Glucagon-like peptide-1 (GLP-1) agonists are a class of medications originally developed to treat Type 2 diabetes but have also proven to be highly effective in managing obesity. 

As research progresses, the industry sees that GLP-1s can offer benefits for patients beyond blood sugar control and weight loss. Dr. Andrew Lewis, Chief Scientific Officer, and Dr. Stuart Mair, Chief Medical Officer, comment on the latest developments in GLP-1s as a follow-up to our recent webinar. 

For more insight, be sure to sign up for news from Quotient Sciences.

How is the potential impact of the permeability enhancers on co-administered medications with low permeability evaluated during drug development? 

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.

Which preclinical animal model best translates well to human in-vivo clinical studies when developing oral peptide drug delivery?  

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.  

What in-vitro testing methodologies have you applied to evaluate the best permeation enhancers for oral peptide delivery?  

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.  

Apart from permeation enhancers, have you worked on other oral delivery technologies?   

Dr. Lewis: We have mainly used permeation enhancers to improve oral peptide bioavailability. To evaluate the optimum site of absorption, we used Enterion and Intellicap capsules in the past 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.

New concerns are being raised about the efficacy of semaglutide on knee osteoarthritis symptoms. A discussion has emerged about the risk of sarcopenic obesity, which is more harmful for joint tissues and pain than non-sarcopenic obesity, that can develop when patients stop treatment. What do you think about this risk?

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.

 Can you comment on the benefits that are being seen linked to reduced chance of chronic kidney disease (CKD) and other conditions? 

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.  

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GLP-1 Agonists and Overcoming CMC Challenges of Oral Peptide Drug Development 

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 webinar featuring Dr. Andrew Lewis and Dr. Stuart Mair. Watch here.

References:

• 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.
• Artificial Intelligence and Machine Learning (AI/ML) for Drug Development | FDA

In a recent article with Pharm Tech discussing how advancements in technology and a more patient-centric focus are pushing drug formulation development into exciting new directions, Asma Patel, VP, Integrated Development Services at Quotient Sciences, discusses how ML and AI allow for rapid innovation.

“From a discovery perspective, [AI and ML] can continue to fuel complexity in small new chemical and new molecular entities (NCEs/NMEs)." says Dr. Patel.

"Regardless of AI/ML, NCEs/NMEs continue to see an increase in average molecular weights and generation of new classes such as PROTACs [Proteolysis targeting chimeras], both creating solubility challenges for pharmaceutical formulation,” she adds.

 “From a discovery perspective, [AI and ML] can continue to fuel complexity in small new chemical and new molecular entities (NCEs/NMEs)".

Continue reading the full article on Pharm Tech.

Quotient Sciences offers FreeThink ASAPprime® software as an add-on service to drug programs to rapidly predict long-term product shelf-life. 

In this Q&A with Helen Baker, Director of Pharmaceutical Sciences, we talk more about how the software works at different stages of the development process and how customers can benefit from adding on analysis with ASAPprime® software to their next drug program with Quotient Sciences. 

What is ASAPprime® software? 

ASAPprime® software is developed by FreeThink, and Quotient Sciences have licensed it for use. A dedicated stability lab to support programs and products utilizing this software has been set up at Quotient Sciences to enable us to support clients in rapidly predicting the long term shelf life of products in development.

How does ASAPprime® work? 

ASAPprime® requires that samples are set down at specific temperature and humidity settings, and analyzed at pre-determined time points. Typically, a study looking at a single entity would require 8-19 conditions over a period of about 28 days.  A scouting study may be required before starting to determine the right conditions for the study (very degraded samples cannot be used and it is critical for the modeling to know the isoconversion times.  For shelf-life prediction, it is essential that all conditions are as close to possible at the isoconversion limit).  

The isoconversion point is the time a certain degradation product, total degradants, potency, or other critical parameter is needed to reach the specification limit. This governs shelf life, or the point at which the product is outside of acceptance limits. Interconversion can be considered “the edge of failure” for a particular product. Rather than follow the traditional approach of using fixed time points whilst monitoring the degradant level, the model looks at variable times at each condition required to hit the specification limit. 

At what stage of drug development should the ASAPprime® software be used? 

Customers can choose when and how much use they want to implement ASAP stability, from use-as-needed to supporting product development as a parallel tool used in tandem throughout any given phase. We can leverage the modelling in a new or existing program to help at various points: 

• In initial stages of development, when there is little or no prior knowledge of stability behavior
• Prototype assessment or side-by-side comparison of new with existing products
• In reformulation into new dosage types, validate new API manufacturing processes and identify potential risks in new equipment or material supplier changes
• In the investigation into failed batches or out of spec trends alongside projects in real-time or retrospectively  
• In commercialized products, to assess the impact of different packaging configurations, API or excipient changes 

How long will ASAPprime® take to generate stability data for my product? 

Study timelines typically range from as little as 7 and up to 28 days. Studies using the ASAPprime® software will vary depending on: 

• Scope of assessment (such as comparing formulation prototypes or packaging options)
• Availability of prior data and intended specification limit (e.g. degradant, potency, slowed dissolution release, total moisture uptake)  
• Intrinsic drug stability or instability  

Contact us today for more information about how we can help you leverage ASAPprime® software for your drug program. 

In this article by International Biopharmaceutical Industry, Martin Wing-King, VP and General Manager, Site Head at our Reading facility, explores the demand for accelerated first-in-human trials and outlines how simple formulations can be leveraged for a faster way to progress through early clinical studies.

"Partners that understand the urgency of reaching clinical milestones under tight timelines by leveraging their extensive experience and specialized equipment are critical to the success of FiH trials."

By leveraging simplified formulation approaches such as capsules filled with API, drug developers can significantly expediate their path to the clinic. Strategic collaborations with experienced partners offering integrated drug development and manufacturing services can also streamline the process.

Continue reading the article here.

Credit:

International Biopharmaceutical Industry (IBI), Volume 7, Issue 3, September 2024, pages 14-16. © IBI Journal

Quotient Sciences is pleased to announce that its Chief Scientific Officer, Dr. Andrew (Andy) Lewis, has joined the scientific advisory board for a new journal by the Royal Society of Chemistry – RSC Pharmaceutics.

In this role, Dr. Lewis will contribute to the success of the journal by advising on scientific topics of interest and other duties to promote the success of the journal. He will have the opportunity to contribute his own work to the journal, while also promoting its contents and encouraging new and existing readers to read and publish in the journal. Dr. Lewis will provide feedback and advise on the development of the journal to ensure it is positioned at the cutting edge of pharmaceutical science. 

Earlier this year, Dr. Lewis was appointed to the role of Chief Scientific Officer for the company. He was also recognized by the Controlled Release Society (CRS) as a recipient of the 2024 Distinguished Service Award, which is given to CRS members in cases where an exceptional member fits the criteria for having given sustained and outstanding service, and inducted into the prestigious College of Fellows of the CRS for his significant contributions to the field of controlled release.

Andy has over 20 years of experience working in the pharmaceutical and biotech industry. His work has focused on advanced drug delivery technologies, particularly protein and peptide drug delivery, solubility enhancement, modified and controlled release. 

"I look forward to joining the Advisory Board for RSC Pharmaceutics journal and supporting its development into a world-leading journal for pharmaceutical scientists. As a Gold Open Access journal, researchers publishing in it can be confident of a wide dissemination of their work to help build their reputation." – Dr. Andrew (Andy) Lewis