New drug for schizophrenia could meet desperate need for better treatments
The field of treating schizophrenia with drugs has been stuck in a long drought but, this month, a late-stage clinical trial found a new drug called KarXT could treat a range of symptoms.
Schizophrenia is a debilitating mental health condition that affects around 24 million people worldwide. Patients experience hallucinations and delusions when they develop schizophrenia, with experts referring to these new thoughts and behaviors as positive symptoms. They also suffer from negative symptoms in which they lose important functions, suffering from dulled emotions, lack of purpose and social withdrawal.
Currently available drugs can control only a portion of these symptoms but, on August 8th, Karuna Therapeutics announced its completion of a phase 3 clinical trial that found a new drug called KarXT could treat both positive and negative symptoms of schizophrenia. It could mean substantial progress against a problem that has stymied scientists for decades.
A long-standing problem
Since the 1950s, antipsychotics have been used to treat schizophrenia. People who suffer from it are thought to have too much of a brain chemical called dopamine, and antipsychotics work by blocking dopamine receptors in the brain. They can be effective in treating positive symptoms but have little impact on the negative ones, which can be devastating for a patient’s quality of life, making it difficult to maintain employment and have successful relationships. About 30 percent of schizophrenia patients don't actually respond to antipsychotics at all. Current drugs can also have adverse side effects including elevated cholesterol, high blood pressure, diabetes and movements that patients cannot control.
The recent clinical trial heralds a new treatment approach. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” says Andrew Miller, COO of Karuna.
Scientists have been looking to develop alternatives. However, “the field of drug treatment of schizophrenia is currently in the doldrums,” says Peter McKenna, a senior researcher at FIDMAG Research Foundation in Spain which specialises in mental health.
In the 2000s there was a major push to target a brain receptor for a chemical called glutamate. Evidence suggested that this receptor is abnormal in the brains of schizophrenia patients, but attempts to try glutamate failed in clinical trials.
After that, many pharmaceutical companies dropped out of the race for a more useful treatment. But some companies continued to search, such as Karuna Therapeutics, led by founder and Chief Operating Officer Andrew Miller and CEO Steve Paul. The recent clinical trial suggests their persistence has led to an important breakthrough with their drug, KarXT. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” Miller says.
How it works
Neurotransmitters are chemical messengers that pass signals between neurons. To work effectively, neurotransmitters need a receptor to bind to. A neurotransmitter called acetylcholine seems to be especially important in schizophrenia. It interacts with sites called muscarinic receptors, which are involved in the network of nerves that calm your body after a stressful event. Post mortem studies in people with schizophrenia have shown that two muscarinic receptors in the brain, the M1 and M4 receptors, are activated at unusually low levels because they don’t receive enough signals from acetylcholine.
The M4 receptor appears to play a role in psychosis. The M1 receptor is also associated with psychosis but is primarily thought to be involved in cognition. KarXT, taken orally, works by activating both of these receptors to signal properly. It is this twofold action that seems to explain its effectiveness. “[The drug’s] design enables the preferential stimulation of these muscarinic receptors in the brain,” Miller says.
How it developed
It all started in the early 1990s when Paul was at pharmaceutical company Eli Lilly. He discovered that Xanomeline, the drug they were testing on Alzheimer's patients, had antipsychotic effects. It worked by stimulating M1 and M4 receptors, so he and his colleagues decided to test Xanomeline on schizophrenia patients, supported by research on the connection between muscarinic receptors and psychosis. They found that Xanomeline reduced both positive and negative symptoms.
Unfortunately, it also caused significant side effects. The problem was that stimulating the M1 and M4 receptors in the brain also stimulated muscarinic receptors in the body that led to severe vomiting, diarrhea and even the temporary loss of consciousness.
In the end, Eli Lilly discontinued the clinical trials for the drug, but Miller set up Karuna Therapeutics to develop a solution. “I was determined to find a way to harness the therapeutic benefit demonstrated in studies of Xanomeline, while eliminating side effects that limited its development,” Miller says.
He analysed over 7,000 possible ways of mixing Xanomeline with other agents before settling on KarXT. It combines Xanomeline with a drug called Trospium Chloride, which blocks muscarinic receptors in the body – taking care of the side effects such as vomiting – but leaves them unblocked in the brain. Paul was so excited by Miller’s progress that he joined Karuna after leaving Eli Lilly and founding two previous startups.
“It's a very important approach,” says Rick Adams, Future Leaders Fellow in the Institute of Cognitive Neuroscience and Centre for Medical Image Computing at University College London. “We are in desperate need of alternative drug targets and this target is one of the best. There are other alternative targets, but not many are as close to being successful as the muscarinic receptor drug.”
Clinical Trial
Following a successful phase 2 clinical trial in 2019, the most recent trial involved 126 patients who were given KarXT, and 126 who were given a placebo. Compared to the placebo, patients taking KarXT had a significant 9.6 point reduction in the positive and negative syndrome scale (PANSS), the standard for rating schizophrenic symptoms.
KarXT also led to statistically significant declines in positive and negative symptoms compared to the placebo. “The results suggest that KarXT could be a potentially game-changing option in the management of both positive and negative symptoms of schizophrenia,” Miller says.
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, is optimistic about the side effects but highlights the need for more safety trials.
McKenna, the researcher at FIDMAG Foundation, agrees about the drug’s potential. “The new [phase 3] study is positive,” he says. “It is reassuring that one is not dealing with a drug that works in one trial and then inexplicably fails in the next one.”
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, said the drug is an unprecedented step forward. “KarXT is one of the first drugs with a novel mechanism of action to show promise in clinical trials.”
Even though the drug blocks muscarine receptors in the body, some patients still suffered from adverse side effects like vomiting, dizziness and diarrhea. But in general, these effects were mild to moderate, especially compared to dopamine-blocking antipsychotics or Xanomeline on its own.
McCutcheon is optimistic about the side effects but highlights the need for more safety trials. “The trial results suggest that gastrointestinal side effects appear to be manageable,” he says. “We know, however, from previous antipsychotic drugs that the full picture regarding the extent of side effects can sometimes take longer to become apparent to clinicians and patients. Careful ongoing assessment during a longer period of treatment will therefore be important.”
The Future
The team is currently conducting three other trials to evaluate the efficacy and long-term safety of KarXT. Their goal is to receive FDA approval next year.
Karuna is also conducting trials to evaluate the effectiveness of KarXT in treating psychosis in patients suffering from Alzheimer’s.
The big hope is that they will soon be able to provide a radically different drug to help many patients with schizophrenia. “We are another step closer to potentially providing the first new class of medicine in more than 50 years to the millions of people worldwide living with schizophrenia,” says Miller.
Scientists Envision a Universal Coronavirus Vaccine
Dr. Deborah Fuller, a professor of microbiology at the Washington University School of Medicine, in her lab.
With several companies progressing through Phase III clinical trials, the much-awaited coronavirus vaccines may finally become reality within a few months.
But some scientists question whether these vaccines will produce a strong and long-lasting immunity, especially if they aren't efficient at mobilizing T-cells, the body's defense soldiers.
"When I look at those vaccines there are pitfalls in every one of them," says Deborah Fuller, professor of microbiology at the Washington University School of Medicine. "Some may induce only transient antibodies, some may not be very good at inducing T-cell responses, and others may not immunize the elderly very well."
Generally, vaccines work by introducing an antigen into the body—either a dead or attenuated pathogen that can't replicate, or parts of the pathogen or its proteins, which the body will recognize as foreign. The pathogens or its parts are usually discovered by cells that chew up the intruders and present them to the immune system fighters, B- and T-cells—like a trespasser's mug shot to the police. In response, B-cells make antibodies to neutralize the virus, and a specialized "crew" called memory B-cells will remember the antigen. Meanwhile, an army of various T-cells attacks the pathogens as well as the cells these pathogens already infected. Special helper T-cells help stimulate B-cells to secrete antibodies and activate cytotoxic T-cells that release chemicals called inflammatory cytokines that kill pathogens and cells they infected.
"Each of these components of the immune system are important and orchestrated to talk to each other," says professor Larry Corey, who studies vaccines and infectious disease at Fred Hutch, a non-profit scientific research organization. "They optimize the assault of the human immune system on the complexity of the viral, bacterial, fungal and parasitic infections that live on our planet, to which we get exposed."
Despite their variety, coronaviruses share certain common proteins and other structural elements, Fuller explains, which the immune system can be trained to identify.
The current frontrunner vaccines aim to train our body to generate a sufficient amount of antibodies to neutralize the virus by shutting off its spike proteins before it enters our cells and begins to replicate. But a truly robust vaccine should also engender a strong response from T-cells, Fuller believes.
"Everyone focuses on the antibodies which block the virus, but it's not always 100 percent effective," she explains. "For example, if there are not enough titers or the antibody starts to wane, and the virus does get into the cells, the cells will become infected. At that point, the body needs to mount a robust T-cytotoxic response. The T-cells should find and recognize cells infected with the virus and eliminate these cells, and the virus with them."
Some of the frontrunner vaccine makers including Moderna, AstraZeneca and CanSino reported that they observed T-cell responses in their trials. Another company, BioNTech, based in Germany, also reported that their vaccine produced T-cell responses.
Fuller and her team are working on their own version of a coronavirus vaccine. In their recent study, the team managed to trigger a strong antibody and T-cell response in mice and primates. Moreover, the aging animals also produced a robust response, which would be important for the human elderly population.
But Fuller's team wants to engage T-cells further. She wants to try training T-cells to recognize not only SARV-CoV-2, but a range of different coronaviruses. Wild hosts, such as bats, carry many different types of coronaviruses, which may spill over onto humans, just like SARS, MERS and SARV-CoV-2 have. There are also four coronaviruses already endemic to humans. Cryptically named 229E, NL63, OC43, and HKU1, they were identified in the 1960s. And while they cause common colds and aren't considered particularly dangerous, the next coronavirus that jumps species may prove deadlier than the previous ones.
Despite their variety, coronaviruses share certain common proteins and other structural elements, Fuller explains, which the immune system can be trained to identify. "T-cells can recognize these shared sequences across multiple different types of coronaviruses," she explains, "so we have this vision for a universal coronavirus vaccine."
Paul Offit at Children's Hospitals in Philadelphia, who specializes in infectious diseases and vaccines, thinks it's a far shot at the moment. "I don't see that as something that is likely to happen, certainly not very soon," he says, adding that a universal flu vaccine has been tried for decades but is not available yet. We still don't know how the current frontrunner vaccines will perform. And until we know how efficient they are, wearing masks and keeping social distance are still important, he notes.
Corey says that while the universal coronavirus vaccine is not impossible, it is certainly not an easy feat. "It is a reasonably scientific hypothesis," he says, but one big challenge is that there are still many unknown coronaviruses so anticipating their structural elements is difficult. The structure of new viruses, particularly the recombinant ones that leap from wild hosts and carry bits and pieces of animal and human genetic material, can be hard to predict. "So whether you can make a vaccine that has universal T-cells to every coronavirus is also difficult to predict," Corey says. But, he adds, "I'm not being negative. I'm just saying that it's a formidable task."
Fuller is certainly up to the task and thinks it's worth the effort. "T-cells can cross-recognize different viruses within the same family," she says, so increasing their abilities to home in on a broader range of coronaviruses would help prevent future pandemics. "If that works, you're just going to take one [vaccine] and you'll have lifetime immunity," she says. "Not just against this coronavirus, but any future pandemic by a coronavirus."
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
New Tests Measure Your Body’s Biological Age, Offering a Glimpse into the Future of Health Care
A senior long jumper competes in the 80-84-year-old age division at the 2007 World Masters Championships Stadia (track and field competition) at Riccione Stadium in Riccione, Italy on September 6, 2007. From the book project Racing Age.
What if a simple blood test revealed how fast you're aging, and this meant more to you and your insurance company than the number of candles on your birthday cake?
The question of why individuals thrive or decline has loomed large in 2020, with COVID-19 harming people of all ages, while leaving others asymptomatic. Meanwhile, scientists have produced new measures, called aging clocks, that attempt to predict mortality and may eventually affect how we perceive aging.
Take, for example, "senior" athletes who perform more like 50-year-olds. But people over 65 are lumped into one category, whether they are winning marathons or using a walker. Meanwhile, I'm entering "middle age," a label just as vague. It's frustrating to have a better grasp on the lifecycle of my phone than my own body.
That could change soon, due to clock technology. In 2013, UCLA biostatistician Steven Horvath took a new approach to an old carnival trick, guessing people's ages by looking at epigenetics: how chemical compounds in our cells turn genetic instructions on or off. Exercise, pollutants, and other aspects of lifestyle and environment can flip these switches, converting a skin cell into a hair cell, for example. Then, hair may sprout from your ears.
Horvath's epigenetic clock approximated age within just a few years; an above-average estimate suggested fast aging. This "basically changed everything," said Vadim Gladyshev, a Harvard geneticist, leading to more epigenetic clocks and, just since May, additional clocks of the heart, products of cell metabolism, and microbes in a person's mouth and gut.
Machine learning is fueling these discoveries. Scientists send algorithms hunting through jungles of health data for factors related to physical demise. "Nothing in [the aging] industry has progressed as much as biomarkers," said Alex Zhavoronkov, CEO of Deep Longevity, a pioneer in learning-based clocks.
Researchers told LeapsMag that this tech could help identify age-related vulnerabilities to diseases—including COVID-19—and protective drugs.
Clocking disease vulnerability
In July, Yale researcher Morgan Levine found people were more likely to be hospitalized and die from COVID-19 if their aging clocks were ticking ahead of their calendar years. This effect held regardless of pre-existing conditions.
The study used Levine's biological aging clock, called PhenoAge, which is more accurate than previous versions. To develop it, she looked at data on health indices over several decades, focusing on nine hallmarks of aging—such as inflammation—that correspond to when people die. Then she used AI to find which epigenetic patterns in blood samples were strongly associated with physical aging. The PhenoAge clock reads these patterns to predict biological age; mortality goes up 62 percent among the fastest agers.
The cocktail, aimed at restoring immune function, reversed age by an average of 2.5 years, according to an epigenetic clock measurement taken before and after the intervention.
Because PhenoAge links chronic inflammation to aging and vulnerability, Levine proposed treating "inflammaging" to counter COVID-19.
Gladyshev reported similar findings, and Nir Barzilai, director of the Institute of Aging Research at Albert Einstein College of Medicine, agreed that biological age deserves greater focus. PhenoAge is an important innovation, he said, but most precise when measuring average age across large populations. Until clocks—including his blood protein version—account for differences in how individuals age, "Multi-morbidity is really the major biomarker" for a given person. Barzilai thinks individuals over 65 with two or more diseases are biologically older than their chronological age—about half the population in this study.
He believes COVID-19 efforts aren't taking stock of these differences. "The scientists are living in silos," he said, with many unaware aging has a biology that can be targeted.
The missed opportunities could be profound, especially for lower-income communities with disproportionately advanced aging. Barzilai has read eight different observational studies finding decreased COVID-19 severity among people taking metformin, the diabetes drug, which is believed to slow down the major hallmarks of biological aging, such as inflammation. Once a vaccine is identified, biologically older people could supplement it with metformin, but the medical establishment requires lengthy clinical trials. "The conservatism is taking over in days of war," Barzilai said.
Drug benefits on time
Clocks, once validated, could gauge drug effectiveness against age-related diseases quicker and cheaper than trials that track health outcomes over many years, expediting FDA approval of such therapies. For this to happen, though, the FDA must see evidence that rewinding clocks or improving related biomarkers leads to clinical benefits for patients. Researchers believe that clinical applications for at least some of these clocks are five to 10 years away.
Progress was made in last year's TRIIM trial, run by immunologist Gregory Fahy at Stanford Medical Center. People in their 50s took growth hormone, metformin and another diabetes drug, dehydroepiandrosterone, for 12 months. The cocktail, aimed at restoring immune function, reversed age by an average of 2.5 years, according to an epigenetic clock measurement taken before and after the intervention. Don't quit your gym just yet; TRIIM included just nine Caucasian men. A follow-up with 85 diverse participants begins next month.
But even group averages of epigenetic measures can be questionable, explained Willard Freeman, a researcher with the Reynolds Oklahoma Center on Aging. Consider this odd finding: heroin addicts tend to have younger epigenetic ages. "With the exception of Keith Richards, I don't think heroin is a great way to live a long healthy life," Freeman said.
Such confounders reveal that scientists—and AI—are still struggling to unearth the roots of aging. Do clocks simply reflect damage, mirrors to show who's the frailest of them all? Or do they programmatically drive aging? The answer involves vast complexity, like trying to deduce the direct causes of a 17-car pileup on a potholed road in foggy conditions. Except, instead of 17 cars, it's millions of epigenetic sites and thousands of potential genes, RNA molecules and blood proteins acting on aging and each other.
Because the various measures—epigenetics, microbes, etc.—capture distinct aging dimensions, an important goal is unifying them into one "mosaic of biological ages," as Levine called it. Gladyshev said more datasets are needed. Just yesterday, though, Zhavoronkov launched Deep Longevity's groundbreaking composite of metrics to consumers – something that was previously available only to clinicians. The iPhone app allows users to upload their own samples and tracks aging on multiple levels – epigenetic, behavioral, microbiome, and more. It even includes a deep psychological clock asking if people feel as old as they are. Perhaps Twain's adage about mind over matter is evidence-backed.
Zhavoronkov appeared youthful in our Zoom interview, but admitted self-testing shows an advanced age because "I do not sleep"; indeed, he'd scheduled me at midnight Hong Kong time. Perhaps explaining his insomnia, he fears economic collapse if age-related diseases cost the global economy over $30 trillion by 2030. Rather than seeking eternal life, researchers like Zhavoronkov aim to increase health span: fully living our final decades without excess pain and hospital bills.
It's also a lucrative sales pitch to 7.8 billion aging humans.
Get your bio age
Levine, the Yale scientist, has partnered with Elysium Health to sell Index, an epigenetic measure launched in late 2019, direct to consumers, using their saliva samples. Elysium will roll out additional measures as research progresses, starting with an assessment of how fast someone is accumulating cells that no longer divide. "The more measures to capture specific processes, the more we can actually understand what's unique for an individual," Levine said.
Another company, InsideTracker, with an advisory board headlined by Harvard's David Sinclair, eschews the quirkiness of epigenetics. Its new InnerAge 2.0 test, announced this month, analyzes 18 blood biomarkers associated with longevity.
"You can imagine payers clamoring to charge people for costs with a kind of personal responsibility to them."
Because aging isn't considered a disease, consumer aging tests don't require FDA approval, and some researchers are skeptical of their use in the near future. "I'm on the fence as to whether these things are ready to be rolled out," said Freeman, the Oklahoma researcher. "We need to do our traditional experimental study design to [be] confident they're actually useful."
Then, 50-year-olds who are biologically 45 may wait five years for their first colonoscopy, Barzilai said. Despite some forerunners, clinical applications for individuals are mostly prospective, yet I was intrigued. Could these clocks reveal if I'm following the footsteps of the super-agers? Or will I rack up the hospital bills of Zhavoronkov's nightmares?
I sent my blood for testing with InsideTracker. Fearing the worst—an InnerAge accelerated by a couple of decades—I asked thought leaders where this technology is headed.
Insurance 2030
With continued advances, by 2030 you'll learn your biological age with a glance at your wristwatch. You won't be the only monitor; your insurance company may send an alert if your age goes too high, threatening lost rewards.
If this seems implausible, consider that life insurer John Hancock already tracks a VitalityAge. With Obamacare incentivizing companies to engage policyholders in improving health, many are dangling rewards for fitness. BlueCross BlueShield covers 25 percent of InsideTracker's cost, and UnitedHealthcare offers a suite of such programs, including "missions" for policyholders to lower their Rally age. "People underestimate the amount of time they're sedentary," said Michael Bess, vice president of healthcare strategies. "So having this technology to drive positive reinforcement is just another way to encourage healthy behavior."
It's unclear if these programs will close health gaps, or simply attract customers already prioritizing fitness. And insurers could raise your premium if you don't measure up. Obamacare forbids discrimination based on pre-existing conditions, but will accelerated age qualify for this protection?
Liz McFall, a sociologist at the University of Edinburgh, thinks the answer depends on whether we view aging as controllable. "You can imagine payers clamoring to charge people for costs with a kind of personal responsibility to them," she said.
That outcome troubles Mark Rothstein, director of the Institute of Bioethics at the University of Louisville. "For those living with air pollution and unsafe water, in food deserts and where you can't safely exercise, then [insurers] take the results in terms of biological stressors, now you're adding insult to injury," he said.
Government could subsidize aging clocks and interventions for older people with fewer resources for controlling their health—and the greatest room for improving their epigenetic age. Rothstein supports that policy, but said, "I don't see it happening."
Bio age working for you
2030 again. A job posting seeks a "go-getter," so you attach a doctor's note to your resume proving you're ten years younger than your chronological age.
This prospect intrigued Cathy Ventrell-Monsees, senior advisor at the Equal Employment Opportunity Commission. "Any marker other than age is a step forward," she said. "Age simply doesn't determine any kind of cognitive or physical ability."
What if the assessment isn't voluntary? Armed with AI, future employers could surveil a candidate's biological age from their head-shot. Haut.ai is already marketing an uncannily accurate PhotoAgeClock. Its CEO, Anastasia Georgievskaya, noted this tech's promise in other contexts; it could help people literally see the connection between healthier lifestyles and looking young and attractive. "The images keep people quite engaged," she told me.
Updating laws could minimize drawbacks. Employers are already prohibited from using genetic information to discriminate (think 23andMe). The ban could be extended to epigenetics. "I would imagine biomarkers for aging go a similar path as genetic nondiscrimination," said McFall, the sociologist.
Will we use aging clocks to screen candidates for the highest office? Barzilai, the Albert Einstein College of Medicine researcher, believes Trump and Biden have similar biological ages. But one of Barzilai's factors, BMI, is warped by Trump miraculously getting taller. "Usually people get shorter with age," Barzilai said. "His weight has been increasing, but his BMI stays the same."
As for my bio age? InnerAge suggested I'm four years younger—and by boosting my iron levels, the program suggests, I could be younger still.
We need standards for these tests, and customers must understand their shortcomings. With such transparency, though, the benefits could be compelling. In March, Theresa Brown, a 44-year-old from Kansas, learned her InnerAge was 57.2. She followed InsideTracker's recommendations, including regular intermittent fasting. Retested five months later, her age had dropped to 34.1. "It's not that I guaranteed another 10 or 20 years to my life. It's that it encourages me. Whether I really am or not, I just feel younger. I'll take that."
Which leads back to Zhavoronkov's psychological clock. Perhaps lowering our InnerAges can be the self-fulfilling prophesy that helps Theresa and me age like the super-athletes who thrive longer than expected. McFall noted the power of simple, sufficiently credible goals for encouraging better health. Think 10,000 steps per day, she said.
Want to be 34 again? Just do it.
Yet, many people's budgets just don't allow gym memberships, nutritious groceries, or futuristic aging clocks. Bill Gates cautioned we overestimate progress in the next two years, while underestimating the next ten. Policies should ensure that age testing and interventions are distributed fairly.
"Within the next 5 to 10 years," said Gladyshev, "there will be drugs and lifestyle changes which could actually increase lifespan or healthspan for the entire population."