A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

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“…In case of patients with established type 2 DM (mean duration between 7 and 9 years) on Metformin treatment (PIONEER 2) the effect of 14 mg oral semaglutide was not significantly better than 25 mg empagliflozine at week 26, but was considered superior to empagliflozine at week 52 when evaluated by the trial product estimand (4.7 compared to 3.8 kg), as opposed to the treatment policy estimand [5,61]. When associated to metformin with or without sulfonylureas, the effect of both 7 and 14 mg oral semaglutide was superior to sitagliptin and reduced body weight with -1.6 and -2.5 kg, respectively [5,63]. At week 26, oral semaglutide was also more effective at reducing weight than liraglutide (estimated treatment difference ETD: -1.2 kg) and placebo (ETD: -3.8 kg) in patients treated with metformin with or without an SGLT2 inhibitor (PIONEER 4) [5,56].…”

“…The concept of oral peptide therapies started from an older idea, and the challenges experienced are best demonstrated by the fact that despite many attempts, no commercially viable oral form of insulin has been developed since its discovery in 1921 [5]. Peptides are small, shorter than 100 amino-acid monomer chains which places them between proteins and tiny molecules.…”

“…The most effective technique to improve drug absorption is to directly change the structure of the molecule and integrate an absorption enhancer, which in the case of semaglutide was SNAC (Sodium-N-[8-(2-hydroxybenzoyl) amino] caprylate) [25]. SNAC is a low molecular weight fatty acid derivate developed by Emisphere (US) in the 1990s that facilitates absorption through the transcellular route and unlike the other carrier-based permeation enhancers does not need a protective enteric coating [3,5]. SNAC and GLP-1 form a noncovalent bond in a concentration-dependent way, which increases semaglutide's lipophilicity and absorption through the gastric epithelium.…”

“…Oral semaglutide monotherapy in case of patients controlled by lifestyle changes in early stages of disease (average duration 3.5 years) significantly reduced body weight from baseline with a 0.1 (3 mg semaglutide), to 2.3 kg (14 mg semaglutide) placebo adjusted treatment differences [6]. In case of patients with established type 2 DM (mean duration between 7 and 9 years) on Metformin treatment (PIONEER 2) the effect of 14 mg oral semaglutide was not significantly better than 25 mg empagliflozine at week 26, but was considered superior to empagliflozine at week 52 when evaluated by the trial product estimand (4.7 compared to 3.8 kg), as opposed to the treatment policy estimand [5,61]. When associated to metformin with or without sulfonylureas, the effect of both 7 and 14 mg oral semaglutide was superior to sitagliptin and reduced body weight with -1.6 and -2.5 kg, respectively [5,63].…”

GLP-1R Signaling and Functional Molecules in Incretin Therapy

“…Novel oral GLP-1R agonists can overcome this problem, to a certain extent, and we are glad to see many small-molecule oral drug candidates under clinical trials. With transcellular permeation enhancers, peptide-based GLP-1R agonists may also be taken orally [ 152 ]. Moreover, polypill (fixed-low-dose combination drug) can also help by simplifying medication [ 153 , 154 , 155 , 156 ] and, if oral antidiabetic drugs were included in the polypill formulation, diabetic patients would further benefit [ 157 , 158 ].…”