Bagsværd, Denmark, 20 June 2018 - Novo Nordisk today announced the successful completion and headline results of the phase 3a trials PIONEER 4 comparing oral semaglutide as a treatment for adults with type 2 diabetes to Victoza^® (1.8 mg liraglutide) and placebo, and PIONEER 7 comparing oral semaglutide as a treatment for adults with type 2 diabetes to sitagliptin 100 mg. Oral semaglutide is a new GLP-1 analogue taken once daily as a tablet.

Two distinct statistical approaches to evaluate the effects of oral semaglutide were applied in the PIONEER 4 and 7 trials; 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.

PIONEER 4
PIONEER 4 was a 52-week double-blinded, double-dummy trial investigating the efficacy and safety of 14 mg oral semaglutide compared with Victoza^® 1.8 mg and placebo in 711 people with type 2 diabetes inadequately controlled on metformin, with or without an SGLT-2 inhibitor.

PIONEER 4 achieved its primary objective according to the primary statistical approach by demonstrating a non-inferior reduction in HbA_1c and statistically significant and superior weight loss at 26 weeks with oral semaglutide compared to Victoza^®. Furthermore, oral semaglutide provided statistically significant and superior reductions in HbA_1c and weight compared to placebo.

When applying the secondary statistical approach for week 26 and week 52, respectively, people treated with oral semaglutide experienced a reduction in HbA_1c of 1.3% and 1.2% compared to 1.1% and 0.9% with Victoza^® whereas placebo declined by 0.1% and increased by 0.2%. Reductions in HbA_1c were statistically significantly greater with oral semaglutide compared to both Victoza^® and placebo. Reduction in body weight from baseline was statistically significantly greater with oral semaglutide at 4.7 and 5.0 kg at 26 and 52 weeks, respectively, compared to 3.2 and 3.1 kg with Victoza^®, and 0.7 and 1.2 kg with placebo. The American Diabetes Association (ADA) treatment target of HbA_1c below 7.0% was achieved by 69% of people treated with oral semaglutide, 63% of people treated with Victoza^® and 18% of people treated with placebo after 52 weeks; the difference between oral semaglutide and placebo was statistical significant.

In the 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 4, 20% of people treated with oral semaglutide experienced nausea, compared to 18% of people treated with Victoza^® and 4% of people treated with placebo. The proportion of people who discontinued treatment due to adverse events was 11% for people treated with oral semaglutide compared to 9% for people treated with Victoza^® and 4% for people receiving placebo.

PIONEER 7
PIONEER 7 was a 52-week open-label trial investigating the efficacy and safety of oral semaglutide with dose adjustment based on clinical evaluation of glycaemic control and drug tolerability compared with the DPP-IV inhibitor 100 mg sitagliptin in 504 people with type 2 diabetes, inadequately controlled on 1-2 oral antidiabetics.

The trial achieved its primary objective according to the primary statistical principle by demonstrating that oral semaglutide was statistically significant and superior to sitagliptin 100 mg in the proportion of people achieving the American Diabetes Association (ADA) treatment target of HbA_1c below 7% at week 52. Oral semaglutide also demonstrated statistically significant and superior reductions in body weight versus sitagliptin.

When applying the secondary statistical approach, people treated with oral semaglutide experienced a statistically significant reduction in HbA_1c of 1.4% compared to 0.7% with sitagliptin at week 52. From a baseline HbA_1c of 8.3%, 63% of people treated with oral semaglutide achieved the target HbA_1c below 7% after 52 weeks of treatment compared to 28% of people treated with sitagliptin, and the difference was statistically significant. The reduction in body weight of 2.9 kg with oral semaglutide was statistically significantly greater at week 52 compared to 0.8 kg with sitagliptin. After 52 weeks of treatment, approximately 9% of the people receiving oral semaglutide treatment were receiving 3 mg oral semaglutide, while approximately 31% and 60% were receiving 7 mg and 14 mg oral semaglutide, respectively.  

In the 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 7, 21% of people treated with oral semaglutide experienced nausea, compared to 2% of people treated with sitagliptin. The proportion of people who discontinued treatment due to adverse events was 9% for people treated with oral semaglutide compared to 3% for people treated with sitagliptin.

"With the significant one-year results in a real-world dose setting, oral semaglutide was superior to sitagliptin by documenting a greater proportion of people achieving the ADA target," said Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk. "At the same time, we have shown that oral semaglutide is even more efficacious in lowering glucose and body weight than the most widely used injectable GLP-1 treatment, Victoza^®".

About PIONEER 4, PIONEER 7 and the PIONEER clinical trial programme
PIONEER 4 was a 52-week, randomised, double-blinded, double-dummy, active- and placebo-controlled, parallel-group, multicentre, multinational trial with three arms comparing the efficacy and safety of 14 mg oral semaglutide compared to Victoza^® and vs placebo in people with type 2 diabetes, inadequately controlled on metformin with or without a sodium-glucose co-transporter-2 (SGLT-2) inhibitor. PIONEER 4 randomised 711 people in a 2:2:1 manner to receive either 14 mg oral semaglutide, Victoza^® 1.8 mg, or placebo 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 52.

PIONEER 7 was a 52-week, randomised, open-label, active-controlled, parallel-group, multicentre, multinational trial with two arms comparing the efficacy and safety of oral semaglutide using a flexible dose adjustment (3, 7 or 14 mg) based on clinical evaluation (glycaemic target and tolerability) of their response to treatment compared with sitagliptin in people with type 2 diabetes mellitus, inadequately controlled on 1-2 oral antidiabetics. PIONEER 7 enrolled 504 people randomised 1:1 to receive either oral semaglutide or 100 mg sitagliptin once daily. The primary endpoint was HbA_1c below 7% as per the ADA treatment target at week 52. Key secondary endpoints included change in HbA_1c and body weight from baseline to week 52.

Novo Nordisk plans to report the PIONEER 3 trial comparing 3, 7 and 14 mg oral semaglutide with 100 mg sitagliptin before the end of second quarter of 2018. 

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

                
Company announcement No 51 / 2018