The Technologies Propelling GLP-1 Analogues
By Sampatkumarr Govind Donthula, MarketsandMarkets
Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that stimulates insulin secretion, gene expression, and ß-cell proliferation. The U.S. FDA has approved dipeptidyl peptidase-4 (DPP-IV) resistant long-acting GLP-1s as injectable drugs for treating patients with type 2 diabetes.
GLP-1 analogues are traditionally a class of antidiabetic medicines and include products Ozempic, Trulicity, Mounjaro, Wegovy, Rybelsus, Saxenda, Victoza, Xultophy, Soliqua, Zepbound, Bydureon, and others. This class has gained popularity and attention in recent years due to its potential to combat obesity. The global GLP-1 analogues market is projected to reach USD 471.10 billion by 2032 from USD 47.49 billion In 2024, at a CAGR of 33.2% during the forecast period. The growth of this market is mostly driven by the presence of a robust R&D pipeline, improved efficacy offered by GLP-1 drugs, and the high demand from end users. Meanwhile, more aggressive growth of the market is restrained due to the current duopoly and high entry barriers to new entrants.
In this article, we’ll delve into the manufacturing or synthesizing technologies used to manufacture GLP-1 drugs as well as the novel drug delivery technologies being used.
Manufacturing Or Synthesizing Technologies
Chemical Synthesis
Chemical synthesis of GLP-1s involves the following steps:
- Peptide Synthesis: The GLP-1 peptide is assembled using solid-phase peptide synthesis, a common method in which the peptide chain is assembled step-by-step on a solid resin.
- Amino Acid Coupling: Each amino acid is coupled to the growing peptide chain via a condensation reaction, typically using carbodiimide or other coupling reagents.
- Cleavage and purification: Once the peptide chain is fully assembled, it is cleaved from the resin using an acid-like trifluoroacetic acid (TFA). The crude peptide is then purified using high-performance liquid chromatography (HPLC) to achieve the desired purity level.
- Chemical Modifications: PEGylation and lipidation are the two kinds of chemical modification carried out. In PEGylation, polyethylene glycol (PEG) chains are attached. In lipidation, fatty acid chains are attached to the peptide, improving its pharmacokinetic properties.
- Analogue formation: Specific amino acid substitutions are made to increase potency and duration of action, creating GLP-1 receptor agonists. These analogues mimic the action of natural GLP-1 but with improved therapeutic profiles.
Liraglutide is a GLP-1 receptor agonist administered subcutaneously. It was synthesized mainly through genetic engineering and other biological methods, which involved technical difficulties and high production costs and was inconducive to large-scale production. To address these challenges, Mylan Laboratories Ltd. employs a hybrid approach, integrating solid-phase peptide synthesis (SPPS) and liquid-phase peptide synthesis (LPPS). This method combines the advantage of both techniques, such as the high efficiency of SPPS and the scalability of LPPS. The hybrid approach was observed to increase the overall yield and reduce production costs. This showed improved purity and quality of the final product, making it more suitable for pharmaceutical applications.
Recombinant DNA Technology
Recombinant DNA (rDNA) technology involves manipulating genetic material outside an organism to create new combinations of DNA sequences not found naturally. This technology enables the combination of DNA from different sources to produce desired traits or products. It is used to produce proteins like GLP-1 by inserting the gene encoding GLP-1 into the DNA of a host organism, such as E. coli.
A research study by the National Center for Biotechnology Information (NCBI) mentions the production of GLP-1s using rDNA technology. The study noted some significant findings. GLP-1, like other small peptides, is typically manufactured using chemical synthesis; however, this method is restricted by high costs and limited production yield. Recombinant DNA technology offers a solution to the limitations of chemical synthesis by enabling high-yield, low-cost peptide production. Bacteria, yeast, and transgenic plants are currently employed as bioreactors to produce recombinant human GLP-1. Notably, small peptides like GLP-1 are challenging to obtain through conventional expression and purification systems, due to their low molecular weight and vulnerability to degradation. Thus, the study concluded that rDNA technology could be lucrative for commercial production.
A patent filed by Novo Nordisk A/S explained the hybrid method using rDNA technology and chemical synthesis for cost-efficient production of GLP-1 analogues. The patent, Semi-Recombinant Preparation Of GLP-I Analogues, describes a method for producing GLP-1s. This method combines the efficiency of recombinant DNA technology with chemical synthesis. The process involves producing shortened GLP-1 precursor molecules through recombinant techniques, which are then chemically modified to yield the final GLP-1 analogues. The chemistry review conducted by CDER for the NDA of liraglutide by Novo Nordisk A/S also mentions a hybrid manufacturing process. The initial peptide is produced using recombinant E. coli, which is then chemically modified to attach the fatty acid chain. Further, several purification steps are employed to ensure the removal of impurities and achieve a purity of the active pharmaceutical ingredient (API). This approach aims to reduce cost and improve the yield and purity of the produced peptides compared to traditional chemical synthesis methods alone.
Novel Drug Delivery Technologies
Hydrogel Depot Technology
Hydrogel depot technology uses injectable hydrogels to create a reservoir or depot at the injection site, allowing for sustained and controlled release of therapeutic substances over time. Biomimetic hydrogel depot technology involves the development of injectable hydrogels that mimic the natural extracellular matrix (ECM) of tissues. In the context of diabetes, biomimetic hydrogel depot technology has been utilized for the sustained delivery of GLP-1 receptor agonists. This technology is being viewed as a way to reduce the number of antidiabetic medication shots required yearly.
According to a November 2023 Stanford Report, Stanford engineers created an injectable hydrogel depot system allowing GLP-1 medications to be given once every four months. This single-injection drug based on hydrogel, showed the potential to substantially decrease the need for treatment, thereby enhancing patient well-being and mitigating diabetes management challenges. Hydrogel depot technology is considered the future of GLP-1 drug delivery as it could significantly reduce long-term costs associated with these treatments.
Chemical Modulation Strategy
Chemical modification, like PEGylation, enhances bioavailability of therapeutic peptides and proteins while preserving their pharmacological potency. PEGylated GLP-1 exhibited a prolonged half-life and improved glycaemic control in diabetic mice. Biotin conjugated GLP-1 derivatives DB-GLP-1 and DBP-GLP-1 displayed increased proteolytic stability and retained insulinotropic activity. Oral administration of these conjugates significantly improved glucose-lowering effects compared to native GLP-1, with DBP-GLP-1 showing superior efficacy likely attributed to enhanced intestinal absorption. This strategy holds promise for developing oral peptide therapeutics with enhanced bioavailability and therapeutic efficacy, exemplified by the success of biotinylated GLP-1 analogues in improving glucose control.
Polymer-Based Particulate Delivery System
In recent years, there has been a surge in utilizing natural and synthetic biodegradable polymers to formulate micro- and nano-particle systems for targeted drug delivery. Poly(lactic-co-glycolic acid) (PLGA), a U.S. FDA-approved synthetic polymer, is extensively employed in developing nanodrug delivery systems for peptides and proteins due to its favourable properties. Various research projects carried out by scientists have revealed the potential of polymer-based nanoparticle systems in improving the oral delivery and therapeutic outcomes of peptide drugs.
Genetically Engineered Plant Delivery Systems
Plants have been researched as green bioreactors for producing recombinant proteins. Utilizing plants for protein production offers advantages over traditional fermentation-based systems, including cost-effectiveness, scalability, and reduced risk of product contamination. Producing therapeutic proteins in food crops allows for direct delivery through consumption without expensive purification processes, leveraging plant cell walls to protect encapsulated drugs in the stomach. Additionally, genetically engineered plants offer flexibility in selecting suitable hosts for expression, enhancing the palatability of plant-based oral therapies. The expression of GLP-1s in genetically modified plants has been found to present a promising cost-effective approach for treating type 2 diabetes mellitus.
Genetically Engineered Food-Grade As Delivery Systems
Lactic acid bacteria (LAB) are diverse, nonsporulating, gram-positive bacteria known for producing lactic acid as their primary fermentation product. They are safe for use in food production and preservation. These bacteria naturally inhabit the human gastrointestinal tract, contributing to gut health and functioning as probiotics. Lactobacillus and Bifidobacterium are commonly used species derived from the intestinal microbiota of healthy individuals. LAB have gained attention as live mucosal vectors for producing and delivering biopharmaceuticals like peptide and protein drugs. They offer cost-effective treatment options because they can self-amplify and autonomously produce therapeutic agents. Recombinant L lactis has been successful in delivering anti-inflammatory cytokines and other therapeutic molecules for conditions like inflammatory bowel disease and oral mucositis and reversing type 1 diabetes.
One notable example of a drug delivery partnership is that NOVO Nordisk A/S has had an ongoing agreement with Emisphere Technologies Inc. since 2007. The company’s oral GLP-1 drug employs Emisphere’s Eligen SNAC drug delivery technology oral formulations of therapeutics. This technology employs synthetic nonacylated amino acids as carriers to facilitate drug absorption through passive transcellular transport processes in the small intestine.
Moving Forward In The GLP-1 Landscape
In terms of dosage form, the single-dose format is projected to reach USD 413.34 billion by 2032 from USD 40.10 billion in 2024, at a CAGR of 33.9% during the forecast period.
The subcutaneous route of administration is projected to reach USD 453.72 billion by 2032 from USD 44.21 billion in 2024, at a CAGR of 33.8% during the forecast period.
As the market for GLP-1 drugs is predominantly concentrated in the U.S. and Europe, the key regulatory authorities reviewing pipeline product trials are the U.S. FDA and the European Medicines Agency (EMA). Consider consulting guidance documents from these agencies for considerations such as efficacy endpoints, patient populations to be considered, and safety assessment considerations.