Your Prescription Is Ready for Download
A close up of a doctor pointing at a smart phone, heralding the new era of prescription digital therapeutics.
You may be familiar with Moore's Law, the prediction made by Intel co-founder Gordon Moore that computer chips would get faster and cheaper with each passing year. That's been borne out by the explosive growth of the tech industry, but you may not know that there is an inverse Moore's Law for drug development.
What if there were a way to apply the fast-moving, low-cost techniques of software development to drug discovery?
Eroom's Law—yes that's "Moore" spelled backward—is the observation that drug discovery has become slower and more expensive over time, despite technological improvements. And just like Moore's Law, it's been borne out by experience—from the 1950s to today, the number of drugs that can be developed per billion dollars in spending has steadily decreased, contributing to the continued growth of health care costs.
But what if there were a way to apply the fast-moving, low-cost techniques of software development to drug discovery? That's what a group of startups in the new field of digital therapeutics are promising. They develop apps that are used—either on their own or in conjunction with conventional drugs—to treat chronic disorders like addiction, diabetes and mental health that have so far resisted a pharmaceutical approach. Unlike the thousands of wellness and health apps that can be downloaded to your phone, digital therapeutics are developed and are meant to be used like drugs, complete with clinical trials, FDA approval and doctor prescriptions.
The field is hot—in 2017 global investment in digital therapeutics jumped to $11.5 billion, a fivefold increase from 2012, and major pharma companies like Novartis are developing their own digital products or partnering with startups. One such startup is the bicoastal Pear Therapeutics. Last month, Pear's reSET-O product became the first digital therapeutic to be approved for use by the millions of Americans who struggle with opioid use disorder, and the company has other products addressing addiction and mental illness in the pipeline.
I spoke with Dr. Corey McCann, Pear's CEO, about the company's efforts to meld software and medicine, designing clinical trials for an entirely new kind of treatment, and the future of digital therapeutics.
The interview has been edited and condensed for clarity and length.
"We're looking at conditions that currently can't be cured with drugs."
BRYAN WALSH: What makes a digital therapeutic different than a wellness app?
COREY MCCANN: What we do is develop therapeutics that are designed to be used under the auspices of a physician, just as a drug developed under good manufacturing would be. We do clinical studies for both safety and efficacy, and then they go through the development process you'd expect for a drug. We look at the commercial side, at the role of doctors. Everything we do is what would be done with a traditional medical product. It's a piece of software developed like a drug.
WALSH: What kind of conditions are you first aiming to treat with digital therapeutics?
MCCANN: We're looking at conditions that currently can't be cured with drugs. A good example is our reSET product, which is designed to treat addiction to alcohol, cannabis, stimulants, cocaine. There really aren't pharmaceutical products that are approved to treat people addicted to these substances. What we're doing is functional therapy, the standard of care for addiction treatment, but delivered via software. But we can also work with medication—our reSET-O product is a great example. It's for patients struggling with opioid addiction, and it's delivered in concert with the drug buprenorphine.
WALSH: Walk me through what the patient experience would be like for someone on a digital therapeutic like reSET.
MCCANN: Imagine you're a patient who has been diagnosed with cocaine addiction by a doctor. You would then receive a prescription for reSET during the same office visit. Instead of a pharmacy, the script is sent to the reSET Connect Patient Service Center, where you are onboarded and given an access code that is used to unlock the product after downloading it onto your device. The product has 60 different modules—each one requiring about a 10 to 15-minute interaction—all derived from a form of cognitive behavioral therapy called community reinforcement approach. The treatment takes place over 90 days.
"The patients receiving the digital therapeutic were more than twice as likely to remain abstinent as those receiving standard care."
Patients report their substance abuse, cravings and triggers, and they are also tested on core proficiencies through the therapy. Physicians have access to all of their data, which helps facilitate their one-on-one meetings. We know from regular urine tests how effective the treatment is.
WALSH: What kind of data did you find when you did clinical studies on reSET?
MCCANN: We had 399 patients in 10 centers taking part in a randomized clinical trial run by the National Institute on Drug Abuse. Every patient enrolled in the study had an active substance abuse disorder. The study was randomized so that patients either received the best current standard of care, which is three hours a week of face-to-face therapy, or they received the digital therapeutic. The primary endpoint was abstinence in weeks 9 to 12—if the patient had a single dirty urine screen in the last month, they counted as a failure.
In the end, the patients receiving the digital therapeutic were more than twice as likely to remain abstinent as those receiving standard care—40 percent versus 17 percent. Those receiving reSET were also much more likely to remain in treatment through the entire trial.
WALSH: Why start by focusing your first digital therapeutics on addiction?
MCCANN: We have tried to build a company that is poised to make a difference in medicine. If you look at addiction, there is little to nothing in the drug pipeline to address this. More than 30 million people in the U.S. suffer from addiction disorders, and not only is efficacy a concern, but so is access. Many patients aren't able to receive anything like the kind of face-to-face therapy our control group received. So we think digital therapeutics can make a difference there as well.
WALSH: reSET was the first digital therapeutic approved by the FDA to treat a specific disorder. What has the approval process been like?
MCCANN: It's been a learning process for all involved, including the FDA. Our philosophy is to work within the clinical trials structure, which has specific disease targets and endpoints, and develop quality software, and bring those two strands together to generate digital therapeutics. We now have two products that have been FDA-approved, and four more in development. The FDA is appropriately cautious about all of this, balancing the tradeoff between patient risk and medical value. As we see it, our company is half tech and half biotech, and we follow regulatory trials that are as rigorous as they would be with any drug company.
"This is a new space, but when you look back in 10 years there will be an entire industry of prescription digital therapeutics."
WALSH: How do you balance those two halves, the tech side and the biology side? Tech companies are known for iterating rapidly and cheaply, while pharma companies develop drugs slowly and expensively.
MCCANN: This is a new space, but when you look back in 10 years there will be an entire industry of prescription digital therapeutics. Right now for us we're combining the rigor of the pharmaceutical model with the speed and agility of a tech company. Our product takes longer to develop than an unverified health app, but less time and with less clinical risk than a new molecular entity. This is still a work in progress and not a day goes by where we don't notice the difference between those disciplines.
WALSH: Who's going to pay for these treatments? Insurers are traditionally slow to accept new innovations in the therapeutic space.
MCCANN: This is just like any drug launch. We need to show medical quality and value, and we need to get clinician demand. We want to focus on demonstrating as many scripts as we can in 2019. And we know we'll need to be persistent—we live in a world where payers will say no to anything three times before they say yes. Demonstrating value is how you get there.
WALSH: Is part of that value the possibility that digital therapeutics could be much cheaper than paying someone for multiple face-to-face therapy sessions?
MCCANN: I believe the cost model is very compelling here, especially when you can treat diseases that were not treatable before. That is something that creates medical value. Then you have the data aspect, which makes our product fundamentally different from a drug. We know everything about every patient that uses our product. We know engagement, we can push patient self-reports to clinicians. We can measure efficiency out in the real world, not just in a measured clinical trial. That is the holy grail in the pharma world—to understand compliance in practice.
WALSH: What's the future of digital therapeutics?
MCCANN: In 10 years, what we think of as digital medicine will just be medicine. This is something that will absolutely become standard of care. We are working on education to help partners and payers figure out where go from here, and to incorporate digital therapeutics into standard care. It will start in 2019 and 2020 with addiction medicine, and then in three to five years you'll see treatments designed to address disorders of the brain. And then past the decade horizon you'll see plenty of products that aim at every facet of medicine.
New Podcast: Dr. Gigi Gronvall Addresses the Risk of Delta and COVID-19’s Possible Origins
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.
Listen to the episode:
Why Neglected Tropical Diseases Should Matter to Americans
Kissing bugs can carry a parasite called Trypanosoma cruzi, which causes Chagas disease.
Daisy Hernández was five years old when one of her favorite aunts was struck with a mysterious illness. Tía Dora had stayed behind in Colombia when Daisy's mother immigrated to Union City, New Jersey. A schoolteacher in her late 20s, she began suffering from fevers and abdominal pain, and her belly grew so big that people thought she was pregnant. Exploratory surgery revealed that her large intestine had swollen to ten times its normal size, and she was fitted with a colostomy bag. Doctors couldn't identify the underlying problem—but whatever it was, they said, it would likely kill her within a year or two.
Tía Dora's sisters in New Jersey—Hernández's mother and two other aunts—weren't about to let that happen. They pooled their savings and flew her to New York City, where a doctor at Columbia-Presbyterian Medical Center with a penchant for obscure ailments provided a diagnosis: Chagas disease. Transmitted by the bite of triatomine insects, commonly known as kissing bugs, Chagas is endemic in many parts of Latin America. It's caused by the parasite Trypanoma cruzi, which usually settles in the heart, where it feeds on muscle tissue. In some cases, however, it attacks the intestines or esophagus. Tía Dora belonged to that minority.
In 1980, U.S. immigration laws were more forgiving than they are today. Tía Dora was able to have surgery to remove a part of her colon, despite not being a citizen or having a green card. She eventually married a legal resident and began teaching Spanish at an elementary school. Over the next three decades, she earned a graduate degree, built a career, and was widowed. Meanwhile, Chagas continued its slow devastation. "Every couple of years, we were back in the hospital with her," Hernández recalls. "When I was in high school, she started feeling like she couldn't swallow anything. It was the parasite, destroying the muscles of her esophagus."
When Tía Dora died in 2010, at 59, her niece was among the family members at her bedside. By then, Hernández had become a journalist and fiction writer. Researching a short story about Chagas disease, she discovered that it affected an estimated 6 million people in South America, Central America, and Mexico—as well as 300,000 in the United States, most of whom were immigrants from those places. "I was shocked to learn it wasn't rare," she says. "That made me hungry to know more about this disease, and about the families grappling with it."
Hernández's curiosity led her to write The Kissing Bug, a lyrical hybrid of memoir and science reporting that was published in June. It also led her to another revelation: Chagas is not unique. It's among the many maladies that global health experts refer to as neglected tropical diseases—often-disabling illnesses that afflict 1.7 billion people worldwide, while getting notably less attention than the "big three" of HIV/AIDs, malaria, and tuberculosis. NTDs cause fewer deaths than those plagues, but they wreak untold suffering and economic loss.
Shortly before Hernández's book hit the shelves, the World Health Organization released its 2021-2030 roadmap for fighting NTDs. The plan sets targets for controlling, eliminating, or eradicating all the diseases on the WHO's list, through measures ranging from developing vaccines to improving healthcare infrastructure, sanitation, and access to clean water. Experts agree that for the campaign to succeed, leadership from wealthy nations—particularly the United States—is essential. But given the inward turn of many such countries in recent years (evidenced in movements ranging from America First to Brexit), and the continuing urgency of the COVID-19 crisis, public support is far from guaranteed.
As Hernández writes: "It is easier to forget a disease that cannot be seen." NTDs primarily affect residents of distant lands. They kill only 80,000 people a year, down from 204,000 in 1990. So why should Americans to bother to look?
Breaking the circle of poverty and disease
The World Health Organization counts 20 diseases as NTDs. Along with Chagas, they include dengue and chikungunya, which cause high fevers and agonizing pain; elephantiasis, which deforms victims' limbs and genitals; onchocerciasis, which causes blindness; schistosomiasis, which can damage the heart, lungs, brain, and genitourinary system; helminths such as roundworm and whipworm, which cause anemia, stunted growth, and cognitive disabilities; and a dozen more. Such ailments often co-occur in the same patient, exacerbating each other's effects and those of illnesses such as malaria.
NTDs may be spread by insects, animals, soil, or tainted water; they may be parasitic, bacterial, viral, or—in the case of snakebite envenoming—non-infectious. What they have in common is their longtime neglect by public health agencies and philanthropies. In part, this reflects their typically low mortality rates. But the biggest factor is undoubtedly their disempowered patient populations.
"These diseases occur in the setting of poverty, and they cause poverty, because of their chronic and debilitating effects," observes Peter Hotez, dean of the National School of Tropical Medicine at Baylor University and co-director of the Texas Children's Hospital for Vaccine Development. And historically, the everyday miseries of impoverished people have seldom been a priority for those who set the global health agenda.
That began to change about 20 years ago, when Hotez and others developed the conceptual framework for NTDs and early proposals for combating them. The WHO released its first roadmap in 2012, targeting 17 NTDs for control, elimination, or eradication by 2020. (Rabies, snakebite, and dengue were added later.) Since then, the number of people at risk for NTDs has fallen by 600 million, and 42 countries have eliminated at least one such disease. Cases of dracunculiasis—known as Guinea worm disease, for the parasite that creates painful blisters in a patient's skin—have dropped from the millions to just 27 in 2020.
Yet the battle is not over, and the COVID-19 pandemic has disrupted prevention and treatment programs around the globe.
A new direction — and longstanding obstacles
The WHO's new roadmap sets even more ambitious goals for 2030. Among them: reducing by 90 percent the number of people requiring treatment for NTDs; eliminating at least one NTD in another 100 countries; and fully eradicating dracunculiasis and yaws, a disfiguring skin infection.
The plan also places an increased focus on "country ownership," relying on nations with high incidence of NTDs to design their own plans based on local expertise. "I was so excited to see that," says Kristina Talbert-Slagle, director of the Yale College Global Health Studies program. "No one is a better expert on how to address these situations than the people who deal with it day by day."
Another fresh approach is what the roadmap calls "cross-cutting" targets. "One of the really cool things about the plan is how much it emphasizes coordination among different sectors of the health system," says Claire Standley, a faculty member at Georgetown University's Center for Global Health Science and Security. "For example, it explicitly takes into account the zoonotic nature of many neglected tropical diseases—the fact that we have to think about animal health as well as human health when we tackle NTDs."
Whether this grand vision can be realized, however, will depend largely on funding—and that, in turn, is a question of political will in the countries most able to provide it. On the upside, the U.S. has ended its Trump-era feud with the WHO. "One thing that's been really encouraging," says Standley, "has been the strong commitment toward global cooperation from the current administration." Even under the previous president, the U.S. remained the single largest contributor to the global health kitty, spending over $100 million annually on NTDs—six times the figure in 2006, when such financing started.
On the downside, America's outlay has remained flat for several years, and the Biden administration has so far not moved to increase it. A "back-of-the-envelope calculation," says Hotez, suggests that the current level of aid could buy medications for the most common NTDs for about 200 million people a year. But the number of people who need treatment, he notes, is at least 750 million.
Up to now, the United Kingdom—long the world's second-most generous health aid donor—has taken up a large portion of the slack. But the UK last month announced deep cuts in its portfolio, eliminating 102 previously supported countries and leaving only 34. "That really concerns me," Hotez says.
The struggle for funds, he notes, is always harder for projects involving NTDs than for those aimed at higher-profile diseases. His lab, which he co-directs with microbiologist Maria Elena Bottazzi, started developing a COVID-19 vaccine soon after the pandemic struck, for example, and is now in Phase 3 trials. The team has been working on vaccines for Chagas, hookworm, and schistosomiasis for much longer, but trials for those potential game-changers lag behind. "We struggle to get the level of resources needed to move quickly," Hotez explains.
Two million reasons to care
One way to prompt a government to open its pocketbook is for voters to clamor for action. A longtime challenge with NTDs, however, has been getting people outside the hardest-hit countries to pay attention.
The reasons to care, global health experts argue, go beyond compassion. "When we have high NTD burden," says Talbert-Slagle, "it can prevent economic growth, prevent innovation, lead to more political instability." That, in turn, can lead to wars and mass migration, affecting economic and political events far beyond an affected country's borders.
Like Hernández's aunt Dora, many people driven out of NTD-wracked regions wind up living elsewhere. And that points to another reason to care about these diseases: Some of your neighbors might have them. In the U.S., up to 14 million people suffer from neglected parasitic infections—including 70,000 with Chagas in California alone.
When Hernández was researching The Kissing Bug, she worried that such statistics would provide ammunition to racists and xenophobes who claim that immigrants "bring disease" or exploit overburdened healthcare systems. (This may help explain some of the stigma around NTDs, which led Tía Dora to hide her condition from most people outside her family.) But as the book makes clear, these infections know no borders; they flourish wherever large numbers of people lack access to resources that most residents of rich countries take for granted.
Indeed, far from gaming U.S. healthcare systems, millions of low-income immigrants can't access them—or must wait until they're sick enough to go to an emergency room. Since Congress changed the rules in 1996, green card holders have to wait five years before they can enroll in Medicaid. Undocumented immigrants can never qualify.
Closing the great divide
Hernández uses a phrase borrowed from global health crusader Paul Farmer to describe this access gap: "the great epi divide." On one side, she explains, "people will die from cancer, from diabetes, from chronic illnesses later in life. On the other side of the epidemiological divide, people are dying because they can't get to the doctor, or they can't get medication. They don't have a hospital anywhere near them. When I read Dr. Farmer's work, I realized how much that applied to neglected diseases as well."
When it comes to Chagas disease, she says, the epi divide is embodied in the lack of a federal mandate for prenatal or newborn screening. Each year, according to the Centers for Disease Control and Prevention, up to 300 babies in the U.S. are born with Chagas, which can be passed from the mother in utero. The disease can be cured with medication if treated in infancy. (It can also be cured in adults in the acute stage, but is seldom detected in time.) Yet the CDC does not require screening for Chagas—even though newborns are tested for 15 diseases that are less common. According to one study, it would be 10 times cheaper to screen and treat babies and their mothers than to cover the costs related to the illness in later years. Few states make the effort.
The gap that enables NTDs to persist, Hernández argues, is the same one that has led to COVID-19 death rates in Black and Latinx communities that are double those elsewhere in America. To close it, she suggests, caring is not enough.
"When I was working on my book," she says, "I thought about HIV in the '80s, when it had so much stigma that no one wanted to talk about it. Then activists stepped up and changed the conversation. I thought a lot about breast cancer, which was stigmatized for years, until people stepped forward and started speaking out. I thought about Lyme disease. And it wasn't only patients—it was also allies, right? The same thing needs to happen with neglected diseases around the world. Allies need to step up and make demands on policymakers. We need to make some noise."