By Deborah Borfitz 

March 20, 2024 | More than a century has passed since the discovery of insulin, the world's first life-saving treatment for diabetes, and it is still being delivered via injection despite several brushes with success in developing an oral version of the drug. Hope is again on the horizon with the emergence of an oral nanotherapeutic formulation of insulin that comes with the possibility of reducing if not eliminating hypoglycemic events, as suggested by results of a baboon study that will now be mimicked in a first-in-human trial. 

The news comes from Nicholas Hunt, Ph.D., senior lecturer in the School of Medical Sciences at the University of Sydney (Australia), who has spent the past decade of his career exploring the drug delivery capabilities of nanotechnology highlighted by the discovery that tiny nanocarriers could deliver medicines to the liver. He was co-lead on the latest preclinical study, published recently in Nature Nanotechnology (DOI: 10.1038/s41565-023-01565-2), showing rapid release of nanocarrier-encapsulated insulin only when blood sugar levels are high and no risk of hypoglycemia—currently one of the biggest backlashes of insulin therapy. 

Hunt is cofounder and CEO of spinout company Endo Axiom, which last April secured $2.2 million in backing from Australian biotech incubator Proto Axiom to help bring the novel drug delivery technology to the clinic. The phase 1 clinical trial is expected to kick off in January 2025, the end goal being approval of the molecule by the U.S. Food and Drug Administration (FDA). 

The “smart insulin” was previously tested in nematodes, mice, and rats, says Hunt. None of the rodents with diabetes were found to have low blood sugar events, gain weight, or accumulate fat in their liver. 

Hunt and his collaborators are now taking the formulation through Good Manufacturing Practices to ensure the investigational product is produced to the highest quality standards for use in humans. A final toxicity study in mice will also be done before researchers complete their clinical strategy for the trial. 

It could take three to four years for the oral insulin capsule to be in clinical use, says Hunt, as the therapeutic may be classified as a biosimilar and not a new drug. Efficacy will therefore be demonstrated by showing that the smart insulin platform provides the same effects as insulin products already on the market. 

Insulin is used to treat all cases of type 1 diabetes and people with type 2 diabetes whose blood sugar cannot be controlled by healthy lifestyle changes and other diabetes treatments. Of the approximately 425 million people worldwide with diabetes, roughly 75 million of them inject themselves with insulin daily, most commonly via needle and syringe. 

Lessons Learned

Among recent significant advances in prevention and treatment of type 1 diabetes, Hunt points to the anti-CD3 therapeutic teplizumab, the first disease-modifying drug in type 1 diabetes to be approved by the FDA. Patient eligibility can be determined by the autoantibodies in their blood, signaling that the body’s immune system is attacking the insulin-producing cells in the pancreas. 

Scientists have been experimenting with oral insulin in people since the 1920s but without much success, he adds. The major challenges have been high within-subject variability of the pharmacodynamic effect, low bioavailability, and the cost of excessive insulin doses requiring to be delivered orally to induce an effect rather than using injection. The harsh environment of the stomach breaks down and neutralizes insulin before it can be absorbed by the intestines and enter the bloodstream. 

Two of the biggest players who were racing to develop the first insulin pill have both moved on to other projects. In 2019, Danish pharmaceutical giant Novo Nordisk dropped development of its candidate drug (I338) despite successful phase 2 clinical trials, because it was so expensive to produce (The Lancet. Diabetes & Endocrinology, DOI: 10.1016/S2213-8587(18)30372-3). Tel-Aviv based Oramed likewise discontinued clinical activities around its oral insulin product (ORA-D-013-1) for type 2 diabetes early last year after the drug failed to meet its primary phase 3 endpoint. 

The lessons learned from those efforts have informed development of the new oral nanotherapeutic formulation of insulin, says Hunt. Accordingly, he and his team set out to create a biosimilar that uses one-sixth of the insulin dose compared to I338 and developed a biosensing polymer to address the complex symptoms seen with type 2 diabetes. 

One of his long-time collaborators is Peter McCourt, Ph.D., a professor in the Department of Medical Biology at the University of Tromsø—The Arctic University of Norway. He is world-renowned expert on how cells take up different materials, says Hunt, which initially focused on small molecules with uncomplicated structures. As a collective they have taken their expertise in the liver microenvironment to design technology within this system in both healthy and diseased states.  

The choice of insulin delivery was prompted by a conversation with clinicians at Concord Hospital, the teaching facility affiliated with the University of Sydney, he continues. High-risk and elderly patients experiencing diabetic emergencies would sometimes spend prolonged periods of time in the hospital to receive insulin injections and continuous monitoring. 

The pursuit of an insulin pill was motivated by a desire to make the therapy safer and easier for patients, says Hunt. Step one was to develop a polymer that could encapsulate the insulin to prevent the nanocarrier from breaking down in the stomach and enable release of its cargo by enzymes in the liver that are active only when blood sugar levels are high. Most importantly, no insulin gets released when glucose levels are low, preventing hypoglycemia. 

This is how insulin works in healthy people, Hunt says, in that the hormone first passes through the liver where a large portion of it is absorbed to maintain stable blood sugar levels. In contrast, when insulin is injected under the skin with a syringe all in one shot, far more of it goes to the muscles and adipose tissues.  

Accelerated Pathway

The same trial design used for the study in 20 animals living at the National Baboon Colony in Australia is now going to be implemented in healthy people with the phase 1a trial, he says, followed by a phase 1b trial in participants with diabetes. Importantly, the same dosages used in the animals will be tested and have already been converted to capsule form. 

As a practical matter in the preclinical baboon study, oral insulin was formulated into pieces of sugar-free chocolate, Hunt adds. Sugar-free jelly was first tried but the animals didn’t take to it. On the other hand, they so readily ate the chocolate that they received additional pieces (minus the insulin) to induce their cooperation for the required finger prick tests.  

The FDA’s regulatory pathway for biological products, such as insulin, is essentially an “abbreviated version of a full application for an BLA [biologics license application], and we aim to demonstrate biosimilarity between the proposed biosimilar and a reference insulin,” according to Hunt. That means the usual five- to six-year timeline for completing all required clinical trials could be cut in half for the oral insulin platform.  

The U.S. is an attractive market for diabetes medications, representing 40% of the overall market versus the 1.3% position held by Australia, Hunt says. Consequently, later-stage clinical trials will be done there.  

For the phase 1a trial, Endo Axiom will perform these trials in Australia, he shares. Participants will be given the oral insulin capsule and 15 minutes later have their blood glucose checked. They’ll then take a glucose solution so investigators can see how quickly the oral insulin clears the added glucose out of their body and start to establish the titer of effectiveness. They’ll also be watching for incidences of hypoglycemia, which they hope will be nil as with the baboons. 

“Oral insulin has been a dream for the last 60 years for a lot of people and is still actively being pursued,” says Hunt, and public support for its development has never waned. The technology platform Endo Axiom is developing isn’t only appliable to insulin, he notes, but also broader peptides to be given orally (e.g., the popular diabetes drug Ozempic). The company is also developing the next generation of this technology that could be useful for patients with autoimmune conditions like type 1 diabetes as a preventive therapy without immune suppression.