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.
Regulation Too Often Shackles the Hands of Innovators
[Editor's Note: Our Big Moral Question this month is, "Do government regulations help or hurt the goal of responsible and timely scientific innovation?"]
After biomedical scientists demonstrated that they could make dangerous viruses like influenza even more dangerous, the National Institutes of Health (NIH) implemented a three-year moratorium on funding such research. But a couple of months ago, in December, the moratorium was lifted, and a tight set of rules were put in its place, such as a mandate for oversight panels.
"The sort of person who thinks like a bureaucratic regulator isn't the sort of person who thinks like a scientist."
The prospect of engineering a deadly pandemic virus in a laboratory suggests that only a fool would wish away government regulation entirely.
However, as a whole, regulation has done more harm than good in the arena of scientific innovation. The reason is that the sort of person who thinks like a bureaucratic regulator isn't the sort of person who thinks like a scientist. The sad fact of the matter is that those most interested in the regulatory process tend to be motivated by politics and ideology rather than scientific inquiry and technological progress.
Consider genetically engineered crops and animals, for instance. Beyond any reasonable doubt, data consistently have shown them to be safe, yet they are routinely held in regulatory limbo. For instance, it took 20 years for the AquAdvantage salmon, which grows faster than ordinary salmon, to gain approval from the FDA. What investor in his right mind would fund an entrepreneurial scientist who wishes to create genetically engineered consumer goods when he is assured that any such product could be subjected to two decades of arbitrary and pointless bureaucratic scrutiny?
Other well-intentioned regulations have created enormous problems for society. Medicine costs too much. One reason is that there is no international competition in the U.S. marketplace because it is nearly impossible to import drugs from other countries. The FDA's overcautious attitude toward approving new medications has ushered in a grassroots "right-to-try" movement, in which terminal patients are demanding access to potentially life-saving (but also potentially dangerous) treatments that are not yet federally approved. The FDA's sluggishness in approving generics also allowed the notorious former hedge fund manager Martin Shkreli to jack up the price of a drug for HIV patients because there were no competitors on the market. Thankfully, the FDA and politicians are now aware of these self-inflicted problems and are proposing possible solutions.
"Other well-intentioned regulations have created enormous problems for society."
The regulatory process itself drags on far too long and consists of procedural farces, none more so than public hearings and the solicitation of public comments. Hearings are often dominated by activists who are more concerned with theatrics and making the front page of a newspaper rather than contributing meaningfully to the scientific debate.
It is frankly absurd to believe that scientifically untrained laypeople have anything substantive to say on matters like biomedical regulation. The generals at the Pentagon quite rightly do not seek the public's council before they draw up battlefield plans, so why should scientists be subjected to an unjustifiable level of public scrutiny? Besides, there is a good chance that a substantial proportion of feedback is fake, anyway: A Wall Street Journal investigation uncovered that thousands of posts on federal websites seeking public comment on topics like net neutrality are fraudulent.
In other cases, out-of-date regulations remain on the books, holding back progress. For more than 20 years, the Dickey-Wicker Amendment has tied the hands of the NIH, essentially preventing it from funding any research that must first create human embryos or derive new embryonic stem cell lines. This seriously impedes progress in regenerative medicine and dampens the potential revolutionary potential of CRISPR, a genome editing tool that could someday be used in adult gene therapy or to "fix" unhealthy human embryos.
"Regulators and especially politicians give the false impression that any new scientific innovation should be made perfectly safe before it is allowed on the market."
Biomedicine isn't the only science to suffer at the hands of regulators. For years, the Nuclear Regulatory Commission (NRC) – an organization ostensibly concerned about nuclear safety – instead has played politics with nuclear power, particularly over a proposed waste storage facility at Yucca Mountain. Going all the way back to the Reagan administration, Yucca has been subjected to partisan assaults, culminating in the Obama administration's mothballing the project. Under the Trump administration, the NRC is once again reconsidering its future.
Perhaps the biggest problem that results from overregulation is a change in the culture. Regulators and especially politicians give the false impression that any new scientific innovation should be made perfectly safe before it is allowed on the market. This notion is known as the precautionary principle, and it is the law in the European Union. The precautionary principle is a form of technological timidity that is partially to blame for Europe's lagging behind America in groundbreaking research.
Besides, perfect safety is an impossible goal. Nothing in life is perfectly safe. The same people who drive to Whole Foods to avoid GMOs and synthetic pesticides seem not to care that automobiles kill 30,000 Americans every single year.
Government regulation is necessary because people rightfully expect a safe place to work and live. However, charlatans and lawbreakers will always exist, no matter how many new rules are added. The proliferation of safety regulations, therefore, often results in increasing the burden on innovators without any concomitant increase in safety. Like an invasive weed, government regulation has spread far beyond its proper place in the ecosystem. It's time for a weedkiller.
[Ed. Note: Check out the opposite viewpoint here, and follow LeapsMag on social media to share your perspective.]
To Speed Treatments, Non-Traditional Partnerships May Be the Future
Drug development becomes even more complex as time passes. Increased regulation, new scientific methods, coupling of drugs with biomarkers, and an attempt to build drugs for much more specific populations – even individuals – all make clinical development more expensive and time-consuming. But the pressure is also constantly increasing to develop new, innovative medicines faster. So companies invest more dollars, with steadily decreasing yields in terms of such drugs on the market.
"Collaborations are in many cases the only possible solution--a powerful force driving old and new models."
The traditional models for clinical development are thus not producing the best results. Can collaboration between companies, academic institutions, and public (government and non-profit) organizations help solve the problem?
Collaboration has in fact yielded important developments in diagnostic and therapeutic products. However, truly collaborative efforts are in the minority. Particularly for biotech, diagnostic, device and pharmaceutical companies with stock traded on the public markets, or with funding from venture capital, private equity, or other investment-oriented platforms, there are strong drivers for limiting collaboration.
Particularly onerous are intellectual property (IP) concerns. Patent attorneys are normally terrified of collaborations, where the ownership of IP may be explicitly or implicitly impaired. Investment banks and fund managers are very nervous about modeling financial returns on new products where IP is shared. Development companies often have overt or implied policies greatly favoring internal development over collaboration. It could be argued that the greatest motivation behind the huge product in-licensing game is the desire to fully own product rights rather than to continue collaborations where the rights are not exclusive.
Bu the good news is that long-standing models and newer innovations in collaboration do work. Some examples are worth exploring. A huge influence currently on collaboration models across the spectrum is the revolution in immuno-oncology. More cash has gone into the development of drugs which enlist the immune system to attack cancer than any other field of drug development in history, some estimate by a factor of three. The great majority of current human clinical trials in the U.S. are in this field. There are over 200 separate drugs in development that attack a single target, PD-1--completely unprecedented. Due to the vast complexity of the human immune system, and also to the great promise that these drugs have shown in previously intractable cancers, the field has recognized that these drugs can only perform to full potential when used in combination. But the rationale for combinations is very obtuse, there are huge numbers of new drug targets and candidates, and there are many hundreds of institutions and companies involved in development of these combinations. Thus, collaborations are in many cases the only possible solution--a powerful force driving old and new models.
"As drugs have become more expensive, a huge drive has emerged, spurred by the brokers of health care, to limit the populations eligible to be prescribed an expensive new drug."
As marketing and reimbursement become increasingly complex, large commercial companies share the marketing of more products. Almost every large pharmaceutical and biotech company has products which are jointly sold with others.
Some pharmaceutical companies do a creditable job, often driven by ethical rather than economic concerns, of identifying drugs in their commercial or development portfolios which would be best in the hands of others, or which should be combined with products owned by others to achieve maximum patient benefit. Pfizer, for example, has a strong internal culture of not allowing products to become "dormant" in its hands, and actively seeks to collaboratively develop or license out such products.
Particularly in the immuno-oncology field, given the lack of firm knowledge about which combinations will work best in patients, both large and small companies are collaborating on both preclinical and clinical development. Merck, with its drug Keytruda, the leading anti-PD-1, has almost 1000 collaborative trials in progress. In most cases, the IP rights to a successful combination are not specified up-front; the desire is to see what works and deal with the rights and financial issues later.
Other companies have specifically engaged non-profit foundations and/or public bodies in collaborative efforts. This is of course not new--there is a very long history of pharmaceutical, diagnostic, and device companies either collaborating with the NIH or disease-focused foundations for development of products born from institutional research. The reverse is also true--both the NIH and foundations are often engaged to collaborate on development of products owned by industry. Sometimes these collaborations can be relatively complex. For example, Astra-Zeneca, Sloan Kettering, the Cancer Research Institute, and the National Cancer institute have engaged in a partnership to conduct clinical trials on combination cancer therapies involving the portfolio owned by Astra-Zeneca in combination with drugs owned by others, with device therapies and procedures, and with diagnostic products.
As drugs have become more expensive, a huge drive has emerged, spurred by the brokers of health care--the so-called 'insurance' companies and pharmaceutical benefit managers--to limit the populations eligible to be prescribed an expensive new drug. Thus, the field of "companion diagnostics" has crystallized. In a number of fields, including cardiology, urology, neurodegenerative disease, and oncology, developers of diagnostics and drugs seek each other out to jointly develop drug/diagnostic pairs which appropriately select patients for treatment. The number of such collaborations is escalating dramatically, although many large pharmaceutical companies have their own in-house programs.
"The lack of clinical trial data sharing has engendered some notable collaborative efforts."
But most large pharmaceutical companies are not in the business of selling diagnostic products, even if those products are so closely linked to a specific drug that they are included in the FDA-approved 'label' of that drug. As a result, some very collaborative relationships are emerging. Merck, which has a very large and active companion diagnostics development group, almost always seeks development and commercialization partners for internally innovated diagnostics – to the extent that the company actually gives away the rights and the commercial benefits of the diagnostic product. Such was the case with the Merck-developed Tau imaging agents related to Alzheimer's disease, which Merck made available without license to the entire industry. The company continues to drive such non-financial collaborations in other clinical disciplines.
Collaborations certainly take place between academic centers, but in comparison to others, they are few and of far less productive outcome. Many appear to be innovative and have great potential, but the results are often different. The collaboration between medical schools and research institutions in Northeast Ohio seems promising, but it is in large part just a means for gathering hard-to-find clinical trial patients into the giant local institutions, Case Western and the Cleveland Clinic. And the actual output of academic versus commercial development programs is usually poor. One new company recently did an exhaustive search for new clinical drug development candidates in a specific therapeutic area in academia and came up empty-handed, only to find a solid handful of candidate drugs "hiding" in pharmaceutical companies that they were willing to provide collaboratively or to license.
The lack of clinical trial data sharing has engendered some notable collaborative efforts. The Parker Institute for Cancer Immunotherapy initially set out to promulgate standards for clinical trial data collection to make trial results in the thousands of combination trials more comparable. However, after some initial frustration, they are now working collaboratively with biotech companies, academia, and pharmaceutical companies to drive forward specific combination trials that experts believe should be done.
Foundations and public organizations also enable or initiate collaborative research. The Prostate Cancer Foundation has aggressively put academic and hospital-based research institutions together with industry to push the development of new effective therapies and diagnostics for prostate cancer, with remarkable success. The Veterans Administration has recently embarked on an aggressive program of collaborations with industry (with the help of funding from the Prostate Cancer Foundation) to allow use of the VA population and the very complete patient records to start clinical trials and other development efforts that would otherwise be very difficult.
"The near future will bring some surprising collaborative successes in the development of new drugs, devices, and diagnostics, but of course, some serious disappointments as well."
Finally, the financial industry at times facilitates collaborations, although they are usually narrow. Fund managers often get two or more of their portfolio companies to pool assets and/or IP to push forward more rapid development, or to provide structure for developments that otherwise could not go forward due to size or other resource limitations. For example, Orbimed, a health-care-focused investment firm, consistently drives cross-company development efforts within its large portfolio of drug and device companies.
So collaborative efforts are very much alive and well, which is great news for patients. Current realities in science, politics, reimbursement, and finance are driving diversity in collaborative arrangements. The near future will bring some surprising collaborative successes in the development of new drugs, devices, and diagnostics, but of course, some serious disappointments as well. And the very negative influence of the IP profession on collaborations will not be soon defeated.