Regulatory Decision Summary for Rybelsus

The efficacy of Rybelsus has been evaluated in 7 randomised, controlled phase 3a trials (PIONEER 1-5, 7, and 8), which comprised 8336 randomised patients with type 2 diabetes (T2DM) (4915 treated with Rybelsus), including 1162 patients with moderate renal impairment. Five of the trials included a comparison of oral semaglutide and placebo; active controls included empagliflozin, sitagliptin, or liraglutide.

An escalating dosing regimen was chosen in multiple trials to mitigate GI symptoms. Patient populations had consistent characteristics across trials and were representative of the real-world adult patients with T2DM. In trials PIONEER 2-5 and 7-8 patients were allowed to receive glucose-lowering background medication(s). Patient discontinuation varied across trials. Trial duration ranged from 26 to 78 weeks; however, the primary endpoint was evaluated at Week 26 in all trials.

In all pivotal trials except PIONEER 7, the primary endpoint was Change from baseline to Week 26 in glycosylated hemoglobin (HbA1c). In all trials, a clinically relevant and statistically significant reduction in HbA1c was observed in subjects receiving Rybelsus. A confirmatory secondary endpoint in several studies was Change from baseline to Week 26 in body weight (kg). Supportive secondary endpoints included Change from baseline to Week 26 in FPG and HbA1c below 7.0% at Week 26. Results from the secondary endpoints favoured Rybelsus and were captured in the Product Monograph.

The efficacy of semaglutide tablets in improving glycemic control in adult T2DM patients was demonstrated in all 7 pivotal trials.

The safety profile of Rybelsus was mostly derived from the Phase 3a clinical trials, which included 4116 subjects dosed with the drug for a total of 4379 patient-years of exposure. Generally, treatment with Rybelsus was associated with an increased rate of adverse events (AEs) relative to placebo treatment, but a similar rate to active comparators commonly used as second line options for treatment of T2DM. The rates of gastrointestinal (GI)-related AEs (most commonly nausea, vomiting and diarrhoea) were higher in Rybelsus -treated subjects compared to placebo and active comparator (excluding other GLP-1 RAs).

The rate of treatment discontinuation due to AE was greater relative to placebo and active comparator, and in subjects receiving higher doses of Rybelsus, most notably with the 14 mg dosage. GI AEs were the principal reason for premature trial discontinuation due to AE; however, the occurrence of GI AEs appeared to decrease as time on treatment increased.

The risk of hypoglycemia was greater in subjects receiving Rybelsus when used in combination with a sulphonylurea or insulin. There were no major differences in the safety profile of Rybelsus by types and incidence of AEs related to baseline demographics or comorbidities, including moderate renal impairment.

The safety profile of Rybelsus, including the frequent GI AEs, was comparable to the other previously authorized GLP-1 RAs.

Overall, based on the clinical data provided and with the risk minimization measures implemented, the benefits of Rybelsus outweigh its risks for the indication sought. The benefit/risk profile of Rybelsus is considered favourable in the target patient population.