For many patients with schizophrenia, other psychiatric illnesses, or diseases such as hypertension and asthma, it can be difficult to take their medicine every day. To help overcome that challenge, MIT researchers have developed a pill that can be taken just once a week and gradually releases medication from within the stomach.In a phase 3 clinical trial conducted by MIT spinout Lyndra Therapeutics, the researchers used the once-a-week pill to deliver a widely used medication for managing the symptoms of schizophrenia. They found that this treatment regimen maintained consistent levels of the drug in patients’ bodies and controlled their symptoms just as well as daily doses of the drug. The results are published today in Lancet Psychiatry.“We’ve converted something that has to be taken once a day to once a week, orally, using a technology that can be adapted for a variety of medications,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, an associate member of the Broad Institute, and an author of the study. “The ability to provide a sustained level of drug for a prolonged period, in an easy-to-administer system, makes it easier to ensure patients are receiving their medication.”Traverso’s lab began developing the ingestible capsule studied in this trial more than 10 years ago, as part of an ongoing effort to make medications easier for patients to take. The capsule is about the size of a multivitamin, and once swallowed, it expands into a star shape that helps it remain in the stomach until all of the drug is released.Richard Scranton, chief medical officer of Lyndra Therapeutics, is the senior author of the paper, and Leslie Citrome, a clinical professor of psychiatry and behavioral sciences at New York Medical College School of Medicine, is the lead author. Nayana Nagaraj, medical director at Lyndra Therapeutics, and Todd Dumas, senior director of pharmacometrics at Certara, are also authors.Sustained deliveryOver the past decade, Traverso’s lab has been working on a variety of capsules that can be swallowed and remain in the digestive tract for days or weeks, slowly releasing their drug payload. In 2016, his team reported the star-shaped device, which was then further developed by Lyndra for clinical trials in patients with schizophrenia.The device contains six arms that can be folded in, allowing it to fit inside a capsule. The capsule dissolves when the device reaches the stomach, allowing the arms to spring out. Once the arms are extended, the device becomes too large to pass through the pylorus (the exit of the stomach), so it remains freely floating in the stomach as drugs are slowly released from the arms. After about a week, the arms break off on their own, and each segment exits the stomach and passes through the digestive tract.For the clinical trials, the capsule was loaded with risperidone, a commonly prescribed medication used to treat schizophrenia. Most patients take the drug orally once a day. There are also injectable versions that can be given every two weeks, every month, or every two months, but they require administration by a health care provider and are not always acceptable to patients.The MIT and Lyndra team chose to focus on schizophrenia in hopes that a drug regimen that could be administered less frequently, through oral delivery, could make treatment easier for patients and their caregivers.“One of the areas of unmet need that was recognized early on is neuropsychiatric conditions, where the illness can limit or impair one’s ability to remember to take their medication,” Traverso says. “With that in mind, one of the conditions that has been a big focus has been schizophrenia.”The phase 3 trial was coordinated by researchers at Lyndra and enrolled 83 patients at five different sites around the United States. Forty-five of those patients completed the full five weeks of the study, in which they took one risperidone-loaded capsule per week.Throughout the study, the researchers measured the amount of drug in each patient’s bloodstream. Each week, they found a sharp increase on the day the pill was given, followed by a slow decline over the next week. The levels were all within the optimal range, and there was less variation over time than is seen when patients take a pill each day.Effective treatmentUsing an evaluation known as the Positive and Negative Syndrome Scale (PANSS), the researchers also found that the patients’ symptoms remained stable throughout the study.“One of the biggest obstacles in the care of people with chronic illnesses in general is that medications are not taken consistently. This leads to worsening symptoms, and in the case of schizophrenia, potential relapse and hospitalization,” Citrome says. “Having the option to take medication by mouth once a week represents an important option that can assist with adherence for the many patients who would prefer oral medications versus injectable formulations.”Side effects from the treatment were minimal, the researchers found. Some patients experienced mild acid reflux and constipation early in the study, but these did not last long. The results, showing effectiveness of the capsule and few side effects, represent a major milestone in this approach to drug delivery, Traverso says.“This really demonstrates that what we had hypothesized a decade ago, which is that a single capsule providing a drug depot within the GI tract could be possible,” he says. “Here what you see is that the capsule can achieve the drug levels that were predicted, and also control symptoms in a sizeable cohort of patients with schizophrenia.”The investigators now hope to complete larger phase 3 studies before applying for FDA approval of this delivery approach for risperidone. They are also preparing for phase 1 trials using this capsule to deliver other drugs, including contraceptives.“We are delighted that this technology which started at MIT has reached the point of phase 3 clinical trials,” says Robert Langer, the David H. Koch Institute Professor at MIT, who was an author of the original study on the star capsule and is a co-founder of Lyndra Therapeutics.The research was funded by Lyndra Therapeutics.
