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.
Genetic Engineering For All: The Last Great Frontier of Human Freedom
[Editor's Note: This op/ed appears in response to January's Big Moral Question: "Where should we draw a line, if any, between the use of gene editing for the prevention and treatment of disease, and for cosmetic enhancement?" Currently, it is illegal to develop human trials for the latter in the U.S.]
Homo sapien: a bipedal primate that is thought to be the only animal to construct a moral code. Despite the genetic differences between members of our species being less than 1 percent, we come in all shapes, sizes and colors. There is no normal for human genetics.
I believe genetic freedom is the most basic human right we all should have.
One DNA base change here, another there brings us humans with light skin, red hair and big muscles. Want to be an NBA All-Star? Your genes are by far the largest determinant of your height and well, there has never been an All-Star under 5'9". Sexual reproduction makes it so that our physical traits seem more a pinch of this and a dash of that than some precise architectural masterpiece. For the most part we have no control over whether we or our children will be the next Cristiano Ronaldo or are born with a debilitating disease--unless we use genetic engineering.
Anywhere from 64% in the US to over 82% of people in China support genetic modification of individuals to help treat diseases. I imagine that number will only increase as people become more familiar with the technology and I don't think most people need convincing that genetic modification for medical treatment is a good thing. In fact, most modern drugs are genetic regulation on a fundamental level. But cosmetic genetic modification is far more controversial with only 39% of people in the US finding it agreeable. Far fewer people support modifying the genes of babies before they are born. My question is: Where does one draw a line between cosmetic and medical genetic changes?
Modifying the genetics of individuals for medical reasons started in the late 1980s and early 1990s when scientists reprogrammed viruses so that instead of causing harm when they infected people, they changed the genetics of their cells. Much has changed and and despite the success of many gene therapy trials, people are still afraid. Perhaps because of concerns over safety, but gene therapies have been tested in over 2000 clinical trials in hundreds of thousands of people. So what are we so afraid of? I asked myself that same question in 2016 and could not find a basis for the fear and so performed the first successfully cosmetic human genetic modification by putting a jellyfish gene in my skin. The experiment was simple, the monetary cost minimal, and though my skin didn't fluoresce like a jellyfish, DNA testing showed it worked and the experiment showed me what was possible.
People are afraid because we are on the cusp of the human race changing as we know it. But isn't that change all we have been striving for?
In late 2017, I wanted to explore bigger cosmetic changes, so I did another genetic experiment on myself; I injected myself with a CRISPR/Cas9 system meant to modify myostatin, a gene responsible for muscle growth and fat loss. I didn't do it because I wanted bigger muscles but because the myostatin gene is a well-studied target that has been modified in many mammals using CRISPR. I feel a responsibility to try and push boundaries that scientists in universities and large corporations can't because of committees, regulations and social acceptability. When this cutting-edge technique was tried for the first time, it wasn't in an expensive lab and it didn't cost millions of dollars. It was done by me, prepared in my home lab, and the cost of this cosmetic treatment was under $500.
Home genetic engineering lab kits like this are sold by Zayner's company for less than $2000.
I have had many people call me crazy and worse, but they don't understand that I've undertaken these experiments with much thought and hesitation. Experimenting on oneself isn't fun; it is an unfortunate situation to be in as a Ph.D. scientist who less than two years ago was fulfilling a prestigious synthetic biology fellowship at NASA. The data points to the experiment being relatively safe, and similar experimental protocols have had success, so why wait? When so much is at stake, we need to show people what is possible so that one day we all can have genetic freedom.
Zayner's arm after attempting the first CRISPR injection showed little immune response; a small red dot in the upper left forearm can be seen at the injection site.
People are afraid because we are on the cusp of the human race changing as we know it. But isn't that change all we have been striving for yet unable to obtain? Have too much or too little hair? There is a non-gene therapy treatment for that. Want to change your appearance? The global cosmetic surgery market is over $15 billion. Tattoos, dyed hair and piercings abound. We sculpt our appearance by exercise, make-up, drugs, chemicals and invasive surgeries. We try so hard to fight against our genetics in every way except genetic modification.
Being human means freedom to be who we want to be. And at the moment, no one gets to choose their genetics. Instead, nature plays a probabilistic role in the most primitive genetic engineering experiment of sexual reproduction. This dice roll can sometimes end in tragedy. Fortunately, in my case I was born with the genetics of a healthy individual. Still, I push for everyone and though my newest genetic modification experiment is ongoing, even if it doesn't work, it is only a matter of time until it does in someone.
If you prevent someone like me from changing my genetics, where do you draw the line? Only people who can't walk can get genetic modification? Only people who can't run? Only people who are predisposed to skin cancer? Don't we all deserve a choice or to give parents better ones? I believe genetic freedom is the most basic human right we all should have. We no longer need to be slaves to genetics so let's break those bonds and embrace the change brought about by allowing human genetic engineering for all no matter the reason.
[Ed. Note: Check out the opposite perspective: "Hacking Your Own Genes: A Recipe for Disaster." Then follow LeapsMag on social media to share your opinion.]
Hacking Your Own Genes: A Recipe for Disaster
Editor's Note: Our Big Moral Question this month is: "Where should we draw a line, if any, between the use of gene editing for the prevention and treatment of disease, and for cosmetic enhancement?" It is illegal in the U.S. to develop human trials for the latter, even though some people think it should be acceptable. The most outspoken supporter recently resorted to self-experimentation using CRISPR in his own makeshift lab. But critics argue that "biohackers" like him are recklessly courting harm. LeapsMag invited a leading intellectual from the Center for Genetics and Society to share her perspective.
"I want to democratize science," says biohacker extraordinaire Josiah Zayner.
This is certainly a worthy-sounding sentiment. And it is central to the ethos of biohacking, a term that's developed a bit of sprawl. Biohacking can mean non-profit community biology labs that promote "citizen science," or clever but not necessarily safe or innocuous garage-based experiments with computers and genetics, or efforts at biological self-optimization via techniques including cybernetic implants, drug supplements, and intermittent fasting.
They appear to have given little thought to whether curiosity should be bound in any way by care for social consequence.
Against that messy background, what should we make of Zayner? The thirty-something ex-NASA scientist, who describes himself as "a global leader in the BioHacker movement," put his interpretation of democracy on display last October during a CRISPR-yourself performance at a San Francisco biotech conference. In that episode, he dramatically jabbed himself with a long needle, injecting his left forearm with a home-made gene-editing concoction that he said would disrupt his myostatin genes and bulk up his muscles.
Zayner sees himself, and is seen by some fellow biohackers, as a rebel hero: an intrepid scientific adventurer willing to risk his own well-being in the tradition of self-experimentation, eager to push the boundaries of established science in the service of forging innovative modes of discovery, ready to stand up to those stodgy bureaucrats at the FDA in the name of biohacker freedom.
To others, including some in the biohacker community, he's a publicity-seeking stunt man, perhaps deluded by touches of toxic masculinity and techno-entrepreneurial ideology, peddling snake-oil with oozing ramifications.
Zayner is hardly coy about his goals being larger than Popeye-like muscles. "I want to live in a world where people are genetically modifying themselves," he told FastCompany. "I think this is, like, literally, a new era of human beings," he mused to CBS in November. "It's gonna create a whole new species of humans."
Nor does he deign to conceal his tactics. The webpage of the company he launched to sell DIY gene-editing kits (which is advised by celebrity geneticist George Church) says that Zayner is "constantly pushing the boundaries of Science outside traditional environments." He is more explicit when performing: "Yes I am a criminal. And my crime is that of curiosity," he said last August to a biohacker audience in Oakland, which according to Gizmodo erupted in applause.
Regrettably, Zayner, along with some other biohackers and their defenders in the mainstream scientific world, appear to have given little thought to whether curiosity should be bound in any way by care for social consequence.
In December, the FDA issued a brief statement warning against using DIY kits for self-administered gene editing.
Though what's most directly at risk in Zayner's self-enhancement hack is his own safety, his bad-boy celebrity status is likely to encourage emulation. A few weeks after his San Francisco performance, 27-year-old Tristan Roberts took to Facebook Live to give himself a DIY gene modification injection to keep his HIV infection in check, because he doesn't like taking the regular medications that prevent AIDS. Whatever it was that he put into his body was provided by a company that Gizmodo describes as a "mysterious biotech firm with transhumanist leanings."
Zayner doesn't outright provide DIY gene hacks to others. But among his company's offerings are a free DIY Human CRISPR Guide and a $20 CRISPR-Cas9 plasmid that targets the human myostatin gene – the one that Zayner said he was targeting to make his muscles grow. Presumably to fend off legal problems, the product page says: "This product is not injectable or meant for direct human use" – a label as toothless as the fine print on cigarette packages that breaks the news that smoking causes cancer.
Some scientists warn that Zayner's style of biohacking carries considerable dangers. Microbiologist Brian Hanley, himself a self-experimenter who now opposes "biohacking humans," focuses on the technical difficulty of purifying what's being injected. "Screwing up can kill you from endotoxin," he says. "If you get in trouble, call me. I will do my best to instruct the physician how to save your life….But I make no guarantees you will survive."
Hanley also commented on the likely effectiveness of Zayner's effort: "Either Josiah Zayner is ignorant or he is deliberately misleading people. What he suggests cannot work as advertised."
Ensuring the safety and effectiveness of medical drugs and devices is the mandate of the US Food and Drug Administration. In December, the agency issued a brief statement warning against using DIY kits for self-administered gene editing, and saying flat out that selling them is against the law.
The stem cell field provides an unfortunate model of what can go wrong.
Zayner is dismissive of the safety risks. He asks in a Buzzfeed article whether DIY CRISPR should be considered more harmful than smoking or chemotherapy, "legal and socially acceptable activities that damage your genes." This is a strange line of argument, given the decades-long battles with the tobacco industry to raise awareness about smoking's significant harms, and since the side effects of chemotherapy are typically not undertaken by choice.
But the implications of what Zayner, Roberts, and some of their fellow biohackers are promoting ripple well beyond direct harms to individuals. Their rhetoric and vision affect the larger project of biomedicine, and the fraught relationships among drug researchers, pharmaceutical companies, clinical trial subjects, patients, and the public. Writing in Scientific American, Eleanor Pauwels of the Wilson Center, who is sympathetic to biohacking, lists the down sides: "blurred boundaries between treatments and self-experimentation, peer pressure to participate in trials, exploitation of vulnerable individuals, lack of oversight concerning quality control and risk of harm, and more."
These prospects are germane to the current state of human gene editing. After decades of dashed hopes, including deaths of research subjects, "gene therapy" may now be close to deserving the promise in its name. But with safety and efficacy still being evaluated, it's especially crucial to be honest about limitations as well as possibilities.
The stem cell field provides an unfortunate model of what can go wrong. Fifteen years ago, scientists, patient advocates, and even politicians routinely indulged in wildly over-optimistic enthusiasm about the imminence of stem cell therapies. That binge of irresponsible promotion helped create the current situation of widespread stem cell fraud: hundreds of clinics in the US alone selling unproven treatments to unsuspecting and sometimes desperate patients. Many have had their wallets lightened; some have gone blind or developed strange tumors that doctors have never before seen. The FDA is scrambling to address this still-worsening situation.
Zayner-style biohacking and promotion may also impact the ongoing controversy about whether new gene editing tools should be used in human reproduction to pre-determine the traits of future children and generations. Much of the widespread opposition to "human germline modification" is grounded in concern that it would lead to a society in which real or purported genetic advantages, marketed by fertility clinics to affluent parents, would exacerbate our already shameful levels of inequality and discrimination.
With powerful new technologies increasingly shaping the world, there's a lot riding on our capacity to democratize science. But as a society we don't yet have much practice at it.
Yet Zayner is all for it. In an interview in The Guardian, he comments, "DNA defines what a species is, and I imagine it wouldn't be too long into the future when the human species almost becomes a new species because of these modifications." He notes in a blog post, "We want to grow as a species and maybe change as a species. Whether that is curing disease or immortality or mutant powers is up to you."
This brings us back to Zayner's claim that he is working to democratize science.
The conviction that gene editing involves social and political challenges, not just technical matters, has been voiced at all points on the spectrum of perspective and uncertainty. But Zayner says there's been enough talk. "I want people to stop arguing about whether it's okay to use CRISPR or not use CRISPR….It's too late: I already made the choice for you. Argument over. Let's get on with it now. Let's use this to help people. Or to give people purple skin." (Emphasis added, in case there's any doubt about Zayner's commitment to democracy.)
With powerful new technologies increasingly shaping the world, there's a lot riding on our capacity to democratize science. But as a society we don't yet have much practice at it. In fact, we're not very sure what it would look like. It would clearly mean, as Arizona State University political scientist David Guston puts it, "considering the societal outcomes of research at least as attentively as the scientific and technological outputs." It would need broad participation and demand hard work.
The involvement of serious citizen scientists in such efforts, biohackers included, could be a very good thing. But Zayner's contributions to date have not been helpful.
[Ed. Note: Check out Zayner's perspective: "Genetic Engineering for All: The Last Great Frontier of Human Freedom." Then follow LeapsMag on social media to share your opinion.]