Novo Nordisk Announces Breakthrough in Oral Semaglutide Phase 3a Trial for Type 2 Diabetes Patients with Moderate Renal Impairment

Diabetes Giant Novo Nordisk Announced on August 20, 2018 (Local Time) That the Results of a Recently Completed Phase 3a Clinical Trial (PIONEER 5) Showed Oral Semaglutide Significantly Outperformed Placebo in Improving HbA1c Levels and Body Weight in Patients with Type 2 Diabetes and Moderate Renal Impairment.

The PIONEER 5 trial was a 26-week study involving 324 patients with type 2 diabetes and moderate renal impairment who had previously been treated with metformin, sulfonylureas, metformin combined with sulfonylureas, basal insulin, or basal insulin combined with metformin but whose condition was not adequately controlled. The study compared the efficacy of oral semaglutide (14 mg once daily) versus placebo in terms of glycemic control and weight management. Two distinct statistical approaches were employed in this clinical trial: the primary statistical method, as required by the latest relevant guidelines, included all participants regardless of whether they had discontinued treatment, were still receiving treatment, or had used rescue medications; whereas the secondary statistical method primarily evaluated patients who remained on treatment and did not use rescue medications.

The PIONEER 5 trial demonstrated that oral semaglutide was well tolerated in patients with type 2 diabetes and moderate renal impairment, with a tolerability profile consistent with that of other GLP-1 receptor agonists. The most common adverse reaction was mild to moderate nausea, reported in 19% of the oral semaglutide group versus 8% of the placebo group. Discontinuation due to adverse reactions occurred in 15% of participants in the oral semaglutide group and 6% in the placebo group.

Novo Nordisk’s Executive Vice President and Chief Scientific Officer stated that kidney impairment is one of the most common complications of type 2 diabetes, yet there are currently very few oral medications available for this patient population. The PIONEER 5 trial confirmed the safety and efficacy of oral semaglutide in patients with type 2 diabetes and kidney impairment, thereby facilitating the regulatory submission for this indication and ultimately bringing significant benefits to patients with type 2 diabetes and kidney impairment.

Semaglutide is the second GLP-1 receptor agonist antidiabetic drug launched by Novo Nordisk following liraglutide. Upon FDA approval of its subcutaneous injection formulation in December 2017, it was hailed as “the best antidiabetic medication” due to its long-acting profile, significant glycemic control efficacy, and clinical benefits beyond glucose management. Since then, in addition to continuing to advance the SUSTAIN clinical trial program, Novo Nordisk has actively organized, participated in, or funded various related clinical trials. Since June 2018, more than twenty studies have been reported, comprehensively demonstrating the safety and efficacy of semaglutide from multiple perspectives.

In addition to the remarkable glucose-lowering and weight-reducing effects of its injectable formulation, the oral formulation of semaglutide, currently in clinical trials, represents another major highlight. If successfully approved for market launch, it is poised to become the first orally administered GLP-1 receptor agonist, bringing substantial commercial returns to the originator company while offering significant benefits to the vast population of patients with type 2 diabetes.

Latest Research Developments on Semaglutide

Sharma R et al. Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy: a systematic literature review and network meta-analysis. Curr Med Res Opin. 2018 Sep;34(9):1595-1603

[Study Type] Review and Meta-Analysis, involving or funded by Novo Nordisk, comparing the effects of once-weekly (qw) semaglutide injection versus sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on glycemic control and other related risk factors in patients with type 2 diabetes

[Main Results] This meta-analysis included eight randomized clinical trials with a duration of ≥20 weeks. The results demonstrated that both the 1.0 mg once-weekly (qw) and 0.5 mg qw doses of semaglutide significantly improved HbA1c levels compared to oral SGLT-2 inhibitors (SGLT-2is). Specifically, the mean differences in the change from baseline in HbA1c for semaglutide 1.0 mg qw versus canagliflozin and dapagliflozin were -0.66% (95% CI: -0.82%, -0.50%) and -1.11% (95% CI: -1.37%, -0.85%), respectively. Furthermore, semaglutide 1.0 mg qw showed significantly greater efficacy in weight reduction and improvement of fasting plasma glucose than all SGLT-2is; however, there was no statistically significant difference in the reduction of systolic blood pressure.

[Conclusion] Once-weekly semaglutide demonstrated significantly superior glycemic control compared with SGLT-2 inhibitors in patients with type 2 diabetes whose condition was not adequately controlled with metformin monotherapy.

Carlsson Petri KC et al. Semaglutide s.c. Once-Weekly in Type 2 Diabetes: A Population Pharmacokinetic Analysis. Diabetes Ther. 2018 Aug;9(4):1533-1547

【Study Type】: Population pharmacokinetic study, sponsored by Novo Nordisk

[Primary Results] This study included pharmacokinetic data from 1,612 participants enrolled in the clinical trials NCT02054897, NCT01930188, NCT01885208, NCT01720446, and NCT02207374. These trials were part of the SUSTAIN development program for once-weekly injectable semaglutide, with durations ranging from 30 to 104 weeks.

This population pharmacokinetic study found that among variables such as sex, age, race, ethnicity, renal function status, body weight, and injection site, only body weight significantly affected the systemic exposure of semaglutide. Furthermore, semaglutide exposure did not change over time. Anti-semaglutide antibodies developed in a small number of subjects, but these antibodies did not affect the drug’s systemic exposure. In addition, the study demonstrated a proportional dose–response relationship for semaglutide at doses of 0.5 mg and 1.0 mg.

[Conclusion] No dosage adjustment of semaglutide is required for glycemic control across different patient populations; however, this conclusion still warrants further validation through exposure-response analysis.

Demmel V et al. No QTc Prolongation with Semaglutide: A Thorough QT Study in Healthy Subjects. Diabetes Ther. 2018 Aug;9(4):1441-1456

[Study Type] Pharmacodynamic study, NCT02064348, participated in or funded by Novo Nordisk, evaluating the effect of semaglutide on the QTc interval in healthy subjects.

[Primary Results] After randomization, 168 healthy subjects received subcutaneous injections of either semaglutide (N=83) or placebo (N=83). The highest dose of semaglutide administered was 1.5 mg, which exceeds the therapeutic dose. Based on 11 electrocardiograms recorded within 0–48 hours after the final 1.5 mg dose, semaglutide at all doses (0.5 mg, 1.0 mg, and 1.5 mg) did not prolong the QTc interval in subjects. The placebo-corrected changes in the QTc interval for semaglutide versus placebo were all <10 ms across all doses and time points. Further exposure-response analysis indicated that the duration of the QTc interval was not influenced by semaglutide concentrations. The safety profile of semaglutide was consistent with that of other GLP-1 receptor agonists.

[Conclusion] Since semaglutide did not prolong the time required for cardiac repolarization in healthy volunteers in this trial, there is no need to be concerned about its potential to induce ventricular arrhythmias.

Bækdal TA et al. A randomized study investigating the effect of omeprazole on the pharmacokinetics of oral semaglutide. Expert Opin Drug Metab Toxicol. 2018 Aug;14(8):869-877.

[Study Type] Drug-drug interaction study, a single-center, randomized, open-label, parallel-group study sponsored by Novo Nordisk to evaluate the pharmacokinetic interaction between oral semaglutide and omeprazole (40 mg once daily)

[Primary Results] A total of 54 healthy volunteers were enrolled in this study. The results showed that, compared with semaglutide administered alone, the systemic exposure to semaglutide was slightly increased when co-administered with omeprazole, but the difference was not statistically significant. Furthermore, gastric pH levels in subjects were higher following co-administration than with semaglutide monotherapy. All adverse events observed during the trial were mild to moderate in severity and were predominantly gastrointestinal in nature.

[Conclusion] Concurrent oral administration of semaglutide and omeprazole increases the systemic exposure of the former; however, this increase is not statistically significant and lacks clinical relevance. Therefore, no dose adjustment is required when both drugs are administered orally in combination.

Overgaard RV. Switching from other GLP-1 receptor agonists to semaglutide - impact on HbA1c and body weight: A model-based approach. Diabetes Obes Metab. 2018 Jul 25.[Epub ahead of print]

[Study Type] Model-based study sponsored by Novo Nordisk, evaluating the impact on HbA1c and body weight in subjects switching from their GLP-1 receptor agonists to semaglutide in clinical trials.

[Key Results] This study utilized observational data with a maximum duration of 30 weeks from four clinical trials within the Phase 3 clinical development program for semaglutide to establish time-course models for HbA1c and body weight, respectively. The analysis results indicated that switching from another GLP-1 receptor agonist to semaglutide increases the overall potency-adjusted effective concentration of GLP-1 receptor agonists. Semaglutide 1.0 mg reduced HbA1c by 0.3%–0.8% percentage points and body weight by 2%–4%. Switching from liraglutide 1.2/1.8 mg or dulaglutide to semaglutide 0.25 mg resulted in a transient worsening of HbA1c levels.

[Conclusion] In patients with type 2 diabetes whose glycemic control was previously maintained with liraglutide, dulaglutide, or extended-release exenatide, switching to semaglutide further reduces HbA1c levels and body weight. Although switching to semaglutide 0.25 mg may result in a slight worsening of outcomes, this can be avoided by initiating treatment with a higher dose of semaglutide.

Lingvay I et al. A 26-Week Randomized Controlled Trial of Semaglutide Once Daily Versus Liraglutide and Placebo in Patients With Type 2 Diabetes Suboptimally Controlled on Diet and Exercise With or Without Metformin. Diabetes Care. 2018 Jul 19. [Epub ahead of print]

[Study Type] A multicenter, double-blind, randomized clinical trial, participated in or funded by Novo Nordisk, comparing the effects of once-daily semaglutide versus liraglutide on HbA1c in patients with type 2 diabetes.

[Primary Results] In this 26-week clinical trial, 705 patients with type 2 diabetes were randomized in a 2:2:1 ratio to receive once-daily (qd) semaglutide, once-daily (qd) liraglutide, or placebo, with volume-matched dosing regimens. At week 26, the change from baseline in HbA1c ranged from -1.1% (0.05 mg) to -1.9% (0.3 mg) in the once-daily semaglutide groups and from -0.5% (0.3 mg) to -1.3% (1.8 mg) in the once-daily liraglutide groups, demonstrating dose-dependent effects. Furthermore, semaglutide was significantly more effective than liraglutide at all volume-matched doses. The most common adverse events in both the semaglutide and liraglutide groups were gastrointestinal disorders, with incidence rates of 32.8–54.0% and 21.9–41.5%, respectively.

[Conclusion] Once-daily semaglutide at the highest dose of 0.3 mg/d significantly reduced HbA1c more effectively than liraglutide or placebo, but was associated with a higher incidence of gastrointestinal adverse events than the latter two.

Korsatko S et al. Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial. Diabetes Obes Metab. 2018 Jun 12. [Epub ahead of print]

[Study Type] A single-center, randomized, placebo-controlled, double-blind clinical trial, participated in or funded by Novo Nordisk, to evaluate the effect of once-weekly semaglutide on hypoglycemic counterregulatory responses in patients with type 2 diabetes.

[Primary Results] In this clinical trial, 38 patients with type 2 diabetes who were receiving metformin monotherapy were randomly assigned to the semaglutide once-weekly (qw) group or the placebo group. After 12 weeks, the treatments were crossed over, and hypoglycemic clamp procedures were performed after each crossover period.

During the hypoglycemic clamp procedure from 5.5 mmol/L plasma glucose to the nadir, changes in glucagon levels were similar between the semaglutide and placebo groups, with values of 88.3 pg/mL and 83.1 pg/mL, respectively (estimated difference: 5.2 pg/mL; 95% CI: -7.7 to 18.1). Both semaglutide and placebo increased other counterregulatory hormones; however, the increases in norepinephrine and cortisol were significantly lower with semaglutide than with placebo. The glucose infusion rates required to maintain the clamp at steady-state levels were similar between the two treatment groups, indicating that the overall counterregulatory responses were comparable. At the nadir, both the mean hypoglycemia symptom score and the proportion of patients experiencing hypoglycemia were lower in the semaglutide group than in the placebo group, while cognitive function test results were similar between the two groups. No new safety concerns were identified in the semaglutide group.

[Conclusion] Semaglutide does not impair the counterregulatory glucagon response to hypoglycemia in patients with type 2 diabetes.

Webb N et al. A Network Meta-Analysis Comparing Semaglutide Once-Weekly with Other GLP-1 Receptor Agonists in Japanese Patients with Type 2 Diabetes. Diabetes Ther. 2018 Jun;9(3):973-986

[Study Type] Meta-analysis, involving or funded by Novo Nordisk, comparing the efficacy and safety of once-weekly semaglutide versus other GLP-1 receptor agonists in Japanese patients with type 2 diabetes.

[Primary Outcomes] This meta-analysis included four randomized controlled clinical trials. The results showed that semaglutide 0.5 mg once weekly was significantly superior to dulaglutide 0.75 mg once weekly in reducing HbA1c [-0.61% (12.3 mmol/mol)], body weight (-1.45 kg), systolic blood pressure (-5.03 mmHg), and fasting plasma glucose (-1.26 mmol/L). However, there were no significant differences between semaglutide 0.5 mg once weekly and dulaglutide 0.75 mg once weekly in the proportion of patients achieving glycemic control with HbA1c <7% (53 mmol/mol) or in the overall risk of hypoglycemia.

[Conclusion] Semaglutide 0.5 mg once weekly demonstrated significantly superior improvements in HbA1c, body weight, systolic blood pressure, and fasting plasma glucose compared with dulaglutide 0.75 mg once daily in Japanese patients with type 2 diabetes.

Wilkinson L et al. Cost of Achieving HbA1c Treatment Targets and Weight Loss Responses with Once-Weekly Semaglutide Versus Dulaglutide in the United States. Diabetes Ther. 2018 Jun;9(3):951-961.

[Study Type] Cost-benefit comparative study, sponsored by Novo Nordisk, comparing the costs required to achieve HbA1c and weight control targets with once-weekly semaglutide versus once-weekly dulaglutide in patients with type 2 diabetes in the United States.

[Primary Results] A greater number of patients achieved the HbA1c control target with once-weekly semaglutide than with once-weekly dulaglutide. The cost per patient to achieve the triple treatment endpoint was $11,961 for semaglutide 1.0 mg qw and $15,204 for dulaglutide 1.5 mg qw, with the latter being 28% higher than the former. The cost of achieving the aforementioned targets with dulaglutide 0.75 mg qw was 68% higher than that with semaglutide 0.5 mg qw. For each patient who achieved the glycemic control target of HbA1c < 7%, the cost of dulaglutide 1.5 mg qw was 18% higher than that of semaglutide 1.0 mg qw.

[Conclusion] For patients with type 2 diabetes in the United States, once-weekly semaglutide demonstrates a more favorable cost-effectiveness profile than once-weekly dulaglutide.

Rodbard HW et al. Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2291-2301

[Study Type] A randomized, double-blind, multicenter, placebo-controlled clinical trial involving Novo Nordisk to evaluate the efficacy and safety of adding semaglutide to basal insulin.

[Primary Results] This study was part of the SUSTAIN clinical development program for semaglutide and enrolled 397 patients with type 2 diabetes whose blood glucose was not adequately controlled despite prior treatment with a stable dose of basal insulin (with or without metformin). After 30 weeks of treatment with semaglutide 0.5 mg once weekly, semaglutide 1.0 mg once weekly, or placebo, the mean reductions in HbA1c (mean baseline level: 8.4%) were 1.4%, 1.8%, and 0.1%, respectively, with both semaglutide doses showing statistically significant differences versus placebo (P < 0.0001). Severe or blood glucose-confirmed hypoglycemia occurred in 11 subjects in the semaglutide 0.5 mg once-weekly group, 14 subjects in the semaglutide 1.0 mg once-weekly group, and 7 subjects in the placebo group; there were no statistically significant differences between either semaglutide dose group and placebo. Mean body weight reductions from baseline were 3.7 kg in the semaglutide 0.5 mg once-weekly group (P < 0.0001 vs. placebo), 6.4 kg in the semaglutide 1.0 mg once-weekly group (P < 0.0001 vs. placebo), and 1.4 kg in the placebo group. Treatment discontinuation due to adverse reactions occurred in 4.5% and 6.1% of subjects in the semaglutide 0.5 mg and 1.0 mg once-weekly groups, respectively, compared with only 0.8% in the placebo group. The adverse reactions leading to premature discontinuation were primarily gastrointestinal disorders.

[Conclusion] Adding semaglutide to basal insulin therapy significantly improves HbA1c and weight control in patients with type 2 diabetes who have suboptimal glycemic control.