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.
Forget Farm-to-Table: Lab-to-Table Fresh Fish Is Making Waves
Ever wonder why you've never heard of wild-caught organic fish? It's because there's no way to certify a food that has a mysterious history. Mike Selden, a 26-year-old biochemist with an animal lover's heart and an entrepreneur's mind, decided there must be better way to consume one of our planet's primary sources of animal protein. A way that would eliminate the need to kill billions of fish per year while also producing toxin-free, cheap, delicious fish meat for your dinner table. Enter Finless Foods, a young startup with a bold vision. Selden took time out of chauffeuring fish carcasses around San Francisco (no joke!) to share his journey with LeapsMag.
What is the biggest problem with the way fish is consumed today?
There are a lot of problems ranging from metals to animal welfare to human health. Technology is solving those problems at the same time. You've got extreme over fishing, which is collapsing ocean ecosystems and removing populations of fish that are traditionally used as food sources in developing nations.
In terms of animal welfare, fish are killed in massive numbers, billions a year. Even if people don't care too much about that, we want to give them another option.
In terms of health, which I think for most people is the most convincing argument, current fish have mercury and plastic in them. And if you're getting that fish from a farm, you will also have high levels of antibiotics and growth hormones if you're getting it from outside the U.S. What we're doing is producing fish that doesn't have any of those contaminants.
What gave you the idea to start a company around lab-grown fish?
I studied biochemistry and molecular biology at UMass Amherst, traditionally an agricultural school out in the woods of Massachusetts. I have always been an environmental activist and cared about animals. I thought, animal agriculture is so incredibly inefficient, what could be done to change it?
"The worst way you can possibly make a hamburger is with a cow."
Agriculture is a system of inputs and outputs, the inputs being feed and the outputs being meat – so why are we wasting all of this input on outputs we don't care about? Why are we creating these animals that waste all this energy through sitting around, moving around, having a heartbeat, blinking? All of this uses energy and that's valuable input.
The worst way you can possibly make a hamburger is with a cow. It's an awful transfer of energy: you have to feed it many times its own weight in food that could have fed other people or other things.
In February, I got funding from Indie Bio, a startup accelerator for synthetic biology, and moved out to San Francisco with my co-founder Brian Wyrwas. We started working in our lab in March. We're the newest company in the space.
Walk me through the process of creating edible fish in the lab. Do you have to catch a real live fish first and get their cells?
We have a deal with the Aquarium of the Bay, and whenever a fish dies, they call me, I get in a zip car, drive over, and bring the fish back to the lab, where Brian cultures it up into a cell culture. We do use real, high-quality fish stock. From there, we get the cells going in a bioreactor in a suspension culture, grow them into large quantities, and then bring them out to differentiate them into the cells people want to eat—the muscle and fat tissue. Then we formulate it and bring it to people's tables.
How long does the whole process take from the phone call about the fish dying to the food on the table?
There are two different processes: One is a research process, getting the initial cells and engineering them to be what we're looking for.
The other is a production process – we have a cell line ready and need to grow it out. That timing depends on how big of a facility we have. Since we're working with cell division: If you have 1 cell, in 24 hours, you'll have two cells. Let's say you have 1 ton of cells, in 24 hours you'll have two tons of cells.
"We want to give people the wholesome food they are used to in a healthier setting."
How are you looking to scale this process?
We're trying to find a middle ground between efficiency and local distribution. Organic farming is hilariously bad for the environment and horrifyingly inefficient, but on the other hand, industrial agriculture requires lots of transport, which is also bad for the environment. We're looking to create regionally distributed facilities which don't require a lot of transit, so people can have fresh fish even extremely far inland.
What kinds of fish are you "cooking"?
Our first product will be Bluefin tuna. It's a high-quality fish with high demand and it's also a conservation issue. We also currently have a culture going with Branzino, European sea bass, that we're really happy with.
There's a concept in science called a model organism – one that is extremely well studied and understood. Like the fruit fly, for example. For fish, it's the zebra fish, which is used for genetic research, but no one eats it. It's tiny, so we started by thinking: what fish do people eat that is also close evolutionarily to the zebra fish? We came up with carp, even though it's not too widely eaten.
But our process is very species agnostic. We've done work in trout, salmon, goldfish. Any fish with a dorsal fin works with our process. We tried a wolf eel but it didn't work. Eels are pretty far evolutionarily from fish, so we dropped that one.
From left to right, Ron Shigeta (IndieBio), Brian Wyrwas (Finless Foods), Amy Fleming (The Guardian), and Jihyun Kim (Finless Foods) tasting the first ever clean carp croquettes.
(Courtesy Mike Selden)
Why fish as opposed to, say, a cow?
Scientifically, there are a lot of advantages. Fish have a simpler structure than land animals. A fillet from a cow has complex marbling going on between the fat and muscle. When it's fish, like sashimi, it's in layers of muscle and fat. So it's simpler to build, plus fish are cold-blooded, so because they breathe underwater, our equipment needs less complexity. We don't need a CO2 line and we don't need to culture our cells at 37 degrees Celsius. We culture them at room temperature.
It's also easier to get to market since there's much higher value. Chicken in the last year was $3.84 per pound in America, whereas Bluefin tuna is between $100 and $1200 a pound. Because this is about dropping cost, we can get to market faster and give investors a better value proposition.
What's also cool is that something like Bluefin tuna is something many people haven't had the opportunity to eat. We can get these down in cost until there is price parity with any cheap conventional fish. We want to give people a choice between buying something like albacore tuna in a can –with mercury and plastic– or high-quality tuna without any contaminants for the same price.
Do you shape them like fish fillets to help the consumer overcome whatever discomfort they might feel about eating a bunch of lab-grown cells?
Yeah, people want to continue eating food they are eating, and that's fine. We want to give people a better option. We don't want to give them something weird and out there. We want to give them the wholesome food they are used to in a healthier setting that also solves some environmental issues.
How about the taste? Have you done any blind side-by-side tests with the real thing and your version?
Not blind taste tests. But we have been tasting it, and it is firmly fish. I even tried leaving it outside of the fridge – and man, that tasted like spoiled fish.
We want it to have the exact same properties as real fish. We don't want people to have to learn how to cook with it. We want them to just bring it into their homes and eat it exactly like they were doing before, but better.
What you're growing isn't the whole fish, right? It is not an actual organism?
Right, we're only growing muscle cells. It doesn't know where it is. There is no brain, nervous system, or pain receptors.
Are you the only people in this lab-grown food space working on fish?
We're the only ones doing fish so far. Other companies are doing chicken, duck, egg white, milk, gelatin, leather, and beef.
Are people generally weirded out by sci-fi lab food, or intrigued?
It's been very positive. When people sit down and talk to us, they realize it's not some crazed money grab or some weird Ted talk, it's real activists using real science trying to solve real problems. Sure, there will be some pushback from people who don't understand it, and that's fine.
When can I expect to see Finless Food at my local Whole Foods?
We plan on being in restaurants in two years, and grocery stores in four years.
What about people who aren't big fans of fish in the first place? Like those who don't eat sushi, because consuming something raw with an unknown history isn't very appetizing.
There are too many examples of food poisoning because fish are in a less clean environment than they should be, swimming around in their own fecal matter, and being doused in antibiotics so their diseases don't transmit. It's a bit of a mess. That's why as an industry, we're calling this clean meat. Fish is a healthy thing, or at least it should be, with Omega 3 and 6, and DHA. This is a way for people to continue getting those nutrients without any of the questions of where it came from. For people who are skeptical of fish, we invite you to dive in.
Brian Wyrwas, Co-Founder & CSO, and Mike Selden, Co-Founder & CEO
(Courtesy Mike Selden)
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.
Why the Panic Over "Designer Babies" Is the Wrong Worry
BIG QUESTION OF THE MONTH: Should we use CRISPR, the new technique that enables precise DNA editing, to change the genes of human embryos to eradicate disease--or even to enhance desirable traits? LeapsMag invited three leading experts to weigh in.
CRISPR is producing an important revolution in the biosciences, a revolution that will change our world in fundamental ways. Its implications need to be discussed and debated, and not just by scientists and ethicists. Unfortunately, so far we are debating the wrong issues.
Controversy has raged about editing human genes, particularly the DNA of embryos that could pass the changes down to their descendants. This technology, human germline editing, seems highly unlikely to be broadly available for at least the next few decades; if and when it is, it may well be unimportant.
Human germline editing is unlikely to happen soon because it has important safety risks but almost no significant benefits.
Human germline editing is unlikely to happen soon because it has important safety risks but almost no significant benefits. The risks – harm to babies – are compelling. We care a lot about babies. A technology that worked 95 percent of the time (and produced disabled or dying infants "only" five percent of the time) would be a disaster. Our concern for babies will lead, at the least, to rigorous legal requirements for preapproval safety testing. Many countries will just impose flat bans.
But these risks also have implications beyond safety regulation. For this technology to take off, physicians, assisted reproduction clinics, and geneticists will have to be willing to put their reputations – and their malpractice liability – on the line. And prospective mothers will have to be willing to take unknown risks with their children.
Sometimes, large and unknown risks are worth taking, but not here. For the next few decades, human germline editing offers almost no substantial benefits, for health or for enhancement.
Prospective parents already have a tried and true alternative to avoid having children with genetic diseases: preimplantation genetic diagnosis (PGD). In PGD, clinicians remove cells from three- to five-day-old embryos. Those cells are then tested to see which embryos would inherit the disease and which would not. This technology has been in use for over 27 years and is safe and effective. Rather than engaging in editing an embryo's disease-causing DNA, parents can just select embryos without those DNA variations. For so-called autosomal recessive diseases, three out of four embryos, on average, will be disease free; for autosomal dominant diseases, half will be.
Only a handful of prospective parents would need to use gene editing to avoid genetic disease.
Couples where each has the same recessive condition (cystic fibrosis) or where one of them has the terrible luck to have two copies of the DNA variant for a dominant disease (Huntington's disease). In those cases, the prospective parents would need to stay alive long enough to be able, and be sufficiently healthy to want, to have children. In a world of 7.3 billion humans, there will be some such cases, but they will probably be no more than a few thousand – or hundred.
People are also concerned about germline editing for genetic enhancement. But this is also unlikely anytime soon. We know basically nothing about genetic variations that enhance people beyond normal. For example, we know hundreds of genes that, when damaged, affect intelligence – but these all cause very low intelligence. We know of no variations that non-trivially increase it.
Over the next few decades, we might (or might not) learn about complex diseases where several genes are involved, making embryo selection less useful. And we might (or might not) learn about genetic enhancements involving DNA sequences not typically found in prospective parents and so not available to embryo selection. By that time, the safety issues could be resolved.
And, even then, how worried should we be – and about what? A bit, but not very and not about much.
"The human germline genome is not the holy essence of humanity."
The human germline genome is not the holy essence of humanity. For one thing, it doesn't really exist. There are 7.3 billion human germline genomes; each of us has a different one. And those genomes change every generation. I do not have exactly the same genetic variations my parents received from my grandparents; my children do not have exactly the ones I received from my parents. The DNA changed, through mutation, during each generation.
And our editing will usually be insignificant in the context of the whole human genome. For medical purposes, we will change some rare DNA variations that cause disease into the much more common DNA variations that do not cause disease. Rare, nasty variants will become rarer, but civilization changes these frequencies all the time. For instance, the use of insulin has increased the number of people with DNA variations that predispose people to type 1 ("juvenile") diabetes – because now those people live long enough to reproduce. Even agriculture changed our DNA, leading, for example, to more copies of starch-digesting genes. And, in any event, what is the meaningful difference between "fixing" a disease gene in an embryo or waiting to fix it with gene therapy in a born baby . . . other than avoiding the need to repeat the gene therapy in the next generation?
If genetic enhancement ever becomes possible in a non-trivial way, it would raise important questions, but questions about enhancement generally and not fundamentally about genetics. Enhancement through drugs, prosthetics, brain-computer interfaces, genes, or tools (like the laptop I wrote this on) all raise similar ethical issues. We can use the decades we will have to try to think more systematically about the ethical and policy issues for all enhancements. We should not panic about germline genetic enhancement.
One superficially appealing argument is that we are not wise enough to change our own genomes. This ignores the fact that we have been changing our genomes, inadvertently, since at least the dawn of civilization. We do not have to be wise enough to change our genome perfectly; we just need to be wise enough to change it better than the random and unforeseen ways we change it now. That should not be beyond our power.
Human germline editing will not be a concern for several decades and it may never be an important concern. What should we be paying attention to?
Non-human genome editing. Governments, researchers, and even do-it-yourself hobbyists can use CRISPR, especially when coupled with a technique called "gene drive," to change the genomes of whole species of living things – domestic or wild; animal, vegetable, or microbial – cheaply, easily, and before we even know it is happening. We care much less about mosquito babies than human ones and our legal structures are not built for wise and nuanced regulation of this kind of genome editing. Those issues demand our urgent attention – if we can tear ourselves away from dramatic but less important visions of "designer babies."
Editor's Note: Check out the viewpoints expressing condemnation and enthusiastic support.