Dr. Lewis talked about the chemistry, manufacturing, and control (CMC) challenges encountered during the development of glucagon-like peptide 1 (GLP-1) and oral peptides.
Watch the full video and read the article on PharmTech Europe.
Acoziborole (Figure 1), an oxaborole-6 carboxamide, is being developed as an oral single dose treatment for Human African trypanosomiasis (also called "sleeping sickness"). As part of the overall development programme, the mass balance, pharmacokinetics, metabolism and excretion of acoziborole were studied in an open-label, phase 1 study. This poster will describe the mass balance and clinical safety assessments from the human ADME study.
Acoziborole, an oxaborole-6 carboxamide, is being developed as an oral single dose treatment for Human African Trypanosomiasis. This poster will describe the metabolite characterization investigations following the human ADME studying a microdose of [14C]-Acoziborole.
Acoziborole, an oxaborole-6 carboxamide, is being developed as an oral single dose treatment for Human African trypanosomiasis (also called "sleeping sickness"). As part of the overall development programme, the mass balance, pharmacokinetics, metabolism and excretion of acoziborole were studied in an open-label, clinical phase 1 study in six healthy male subjects. This poster describes the radiolabelling and purification of [14C]acoziborole as a GMP radiolabelled drug substance to support the human metabolism investigation.
This is part of a series of 3 posters presented at ISSX 2024:
Thierry talks through what strategies Quotient Sciences is implementing to address supply chain challenges in a post-pandemic world and what roles do digital transformation and AI play in improving efficiency in your manufacturing processes.
Continue reading the full article on Pharmaceutical Manufacturer.
Thierry also discusses how the company is expanding its Translational Pharmaceutics® platforms into new therapeutic areas like mRNA.
Continue reading the full article on Outsourcing Pharma.
Drug solubility and bioavailability challenges are omnipresent in the pharmaceutical industry today, with over 80% of new drugs classified as poorly soluble relative to human dose requirements. Even before entering clinical evaluation stages, new therapeutics must overcome higher solubility hurdles required for concomitant non-GLP PK and initial dose range finding (DRF) studies where a linear dose-exposure relationship is required to justify further development effort and financial expenditure.
Summary: Dr. Andrew Lewis and Dr. Stuart Mair discuss the expanding therapeutic applications of GLP-1 agonists, initially designed for Type 2 diabetes but now also effective in obesity management. They emphasize the importance of in vivo studies over preclinical models for evaluating permeation enhancers in oral peptide delivery, noting that animal models often poorly predict human outcomes. The discussion also highlights the new potential of GLP-1 agonists in reducing risks of cardiovascular events, while addressing concerns about sarcopenic obesity and the need for combination therapies to preserve muscle mass during weight loss.
As research progresses, the industry sees that GLP-1s can offer benefits for patients beyond blood sugar control and weight loss. Dr. Andrew Lewis and Dr. Stuart Mair comment on the latest developments in GLP-1s as a follow-up to our recent webinar.
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Dr. Mair: Investigating the impact of formulations containing permeation enhancers on co-administered medications would require an in vivo Phase I clinical pharmacology drug-drug interaction (DDI) study in healthy subjects.
In this case, the co-administered medications would be administered alone and following a washout (WO) period exceeding a minimum of 5 half-lives. This would be done in combination with the investigational medicine product (IMP) with permeability enhancers. With this type of study, the PK profiles/areas under the curve (AUCs) of the co-administered medications given alone and with the permeability enhancers would be compared statistically to assess the potential impact.
For example, DDI studies performed by Novo Nordisk supported the approval of Rybelsus and used SNAC as the permeation enhancer. The FDA pharmacology review submitted for this product evaluated the combination of semaglutide and SNAC with selection criteria for drugs to be assessed, including those containing narrow therapeutic indexes and with limited permeability and incomplete absorption. (1)
Quotient Sciences has designed and conducted many similar drug-drug interaction studies at our clinics in Miami and Nottingham to support numerous NDAs and MAAs for our clients.
Dr. Lewis: We have compared preclinical bioavailability across several species to that achieved in human subjects in our studies, which shows preclinical models are not a great predictor of performance in humans but that the dog is maybe the closest.
In our experience, the best-performing formulation in humans differs from that in preclinical models. This is likely due to the well-documented differences in physiology between species, but there is still a lot to be understood in the biopharmaceutics of orally delivered peptides.
Preclinical pharmacokinetic studies are helpful to establish proof of principle that orally delivered peptides can be absorbed systemically, and formulations should then be rapidly advanced into the clinic to be optimized in human subjects.
Dr. Lewis: There is a poor correlation between in vitro performance testing of permeation enhancers and clinical performance. We strongly believe these are best evaluated in vivo and advanced into the clinic to be assessed and optimized in human subjects.
Dr. Lewis: We have mainly used permeation enhancers to improve oral peptide bioavailability. To evaluate the optimum site of absorption, in the past we used Enterion and Intellicap capsules and gamma scintigraphy. We also have experience in other oral device technologies, although not for oral peptide delivery.
We have a full range of oral drug delivery technologies for small molecular weight drugs, including solubility improvement with amorphous or lipid systems, delayed/controlled and sustained release systems, multiparticulates, and gastroretentive formulations.
Dr. Mair: This sarcopenic weight loss is a known adverse effect associated with GLP-1s, and current investigation is being done on co-administering medicines designed to treat muscle atrophy alongside GLP-1 agonists.
For example, Regeneron is testing drugs that block myostatin and activin, proteins that inhibit muscle growth in the body. Taken with semaglutide, this combination could boost the quality of weight loss while preserving lean muscle. BioAge is also testing a drug, azelaprag, that can be taken alongside Eli Lilly’s tirzepatide.
Azelaprag mimics apelin, a hormone secreted after exercise that acts on skeletal muscle, the heart, and the central nervous system to regulate metabolism and promote muscle regeneration. In preclinical studies conducted with obese mice, the combination led to more significant weight loss than tirzepatide alone, preserving lean body tissue.
Dr. Mair: We are seeing some positive news in these areas. This year, research from Novo Nordisk showed that semaglutide may help protect kidney function and reduce complications such as chronic kidney disease (CKD) and end-stage renal disease, two known comorbidities of obesity. (2)
Additionally, GLP-1 receptor agonists are showing that they can help reduce major cardiovascular events, such as heart attack and stroke. Organizations, including the American Diabetes Association, have recommended that physicians use GLP-1s in patients diagnosed with type 2 diabetes and concurrent cardiovascular disease for the benefits that they are providing. (3) Ultimately, these are positive steps showing the advantages of GLP1s in lowering patient mortality risk.
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.
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.
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.
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.
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.
Daniel Schaufelberger, PhD is a pharmaceutical executive with over 30 years of experience in pharmaceutical development and drug delivery, including pediatric products. Daniel retired from Janssen R&D LLC (Johnson & Johnson) as Sr. Scientific Director, where he co-chaired the J&J internal Pediatric Formulation Network. He is currently the Head of the Pediatric Center of Excellence at NGT BioPharma Consulting LLC. He is a CMC consultant for NIH/NIAID/DAIDS and for WHO’s Global Accelerator for Paediatric Formulation Development (GAP-f).
Daniel holds a degree in pharmacy (ETH Zurich) and a doctorate from the University of Lausanne. He is a member of the Pediatric Working Group of the International Consortium (IQ) for Quality in Pharmaceutical Development and has been appointed formulation expert for the pan-European "Conect4Children" initiative. Daniel is a founding member of the society of “Paediatric Medicines and Health Initiative”, based in Mumbai, India. In 2020, he joined Johns Hopkins University, School of Medicine, All Children’s Hospital in St. Petersburg, FL as adjunct assistant Professor. Daniel is a speaker and moderator at domestic and international conferences with a focus and passion for “developing better medicines for children."
Quotient Sciences were delighted to have Daniel as a guest speaker at our 2025 Garnet Valley, PA open house event. To request a tour of our facility or get information about our capabilities in pediatric drug development or drug product manufacturing from our Philadelphia sites, please contact us.
