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.
NASA Has the Technology to Save Us From an Asteroid Strike, But Congress Won’t Fund It
At the biannual Planetary Defense Conference earlier this year, NASA ran a simulation of an asteroid slamming into the center of Manhattan.
For several millennia now, we've been lucky, but our luck won't hold out forever.
The gathering of astronomers, planetary scientists, and FEMA disaster-response experts attempted a number of interventions that might be possible within a time window of eight years, the given warning period before impact.
Catastrophic asteroid crashes are not without precedent, and scientists say it's only a matter of time before another one occurs—that is, if we do nothing to prevent it. It's believed that a huge asteroid crash off the coast of Mexico's Yucatan Peninsula created a worldwide disaster that helped to speed the extinction of the dinosaurs 65 million years ago.
In 1908, a meteoroid less than 300 feet in diameter exploded in the air over the Tunguska region of Siberia, creating a shockwave that leveled trees for hundreds of square miles. It's a matter of sheer luck it didn't hit a major population center, where human casualties could have been enormous.
For several millennia now, we've been lucky, but our luck won't hold out forever. There are millions of asteroids circulating about in our solar system, some of them hundreds of miles across, and although the odds of a massive one crashing to Earth in the near future is statistically low, the devastation could be apocalyptic.
Back at the conference, the experts tried sending several spacecrafts to knock the asteroid off-course by slamming into it. They considered blasting it with nuclear weapons. They even considered painting it white so it absorbed less of the sun's energy, hoping that would shift the asteroid's trajectory. In the simulations, all of the interventions failed and the giant space rock crashed into Manhattan, killing 1.3 million people in a massive explosion that was 1,000 times more powerful than the Hiroshima bomb.
NEOCam is designed, tested, and ready to build, but the project is currently frozen because of a $40 million gap in NASA funding.
Given more time, the scientists said, they might have succeeded in preventing the disaster. However, with today's asteroid-hunting telescopes, it's not likely we would have more warning. Our current telescopes are not powerful enough to detect all the near-earth asteroids, nor are they positioned well enough for sufficient detection. As recently as last week, for example, an asteroid traveling 15 miles a second narrowly missed crashing into the Earth, and it was only noticed several days in advance.
Now for the good news: There is a new technology that could buy us the time we need, says MIT planetary sciences professor Richard P. Binzel and colleagues who attended the conference. The Near-Earth Object Camera, or NEOCam, designed by NASA's Jet Propulsion Laboratory, would detect more than 90 percent of nearby objects that are 420 feet across or larger, according to Binzel.
The powerful infrared telescope is designed to sit within the L1 Lagrange point, a stable location in space where the gravitational pulls of the Earth and the sun cancel each other out. From there, large space bodies could be detected early enough to give scientists decades of warning when an asteroid is heading for Earth. NEOCam is designed, tested, and ready to build, but the project is currently frozen because of a $40 million gap in NASA funding.
The status of NEOCam, according to Binzel, is a case-study in short-sightedness and a lack of leadership. Congress needs to raise NASA's Planetary Defense budget from its current $160 million to $200 million to get the telescope built and launched into space, a goal that would seem eminently doable within the strictures of 2020's $4.75 trillion government budget. But Binzel describes a current deadlock between NASA, Congress, and the Office of Management and Budget as a "cosmic game of chicken."
If we don't use our technology to defend the planet, "it would be the most epic failure in the history of science."
In an excruciatingly budget-conscious atmosphere, "No one wants to stick their neck out and take adult responsibility" for getting the funding allocated that would unfreeze the project, says Binzel. But, he adds, "We have a moral obligation to act."
NEOCam would not only spot the overwhelming majority of asteroids in Earth's vicinity, it would determine their size and pinpoint exactly where they are likely to strike the Earth. And it would allow us decades to act, according to Binzel. Repeated ramming by an international armada of specialized spacecraft could slightly change the trajectory of an asteroid, he says. Changing the trajectory only a tiny bit, given the scale of millions of miles and several decades for the course change to take effect, could cause an asteroid to miss the Earth altogether.
"So far we've been relying on luck," says Binzel, "but luck is not a plan." Now that we have the technology to discover what's careening through our space neighborhood, it's our ethical duty to deploy it. If we don't use our technology to gain the knowledge we need to defend the planet, Binzel concludes, "it would be the most epic failure in the history of science."
Should Congress green light the $40 million budget for the new asteroid-hunting telescope? @NASA #NASA #astroid— leapsmag (@leapsmag) 1564681293.0
A ‘Press Release from the Future’ Announces Service for Parents to Genetically Engineer Their Kids
Most people don't recognize how significantly and soon the genetic revolution will transform healthcare, the way we make babies, and the nature of the babies we make. The press release below is a thought experiment today. Within a decade, it won't be. * * *
Genomix Launches uDarwin, a New Business to Help Parents Optimize the Health, Well-Being, and Beneficial Traits of their Future Offspring
NEW YORK, July 29, 2029 /PRMediawire/ -- Genomix, a Caribbean-based health and wellness company, today announced the launch of uDarwin, a discrete, confidential service helping parents select and edit the pre-implanted embryos of their future children.
"Our mission is to help prospective parents realize their dream of parenthood in the safest manner possible while helping them optimize their future children's potential."
"We often fetishize nature," said Genomix Medical Director and Co-Founder Dr. Noam Heller, "but the traditional process of conception through sex confers risks on future children that can be significantly reduced through the careful and safe application of powerful new technologies."
Approximately three percent of all children are born with some type of harmful genetic mutation. Through its patented process of extracting eggs from the prospective mother, fertilizing these eggs with sperm from the intended father or from one of the superstar donor samples in the proprietary uDarwin gene bank, and screening up to twenty of these embryos prior to implantation, this risk can be brought down to under one percent.
"Having a baby is the most intimate and important experience in most people's lives," said Genomix CEO and co-founder Rich Azadian. "Our mission is to help prospective parents realize their dream of parenthood in the safest manner possible while helping them optimize their future children's potential."
In addition to screening pre-implanted embryos to significantly reduce disease risk, uDarwin uses its proprietary algorithm for the "polygenic scoring" of embryos to directionally predict potential future attributes including healthspan, height, IQ, personality style, and other complex genetic traits. Attributes once accepted as being the result of fate or chance can now increasingly be selected by parents from among their own natural embryos using this entirely safe process.
A premium product offering, uDarwin+, provides parents the opportunity to make up to three single gene mutations to their selected embryo to reduce a risk or confer a particular benefit. Among the most popular options for this service include increased resistance to HIV and other viruses, a greater ability to build muscle mass, and enhanced cognition. Additional edits will be made available as the science of human genome editing further advances.
Jamie Metzl's new book, Hacking Darwin: Genetic Engineering and the Future of Humanity, explores how the genetic revolution is transforming our healthcare, the way we make babies, and the nature of and babies we make, what this means for each of us, and what we must all do now to prepare for what's coming.
"uDarwin is proud to be the first company in the world offering the highest level of reproductive choice to parents," Mr. Azadian continued. "Genetic technologies are allowing us for the first time to crack the code of our health and identity. As pioneers in applying the most advanced genetic technologies to human reproduction, we recognize that prospective parents' desire for the services we offer exceeds societal levels of comfort with this technology. Our highest levels of customer service, comfort, and confidentiality ensure parents can secure massive benefits for their future children while avoiding unnecessary attention or any compromise of privacy."
All uDarwin services will be carried out in the company's state-of-the-art clinic aboard a super-luxury 500-foot yacht operating in international waters. After applying on the secure uDarwin website and gaining approval, clients are provided a date, time, and location to meet a company representative at a conveniently located Caribbean marina from where they will be shuttled to the uDarwin clinic. "Pioneers have always traveled beyond boundaries to create new possibilities," Mr. Azadian added. "Conceiving a child in a location where it can receive the greatest benefits of advanced science is no different."
"Pioneers have always traveled beyond boundaries to create new possibilities."
The cost of the basic uDawin service is $5 million, with half paid up front and half paid following the successful birth of a baby. Charges for uDarwin+, premium sperm or egg donors, surrogates, and other services are additional. "uDarwin is not for everyone," Mr. Azadian said, "but most parents of significant means understand that the benefits of optimal genetics far exceed almost any monetary cost."
"The genetic revolution has already begun," Medical Director Heller added. "The question for prospective parents is whether they want to be the last parents who left the health and identity of their future children to chance or the first to give their future children the greatest chance of optimal health and maximal fulfillment in the new reality that will arrive far sooner than most people appreciate."
If you could genetically alter your future children, would you? https://t.co/N0tqwX4Qd3— leapsmag (@leapsmag) 1564426548.0