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.
With Mentors, Models, and #MeToo, Femtech Comes of Age
In her quest to become a tech entrepreneur, Stacy Chin has been an ace at tackling thorny intellectual challenges, mastering everything from molecules to manufacturing.
These mostly female leaders of firms with products addressing women's health concerns are winning in a big way, raising about $1.1 billion in startup funds over the past few years.
But the 28-year-old founder of HydroGlyde Coatings, based in Worcester, Mass., admitted to being momentarily stumped recently when pitching her product – a new kind of self-lubricating condom – to venture capitalists.
"Being a young female scientist and going into that sexual healthcare space, it was definitely a little bit challenging to learn how to navigate during presentations and pitches when there were a lot of older males in the audience," said Chin, whose product is of special appeal to older women suffering from vaginal dryness. "I eventually figured it out, but it wasn't easy."
Chin is at the vanguard of a new generation of "femtech" entrepreneurs heading companies with names like LOLA Tampons, Prelude Fertility, and Peach, bringing once-taboo topics like menstruation, ovulation, incontinence, breastfeeding, pelvic pain and, yes, female sexual pleasure to the highest chambers of finance. These mostly female leaders of firms with products addressing women's health concerns are winning in a big way, raising about $1.1 billion in startup funds over the past few years, according to the New York data analytics firm CB Insights.
"We are definitely at a watershed moment for femtech. But we need to remember that [it's] an overnight sensation that is decades in the making."
If the question is "Why now?", the answer may be that femtech leaders are benefiting from the current conversations around respect for women in the workplace, and long-term efforts to achieve gender equality in the male-dominated tech industry.
"We are definitely at a watershed moment for femtech," said Rachel Braun Scherl, a self-described "vaginepreneur" whose new book, "Orgasmic Leadership," profiles femtech leaders. "But we need to remember that femtech is an overnight sensation that is decades in the making."
In contrast with earlier and perhaps less successful generations of women in tech, these pioneers can point to mentors who are readily accessible, as well as more female VC and corporate heads they can directly address when making pitches. There's also a changing cultural landscape where sexual harassment is in the news and women who talk openly about sex in a business context can be taken seriously.
"Change is definitely in the air," said Kevin O'Sullivan, the president and CEO of Massachusetts Biomedical Initiatives, who sponsored Chin and has helped launch more than a hundred biotech companies in his home state since the 1980s.
Like a pinprick bursting a balloon, the #MeToo social movement and its focus on the prevalence of sexual harassment and assault is a factor in the success of femtech, some experts believe, provoking heightened awareness about the role of women in society -- including equal access to start-up capital.
"If such a difficult topic is being discussed in the open, that means more and more people are speaking out and are no longer afraid about sharing their own concerns," said Debbie Hart, president and CEO of BioNJ, a business trade group she founded in 1994. "That's empowering the whole women's movement."
The power of programs that allow young women to witness successful older women in leadership cannot be overstated.
Observers like Hart say that femtech's advent is also due to a payoff from longer-term investments in a slew of programs encouraging girls to pursue STEM careers and women to be hired as leaders, as well as changing social norms to allow female health to be part of the public discourse.
The power of programs that allow young women to witness successful older women in leadership cannot be overstated, according to Susan Scherreik of the Stillman School of Business at Seton Hall University in New Jersey.
"What I have found in entrepreneurship is that it's all about two things: role models and mentoring," said Scherreik, director of the university's Center for Entrepreneurial Studies.
One of Scherreik's top students, Madison Schott, is convinced that the availability of female mentors has been instrumental to her success and will remain so in her future. "It definitely is very encouraging," said Schott, who won the "Pirates Pitch" university-wide business start-up competition in April for an app she is developing that uses AI to guide readers to reliable news sources. "Woman to woman," she added, "you can be more open when you have questions or problems."
Programs that showcase successful females in leadership positions are beginning to bear fruit, inspiring a new generation of females in business, according to Susan Scherreik (at left), director of Seton Hall University's Center for Entrepreneurial Studies at the Stillman School of Business. Her student, Madison Schott (right), is the winner of a university-wide business start-up competition for an app she is developing.
While femtech entrepreneurs may be the beneficiaries of change, they also may be its agents. Scherl, the author, who has been working in the female healthcare sector for more than a decade, believes in persistence. In 2010, organizers of a major awards show banned a product she was marketing, Zestra Essential Arousal Oils*, from a gift bag for honorees. Two years ago, however, times changed and femtech prevailed. The company making goodie bags for Academy Awards nominees included another one of her products, Nuelle's Fiera, a $250 vibrator.
"We come from so many different perspectives when it comes to sex, whether it is cultural, religious, age-related, or even from a trauma, so we never have created a common language," Scherl said. "But we in femtech are making huge progress. We are not only selling products now, we are selling conversation, and we are selling a comfort with sexuality in all its complex forms."
[*Correction: Due to a reporting error, the product that was banned in 2010 was initially identified as Nuelle's Fiera, not Zestra Essential Arousal Oils. The article has been updated for accuracy. --Editor]
Worried About Eating GMOs? That’s Not the Real Problem
The 21st century food system is awash in ethical issues. To name just a handful: There's the environmental impacts of farming, the human health effects of diets based on animal products and processed foods, the growing clamor around food waste, and the longstanding concerns about agricultural labor. The last decade has seen the emergence of "ethical consumption," as people have been encouraged to avoid products that are associated with animal cruelty or unfair to farmers.
Misguided concerns about GMOs are missing the point altogether and distracting from a far more substantive ethical problem.
But consumers have never been so ignorant about where food comes from, and they are vulnerable to oversimplifications and faulty messaging. Many would include the first generation of crops from agricultural applications of recombinant DNA methods for genetic improvement—so called GMOs—among the foods they should avoid for ethical reasons. Unfortunately, these misguided concerns are missing the point altogether and distracting from a far more substantive ethical problem.
As we stand on the precipice of a new era in food and biotechnology – crops and animals with genomes altered through gene editing – it is more important than ever to let go of unnecessary fears and to pay attention to the real hazards of agricultural innovation.
But first, as a bioethicist with almost 40 years of experience working on issues in the food system, let me stress the overall context and rationale for trying to make changes in plant and animal genetics. Doing so, whether through conventional breeding or biotechnology, allows producers to meet the challenges of seasonal climate differences and increase yields.
And just because a food was created through ordinary plant breeding vs. genetic modification does not automatically make it safe. Things can and do go wrong in ordinary plant breeding, such as with potatoes and tomatoes. These both produce toxins in the green parts of the plant, and breeders exercise caution to ensure that toxins aren't transferred to edible parts.
Despite real risks, there is no regulatory oversight that protects us from these known hazards. We rely on the professional ethics of agricultural scientists. And GMOs are, in comparison, much more carefully tested and regulated. The claim that they are "unregulated" is just false.
We should not ignore the role that all gene technologies have played in displacing small farmers, depleting rural communities, and shifting economic control.
I do want to shift the public's attention away from the anti-GMO debate to more substantive questions about contemporary agriculture that really have little to do with where the genes in their food came from, or how they got there.
No matter how important genetic improvements might be in terms of total global food production, we should not ignore the role that all gene technologies—including breeding—have played in displacing small farmers, depleting rural communities and shifting economic control of agriculture into a small circle of powerful actors. Globally, these changes have had disproportionately harmful effects on women and people of color.
Combined with mechanization and chemicals, gene technologies have freed planters from their dependence on impoverished and poorly educated field hands, but they did nothing to help the fieldworkers transition to a new line of work. These are the real problems that deserve the public's and the science community's attention, not the overly narrow worries about eating GMOs.
But these problems are viewed as "not ours" by agricultural insiders, and they continue to be ignored by scientists whose focus is solely on biology. Many of the concerns that are today viewed as "urban problems" or "social issues" have origins in agriculture. For example, in California tomatoes, the development of mechanical harvesting led to a rapid concentration of ownership and the displacement of thousands of field hands. In the South, similar technologies displaced black farmers working land owned by whites, causing migration to urban centers and unskilled jobs. I must fault the science community for a lack of willingness to even take the thrust of these more socially oriented critiques seriously.
The new suite of tools for genetic modification that go under the name "gene editing" promise greater precision. They should allow scientists to target the locus for new genes in a plant or animal genome, and minimize the chance for causing unwanted impacts on gene functioning. This added precision is reducing some of the uncertainties in the mind of technology developers, and they have been expressing hope that their own confidence will be shared by regulators and by the public at large. In fact, the U.S. government recently issued a statement that gene-edited crops do not require additional regulation because they're just as safe as crops produced through conventional breeding.
It is indeed possible that the public doubts about genetically modified food will be assuaged by this argument. We can only wait and see. Whether or not gene editing will lead to more reflection about agriculture's complicity in problems of economic inequality or structural racism depends much more on the culture of the science community than it does on the technology itself.