Researchers are hopeful that within three to five years the first once-a-month oral contraceptive could reach human testing. They achieved an early step on that path with the publication of research testing the long-lasting drug delivery device from Watertown, Mass.-based startup Lyndra Therapeutics Inc. in the Dec. 4 issue of Science Translational Medicine.
They used the contraceptive levonorgestrel in three pigs in a specially adapted version of the Lyndra long-lasting pill and achieved 29 days of detectable serum levels of that synthetic hormone, which has a similar effect to progesterone. They found that serum levels in the pigs were comparable to those achieved with an oral, immediate-release oral tablet version of levonorgestrel, known as Levora, although hormone levels were more sustained and constant with the long-lasting drug delivery device.
“We set out to really try and develop a system that that makes it easier for patients to receive medication. So, initially we showed that we could have a capsule remain in the body for somewhere between one to two weeks and we applied that to malaria and HIV,” co-corresponding author Giovanni Traverso, a gastroenterologist and physician at the Brigham and Women's Hospital and the Massachusetts Institute of Technology, explained to BioWorld MedTech. “But really what we recognized from the outset is that if we could get out to one month, it would start to open up new opportunities such as ones where we could have a significant impact in family-planning.”
Traverso is a Lyndra co-founder alongside prolific drug-delivery entrepreneur Robert Langer, who is the David Koch Institute Professor in the Biological Engineering Department at MIT. Both sit on the company’s board. The Bill & Melinda Gates Foundation has helped to finance the Lyndra technology research, including with a $13 million grant that the company disclosed last July specifically for the development of a once-a-month birth control pill.
"We are hopeful that this work – the first example ever of a month-long pill or capsule to our knowledge – will someday lead to potentially new modalities and options for women's health as well as other indications," said Langer.
Lyndra was founded in 2015 and conducted first-in-human testing in 2017. It has since conducted Phase I safety testing in healthy adults, including with Alzheimer’s drug memantine hydrochloride that is used to reduce moderate to severe confusion. Lyndra aims to start phase II trials next year. It raised a $55 million series B round in January to support its research efforts.
In addition to oral contraceptives, the company is pursuing several indications where patients could benefit with super long-acting dosing including schizophrenia, Alzheimer’s disease, HIV, transplant rejection, opioid use disorder, and malaria prevention. It has partnered with Dublin-based Allergan plc in Alzheimer’s disease and with Foster City, Calif.-based Gilead Sciences Inc. in HIV.
The drug delivery device is embedded in a swallowable gelatin capsule and then expands in the stomach to open its six arms. Once unfolded, it is too large to pass through the opening of a human’s pylorus, which is the opening of the stomach into the small intestine. So, it therefore resides in the stomach where it releases drug over time.
In the contraceptive animal study, it was adapted to reside in the stomach of the three pigs for 28 days – with levonorgestrel persisting for 29 days. Two of the 18 arms in the three devices broke off and exited the stomach prematurely, one at day 7 and the other at day 24. However, despite these events, drug concentrations remained consistent.
"Coming up with a monthly version of a contraceptive drug could have a tremendous impact on global health," said Ameya Kirtane, a senior postdoc at MIT's Koch Institute for Integrative Cancer Research who was a lead author on the study. "The impact that oral contraceptives can have on human health and gender equality cannot be overstated."
"Even with all these long-acting devices available, there's a certain population who prefers to take medications orally rather than have something implanted," she added. "For those patients, something like this would be extremely helpful."
The Gates Foundation aims to create a viable option for the roughly 214 million women globally who are of reproductive age, but do not use any modern contraceptive methods such as birth control pills or IUDs.
In addition, among women who already do use birth control pills for contraception, missed doses are common. A multinational survey in 2010 found that roughly half of women on the pill reported missing at least one dose every three months or taking a pill at the wrong time. These inconsistencies result in reduced efficacy; an estimated average of 9% of women on birth control pills get pregnant annually.
This study was not designed to test the disintegration and excretion of the contraceptive device after the treatment period, which is the intended final result. The researchers are continuing to experiment with materials for the pill, as well as mechanisms to trigger the arms to break off and enable excretion such as pH or temperature change as well as perhaps exposure to a particular chemical. The span of the device is about 5.4 cm, while the human pylorus is about 1.7 to 1.9 cm.
Prior to this study, the researchers experimented with various materials by soaking them for long periods in simulated gastric fluid, which is highly acidic. That is how they arrived upon the two types of polyurethane to construct this version of the arms and the central core of the star.
“Currently, Lyndra’s focus is really around the fundamental development around manufacturing processes for preclinical testing, including the linker segments that connect the starfish arms to the central body,” summed up Traverso. “The development is also of this entire system, including the drug-releasing portion to make sure they get enough progesterone. There will be more preclinical testing in large animals, including pigs and dogs, to really help inform a human trial with a once-a-month, oral contraceptive system.