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.
Just announced! Register for our next webinar to hear more about the developments in this exciting space and for more insight, be sure to sign up for email news and updates 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 that are showing the advantages of GLP1s in lowering mortality risk for patients.