FDA Eyes Weekly Semaglutide for Diabetes as Oral Version Advances

Miriam E Tucker

October 17, 2017

As Novo Nordisk's investigational injectable once-weekly glucagonlike peptide-1 (GLP-1) receptor agonist, semaglutide, faces a US Food and Drug Administration (FDA) advisory panel this week, a daily oral version is moving up the pipeline. 

On Wednesday October 18, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) will review Novo Nordisk's application for use of the once-weekly injectable semaglutide as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, based on data from seven phase 3 studies and a 2-year cardiovascular-outcomes trial (SUSTAIN-6).

In addition to assessing the drug's efficacy, panel members will be tasked with advising the FDA on their level of concern about a significant increase in retinopathy, a prespecified composite end point, seen in SUSTAIN-6 (hazard ratio, 1.76).

The increased risk was seen primarily among subjects with diabetic retinopathy at baseline, and one theory is that transient retinopathy often accompanies a rapid reduction in HbA1c levels among susceptible individuals.

If the FDA approves semaglutide for the treatment of type 2 diabetes, it would become the third once-weekly injectable GLP-1 receptor agonist on the US market, joining exenatide extended-release (Bydureon, AstraZeneca) and dulaglutide (Trulicity, Eli Lilly). (Another one, albiglutide [Tanzeum, GlaxoSmithKline], is being withdrawn.)

Advisory Committee Will Look at Adequacy of CV Data in SUSTAIN-6

The FDA is also asking EMDAC to advise on the adequacy of the cardiovascular-outcomes data for weekly semaglutide.

In SUSTAIN-6, semaglutide was associated with a 26% lower risk for the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke over 2 years, but that difference was driven exclusively by a 39% decrease in nonfatal stroke, and there was no difference in cardiovascular deaths.

Due to the insufficient statistical power of SUSTAIN-6, Novo Nordisk is not seeking an indication for reduction in cardiovascular end points or survival benefit, as have been granted thus far to its other daily administered GLP-1 agonist, liraglutide (Victoza, Novo Nordisk) based on the LEADER trial and to a different class of agent, the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) based on data from the EMPA-REG OUTCOME trial.

A supplemental new drug application for reduction of cardiovascular disease events has also been filed for a third agent, the SGLT2 inhibitor canagliflozin (Invokana, Janssen), based on the CANVAS trial results reported at ADA this summer).

Oral Semaglutide Passes Phase 2 Test

As Novo Nordisk works to bring injectable once-weekly semaglutide to the US market, it's also developing a formulation that can be taken by mouth.

To evade degradation of the GLP-1 receptor agonist in the gastrointestinal tract, this version will combine semaglutide with the absorption enhancer sodium N-[8 (2-hydroxylbenzoyl) amino] caprylate, leading to a local increase in pH and consequently higher solubility and protection.

Findings from a phase 2, randomized, parallel-group, dose-finding study of daily oral semaglutide in 632 patients with type 2 diabetes have just been published in the October 17 issue of the Journal of the American Medical Association, by Melanie Davies, MD, of the Diabetes Research Centre, University of Leicester, United Kingdom, and colleagues.

The 26-week study was conducted at 100 sites in 14 countries, enrolling patients with HBA1c 7.0% to 9.5% on lifestyle alone or with a stable metformin dose. Treatment groups included oral doses of semaglutide 2.5, 5.0, 10, 20, or 40 mg; an oral placebo; or a once-weekly 1.0-mg subcutaneously injected dose. The study was open-label to reduce the number of unnecessary injections.

At week 26, all doses of semaglutide dose-dependently reduced HbA1c significantly more than placebo, ranging from percentage point reductions of 0.4 for 2.5 mg up to 1.6 for 40 mg (= .007 for 2.5 mg, < .001 for the other dosages).

The HbA1c reduction for the injected semaglutide dose of 1.0 mg was 1.9 percentage points from baseline, significantly greater than placebo (< .001) and similar to the 20-mg and 40-mg oral doses.

Achievement of HbA1c < 7.0% at 26 weeks ranged from 44% of the 2.5-mg group to 90% of the 40-mg oral group and 93% for the subcutaneous formulation (= .04 for 2.5 mg and < .001 for the other doses).

Results Support Phase 3 Studies of Oral Semaglutide

Reductions in body weight were also dose-dependent and significant beginning with the 10-mg dose, with a mean weight loss compared with placebo of 3.6 kg, up to 5.7 kg with 40 mg (< .001 for doses of 10 mg and above). The proportions achieving 5% or greater body weight loss was also significant at semaglutide doses of 10 mg or greater (< .001).

There were no fatal events, and adverse-event rates were low (overall 31 reported in 21 patients). Gastrointestinal events were the most commonly reported side effect with oral semaglutide, ranging from 31% to 77% in the oral dose groups and 54% in the subcutaneous group, vs 28% with placebo. Most were mild to moderate in severity.

Nausea rates tended to decrease in prevalence and severity with time, in part because of premature discontinuations. The proportions discontinuing treatment due to any adverse event ranged from 9% to 27% in the oral semaglutide dose groups and 14% for subcutaneous semaglutide, compared with just 1% of the placebo group.

Hypoglycemia rates were low and didn't differ among oral semaglutide, injected semaglutide, and placebo.

Three patients developed confirmed cases of pancreatitis, all with semaglutide (one each in the subcutaneous, 20-mg and 40-mg dose groups).

"These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety," Dr Davies and colleagues write.

Not surprisingly, this product has competition too. At least one other company, Oramed, is developing an oral GLP-1 receptor agonist as well as an oral insulin product for both type 1 and type 2 diabetes.

The oral semaglutide study was funded by Novo Nordisk. Dr Davies reported board membership and consultancy fees from Novo Nordisk, Sanofi, Lilly, Merck, Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, Servier, and Janssen; institutional grants from Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim, and Janssen; and payment for lectures or speaker's bureaus from Novo Nordisk, Sanofi, Lilly, Merck, Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, Janssen, Mitsubishi Tanabe Pharma, and Takeda Pharmaceuticals International. Disclosures for the coauthors are listed in the paper.

JAMA. 2017;318:1460-1470. Abstract

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