Ozempic (semaglutide): NDA 213051

Based on the data reviewed, Dr. Elena Braithwaite recommends approval.

Overall, the data support that the intended maintenance doses of semaglutide (7 mg and 14 mg) were effective in reducing HbA1c, and Dr. Abugov, the statistical reviewer, recommends approval.

While the reduction in HbA1c compared to placebo was somewhat less for oral semaglutide as compared to sq semaglutide based on historical data, oral semaglutide demonstrated substantial evidence of effectiveness for glycemic control from adequate and well controlled trials, and the oral formulation offers a therapeutic alternative from injectable therapies.

PIONEER 6 was conducted to evaluate cardiovascular safety, and efficacy data for this trial will be discussed in the review for NDA 213182. See Table 2 for a list of the key efficacy trials.

In PIONEER 6, there was a lower incidence of SAEs reported with semaglutide versus placebo (18.9% vs. 22.5%, respectively).

There were a total of 137 first MACE events which occurred during the trial, with 61 subjects (3.8%) in the semaglutide group versus 76 subjects (4.8%) in the placebo group.

In the placebo pool, there were 3.8% subjects in the semaglutide arm, vs. 2.9% subjects in the placebo group, and in PIONEER 6, there were 7.1% subjects in the semaglutide arm, vs. 6.3% subjects in the placebo group.

The phase 3 program included a trial in patients with moderate renal impairment, PIONEER 5. An event-driven pre-market cardiovascular outcomes trial (PIONEER 6) compared semaglutide vs placebo on a background ranging from monotherapy to OADs, basal or pre-mixed insulin.

In summary, the clinical development program demonstrated semaglutide has a favorable benefit-risk profile.

Conduct a medullary thyroid carcinoma registry-based case series of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Rybelsus (semaglutide) tablets into the marketplace.

Semaglutide by itself does not appear to increase the risk for hypoglycemia, but it is expected to lead to an increased risk for hypoglycemia when used in combination with sulfonylurea or insulin.

So far, for the currently marketed GLP-1 RAs, the benefit-risk profile has not changed significantly in the post-marketing setting.

No REMS was deemed to be necessary for semaglutide.

• Prior serious hypersensitivity reaction to semaglutide or any of the excipients in RYBELSUS (4).

In addition, a post-marketing requirement (PMR) for a milk-only lactation study to assess concentration of semaglutide and SNAC in breast milk is recommended.

This trial was conducted to address the following postmarketing requirement (PMR) established in the September 20, 2019, Approval letter.

Since there are concerns based on animal studies, that the drug may accumulate in human milk, DPMH recommends a PMR for the applicant to conduct a milk only lactation study.