New drug for schizophrenia could meet desperate need for better treatments
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.
The recent Ebola virus outbreak in the Democratic Republic of Congo has refocused attention on the vaccine and treatment prospects for the highly contagious and deadly disease. As of late May, more than 7,500 doses of an experimental vaccine made by Merck Pharmaceuticals had been shipped to the beleaguered African nation, according to a World Health Organization press release.
Research was focused on the production of antibodies and vaccines in a novel manufacturing system: the tobacco plant.
Meanwhile, Ebola treatments were also sent. One of these, ZMapp, was successfully used to treat two American missionaries in Liberia in 2014. Charles Arntzen, who helped develop the treatment, calls that moment the highlight of his career: "It started in a lab as a fanciful idea that needed to be validated. In ten years, it was being used and people went from almost dead to almost recovered."
His initial research was focused on the production of antibodies and vaccines in a novel manufacturing system. That system was the tobacco plant—not the smoking variety, or nicotiana tabacum. But rather, a distant cousin called nicotiana benthamiana, which is native to Australia, where it grows abundantly.
ZMapp is made from the plant, as are other therapeutics and vaccines. Indeed, the once-maligned plant family has turned its image upside down in the public health world, now holding promise to prevent and treat many conditions.
Cheap, easy and plentiful
Research on the tobacco plant's medicinal potential goes back a few decades. In the early 1990s, research on plants as vaccine production platforms was just beginning. "We wanted to make a lower-cost vaccine manufacturing system to be used in developing countries to broaden our manufacturing base in the developing world," said Arntzen, who is the founding director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy at Arizona State University. "There was and still is a shortage of vaccines in the poorest countries."
"I've got a list of about fifty vaccines that should be made in tobacco."
Initially, research focused on food plants: bananas, tomatoes, and potatoes. While these efforts were successful, they were stymied by the "anti-GMO food establishment," Arntzen said. "I didn't want to spend my time fighting." So, they switched to the tobacco plant.
"I've got a list of about fifty vaccines that should be made in tobacco," said Denis Murphy, professor of biotechnology at the University of South Wales. "We know a lot about how to express genes in tobacco and get it made."
Unlike egg-based vaccines, which require a clean, sterile laboratory to make, and can therefore be an expensive process, Murphy said, tobacco-based vaccines are relatively cheap to make. The process is simple: Three weeks after being planted, the plants are dipped into a liquid containing proteins from the given virus. The plants grow the proteins for another week and then are harvested and chopped up. The green liquid that results is the vaccine, which is purified and then bottled up in precise doses.
"The tobacco plant doesn't seem to mind making all this foreign protein," Murphy added. "The plants will stay alive and look okay, and they will be full of vaccine protein. If you did this with an animal, you'd probably kill it."
Still, there are certain challenges to producing tobacco-based vaccines, particularly in the developing world, said Murphy, who is also a biotech consultant for the Food and Agricultural Organization of the United Nations.
"The purification process of the vaccine protein from leaves is still something for which you need a specialized lab. You couldn't have that in the Congo," he said. Security is another concern. "Someone could steal the plant and grow it themselves as a pirate version."
Even birds could be the culprit for tobacco plant theft. "What if a bird came and started eating the leaves? You might want netting or greenhouse growing. That can be much more problematic in a developing country."
While the ZMapp treatment for Ebola is produced from tobacco, efforts to develop a vaccine this way have not proved fruitful so far. (Merck's Ebola vaccine is made from livestock.) "Our tobacco-based vaccine would require three doses for a full effect, while the vaccine made by Merck may only require a single dose," Arntzen said. "Having to give three doses, over about a month, makes the tobacco-made vaccine much more cumbersome and expensive to deliver." Yet a tobacco-derived vaccine for another newsworthy illness is in the works.
On the frontier of a flu vaccine
Quebec City-based biopharmaceutical company Medicago is using a novel technique to make a flu vaccine with tobacco. This offers several advantages over the current method of developing the vaccine from eggs.
First of all, the production is quicker: five to six weeks, versus four to six months, which means that researchers can wait to identify the circulating flu strain for the upcoming season, rather than guess and risk being wrong.
Also, with tobacco, developers can use something called virus-like particles, instead of the actual flu virus.
"We hope to be on the market by the 2020/21 flu season."
"They have the structure of the flu virus, but not its full genetic code, so the virus doesn't replicate," said Anne Shiraishi, Medicago's communications manager. That's a big deal because the flu is a rapidly mutating virus, and traditional egg-based vaccines encourage those mutations – which wind up making the vaccines less effective.
This problem happens because the flu virus mutates a key protein to better attach to receptors in bird cells, but in humans, this mutation won't trigger an effective immune response, according to a Medicago fact sheet. That's why some people who have been vaccinated still get the flu. Indeed, the 2017 flu season had the lowest vaccine effectiveness record ever for H3N2 at 10 percent in the Southern Hemisphere, and 0 percent effective in the EU and UK in people over age 65. At least theoretically, their tobacco-derived flu vaccine could be far more successful, since no such mutations occur with the virus-like particles.
Last year, Medicago, which is 40 percent owned by cigarette company Philip Morris, began a phase 3 trial of the flu vaccine with 10,000 subjects in five countries: half are getting the vaccine, and half are getting a placebo. "We hope to announce really good results this fall," Shiraishi said. "We hope to be on the market by the 2020/21 flu season."
They're also preparing phase I trials for vaccines for the rotavirus and norovirus, two intractable gastro-intestinal viruses. They hope to roll those trials out in the next year or two.
Meanwhile, other research on antibodies is in their pipeline—all of it using tobacco, Shiraishi said. "We've taken something bad for public health and made it our mini factories."
Enhancing Humans: Should We or Shouldn’t We?
A panel of leading experts gathered this week at a sold-out event in downtown Manhattan to talk about the science and the ethics of enhancing human beings -- making people "better than well" through biomedical interventions. Here are the ten most memorable quotes from their lively discussion, which was organized by the New York Academy of Sciences, the Aspen Brain Institute, and the Hastings Center.
1) "It's okay for us to be enhanced relative to our ancestors; we are with the smallpox vaccine." —Dr. George Church, iconic genetics pioneer; professor at Harvard University and MIT
Church was more concerned with equitable access to enhancements than the morality of intervening in the first place. "We missed the last person with polio and now it's spread around the world again," he lamented.
Discussing how enhancements might become part of our species in the near-future, he mentioned the possibility of doctors slightly "overshooting" an intervention to reverse cognitive decline, for example; or younger people using such an intervention off-label. Another way might be through organ transplants, using organs that are engineered to not get cancer, or to be resistant to pain, pathogens, or senescence.
2) "All the technology we will need to fundamentally transform our species already exists. Humans are made of code, and that code is writable, readable and hackable." —Dr. Jamie Metzl, a technology futurist and geopolitical expert; Senior Fellow of the Atlantic Council, an international affairs think tank
The speed of change is on an exponential curve, and the world where we're going is changing at a much faster rate than we're used to, Metzl said. For example, a baby born 1000 years ago compared to one born today would be basically the same. But a baby born 1000 years in the future would seem like superman to us now, thanks to new capabilities that will become embedded in future people's genes over time. So how will we get from here to there?
"We will line up for small incremental benefits. By the time people are that changed, we will have adapted to a whole new set of social norms."
But, he asked, will well-meaning changes dangerously limit the diversity of our species?
3) "We are locked in a competitive arms race on both an individual and communal level, which will make it very difficult to put the brakes on. Everybody needs to be part of this conversation because it's a conversation about the future of our species." —Jamie Metzl
China, for one, plans to genetically sequence half of all newborns by 2020. In the U.S., it is standard to screen for 34 health conditions in newborns (though the exact number varies by state). There are no national guidelines for newborn genomic screening, though the National Institutes of Health is currently funding several research studies to explore the ethical concerns, potential benefits, and limitations of doing so on a large scale.
4) "I find freedom in not directing exactly how my child will be." —Josephine Johnston, Director of Research at the Hastings Center, the world's oldest bioethics research institute
Johnston cautioned against a full-throttled embrace of biomedical enhancements. Parents seeking to remake nature to serve their own purpose would be "like helicopter parenting on steroids," she said. "It could be a kind of felt obligation, something parents don't want to do but feel they must in order to compete." She warned this would be "one way to totally ruin the parenting experience altogether. I would hate to be the kind of parent who selects and controls her child's traits and talents."
Among other concerns, she worried about parents aiming to comply with social norms through technological intervention. Would a black mom, for example, feel pressure to make her child's skin paler to alleviate racial bias?
5) "We need to seriously consider the risks of a future if a handful of private companies own and monetize a map of our thoughts at any given moment." – Meredith Whittaker, Research Scientist, Open Research Lead at Google, and Co-Director of New York University's AI Now Institute, examining the social implications of artificial intelligence
The recent boom in AI research is the result of the consolidation of the tech industry's resources; only seven companies have the means to create artificial intelligence at scale, and one of the innovations on the horizon is brain-computer interfaces.
Facebook, for example, has a team of 60 engineers working on BCIs to let you type with your mind. Elon Musk's company Neuralink is working on technology that is aiming for "direct lag-free interactions between our brains and our devices."
But who will own this data? In the future, could the National Security Agency ask Neuralink, et al. for your thought log?
6) "The economic, political, and social contexts are as important as the tech itself. We need to look at power, who gets to define normal, and who falls outside of this category?" – Meredith Whittaker
Raising concerns about AI bias, Whittaker discussed how data is often coded by affluent white men from the Bay Area, potentially perpetuating discrimination against women and racial minorities.
Facial recognition, she said, is 30 percent less accurate for black women than for white men. And voice recognition systems don't hear women's voices as well as men's, among many other examples. The big question is: "Who gets to decide what's normal? And how do we ensure that different versions of normal can exist between cultures and communities? It is impossible not see the high stakes here, and how oppressive classifications of normal can marginalize people."
From left: George Church, Jamie Metzl, Josephine Johnston, Meredith Whittaker
7) "We might draw a red line at cloning or germline enhancements, but when you define those or think of specific cases, you realize you threw the baby out with the bathwater." —George Church, answering a question about whether society should agree on any red lines to prohibit certain interventions
"We should be focusing on outcomes," he suggested. "Could enhancement be a consequence of curing a disease like cognitive decline? That would concern me about drawing red lines."
8) "We have the technology to create Black Mirror. We could create a social credit score and it's terrifying." —Meredith Whittaker
In China, she said, the government is calculating scores to rank citizens based on aggregates of data like their educational history, their friend graphs, their employment and credit history, and their record of being critical of the government. These scores have already been used to bar 12 million people from travel.
"If we don't have the ability to make a choice," she said, "it could be a very frightening future."
9) "These tools will make all kinds of wonderful realities possible. Nobody looks at someone dying of cancer and says that's natural." —Jamie Metzl
Using biomedical interventions to restore health is an unequivocal moral good. But other experts questioned whether there should be a limit in how far these technologies are taken to achieve normalcy and beyond.
10) "Cancer's the easy one; what about deafness?" —Josephine Johnston, in retort
Could one person's disability be another person's desired state? "We should be so suspicious" of using technology to eradicate different ways of being in the world, she warned. Hubris has led us down the wrong path in the past, such as when homosexuality was considered a mental disorder.
"If we sometimes make mistakes about disease or dysfunction," she said, "we might make mistakes about what is a valid experience of the human condition."
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.