New drug for schizophrenia could meet desperate need for better treatments
The field of treating schizophrenia with drugs has been stuck in a long drought but, this month, a late-stage clinical trial found a new drug called KarXT could treat a range of symptoms.
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.
Is Carbon Dioxide the New Black? Yes, If These Fabric-Designing Scientists Have Their Way
The entrepreneurs Tawfiq Nasr Allah (left, standing) and Benoit Illy (right, sitting down) at Fairbrics' lab in Clichy, France.
Each year the world releases around 33 billion tons of carbon dioxide into the atmosphere. What if we could use this waste carbon dioxide to make shirts, dresses and hats? It sounds unbelievable. But two innovators are trying to tackle climate change in this truly unique way.
Chemist Tawfiq Nasr Allah set up Fairbrics with material scientist Benoît Illy in 2019. They're using waste carbon dioxide from industrial fumes as a raw material to create polyester, identical to the everyday polyester we use now. They want to take a new and very different approach to make the fashion industry more sustainable.
The Dark Side of Fast Fashion
The fashion industry is responsible for around 4% of global emissions. In a 2015 report, the MIT Materials Systems Laboratory predicted that the global impact of polyester fabric will grow from around 880 billion kg of CO2 in 2015 to 1.5 trillion kg of CO2 by 2030.
Professor Greg Peters, an expert in environmental science and sustainability, highlights the wide-ranging difficulties caused by the production of polyester. "Because it is made from petrochemical crude oil there is no real limit on how much polyester can be produced...You have to consider the ecological damage (oil spills, fracking etc.) caused by the oil and gas industry."
Many big-name brands have pledged to become carbon neutral by 2050. But nothing has really changed in the way polyester is produced.
Some companies are recycling plastic bottles into polyester. The plastic is melted into ultra-fine strands and then spun to create polyester. However, only a limited number of bottles are available. New materials must be added because of the amount of plastic degradation that takes place. Ultimately, recycling accounts for only a small percentage of the total amount of polyester produced.
Nasr Allah and Illy hope they can offer the solution the fashion industry is looking for. They are not just reducing the carbon emissions that are conventionally produced by making polyester. Their process actually goes much further. It's carbon negative and works by using up emissions from other industries.
"In a sense we imitate what nature does so well: plants capture CO2 and turn it into natural fibers using sunlight, we capture CO2 and turn it into synthetic fibers using electricity."
Experts in the field see a lot of promise. Dr Phil de Luna is an expert in carbon valorization -- the process of converting carbon dioxide into high-value chemicals. He leads a $57-million research program developing the technology to decarbonize Canada.
"I think the approach is great," he says. "Being able to take CO2 and then convert it into polymers or polyester is an excellent way to think about utilizing waste emissions and replacing fossil fuel-based materials. That is overall a net negative as compared to making polyester from fossil fuels."
From Harmful Waste to Useful Raw Material
It all started with Nasr Allah's academic research, primarily at the French Alternative Energies and Atomic Energy Commission (CEA). He spent almost 5 years investigating CO2 valorization. In essence, this involves breaking the bonds between the carbon and oxygen atoms in CO2 to create bonds with other elements.
Recycling carbon dioxide in this way requires extremely high temperatures and pressures. Catalysts are needed to break the strong bonds between the atoms. However, these are toxic, volatile and quickly lose their effectiveness over time. So, directly converting carbon dioxide into the raw material for making polyester fibers is very difficult.
Nasr Allah developed a process involving multiple simpler stages. His innovative approach involves converting carbon dioxide to intermediate chemicals. These chemicals can then be transformed into the raw material which is used in the production of polyester. After many experiments, Nasr Allah developed new processes and new catalysts that worked more effectively.
"We use a catalyst to transform CO2 into the chemicals that are used for polyester manufacturing," Illy says. "In a sense we imitate what nature does so well: plants capture CO2 and turn it into natural fibers using sunlight, we capture CO2 and turn it into synthetic fibers using electricity."
The Challenges Ahead
Nasr Allah met material scientist Illy through Entrepreneur First, a programme which pairs individuals looking to form technical start-ups. Together they set up Fairbrics and worked on converting Nasr Allah's lab findings into commercial applications and industrial success.
"The main challenge we faced was to scale up the process," Illy reveals. "[It had to be] consistent and safe to be carried out by a trained technician, not a specialist PhD as was the case in the beginning."
They recruited a team of scientists to help them develop a more effective and robust manufacturing process. Together, the team gained a more detailed theoretical understanding about what was happening at each stage of the chemical reactions. Eventually, they were able to fine tune the process and produce consistent batches of polyester.
They're making significant progress. They've produced their first samples and signed their first commercial contract to make polyester, which will then be both fabricated into clothes and sold by partner companies.
Currently, one of the largest challenges is financial. "We need to raise a fair amount to buy the equipment we need to produce at a large scale," Illy explains.
How to Power the Process?
At the moment, their main scientific focus is getting the process working reliably so they can begin commercialization. In order to remain sustainable and economically viable once they start producing polyester on a large scale, they need to consider the amount of energy they use for carbon valorization and the emissions they produce.
The more they optimize the way their catalyst works, the easier it will be to transform the CO2. The whole process can then become more cost effective and energy efficient.
De Luna explains: "My concern is...whether their process will be economical at scale. The problem is the energy cost to take carbon dioxide and transform it into these other products and that's where the science and innovation has to happen. [Whether they can scale up economically] depends on the performance of their catalyst."
They don't just need to think about the amount of energy they use to produce polyester; they also have to consider where this energy comes from.
"They need access to cheap renewable energy," De Luna says, "...so they're not using or emitting CO2 to do the conversion." If the energy they use to transform CO2 into polyester actually ends up producing more CO2, this will end up cancelling out their positive environmental impact.
Based in France, they're well located to address this issue. France has a clean electricity system, with only about 10% of their electric power coming from fossil fuels due to their reliance on nuclear energy and renewables.
Where Do They Get the Carbon Dioxide?
As they scale up, they also need to be able to access a source of CO2. They intend to obtain this from the steel industry, the cement industry, and hydrogen production.
The technology to purify and capture waste carbon dioxide from these industries is available on a large scale. However, there are only around 20 commercial operations in the world. The high cost of carbon capture means that development continues to be slow. There are a growing number of startups capturing carbon dioxide straight from the air, but this is even more costly.
One major problem is that storing captured carbon dioxide is expensive. "There are somewhat limited options for permanently storing captured CO2, so innovations like this are important,'' says T. Reed Miller, a researcher at the Yale University Center for Industrial Ecology.
Illy says: "The challenge is now to decrease the cost [of carbon capture]. By using CO2 as a raw material, we can try to increase the number of industries that capture CO2. Our goal is to turn CO2 from a waste into a valuable product."
Beyond Fashion
For Nasr Allah and Illy, fashion is just the beginning. There are many markets they can potentially break into. Next, they hope to use the polyester they've created in the packaging industry. Today, a lot of polyester is consumed to make bottles and jars. Illy believes that eventually they can produce many different chemicals from CO2. These chemicals could then be used to make paints, adhesives, and even plastics.
The Fairbrics scientists are providing a vital alternative to fossil fuels and showcasing the real potential of carbon dioxide to become a worthy resource instead of a harmful polluter.
Illy believes they can make a real difference through innovation: "We can have a significant impact in reducing climate change."
Vaccine passports, if required by businesses and universities, may give people a false sense of security, one expert cautions.
Vaccines are one of the greatest public health accomplishments of all time. For centuries, public health has relied on vaccinations to prevent and control disease outbreaks for a plethora of infectious scourges, with our crowning achievement being the successful eradication of smallpox.
The purpose of vaccine documentation is to provide proof of an individual's protection from either becoming infected or transmitting a vaccine-preventable disease. Vouching for these protections requires a firm knowledge about the epidemiology of the disease, as well as scientific knowledge concerning the efficacy of the vaccine. The vaccines we currently require be documented have met these tests; the vaccine for COVID-19 has not yet been proven to do so.
Let's acknowledge that the term "vaccine passport" is a poor choice of words. Passports are a legal travel document created by nations and governed by law for identification of the bearer to control entry and exit from nation states. They often serve as legal forms of identification and as a record of international travel. They are generally very sophisticated documents that have been created in a secure manner and may include a range of electronic and, in some cases, biometric measures such as fingerprints to ensure the holder is indeed who they say they are. Vaccine passports are medical documents used to document the vaccination status of an individual. They do not undergo the same level of administrative scrutiny and cannot be used to verify that the presenter is indeed the vaccinated individual. Some companies do have electronic methods to address concerns about verification; however, most people currently have paper records that can be easily falsified.
"Vaccine passports" as currently proposed risk giving people a false sense of security.
Successful disease control from vaccination programs relies on the ability to vaccinate at a level that prevents large-scale disease spread and the ability to rapidly identify the presence of disease outbreaks. It requires reliable, safe, and effective vaccines that are easily delivered in clinical and nonclinical settings. Keeping vaccination information as a part of the medical record, and even having a separate specialized vaccine record for personal use, is a time-honored tradition.
Keeping a vaccination record provides a method to keep track of the many shots one receives and serves as a visual reminder to help ensure the appropriate vaccine shot schedule is maintained for vaccines requiring multiple doses. The vaccine record, when combined with vaccine safety monitoring systems, serves as a mechanism to track adverse events to monitor and ensure the safety of vaccines as a consumer product. The record also serves as the official record of vaccination when required for administrative or legally prescribed purposes.
"Vaccine passports" as currently proposed risk giving people a false sense of security. In the case of the COVID-19 vaccines currently approved for use, many of the essential questions remain unanswered. While we do know the current three vaccines are highly protective against severe disease and death, and there is some evidence that these vaccinations do reduce infections and virus transmission of SARS-CoV-2, we do not yet know the full degree to which this occurs.
For example, we know there have been some cases of people that have been infected in close proximity to getting their full vaccination and rare cases of breakthrough reinfections. A breakthrough infection in a restaurant is a challenge for contact tracing, but an outbreak from a movie theater exposure or a baseball game could spark a major outbreak at our current level of vaccination. Current CDC guidance recommends continued mask wearing in order to address these concerns.
We also do not yet know how long the protections will last and if or when a booster or revaccination is required. In effect, it is too soon to know. Should an annual booster shot be required, then a vaccine passport would require annual updating, a process more frequent than renewal of a driver's license.
We also know that the current SARS-CoV-2 virus is mutating briskly. While the current approved vaccines have remained effective overall, there is evidence of some degree of degradation in vaccine effectiveness against some of the circulating strains. We also have sparse data on many of the other emerging strains of concern because we have not had the surveillance capacity in the U.S. to gain an adequate sense of how the virus is changing to fully align vaccine effectiveness with viral capabilities.
The risk of people misusing these "passports" is troubling. The potential for using these documents for hiring, firing or job limitation is a serious concern. Unvaccinated workers are at risk of this form of discrimination even from well-meaning employers or supervisors. Health insurers are prohibited by the Affordable Care Act from discriminating based on preexisting conditions, but they could probably charge a higher premium for unvaccinated individuals. There also is a risk of stigmatizing individuals who are not vaccinated or have left their vaccine documentation at home. Another concern: the opportunity to discriminate based on race, gender, sexual orientation, or religion, using one's vaccination status as an excuse.
These "passports" are being discussed as a "ticket verification" for entry to many activities, including dining at restaurants, flying domestically and/or internationally, going to movie theaters and sporting events, etc. These are all activities we already are doing at reduced levels and for which wearing a mask, hand hygiene and physical distancing are effective disease control practices. COVID-19 vaccines are indeed the measure that will make the ability to totally reopen our society complete, but we are not there yet. Documentation of one's COVID-19 vaccine status may be useful in selected situations in the future. That remains to be seen.
Finally, inadequate vaccine supply and disparities in vaccine delivery have created enormous challenges in providing equal access to vaccination. Also, the amount of misinformation, disinformation, and lingering vaccine hesitancy continue to limit the speed at which we will reach the level of vaccination of the population that would make this documentation meaningful. The requirement for "vaccine passports" is already alienating people who are opposed to vaccinations for a variety of reasons, paradoxically risking reduced vaccine uptake. This politicization of the vaccination effort is of concern. There are indeed people who, due to medical contraindications or legal exemptions, will not be vaccinated, and we do not yet have a national framework on how to address this.
Vaccine passports are not the solution for reopening our society — a robust vaccination program is. The requirement to document one's vaccination status for COVID-19 may one day have its place. For now, it is an idea whose time has not yet come.
Editor's Note: This op/ed is part of a "Big Question" series on the ethics of vaccine passports. Read the flip side argument here.