Semaglutide is a GLP-1 analogue that can help lower blood glucose. It may have a low risk of hypoglycaemia and may induce weight loss by decreasing appetite and food intake. The oral formulation of semaglutide is provided in a tablet formulation with SNAC, an absorption-enhancing excipient included in the Eligen® Carrier Concept [3,4].
PIII PIONEER 2 RCT (n=787) found that oral semaglutide (SG) provided superior reductions in HbA1c versus empagliflozin at week 26 (difference -0.4%, p<0.0001). SG also linked to superior weight loss at week 52 (-4.7 vs -3.8 kg, p=0.0114), but significant difference was not achieved at week 26 .
PIII PIONEER 8 RCT (n=549) found that oral semaglutide 3 mg, 7 mg and 14 mg improved HbA1c vs placebo (difference -0.5%, -0.9% and -1.2% respectively, p<0.001) as well as body weight (-0.9kg, -2.0kg, and -3.3kg, p<0.0001). Nausea occurred in 11.4-23.2% patients with semaglutide .
In the US, a draft report from the Institute for Clinical and Economic Review (ICER) concluded that oral semaglutide plus background therapy would underperform the SGLT-2 inhibitor, empagliflozin, in cost effectiveness, as measured by quality-adjusted life years gained. ICER evaluation of clinical trial data for oral semaglutide vs empagliflozin, liraglutide, and sitagliptin concluded that oral semaglutide provided incremental benefit in preventing MACE but that MACE prevention is only part of the treatment puzzle, and other treatments may provide better overall benefit and at lower cost. The final report is due Dec 19 .
Results of PIONEER 6 (n=3,183) are published; the study found semaglutide was non-inferior to placebo for the composite outcome of death from CV disease, non-fatal MI or non-fatal stroke (after median 15.9 months rate = 3.8% for semaglutide vs 4.8% for placebo, HR 0.79, 95% CI 0.57-1.11, p<0.001 for non-inferiority) .
Results of PIONEER 1 (n=703) are published; the study found that semaglutide reduced HbA1c (3mg, 7mg & 1 mg doses) and improved weight loss (14mg dose) vs placebo (-1.4% and -2.6kg treatment difference for 14 mg vs placebo, p<0.001 for both). The safety profile was consistent with other GLP-1 receptor agonists .
Results of PIONEER 7 (n=504) are published; at week 52 the odds of achieving an HbA1c < 7% was significantly better with flexible dose adjustments of oral semaglutide (3, 7, or 14 mg per day) than sitagliptin (OR, 4.40, 95% CI 2.89–6.70, p<0.0001) .
Results of PIONEER 5 (n=324) are published; at 26 weeks, oral semaglutide (14 mg per day) was superior to placebo in decreasing HbA1c from baseline (estimated treatment difference: −0.8 percentage points, 95% CI −1.0 to −0.6; p<0.0001) .
Results of PIONEER 4 (n=711) are published; at week 26, semaglutide was non-inferior to liraglutide and superior to placebo in decreasing HbA1c, (-1.2%, -1.1% and -0.2%, respectively) and superior in decreasing BMI vs liraglutide and placebo (difference −1.5 and−4.0 kg; p<0.0001) .
Novo Nordisk initiate PIII PIONEER 4 (NCT02863419) trial to investigate the efficacy and safety of oral semaglutide vs SC liraglutide and vs placebo. Estimated primary completion date is Apr 18 .
Results of PIII PIONEER 3 (n=1864) are published; oral semaglutide (7 mg/d and 14 mg/d), vs sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks (differences from baseline, -0.3% and -0.5%, respectively; p<0.001 for both). No significant benefit was noted with 3-mg/d dosage .
PIII trial PIONEER 8 results announced: 52-week trial investigated efficacy and safety of 3, 7 and 14 mg oral semaglutide compared with placebo in 731 people with type 2 diabetes with mean baseline of 8.2%. Those treated with 3, 7 and 14 mg oral semaglutide achieved reductions in HbA1c of 0.6%, 1.0% and 1.4% respectively, compared to no reduction (0.0%) in placebo group .
Positive data announced from PIII PIONEER 5 trial (NCT02827708) in 324 pts with T2DM and moderate renal impairment who are on a stable dose of metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin. The trial demonstrated superior reductions in HbA1c with semaglutide 14mg od vs. placebo at week 26 (-1.1% vs. -0.1%, ). The number of pts who acheived target HbA1c was 64% with semaglutide vs. 21% with placebo. Pts who took semaglutide lost ~3.7 kg vs. 1.1kg with placebo. Semaglutide was well-tolerated by pts with moderate renal impairment and the most common adverse event for oral semaglutide was mild to moderate nausea.
Results of PIII study published in Diabetes Care. RCT (n=705) found once-daily semaglutide at doses up to 0.3 mg/day resulted in greater reductions in HbA1c (from-1.1 to -1.9%) compared with liraglutide (-0.5 to-1.3%) or placebo (all p<0.001) at 26 weeks, but with higher frequency of GI adverse effects (32.8–54.0% & 21.9–41.5%,respectively) .
PIII study (PIONEER 3) finds oral semaglutide resulted in larger HbA1c reductions than sitagliptin in T2DM. At 26 and 78 weeks people treated with oral semaglutide experienced statistically significant reductions in HbA1c of 1.1% and 0.7% with 7mg and 1.4% and 1.1% with 14mg vs 0.8% and 0.4% .
PIONEER 3 trial expected to readout before Q3 2018.
Novo Nordisk reported the results of two PIII trials, PIONEER 4 (semaglutide vs. liraglutide injection or placebo) and PIONEER 7 (semaglutide vs. sitagliptin). PIONEER 4 was a yearlong double-blinded trial in 711 pts with T2DM (not controlled by metformin +/- SGLT-2 inhibitor). It met its primary objective, showing a non-inferior reduction in HbA(1c) of 1.2% at wk 52 vs. 0.9% with Victoza. Reduction in body weight with semaglutide was 5kg at 52 weeks vs. 3.1kg with Victoza and 1.2kg for placebo. PIONEER 7 also achieved its primary endpoint. Pts in the semaglutide group experienced reduction in HbA1c of 1.4% vs. 0.7% with Januvia at week 52. In addition, 63% of pts given semaglutide achieved target HbA1c of <7% at 52 weeks vs. 28% of pts given Januvia. Reduction in body weight at week 52 was 2.9kg with semaglutide vs. 0.8kg with Januvia.
Results from PIII PIONEER 2 (NCT02863328) trial reported the primary endpoint was met with oral semaglutide 14mg daily demonstrating a statistically significant and superior improvement in HbA1c (1.4%) vs. empagliflozin 25mg daily (0.9%) at 26 weeks. Difference in weight loss was not statistically significant at 26 weeks - 4.2kg with semaglutide vs 3.8kg with empagliflozin, but was at 52 weeks - 4.7kg vs 3.8kg. Oral semaglutide was well-tolerated with a profile consistent with GLP-1-based therapy. The most common adverse event was mild to moderate nausea, which diminished over time. The proportion of subjects who discontinued treatment due to adverse events was 11% with oral semaglutide vs. 4% with empagliflozin .
Headline results of PIONEER 1 trial announced. The trial (n=703) achieved its primary endpoint by demonstrating significant and superior improvements in HbA1c in patients with type 2 diabetes for all three doses (3, 7 and 14mg) of oral semaglutide vs placebo. The 14 mg dose of oral semaglutide also demonstrated significant and superior weight loss vs placebo. Oral semaglutide appeared to have a safe and well-tolerated clinical profile. The most common adverse event for all three oral semaglutide doses was mild to moderate nausea, which diminished over time. Premature treatment discontinuation due to adverse events ranged from 2% to 7% with oral semaglutide, vs 2% with placebo .
Estimated primary completion dates are March 18 for PIONEER 2 (NCT02863328), PIONEER 3 (NCT02607865) and PIONEER 4 (NCT02863419), May 18 for PIONEER 5 (NCT02827708), Oct 18 for PIONEER 6 (NCT02692716), Aug 18 for PIONEER 8 (NCT03021187), and PIONEER 9 (NCT03018028), and July 18 for PIONEER 10 (NCT03015220). PIONEER 1 (NCT02906930) completed Dec 17 .
Results of PII dose-ranging trial (NCT01923181) published in JAMA. RCT (n=632) reports once-daily oral semaglutide (dose range 2.5 to 40mg od) produced mean change in HbA1c level from baseline to week 26 of −0.7 to −1.9%, -1.9% with sc semaglutide and -0.3% with placebo .
Novo Nordisk initiate PIII PIONEER 7 (NCT02849080) trial to investigate the efficacy and safety of oral semaglutide using a flexible dose adjustment based on clinical evaluation, compared with sitagliptin, in patients with type 2 diabetes. Estimated primary completion date is Mar 19 .
Novo Nordisk initiate PIII PIONEER 5 (NCT02827708) trial to investigate the efficacy and safety of oral once-daily dosing of semaglutide 14mg tablet vs placebo, in patients with T2DM and moderate renal impairment who are on a stable dose of metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin. Estimated primary completion date is Jan 18 .
Novo Nordisk initiate PIII PIONEER 1 (NCT02906930) trial to investigate the efficacy and safety of three dose levels of once-daily oral dosing of semaglutide, in patients with T2DM treated with diet and exercise only. Estimated primary completion date is Nov 17 .
Novo Nordisk initiate PIII PIONEER 2 (NCT02863328) trial to investigate the efficacy and safety of oral once-daily dosing of semaglutide 14mg tablet vs empagliflozin 25mg tablet, both in combination with metformin, on glycaemic control in patients with T2DM. Estimated primary completion date is Mar 18 .
Novo Nordisk initiate PIII PIONEER 3 (NCT02607865) trial to investigate the long-term safety of oral semaglutide versus sitagliptin in patients with T2DM. Estimated primary completion date is Mar 18 .
Novo Nordisk plans to initiate PIII PIONEER 8 trial (NCT03021187) to investigate the efficacy and safety of oral semaglutide vs placebo in patients with T2DM treated with insulin. Estimated primary completion date is Jan 18 .
Novo Nordisk plans to initiate PIII PIONEER 6 trial (NCT02692716) to investigate the CV safety of oral semaglutide in patients with T2DM. Estimated primary completion date is Apr 18 .
Novo Nordisk plans a PIII trial in type 2 diabetes in countries including US and UK (NCT02607865) .
Novo Nordisk announced plans to initiate a global PIII3a development program (PIONEER) with oral semaglutide for type 2 diabetes. The PIONEER program will include 6 safety and efficacy trials and one trial for evaluating the cardio-vascular safety of oral semaglutide in approximately 8,000 pts with type 2 diabetes. The first trial in the programme is planned for initiation in Q1 2016 and will investigate the efficacy and safety of once-daily oral semaglutide doses of 3 mg, 7 mg and 14 mg vs. once-daily oral anti-diabetic sitagliptin dose of 100 mg. The remaining six trials of the PIONEER programme are all expected to be initiated during 2016. Completion dates for the trials are not yet available [3,4].
Positive data from PII dose-ranging trial (NCT01923181) of OG217SC administered in 600 people with type 2 diabetes over the course of 26 weeks. All doses of oral semaglutide were statistically significantly superior to the placebo.