Few people like injections, which can limit adherence to therapy and even cause some patients to avoid potentially beneficial treatments altogether. As a result, drug developers have commonly viewed oral delivery as the “gold standard” for many therapies, especially for common chronic conditions. Formulating protein therapeutics for efficient delivery in a pill or capsule, however, has been a considerable challenge. Proteins are typically broken down in the digestive tract by stomach and microbially generated enzymes. In addition, it can be difficult for such large molecules to be absorbed through the stomach’s thick mucus layers and cell wall. Past attempts at delivering protein therapeutics orally have resulted in as little as 1% of the active drug in circulation. Recently, however, several research teams have made significant advances toward the development of high-tech pills for the oral delivery of protein therapeutics.
Rani Therapeutics has created an enteric-coated robotic pill that the company hopes to develop as a delivery vehicle for a range of therapeutic proteins. Once in the intestine, rising pH levels dissolve the protective coating around a blueberry-sized pill containing the drug. A chemical reaction is then triggered by digestive acids to inflate a tiny balloon that pushes a drug-filled microneedle into the intestinal wall. Animal studies using this pill to deliver insulin orally showed that the amount of circulating drug delivered in this manner was equal or higher to that achieved through subcutaneous injection. Rani is initially planning to develop its robotic pill to deliver octreotide, a biologic for the treatment of the hormonal disorder acromegaly. The company expects to initiate human clinical trials in 2019.
A research team from the Massachusetts Institute of Technology, Brigham & Women’s Hospital, and Novo Nordisk have created a similar capsule that they hope to develop for the oral delivery of insulin. The capsule’s design was inspired by a type of tortoise, whose angled shell ensures the animal can right itself when flipped onto its back. The capsule is a miniature device with a single microneedle whose tip is freeze-dried insulin. Injection of the insulin is controlled by a compressed spring that is restrained by a sugar disk. When the pill is swallowed and reaches the stomach, water dissolves the disk, triggering release of the spring and injection of the needle into the stomach wall. The capsule then travels through the intestinal track and is eventually eliminated. The device’s tortoise shell-like shape ensures that it will land in the proper orientation in the stomach so that it always has contact with the stomach tissue before it injects its medication.
We first wrote about the advent of digital pills when Proteus Digital Therapeutics gained approval for Abilify MyCite, the first pill fitted with a sensor to help track adherence to therapy. Since then, the company has pursued efforts to encapsulate as many as 40 already approved medications with a sensor to help patients keep track of their dosing and provide early warnings to physicians of problems with compliance to therapy. Doctors estimate about half of all medications for chronic conditions are not taken as prescribed, resulting in up to $289 billion in preventable healthcare costs and an estimated 100,000 U.S. deaths per year. Nine healthcare systems in the United States have so far used the Proteus technology to help patients with conditions such as HIV infection, diabetes, heart failure, and hypertension.
Now Proteus has partnered with the Minnesota health system, Fairview Health Services, to test chemotherapy pills packaged with a sensor that alerts a patient’s physician, pharmacist, and/or caregiver after the pill has been taken. The chemotherapeutic agent is capecitabine, a commonly used drug that is subject to a challenging treatment regimen: patients must take 6-8 pills each day for two weeks, with one week off, for eight cycles of therapy. Uniquely, Fairview Health Services will only pay Proteus if the patients take the digital chemotherapeutic as prescribed at least 80% of the time. Proteus says that average adherence to therapy is approximately 87%, and projects it will increase to at least 96% with use of the high-tech pills. The company is now planning a clinical trial to gauge whether patients on the digital chemotherapeutic see better clinical outcomes than the general population on capecitabine, and whether the digital pill ultimately saves money.
The verdict on how well doctors and patients will accept such high-tech pills is still mixed. A survey by Ernst & Young found that 38% of those asked were completely or mostly willing to use such medications, but 32% were only somewhat or not at all willing to try them.