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.
Your Privacy vs. the Public's Health: High-Tech Tracking to Fight COVID-19 Evokes Orwell
The COVID-19 pandemic has placed public health and personal privacy on a collision course, as smartphone technology has completely rewritten the book on contact tracing.
It's not surprising that an autocratic regime like China would adopt such measures, but democracies such as Israel have taken a similar path.
The gold standard – patient interviews and detective work – had been in place for more than a century. It's been all but replaced by GPS data in smartphones, which allows contact tracing to occur not only virtually in real time, but with vastly more precision.
China has gone the furthest in using such tech to monitor and prevent the spread of the coronavirus. It developed an app called Health Code to determine which of its citizens are infected or at risk of becoming infected. It has assigned each individual a color code – red, yellow or green – and restricts their movement depending on their assignment. It has also leveraged its millions of public video cameras in conjunction with facial recognition tech to identify people in public who are not wearing masks.
It's not surprising that an autocratic regime like China would adopt such measures, but democracies such as Israel have taken a similar path. The national security agency Shin Bet this week began analyzing all personal cellphone data under emergency measures approved by the government. It texts individuals when it's determined they had been in contact with someone who had the coronavirus. In Spain and China, police have sent drones aloft searching for people violating stay-at-home orders. Commands to disperse can be issued through audio systems built into the aircraft. In the U.S., efforts are underway to lift federal restrictions on drones so that police can use them to prevent people from gathering.
The chief executive of a drone manufacturer in the U.S. aptly summed up the situation in an interview with the Financial Times: "It seems a little Orwellian, but this could save lives."
Epidemics and how they're surveilled often pose thorny dilemmas, according to Craig Klugman, a bioethicist and professor of health sciences at DePaul University in Chicago. "There's always a moral issue to contact tracing," he said, adding that the issue doesn't change by nation, only in the way it's resolved.
"Once certain privacy barriers have been breached, it can be difficult to roll them back again."
In China, there's little to no expectation for privacy, so their decision to take the most extreme measures makes sense to Klugman. "In China, the community comes first. In the U.S., individual rights come first," he said.
As the U.S. has scrambled to develop testing kits and manufacture ventilators to identify potential patients and treat them, individual rights have mostly not received any scrutiny. However, that could change in the coming weeks.
The American approach is also leaning toward using smartphone apps, but in a way that may preserve the privacy of users. Researchers at MIT have released a prototype known as Private Kit: Safe Paths. Patients diagnosed with the coronavirus can use the app to disclose their location trail for the prior 28 days to other users without releasing their specific identity. They also have the option of sharing the data with public health officials. But such an app would only be effective if there is a significant number of users.
Singapore is offering a similar app to its citizens known as TraceTogether, which uses both GPS and Bluetooth pings among users to trace potential encounters. It's being offered on a voluntary basis.
The Electronic Frontier Foundation, the leading nonprofit organization defending civil liberties in the digital world, said it is monitoring how these apps are developed and deployed. "Governments around the world are demanding new dragnet location surveillance powers to contain the COVID-19 outbreak," it said in a statement. "But before the public allows their governments to implement such systems, governments must explain to the public how these systems would be effective in stopping the spread of COVID-19. There's no questioning the need for far-reaching public health measures to meet this urgent challenge, but those measures must be scientifically rigorous, and based on the expertise of public health professionals."
Andrew Geronimo, director of the intellectual property venture clinic at the Case Western University School of Law, said that the U.S. government is currently in talks with Facebook, Google and other tech companies about using deidentified location data from smartphones to better monitor the progress of the outbreak. He was hesitant to endorse such a step.
"These companies may say that all of this data is anonymized," he said, "but studies have shown that it is difficult to fully anonymize data sets that contain so much information about us."
Beyond the technical issues, social attitudes may mount another challenge. Epic events such as 9/11 tend to loosen vigilance toward protecting privacy, according to Klugman and Geronimo. And as more people are sickened and hospitalized in the U.S. with COVID-19, Klugman believes more Americans will be willing to allow themselves to be tracked. "If that happens, there needs to be a time limitation," he said.
However, even if time limits are put in place, Geronimo believes it would lead to an even greater rollback of privacy during the next crisis.
"Once certain privacy barriers have been breached, it can be difficult to roll them back again," he warned. "And the prior incidents could always be used as a precedent – or as proof of concept."
Stem Cell Therapy for COVID-19 Is Gaining Steam in China, But Some Skeptical Scientists Urge Caution
Over the past two months, China's frantic search for an effective COVID-19 treatment has seen doctors trying everything from influenza drugs to traditional herbal remedies and even acupuncture, in a bid to help patients suffering from coronavirus-induced pneumonia.
"This treatment is particularly aimed at older patients who are seriously ill. These kinds of patients are in the danger zone."
Since mid February, one approach that has gained increasing traction is stem cell therapies, treatments that have often been viewed as a potential panacea by desperate patients suffering from degenerative incurable conditions ranging from Parkinson's to ALS. In many of these diseases, reality has yet to match the hype.
In COVID-19, there are hopes it might, though some experts are warning not to count on it. At Beijing's YouAn Hospital, doctors have been treating patients at various stages of the illness with intravenous infusions of so-called mesenchymal stem cells taken from umbilical cord tissue, as part of an ongoing clinical trial since January 21. The outcomes of the initial seven patients – published last month – appeared promising and the trial has since been expanded to 31 patients according to Dr. Kunlin Jin, a researcher at University of North Texas Health Science Center who is collaborating with the doctors in Beijing.
"Sixteen of these patients had mild symptoms, eight are severe, and seven are critically severe," Jin told leapsmag. "But all patients have shown improvements in lung function following the treatment, based on CT scans -- most of them in the first three days and seven have now been completely discharged from hospital. This treatment is particularly aimed at older patients who are seriously ill. These kinds of patients are in the danger zone; it's essential that they receive treatment, but right now we have nothing for most of them. No drugs or anything."
The apparent success of the very small Beijing trial has since led to a nationwide initiative to fast-track stem cell therapies for COVID-19. Across China, there are currently 36 clinical trials intending to use mesenchymal stem cells to treat COVID-19 patients that are either in the planning or recruiting phases. The Chinese Medical Association has now issued guidelines to standardize stem cell treatment for COVID-19, while Zhang Xinmin, an official in China's Ministry of Science and Technology, revealed in a press conference last week that a stem cell-based drug has been approved for clinical trials.
The thinking behind why stem cells could be a fast-acting and effective treatment is due to the nature of COVID-19. The thousands of fatalities worldwide are not from the virus directly, but from a dysfunctional immune response to the infection. Patients die because their respiratory systems become overwhelmed by a storm of inflammatory molecules called cytokines, causing lung damage and failure. However, studies in mice have long shown that stem cells have anti-inflammatory properties with the ability to switch off such cytokine storms, reducing such virus-induced lung injuries.
"There has been an enormous amount of hype about these cells, and there is scant scientific evidence that they have any therapeutic effect in any situation. "
"The therapy can inhibit the overactivation of the immune system and promote repair by improving the pulmonary microenvironment and improve lung function," explained Wei Hou, one of the doctors conducting the trial at YouAn Hospital.
However not everyone is convinced, citing the small number of patients treated to date, and potential risks from such therapy. "We just don't know enough to believe that stem cells might be helpful with COVID-19," said Paul Knoepfler, professor of cell biology at UC Davis. "The new stem cell studies are too small and lack controls, making it impossible to come to any solid conclusions. The chance of benefit is low based on the little we know so far and there are going to be risks that are hard to pin down. For instance, what if a stem cell infusion impairs some kind of needed immune response?"
Other scientists are even more skeptical. "I am concerned about all treatments that use mesenchymal stem cells," warned Jeanne Loring, the Director of the Center for Regenerative Medicine at Scripps Research in La Jolla, Calif. "There has been an enormous amount of hype about these cells, and there is scant scientific evidence that they have any therapeutic effect in any situation. Typically, these treatments are offered to people who have diseases without cures. I'm certain that there will be evidence-based treatments for COVID19, but I understand that they are not yet available, people are desperate, and they will try anything. I hope the sick are not taken advantage of because of their desperation."
Despite such concerns, the steadily rising death toll from COVID-19 means other nations are preparing to proceed with their own clinical trials of mesenchymal stem cells. Jin said he has been contacted by researchers and clinicians around the world seeking information on how to conduct their own trials, with the University of Cambridge's Stem Cell Institute in the U.K. reportedly looking to initiate a trial.
The scale of the global emergency has seen governments repeatedly calling on the corporate world to invest in the search for a cure, and the Australian company Mesoblast – a global leader in cell-based therapies for a range of diseases – are expecting to receive the green light to initiate clinical trials of their own stem cell based product against COVID-19.
"We're talking to at least three major governments," said Silviu Itescu, CEO and Managing Director of Mesoblast. "We are working with groups in Australia, the U.S. and the U.K., and I expect there'll be trials starting imminently in all those jurisdictions."
Itescu is bullish that the therapy has a good chance of proving effective, as it recently successfully completed Phase III trials for severe steroid-refractory acute graft versus host disease (GVHD) – a condition which leads to a very similar disease profile to COVID-19.
"The exact same cytokine profile is occurring in the lungs of COVID-19 infected patients as in GVHD which is destructive to the local lung environment," he said. "If our cells are able to target that in GVHD, they ought to be able to switch off the cytokine response in COVID lung disease as well."
"What we should be focusing on now is not the possible boost to the stem cell field, but rather doing rigorous science to test whether stem cells can help COVID-19 patients."
Jin is hopeful that if the imminent trials yield successful results, the U.S. FDA could fast-track mesenchymal stem cells as an approved emergency therapy for COVID-19. However, Knoepfler cautions that there is a need for far more concrete and widespread proof of the benefit before regulatory bodies start ushering through the green light.
"What we should be focusing on now is not the possible boost to the stem cell field, but rather doing rigorous science to test whether stem cells can help COVID-19 patients," he said. "During a pandemic, it's reasonable to do some testing of unproven interventions like stem cells in small studies, but results from them should be discussed in a sober, conservative manner until there is more evidence."