous leukemia today can look optimistically into their future in a way that patients a quarter-century ago could not have imagined.

The problem with personalized medicine’s poster child is not that those things are untrue. The problem is with what typically gets left out or added on to those facts.

Added on are expectations that the Gleevec story generalizes, to all cancers or even to all diseases. That’s just not the case. Personalized medicine gets clinical purchase where diseases have a known molecular-genetic cause, but those are the exception in medicine, not the norm. Suggesting otherwise risks leaving the public generally and patient populations specifically distrustful of a medical revolution that’s always just over the horizon.

Left out are the financial realities. For those rare conditions that do have a molecular-genetic cause, what makes it from biological insights to available therapies are largely controlled by private industry—pharmaceutical companies like Novartis. That means the prices of those therapies are set with corporate profit as the prime motivator, not making sure that everybody who needs some drug can get it.

Gleevec deserves its place as personalized medicine’s poster child. Understood fully, its story makes dramatically clear what we should and should not expect from that approach to health care.

Adapted from Tyranny of the Gene: Personalized Medicine and Its Threat to Public Health by James Tabery. Reprinted by permission of Alfred A. Knopf, an imprint of the Knopf Doubleday Publishing Group, a division of Penguin Random House LLC. Copyright © 2023 by James Tabery.

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