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.
Artificial Intelligence Needs Doctors As Much As They Need It
The media loves to hype concerns about artificial intelligence: What if machines become super-intelligent and self-aware? How will humanity compete and survive? But artificial intelligence today is a far cry from a robot takeover. "AI" is a catch-all term that often refers to machine training or machine learning: There is an abundance of data, vastly more than the human mind can assimilate, being tagged, captured and stored. This systematic data processing requires methodologies that can put it in usable form and formats. While these new developments stoke fear in some corners, the ability to predict outcomes is generally seen as a good thing, as it can mitigate risks and even save lives.
We, collectively, want AI even though it is seldom expressed this way.
The prospects and attempts toward artificial intelligence has been with us for decades. Only recently have the underlying technologies and infrastructure--including computer processing, storage, networking speed and advanced software platforms--become omnipresent. These technological advances enabled the implementation of data mining concepts and the subsequent advantages that were not feasible just a decade ago.
AI is fantastical by vision, evolutionary by experience, and disruptive upon reflection. In the world of health care, AI is already transforming research and clinical practice. We, collectively, want AI even though it is seldom expressed this way. What we, the patient population, patient advocates and caregivers, agree on and want is: (1) timely, precise and inexpensive diagnoses of our ailments, injuries and disorders; (2) timely, personalized, highly effective and efficient courses of therapies; and (3) expedited recovery with minimum deficits, complications and recurrence.
"Artificial intelligence and machine learning will impact healthcare as profoundly as the discovery of the microscope."
Implicitly, we all are saying that we want our healthcare systems and clinicians to accomplish truly inhuman feats: to incorporate all sources of structured data (such as published statistics and reports) and unstructured data (including news articles, conversational analysis by care givers, nuances of similar cases, talks at professional societies); to analyze the data sourced and uncover patterns, reveal side effects, define probable success and outcomes; and to present the best personalized course of treatment for the patient that addresses the ailment and mitigates associated risks. It is hard to argue against any of this.
In a recent published interview, Keith J. Dreyer, executive director of the Massachusetts General Hospital and Brigham and Women's Hospital Center for Clinical Data Science, says that "artificial intelligence and machine learning will impact healthcare as profoundly as the discovery of the microscope."
But as AI helps physicians in profound ways, like detecting subtle lesions on scans or distinguishing the symptoms of a stroke from a brain tumor, we humans can't get too complacent. Evolving AI platforms will provide more sophisticated sets of "tools" to address both mundane and complex medical challenges, albeit with humans very much in the mix and routinely at the helm.
Humans do not appear endangered to be replaced anytime soon.
Human beings are capable of a level of nuance and contextual understanding of complex medical scenarios and, consequently, do not appear endangered to be replaced anytime soon. These platforms will do some heavy lifting for sure and provide considerable assistance across the healthcare industry. But human involvement is crucial, as we are best at adaptive learning, cognition, ensuring accuracy of the data, and continually providing feedback to improve the machine learning components of the AI platforms that the health industry will increasingly rely upon.
The human/machine interface is not binary; there is no line in the sand. It is fuzzy and evolutionary, a synchronicity that we all will surely witness and experience. In the future, it may be possible that all recorded knowledge, including genetic, genomic and laboratory data, from structured and unstructured sources, can be at the fingertips of your clinician, and then factored into diagnosing your condition and prescribing your course of treatment. This is precision and personalized medicine on a grand scale applied at the micro level--you!
But none of this will diminish the importance of doctors, nurses and all assortment of care providers. Though they all will undoubtedly become more effective with such awesome AI assistance, their job will always be to heal you with compassion, wisdom, and kindness, for the essence of humanity cannot be automated.
This Revolutionary Medical Breakthrough Is Not a Treatment or a Cure
What is a disease? This seemingly abstract and theoretical question is actually among the most practical questions in all of biomedicine. How patients are diagnosed, treated, managed and excused from various social and moral obligations hinges on the answer that is given. So do issues of how research is done and health care paid for. The question is also becoming one of the most problematic issues that those in health care will face in the next decade.
"The revolution in our understanding of the human genome, molecular biology, and genetics is creating a huge--if little acknowledged--shift in the understanding of what a disease is."
That is because the current conception of disease is undergoing a revolutionary change, fueled by progress in genetics and molecular biology. The consequences of this shift in the definition of disease promise to be as impactful as any other advance in biomedicine has ever been, which is admittedly saying a lot for what is in essence a conceptual change rather than one based on an empirical scientific advance.
For a long time, disease was defined by patient reports of feeling sick. It was not until the twentieth century that a shift occurred away from subjective reports of clusters of symptoms to defining diseases in terms of physiological states. Doctors began to realize that not all symptoms of fever represented the presence of the same disease. Flu got distinguished from malaria. Diseases such as hypertension, osteoporosis, cancer, lipidemia, silent myocardial infarction, retinopathy, blood clots and many others were recognized as not producing any or slight symptoms until suddenly the patient had a stroke or died.
The ability to assess both biology and biochemistry and to predict the consequences of subclinical pathological processes caused a distinction to be made between illness—what a person experiences—and disease—an underlying pathological process with a predictable course. Some conditions, such as Gulf War Syndrome, PTSD, many mental illnesses and fibromyalgia, remain controversial because no underlying pathological process has been found that correlates with them—a landmark criterion for diagnosing disease throughout most of the last century.
"Diseases for which no relationship had ever been posited are being lumped together due to common biochemical causal pathways...that are amenable to the same curative intervention."
The revolution in our understanding of the human genome, molecular biology, and genetics is creating a huge--if little acknowledged--shift in the understanding of what a disease is. A better understanding of the genetic and molecular roots of pathophysiology is leading to the reclassification of many familiar diseases. The test of disease is now not the pathophysiology but the presence of a gene, set of genes or molecular pathway that causes pathophysiology. Just as fever was differentiated into a multitude of diseases in the last century, cancer, cognitive impairment, addiction and many other diseases are being broken or split into many subkinds. And other diseases for which no relationship had ever been posited are being lumped together due to common biochemical causal pathways or the presence of similar dangerous biochemical products that are amenable to the same curative intervention, no matter how disparate the patients' symptoms or organic pathologies might appear.
We used to differentiate ovarian and breast cancers. Now we are thinking of them as outcomes of the same mutations in certain genes in the BRCA regions. They may eventually lump together as BRCA disease.
Other diseases such as familial amyloid polyneuropathy (FAP) which causes polyneuropathy and autonomic dysfunction are being split apart into new types or kinds. The disease is the product of mutations in the transthyretin gene. It was thought to be an autosomal dominant disease with symptomatic onset between 20-40 years of age. However, as genetic testing has improved, it has become clear that FAP's traditional clinical presentation represents a relatively small portion of those with FAP. Many patients with mutations in transthyretin — even mutations commonly seen in traditional FAP patients — do not fit the common clinical presentation. As the mutations begin to be understood, some people that were previously thought to have other polyneuropathies, such as chronic inflammatory demyelinating neuropathy, are now being rediagnosed with newly discovered variants of FAP.
"We are at the start of a major conceptual shift in how we organize the world of disease, and for that matter, health promotion."
Genome-wide association studies are beginning to find many links between diseases not thought to have any connection or association. For example some forms of diabetes, rheumatoid arthritis and thyroid disease may be the products of a small family of genetic mutations.
So why is this shift toward a genetic and molecular diagnostics likely to shake up medicine? One obvious way is that research projects may propose to recruit subjects not according to current standards of disease but on the basis of common genetic mutations or similar errors in biochemical pathways. It won't matter in a future study if subjects in a trial have what today might be termed nicotine addiction or Parkinsonism. If the molecular pathways producing the pathology are the same, then both groups might well wind up in the same trial of a drug.
In addition, what today look like common maladies—pancreatic cancer, severe depression, or acne, for example, could wind up being subdivided into so many highly differentiated versions of these conditions that each must be treated as what we now classify as a rare or ultra-rare disease. Unique biochemical markers or genetic messages may see many diseases broken into a huge number of distinct individual disease entities.
Patients may find that common genetic pathways or multiple effects from a single gene may create new alliances for fund-raising and advocacy. Groups fighting to cure mental and physical illnesses may wind up forgetting about their outward differences in the effort to alter genes or attack common protein markers.
Disease classification appears stable to us—until it isn't. And we are at the start of a major conceptual shift in how we organize the world of disease, and for that matter, health promotion. Classic reductionism, the view that all observable biological phenomena can be explained in terms of underlying chemical and physical principles, may turn out not to be true. But the molecular and genetic revolutions churning through medicine are illustrating that reductionism is going to have an enormous influence on disease classification. That is not a bad thing, but it is something that is going to take a lot to get used to.