In this interview with Dr. Andrew Lewis, Quotient Sciences’ Chief Scientific Officer, we explore the advancements in orally delivered GLP-1 agonists. We discuss the latest developments and how Quotient Sciences' expertise and innovative approach are overcoming the challenges of oral peptide drug development.
What makes GLP-1 a promising drug target in treating Type 2 diabetes and obesity?
GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) are key incretin hormones involved in regulating glucose metabolism. Both are produced in the gastrointestinal tract in response to food intake, specifically glucose and fats.
GLP-1 enhances insulin secretion from the pancreas, but only in response to elevated blood glucose levels. That’s important because it reduces the risk of hypoglycemia. GLP-1 also decreases the production of glucagon from the pancreas, slows gastric emptying, and it has a direct effect on the brainstem to reduce appetite.
GIP has got overlapping and slightly contradictory effects as it promotes the production of glucagon, which can counteract its glucose-lowering effects.
In people with Type 2 diabetes, the body’s response to incretin hormones is impaired. However, the GLP-1 pathway remains relatively intact, allowing it to still stimulate insulin production. For GIP, there is a more significant impairment, meaning it’s not as effective. This makes GLP-1 a more attractive target for treatment and has led to the development of several GLP-1 receptor agonists for managing Type 2 diabetes, obesity, and potentially other conditions.
There is increased interest in the oral delivery of GLP-1s and other peptides, but this comes with challenges. Why?
Incretin analogs, like GLP-1 agonists, have traditionally been difficult to deliver orally. As a result, these medications are most often given by injection, with Rybelsus® (a NovoNordisk product) being a recent exception designed for oral use. Oral delivery is generally preferred by patients, especially those who are less familiar or comfortable with injections.
Peptides such as GLP-1 agonists have challenging routes to get to the point they’re absorbed. The GI tract functions to digest these into short polypeptides and their constituent amino acids for absorption. Even if the peptides get to the epithelium, they tend to be poorly permeable, so it’s a real challenge developing oral formulations of GLP-1 agonists. This results in very low and variable bioavailability, often less than 1%.
Various technologies have been developed to overcome this, with permeation enhancers being the most advanced and validated. For example, SNAC is currently the permeation enhancer used in Rybelsus to promote semaglutide absorption, while Mycapssa® (oral octreotide, marketed by Chiesi USA, Inc.) employs the Transient Permeation Enhancer (TPE) technology, which utilizes the medium-chain fatty acid (MCFA) sodium caprylate (C8) to augment the absorption of the somatostatin analog octreotide.
At Quotient Sciences, we’ve worked on over 14 oral peptide programs over the last decade and evaluated 10 different permeation enhancers. There are some common challenges that we’ve seen from a manufacturing and analytics perspective.
In terms of manufacturing challenges, permeation enhancers tend to be required in relatively large amounts in the tablet. These are often waxy materials with poor flow and frequently poorly compressible. As a result, the tablet formulation and manufacturing process requires careful design to develop a robust drug product. From an analytics perspective, many of the standard QC tests for oral dosage forms require optimization for use with peptides taking into account the potential for peptides to aggregate in different buffer systems, and may require additional work to develop suitable methods.
Given the manufacturing challenges with orally delivered peptides, how does Quotient Sciences handle the transition from preclinical to clinical development?
We’ve pioneered an integrated approach that combines drug product manufacturing with clinical testing in healthy volunteers, which allows us to be incredibly adaptive in our trial designs - our Translational Pharmaceutics® platform.
By tightly integrating manufacturing and clinical testing, we can manufacture a drug product, dose it to healthy volunteers, perform bioanalysis and pharmacokinetic analysis, and use the emerging clinical data to inform our next steps. For example, following evaluation of the pharmacokinetic data, we can adjust the formulation to be dosed in the next dosing period to target the optimum drug exposure.
One extension to this is where we define a formulation design space and obtain regulatory approval to dose any formulation within that space. Typically, once a critical-to-performance formulation variable has been identified e.g. levels of a functional excipient such as a permeation enhancer, demonstration batches are manufactured at the extremes of the design space and batch analysis and stability data generated to bracket the design space. This provides maximum flexibility to explore how changes to the formulation impact performance in humans, all enabled by on-demand manufacturing within the clinical study.
We’ve applied the Translational Pharmaceutics® platform, with and without a design space concept, across hundreds of modified release programs in both the USA and the UK under the FDA and MHRA respectively. In oral peptides programs, we’ve performed numerous studies where we’ve looked at the dose of the peptide, the levels of a permeation enhancer, the ratio of peptide:permeation enhancer and even combinations of permeation enhancers.
Our unique capability has given us a privileged insight into the state of the art in oral peptide delivery having worked on so many programs with different peptides and permeation enhancers, and we have built up unique expertise in understanding the biopharmaceutics of oral peptide drug products.
What are the most exciting innovations on the horizon for oral peptide delivery in the next few years?
The success of Rybelsus® (a NovoNordisk product) has really pushed the field forward. In the coming years, we expect to see GLP-1s applied in more therapeutic areas and are already starting to hear about the potential benefits in a range of indications such as cardiovascular disease where oral formulations may be more competitive.
With this in mind alternative technologies for oral peptide delivery aimed at improving bioavailability in particular are an active area of research. This includes different methods to enhance permeability, such as exploiting active uptake mechanisms, ionic liquids, and ingestible devices. Additionally, solving issues related to food effects and the impact of water intake on absorption would be a big step forward. These developments promise to make oral peptide therapies more effective and convenient for patients.
Finally, I would expect to see artificial intelligence (AI) benefit oral peptide delivery in the years to come. The FDA reported that in 2021, it saw more than 100 drug and biologic application submissions containing elements of AI or machine learning (ML) used as part of the development process. These technologies have the potential to provide powerful insights into oral peptide biopharmaceutics that could enable the development of more products for the benefit of patients with a wide variety of diseases.
For a deeper dive into the latest advancements in orally delivered GLP-1 agonists and potential future innovations, check out our latest webinar featuring Dr. Andrew Lewis and Dr. Stuart Mair. Watch it here.
Sources:
Antza, C., Nirantharakumar, K., Doundoulakis, I., Tahrani, A. A., & Toulis, K. A. (2019). The development of an oral GLP-1 receptor agonist for managing type 2 diabetes: evidence to date. Drug design, development and therapy, 13, 2985–2996.
Brayden, D. J., & Maher, S. (2021). Transient Permeation Enhancer® (TPE®) technology for oral delivery of octreotide: a technological evaluation. Expert Opinion on Drug Delivery, 18(10), 1501–1512.
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