Oral semaglutide shows superior reductions in HbA1c and weight compared to sitagliptin in the long-term safety and efficacy trial, PIONEER 3

Bagsværd, Denmark, 28 June 2018 -Novo Nordisk today announced the headline results from PIONEER 3, a phase 3a trial with oral semaglutide for the treatment of adults with type 2 diabetes. Oral semaglutide is an investigational GLP-1 analogue taken once daily as a tablet. The 78-week trial investigated the efficacy and long-term safety of 3, 7 and 14 mg oral semaglutide compared with 100 mg sitagliptin in 1,864 people with type 2 diabetes inadequately controlled with metformin, with or without sulfonylurea. The confirmatory endpoints were assessed after 26 weeks of treatment.

Two distinct statistical approaches to evaluating the effects of oral semaglutide were applied in the PIONEER 3 trial; a primary statistical approach^[1] required by recent regulatory guidance evaluating the effect regardless of discontinuation of treatment and use of rescue medication, and a secondary statistical approach^[2] describing the effect while on treatment and without use of rescue medication.

The trial achieved its primary objective according to the primary statistical approach by demonstrating statistically significant and superior reductions in HbA_1c with oral semaglutide 7 and 14 mg compared to sitagliptin at week 26. Furthermore, people treated with oral semaglutide 7 and 14 mg achieved statistically significant and superior reductions in body weight compared to sitagliptin at week 26.

When applying the secondary statistical approach for week 26 and week 78, respectively, people treated with 7 and 14 mg oral semaglutide experienced statistically significantly greater reductions in HbA_1c of 1.1% and 0.7% with 7 mg oral semaglutide, 1.4% and 1.1% with 14 mg oral semaglutide compared to 0.8% and 0.4% with sitagliptin.  Reductions in HbA_1c with 3 mg oral semaglutide at 26 and 78 weeks were 0.5% and 0.3%, respectively, and the reduction was statistically significantly less than sitagliptin at 26 week, but was not statistically different at week 78. Reductions in body weight from baseline were statistically significantly greater with 3, 7 and 14 mg oral semaglutide at week 26 and 78, respectively, with reductions of 1.2 and 1.9 kg for 3 mg oral semaglutide, 2.2 and 2.7 kg for 7 mg oral semaglutide and 3.3 and 3.5 kg for 14 mg oral semaglutide compared to 0.7 and 1.1 kg with sitagliptin.

In this 78-week trial, oral semaglutide was well-tolerated and with a profile consistent with GLP-1-based therapy. The most common adverse event for oral semaglutide was mild to moderate nausea, which diminished over time. In PIONEER 3, 7-15% of people treated with oral semaglutide experienced nausea, compared to 7% of people treated with sitagliptin. The proportion of people who discontinued treatment due to adverse events was 6-12% for people treated with oral semaglutide compared to 5% with sitagliptin.

"With the results from the PIONEER 3 trial, we have shown that the two highest doses of oral semaglutide achieved superior improvements in glycaemic control and body weight compared to sitagliptin with a favourable safety profile consistent with GLP-1-based therapy" said Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk. "Furthermore, PIONEER 3 is an important trial, as it demonstrates long-term safety and efficacy of oral semaglutide"

About PIONEER 3 and the PIONEER clinical trial programme
PIONEER 3 was a 78-week, randomised, double-blind, double-dummy, active-controlled, parallel-group, multicentre, multinational trial with four arms comparing the efficacy and safety of 3, 7 and 14 mg oral semaglutide with 100 mg sitagliptin in people with type 2 diabetes inadequately controlled with metformin, with or without sulfonylurea. PIONEER 3 randomised 1,864 people in a 1:1:1:1 manner to receive either a dose of oral semaglutide 3, 7 and 14 mg or 100 mg sitagliptin once daily. The primary endpoint was change from baseline to week 26 in HbA_1c. Key secondary endpoints included change in HbA_1c and body weight from baseline to week 78.

The PIONEER phase 3a clinical development programme for oral semaglutide is a global development programme with enrolment of 8,845 people with type 2 diabetes across 10 clinical trials, which are all expected to complete in 2018.

Further information

^[1] Treatment policy estimand approach: treatment effect regardless of discontinuation of treatment or initiation of rescue medication (analysed by pattern mixture model using multiple imputations to handle missing data with an analysis of covariance (ANCOVA)).

^[2] Hypothetical estimand approach: treatment effect while on treatment without use of rescue medication (analysed by Mixed Models for Repeated Measurements (MMRM)). Similar statistical methodology as applied in the SUSTAIN programme for subcutaneous semaglutide.

Company announcement No 53 / 2017

Attachment

• PR180628_PIONEER_3_UK.pdf

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