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.
Science's dream of creating perfect custom organs on demand as soon as a patient needs one is still a long way off. But tiny versions are already serving as useful research tools and stepping stones toward full-fledged replacements.
Although organoids cannot yet replace kidneys, they are invaluable tools for research.
The Lowdown
Australian researchers have grown hundreds of mini human kidneys in the past few years. Known as organoids, they function much like their full-grown counterparts, minus a few features due to a lack of blood supply.
Cultivated in a petri dish, these kidneys are still a shadow of their human counterparts. They grow no larger than one-sixth of an inch in diameter; fully developed organs are up to five inches in length. They contain no more than a few dozen nephrons, the kidney's individual blood-filtering unit, whereas a fully-grown kidney has about 1 million nephrons. And the dish variety live for just a few weeks.
An organoid kidney created by the Murdoch Children's Institute in Melbourne, Australia.
Photo Credit: Shahnaz Khan.
But Melissa Little, head of the kidney research laboratory at the Murdoch Children's Institute in Melbourne, says these organoids are invaluable tools for research. Although renal failure is rare in children, more than half of those who suffer from such a disorder inherited it.
The mini kidneys enable scientists to better understand the progression of such disorders because they can be grown with a patient's specific genetic condition.
Mature stem cells can be extracted from a patient's blood sample and then reprogrammed to become like embryonic cells, able to turn into any type of cell in the body. It's akin to walking back the clock so that the cells regain unlimited potential for development. (The Japanese scientist who pioneered this technique was awarded the Nobel Prize in 2012.) These "induced pluripotent stem cells" can then be chemically coaxed to grow into mini kidneys that have the patient's genetic disorder.
"The (genetic) defects are quite clear in the organoids, and they can be monitored in the dish," Little says. To date, her research team has created organoids from 20 different stem cell lines.
Medication regimens can also be tested on the organoids, allowing specific tailoring for each patient. For now, such testing remains restricted to mice, but Little says it eventually will be done on human organoids so that the results can more accurately reflect how a given patient will respond to particular drugs.
Next Steps
Although these organoids cannot yet replace kidneys, Little says they may plug a huge gap in renal care by assisting in developing new treatments for chronic conditions. Currently, most patients with a serious kidney disorder see their options narrow to dialysis or organ transplantation. The former not only requires multiple sessions a week, but takes a huge toll on patient health.
Ten percent of older patients on dialysis die every year in the U.S. Aside from the physical trauma of organ transplantation, finding a suitable donor outside of a family member can be difficult.
"This is just another great example of the potential of pluripotent stem cells."
Meanwhile, the ongoing creation of organoids is supplying Little and her colleagues with enough information to create larger and more functional organs in the future. According to Little, researchers in the Netherlands, for example, have found that implanting organoids in mice leads to the creation of vascular growth, a potential pathway toward creating bigger and better kidneys.
And while Little acknowledges that creating a fully-formed custom organ is the ultimate goal, the mini organs are an important bridge step.
"This is just another great example of the potential of pluripotent stem cells, and I am just passionate to see it do some good."
Phil Gutis never had a stellar memory, but when he reached his early 50s, it became a problem he could no longer ignore. He had trouble calculating how much to tip after a meal, finding things he had just put on his desk, and understanding simple driving directions.
From 1998-2017, industry sources reported 146 failed attempts at developing Alzheimer's drugs.
So three years ago, at age 54, he answered an ad for a drug trial seeking people experiencing memory issues. He scored so low in the memory testing he was told something was wrong. M.R.I.s and PET scans confirmed that he had early-onset Alzheimer's disease.
Gutis, who is a former New York Times reporter and American Civil Liberties Union spokesman, felt fortunate to get into an advanced clinical trial of a new treatment for Alzheimer's disease. The drug, called aducanumab, had shown promising results in earlier studies.
Four years of data had found that the drug effectively reduced the burden of protein fragments called beta-amyloids, which destroy connections between nerve cells. Amyloid plaques are found in the brains of patients with Alzheimer's disease and are associated with impairments in thinking and memory.
Gutis eagerly participated in the clinical trial and received 35 monthly infusions. "For the first 20 infusions, I did not know whether I was receiving the drug or the placebo," he says. "During the last 15 months, I received aducanumab. But it really didn't matter if I was receiving the drug or the placebo because on March 21, the trial was stopped because [the drug company] Biogen found that the treatments were ineffective."
The news was devastating to the trial participants, but also to the Alzheimer's research community. Earlier this year, another pharmaceutical company, Roche, announced it was discontinuing two of its Alzheimer's clinical trials. From 1998-2017, industry sources reported 146 failed attempts at developing Alzheimer's drugs. There are five prescription drugs approved to treat its symptoms, but a cure remains elusive. The latest failures have left researchers scratching their heads about how to approach attacking the disease.
The failure of aducanumab was also another setback for the estimated 5.8 million people who have Alzheimer's in the United States. Of these, around 5.6 million are older than 65 and 200,000 suffer from the younger-onset form, including Gutis.
Gutis is understandably distraught about the cancellation of the trial. "I really had hopes it would work. So did all the patients."
While drug companies have failed so far, another group is stepping up to expedite the development of a cure: venture philanthropists.
For now, he is exercising every day to keep his blood flowing, which is supposed to delay the progression of the disease, and trying to eat a low-fat diet. "But I know that none of it will make a difference. Alzheimer's is a progressive disease. There are no treatments to delay it, let alone cure it."
But while drug companies have failed so far, another group is stepping up to expedite the development of a cure: venture philanthropists. These are successful titans of industry and dedicated foundations who are donating large sums of money to fill a much-needed void – funding research to look for new biomarkers.
Biomarkers are neurochemical indicators that can be used to detect the presence of a disease and objectively measure its progression. There are currently no validated biomarkers for Alzheimer's, but researchers are actively studying promising candidates. The hope is that they will find a reliable way to identify the disease even before the symptoms of mental decline show up, so that treatments can be directed at a very early stage.
Howard Fillit, Founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, says, "We need novel biomarkers to diagnose Alzheimer's disease and related dementias. But pharmaceutical companies don't put money into biomarkers research."
One of the venture philanthropists who has recently stepped up to the task is Bill Gates. In January 2018, he announced his father had Alzheimer's disease in an interview on the Today Show with Maria Shriver, whose father Sargent Shriver, died of Alzheimer's disease in 2011. Gates told Ms. Shriver that he had invested $100 million into Alzheimer's research, with $50 million of his donation going to Dementia Discovery Fund, which looks for new cures and treatments.
That August, Gates joined other investors in a new fund called Diagnostics Accelerator. The project aims to supports researchers looking to speed up new ideas for earlier and better diagnosis of the disease.
Gates and other donors committed more than $35 million to help launch it, and this April, Jeff and Mackenzie Bezos joined the coalition, bringing the current program funding to nearly $50 million.
"It makes sense that a challenge this significant would draw the attention of some of the world's leading thinkers."
None of these funders stand to make a profit on their donation, unlike traditional research investments by drug companies. The standard alternatives to such funding have upsides -- and downsides.
As Bill Gates wrote on his blog, "Investments from governments or charitable organizations are fantastic at generating new ideas and cutting-edge research -- but they're not always great at creating usable products, since no one stands to make a profit at the end of the day.
"Venture capital, on the other end of the spectrum, is more likely to develop a test that will reach patients, but its financial model favors projects that will earn big returns for investors. Venture philanthropy splits the difference. It incentivizes a bold, risk-taking approach to research with an end goal of a real product for real patients. If any of the projects backed by Diagnostics Accelerator succeed, our share of the financial windfall goes right back into the fund."
Gutis said he is thankful for any attention given to finding a cure for Alzheimer's.
"Most doctors and scientists will tell you that we're still in the dark ages when it comes to fully understanding how the brain works, let alone figuring out the cause or treatment for Alzheimer's.
"It makes sense that a challenge this significant would draw the attention of some of the world's leading thinkers. I only hope they can be more successful with their entrepreneurial approach to finding a cure than the drug companies have been with their more traditional paths."