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New Oral GLP-1 Application Submitted to FDA

Mar 23, 2019

Novo Nordisk requests approval for new type 2 treatment with heart benefits.

On March 20, 2019, Novo Nordisk announced the official submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for oral tablet semaglutide, a once-daily glucagon-like peptide-1 (GLP-1) analogue. Novo Nordisk is requesting approval for an oral semaglutide with indication of type 2 diabetes treatment. In order to speed up the process, a priority review voucher (PRV) along with NDA was filed. Therefore, a review time of six months from the submission date is anticipated. The results from 10 PIONEER clinical trials, including included 9,543 adults with type 2 diabetes, are the fundamental data behind the NDA submission.


The PIONEER clinical trial program consisted of 10 phase 3a clinical trials, which included a cardiovascular outcome trial. The PIONEER program was conducted to evaluate the efficacy and safety of oral semaglutide in comparison to sitagliptin, empagliflozin, liraglutide, and placebo.

PIONEER 1 trial assessed the effectiveness and safety of oral semaglutide (3, 7, or 14mg once daily), compared to placebo, as a monotherapy treatment option in patients with type 2 diabetes. This study used the change in HbA1c  from the baseline to the end of week 26 as the primary outcome measurement. PIONEER 1 results showed that oral semaglutide caused a clinically significant reductions in both HbA1c (all doses) and body weight (higher doses). The primary outcomes are as follows:

  •     Change in HbA1c%: -0.6 with 3mg , -0.9 with 7mg and -1.1 with 14mg (p<0.001)
  •     Change in weight (kg): -0.1 with 3mg, -0.9 with 7mg and -2.3 with 14mg (p<0.001)

Adverse effects occurred in 58% of participants on 3mg dose, 53% who were on 7mg dose, and 57% for 14 mg oral semaglutide in comparison to 56% with placebo. Transient mild or moderate nausea was noted to be the most common side effect of oral semaglutide, occurring in 5-16% of patients on oral semaglutide vs. 6% with placebo.

PIONEER 2 was an open-label study that examined the safety of once-a-day semaglutide 14mg compared to Jardiance 25mg in 816 patients with type 2 diabetes who did not achieve adequate control with metformin. Primary outcomes were defined similar to PIONEER 1 as change in HbA1C, upon data analysis. Semaglutide 14mg showed superiority in reduction of HbA1c when compared with Jardiance. Weight loss difference was not significant. In PIONEER 3, in a 78-week trial, oral semaglutide appeared to be well-tolerated, with a similar profile to other GLP-1. Oral semaglutide appeared to cause more nausea (7-15%) when compared to sitagliptin (7%).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.

Furthermore, Novo Nordisk filed a second NDA with the FDA for oral semaglutide, to obtain an approval for a cardiovascular (CV) risk reduction indication in adults with type 2 diabetes. According to standard FDA review timelines, the NDA for an oral semaglutide CV risk reduction indication may take up to 10 months from the submission date.

Lastly, a supplemental NDA (sNDA) for once-weekly Ozempic (semaglutide) injection 0.5 mg or 1 mg, seeking an approval on indication to reduce the risk of MACE, such as heart attack, stroke, or death in adults with type 2 diabetes and established CVD.

PIONEER 6 with oral semaglutide and SUSTAIN 6 with Ozempic are two cardiovascular outcomes trials (CVOTs) evaluating the effects of adding semaglutide or placebo to standard of care on the risk of cardiovascular events. The applications for the oral semaglutide and Ozempic CV risk reduction indications are based on the results of these two trials.

PIONEER 6 was a multinational, randomized, placebo-controlled, double-blind trial. This study was conducted in patients with type 2 diabetes at high risk of CV events. A total of 3,183 individuals included in this study were randomly assigned to once-daily oral semaglutide (up to 14 mg) or matching placebo, which was added to the standard of care. High risk of CV was defined as follows: age ≥50 years, established CV disease or stage 3 chronic kidney disease, or age ≥60 years with at least 1 CV risk factor. The time of first incidence of CV death or non-fatal MI or non-fatal stroke were the primary composite endpoints. Additionally, increases in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint were considered as the primary hypothesis. PIONEER 6 results showed an achievement in its primary endpoint and demonstrated a noninferiority of MACE with oral semaglutide compared with placebo, both in addition to standard of care.

The SUSTAIN 6 included randomly 3,297 patients with type 2 diabetes. Participants were randomized into groups to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo in addition to their standard of care for 104 weeks. SUSTAIN 6 defined the primary composite outcome as the initial incidence of death due to CV, nonfatal MI, or nonfatal stroke. Results showed the primary outcome happened in 6.6% of subjects in the semaglutide group versus 8.9% of the placebo group (P<0.001). Moreover, 2.9% of the semaglutide group and 3.9% of the placebo group experienced nonfatal myocardial infarction (P=0.12). Nonfatal stroke was observed in 1.6% of semaglutide arm and 2.7% of placebo arm (P=0.04). It was noted that both groups had similar results in terms of death due to CV causes.

Practice Pearls:

  •        Oral semaglutide caused clinically significant reductions in both HbA1c and body weight when compared to placebo.
  •        The most common side effect of oral semaglutide appears to be nausea.
  •        The rate of CV death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than placebo.

Note: For the once-weekly injectable semaglutide results of SUSTAIN 1 trail for ozempic: HbA1c significantly decreased by 1·45% with 0·5 mg semaglutide  (p<0·0001), significantly decreased by 1·55% with 1·0 mg semaglutide (p<0·0001). at week 30, body weight significantly decreased by 3·73 kg with 0·5 mg semaglutide (p<0·0001), significantly decreased by 4·53 kg with 1·0 mg semaglutide (p<0·0001).


“Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | NEJM.” New England Journal of Medicine, www.nejm.org/doi/full/10.1056/nejmoa1607141.

Bain, Stephen C., et al. “Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes: Rationale, Design and Patient Baseline Characteristics for the PIONEER 6 Trial.” Diabetes, Obesity and Metabolism, John Wiley & Sons, Ltd (10.1111), 11 Nov. 2018, onlinelibrary.wiley.com/doi/full/10.1111/dom.13553.

Aroda, Vanita R., et al. “Effect and Safety of Oral Semaglutide Monotherapy in Type 2 Diabetes-PIONEER 1 Trial.” Diabetes, American Diabetes Association, 1 July 2018, diabetes.diabetesjournals.org/content/67/Supplement_1/2-LB.

“Novo Nordisk Files Oral Semaglutide for US Regulatory Approval of Glycaemic Control, as Well as for CV Risk Reduction for Oral Semaglutide and Ozempic®.” NASDAQ.com, www.nasdaq.com/press-release/novo-nordisk-files-oral-semaglutide-for-us-regulatory-approval-of-glycaemic-control-as-well-as-for-20190320-00510.

Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy