Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration.

INTRODUCTION: Oral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave. METHODS: Part A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF). RESULTS: All subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure-response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms. CONCLUSION: This QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02911870.

Medications that are taken orally can be broken down by acid in the stomach before they are absorbed and therefore be less effective. Oral semaglutide is a novel type 2 diabetes medication that is formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which helps to protect against semaglutide degradation in the stomach. Regulatory authority guidelines recommend that new therapies should be tested for prolongation of the QT interval, an important part of the heart's electrical cycle. A previous trial demonstrated that semaglutide alone, which is currently available as an injectable diabetes therapy, did not prolong the QT interval when given in doses higher than those used in patients. Therefore, the current trial was conducted to assess whether the SNAC component of oral semaglutide has any relevant prolonging effect on the QT interval. Following regulatory guidelines for trials evaluating prolongation of the QT interval, the first part of the trial aimed to find a suitably high dose of SNAC. The second part of the trial aimed to confirm that SNAC does not prolong the QT interval. The results of this trial demonstrated that a 3.6 g dose of SNAC, which is 12-fold higher than the amount contained in oral semaglutide, does not prolong the QT interval. The safety and tolerability of SNAC 1.2 g, 2.4 g and 3.6 g were assessed in this trial and no concerns were identified. These results, taken alongside those of the previous QT interval study with subcutaneous semaglutide, indicate no relevant effect of oral semaglutide on the QT interval.

Effect of Various Dosing Conditions on the Pharmacokinetics of Oral Semaglutide, a Human Glucagon-Like Peptide-1 Analogue in a Tablet Formulation.

INTRODUCTION: Oral semaglutide is a novel tablet formulation of the human glucagon-like peptide-1 analogue semaglutide. In two trials, the effects of prior food ingestion (food effect), post-dose fasting period and water volume with dosing (dosing conditions) on oral semaglutide pharmacokinetics were investigated. METHODS: Subjects received once-daily oral semaglutide for 10 days. In the food-effect trial, 78 healthy subjects were randomised 1:1:1 to fed (meal 30 min pre-dose; 240 mL water with dosing), fasting (overnight until 4 h post-dose; 240 mL) or reference (fasting overnight until 30 min post-dose; 120 mL) arms. In the dosing conditions trial, 161 healthy men were randomised into eight dosing groups (overnight fasted with 50/120 mL water and 15/30/60/120 min post-dose fasting). Semaglutide plasma concentrations were measured frequently until 504 h after the 10th dose. RESULTS: In the food-effect trial, limited or no measurable semaglutide exposure was observed in the fed arm, while all subjects in the fasting arm had measurable semaglutide exposure. Area under the semaglutide concentration-time curve (AUC0-24h,semaglutide,day10) and maximum semaglutide concentration (Cmax,semaglutide,day10) were numerically greater by approximately 40% for the fasting versus reference arm (p = 0.082 and p = 0.080, respectively). In the dosing conditions trial, AUC0-24h,semaglutide,day10 and Cmax,semaglutide,day10 were not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p < 0.001). CONCLUSION: Administration of oral semaglutide in the fasting state with up to 120 mL water and at least 30 min post-dose fasting results in clinically relevant semaglutide exposure. These dosing conditions have been used in the oral semaglutide phase 3 trials and are part of the approved label. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02172313, NCT01572753.

Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study.

Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single-center (Quotient Sciences, UK), open-label, 2-period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96-2.37; P = .072). Area under the semaglutide concentration-time curve from 0 to 24 hours (AUC0-24h,semaglutide ) and maximum semaglutide concentration (Cmax,semaglutide ) were ∼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum semaglutide concentration (tmax,semaglutide ) was 1.5 hours independent of water volume with dosing. Higher AUC0-24h,semaglutide and Cmax,semaglutide and longer tmax,semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP-1 receptor agonist drug class. In conclusion, the oral semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher semaglutide plasma exposure.

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes.

BACKGROUND: Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP­1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials. METHODS: In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide co-formulated with 150-600 mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC. RESULTS: Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20 mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1 week in all groups. CONCLUSION: The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300 mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. CLINICALTRIALS. GOV IDENTIFIERS: NCT01037582, NCT01686945.

Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.

Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as a tablet for oral administration. This trial (NCT02014259) investigated the pharmacokinetics, safety and tolerability of oral semaglutide in subjects with and without renal impairment. METHODS: Subjects were categorised as having normal renal function (n = 24), mild (n = 12), moderate (n = 12) or severe (n = 12) renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (n = 11) and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days) in the fasting state, followed by 30 min fasting after dosing. Semaglutide plasma concentrations were measured during dosing and for up to 21 days after the last dose. RESULTS: Semaglutide exposure (area under the plasma concentration-time curve from time zero to 24 h after the tenth dose and maximum concentration after the tenth dose) did not vary in a consistent pattern across the renal function groups. Similarly, there was no apparent effect of renal impairment on the semaglutide half-life (geometric mean range 152-165 h). Except for one subject in the ESRD group, semaglutide was not detected in urine. Haemodialysis did not affect the pharmacokinetics of semaglutide. Adverse events were in line with those observed for other GLP-1 receptor agonists and no safety concerns were identified. CONCLUSION: There was no apparent effect of renal impairment or haemodialysis on the pharmacokinetics of oral semaglutide. Based on this trial, renal impairment should not affect dose recommendations for oral semaglutide.