From daily phone alarms to days-of-the-week pill boxes, people use all sorts of tricks to remind themselves to take their medication. Depending on the drug and the condition it treats, people may need to remember to take their medication once or even multiple times per day because the body metabolizes different drugs at different rates.
Drug developers typically formulate daily medications to release the active drug component so that its levels fluctuate within an average concentration in the blood throughout the day, but sometimes this means that drug levels may be too high during one part of the day and too low during another. These large fluctuations in drug levels, particularly when they are too high, can lead to side effects that discourage people from taking their medications, let alone remembering to take them at all.
Rather than asking people to take smaller doses of drugs more often throughout the day, a research team led by Giovanni Traverso, a bioengineer and gastroenterologist at the Massachusetts Institute of Technology (MIT), and Robert Langer, a chemical engineer also at MIT, designed something new.
“It's very hard to change the patient, but if we can change the pill, that certainly, we believe, stands to transform how we can better care for patients,” said Traverso.
Langer, Traverso, and their colleagues designed a drug delivery platform that can stay in the stomach and release single or multiple drugs at a constant rate for one week or even longer. They founded the company Lyndra Therapeutics based on this technology, which they named LYNX, and now they are testing this platform for delivering a weekly dose of risperidone (LYN-005) for schizophrenia and schizoaffective disorder in a Phase 3 clinical trial. With additional indications in oral contraception, malaria prevention, and opioid use disorder among others on the horizon, the team at Lyndra Therapeutics is ready to revolutionize how people take their medications.
A Thanksgiving proposal
The spark that became the LYNX platform ignited when Bill Gates paid a visit to Langer’s laboratory in 2012. “He was particularly interested in systems that might be very useful for people in the developing world to treat malaria and other things, and one of the problems is that people don't come back for a second pill or injection,” Langer said. “The Gates Foundation was interested in something that would be able to deliver ivermectin [orally] for two weeks. Of course, that had never been done before.”
At the time, Traverso was a postdoctoral researcher in Langer’s group, and he was interested in developing long-acting, oral drug delivery systems to address this problem. He and Langer discussed their research with the Gates Foundation, and then on the Wednesday before Thanksgiving, the foundation came calling again.
“They asked, ‘Could you help us develop or think about how we might develop orally delivered systems?’ And then the next question was, ‘Well, could you put a five-page proposal in and get it to us by Sunday when we're having dinner with Bill?’” said Traverso.
Working through the holiday, Traverso and Langer proposed a wide range of approaches to deliver drugs that could stay in the body on the order of several days to potentially weeks and months after a single ingestion event. In the end, they received their first grant from the Gates Foundation to develop this platform.
Their first challenge was to find a way to keep the drug delivery device in the stomach for at least a week. They needed to develop something that could withstand the highly acidic gastric juices and the rolling peristaltic waves of the stomach while also not blocking food from entering the pylorus, the opening that leads from the stomach to the small intestine.
“We got a few things that looked promising and many things that did not work. But we were able to iterate relatively quickly and efficiently, arriving eventually at this star-like system which eventually became the Lyndra system, and now it's called LYNX,” said Traverso. LYNX looks like a star with six long arms. Each arm contains a compartment for storing a drug, and a flexible region joins all six arms in the center.
The researchers then had to figure out how to get the LYNX into the stomach in the first place. They developed the central silicone core such that the LYNX could start in a folded-up conformation that fit inside a typical vitamin capsule. The team then developed a proprietary coating for the capsule that reduced its coefficient of friction so that it slid down the throat easily.
“When it gets into the stomach, the acid will dissolve that capsule, and out this pops,” said Langer.
Once it fully extends into its star shape in the stomach, the LYNX platform goes to work. The researchers engineered each arm of the platform to release drug at a controlled rate by suspending the drug in a polymer matrix. A structural polymer backbone lends support to that drug-polymer matrix in each of the six arms.
“We control the rate of how the water enters into that drug arm. The drug gets solubilized, and then it elutes out,” said Richard Scranton, the president of Global Product Development and chief medical officer at Lyndra Therapeutics. As the gastric juices enter the drug arm from all sides, the outer layers of the drug-polymer matrix release the drug at a steady rate. “The inner core of the drug [arm] does not see the fluid until the seventh day, so that's why the drug can stay in your stomach for that period of time,” he added.
After a calibrated amount of time, a piece of the LYNX arm breaks down, causing the entire drug arm to bend or break. As soon as LYNX loses its shape, it passes through the pylorus and flows through the GI tract like a piece of undigested fiber.
By designing each piece of LYNX to do one specific job — unfold, persist in the stomach, release drug, breakdown in a time-dependent way — the team designed a modular platform with the versatility to treat a seemingly limitless number of conditions.
From schizophrenia to malaria and beyond
After months of collaboration among physicians, polymer chemists, bioengineers, pharmaceutical scientists, and other experts, “by the middle to end of 2014, we already had some of that early data supporting the capacity of this system to deliver drugs for a prolonged period,” Traverso said. Through multiple preclinical studies in pigs, the researchers obtained promising results using their platform to deliver ivermectin for malaria prevention for two weeks, three different antiretroviral therapies against HIV for one week, and an oral contraceptive for one month (1-3).
Now, their furthest candidate in the clinical pipeline is a week-long dose of risperidone for treating schizophrenia. People with schizophrenia can have difficulty regularly taking their medication owing to the nature of their ailment, which can lead to relapse, worsening their disease outcomes.
“It's a patient population that is vulnerable; that weekly [administration] will give them all the things that they need to manage their illness better,” said Scranton. “It's weekly, so they don't have to think about their illness every day.”
With promising results in a Phase 2 clinical trial, the Lyndra Therapeutics team is now in the middle of a Phase 3 trial where they are comparing the pharmacokinetics of risperidone in patients who first take the medication as a daily pill and then switch to the weekly dose delivered via LYNX. Scranton hopes to have interim results soon, and if the results look promising, they plan to stop the Phase 3 study and initiate a larger safety study.
For Traverso, getting to see a drug delivery platform that he designed in the lab go through clinical trials has been extremely gratifying.
“Reaching clinical testing is, I would say, exhilarating. I still remember the very first time I saw an MRI of one of these systems inside of a person. That was just really moving,” said Traverso.
Beyond treating schizophrenia, the Lyndra Therapeutics team has their sights set on malaria, contraception, HIV, and multiple other indications. But most of all, they’re eager to see the effects that dosing people less frequently has on increasing medication compliance and improving people’s daily lives by not having to visit the doctor’s office as often or be reminded of their disease.
“There're several really compelling products in the pipeline that could really help people around the globe, not just here, and I think this is really exciting,” said Traverso. “Long-acting drug delivery systems really, in my opinion, stand to transform how we look after populations.”
References
- Bellinger, A.M. et al. Oral, ultra–long-lasting drug delivery: Application toward malaria elimination goals. Sci Transl Med 8, 365ra157 (2016).
- Kirtane, A.R. et al. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nat Commun 9, 2 (2018).
- Kirtane, A.R. et al. A once-a-month oral contraceptive. Sci Transl Med 11, eaay2602 (2019).
