PIONEER: First Phase 3 Data on Oral Semaglutide in Diabetes

ORLANDO — An oral version of the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Ozempic, Novo Nordisk) has shown encouraging results in the first phase 3 trial of an oral drug in this class, although it seems the highest dose tested might be needed to garner the greatest benefits.

Patients with type 2 diabetes treated with semaglutide monotherapy for 26 weeks in the PIONEER-1 trial showed a statistically significant lowering of HbA1c by an average of 1.5% in the group that received the highest dose (14 mg once daily). Weight loss was also statistically significant in this group, at a mean of 4.3 kg by study end.

Results were reported in a late-breaking poster here at the American Diabetes Association (ADA) 2018 Scientific Session.

"This is the first phase 3 study showing that we have an oral GLP-1 in development that is...glucose lowering and looks like it has positive effects on weight loss in typical patients with type 2 diabetes. It also has safety and tolerability similar to what we already know of this class of drugs [injectable GLP-1 receptor agonists]," said Vanita Aroda, MD, associate director of diabetes clinical research at the Brigham and Women's Hospital, Boston, Massachusetts, who presented the research.

She added that the oral formulation was a true innovation above and beyond the injectable versions. "Currently available GLP-1 receptor agonists are all injectable because these molecules are proteins. The challenge is in getting a protein through the gastrointestinal tract, because proteins denature."

Ultimately, an oral formulation needs to show comparable results to the injectable versions of GLP-1 agonists, the first of which has been available for a number of years now, explained Aroda; that seems to be the case with these results, she suggested.

Semaglutide is said to be the most potent GLP-1 agonist yet. The once-weekly injectable version was approved for type 2 diabetes by the US Food and Drug Administration last December, as reported by Medscape Medical News, and it has also been endorsed by the European Medicines Agency.

Semaglutide is the third once-weekly injectable GLP-1 receptor agonist on the US market. The GLP-1 agonists that have been available longest are once-daily injectables, such as liraglutide (Victoza, Novo Nordisk).

After viewing the poster, Sree Nair, MD, PhD, professor of medicine, Mayo Clinic School of Medicine, Rochester, Minnesota, told Medscape Medical News: "Being an oral medication is an advantage, and the 1.5% reduction in HbA1c is clinically significant."

But he cautioned that "it is a placebo-controlled study, and no other well-established drugs were included in the trial, which is important. The price also will matter on how well [oral] semaglutide will be used."

John Wilding, DM, professor of medicine, University of Liverpool and Aintree University Hospital, United Kingdom, welcomed the innovation of an oral formulation but also has reservations regarding cost.

"The science to enable oral administration of a peptide is truly innovative," he said, impressed by what he had seen.

"The data seem encouraging and are largely consistent with what we already see with semaglutide 0.5 mg and 1 mg given as a weekly subcutaneous injection. There is the modest advantage for oral dosing, for example, for patients with needle phobia, but given that a much higher dose is needed, this might end up being more expensive than the injectable option," he indicated.

Highest Dose Linked to Weight Loss

The 703 participants in PIONEER-1 were representative of a typical drug-naive type 2 diabetes population. The average age of the participants was 55 years; there was an even distribution of male and female patients; the baseline HbA1c level was approximately 8%; and the average duration of diabetes among the patients was of 3.5 years.

All patients were told to diet and exercise; no other mediations were allowed.

The multicenter, double-blind trial randomly allocated patients to receive one of three once-daily doses of oral semaglutide (3, 7, or 14 mg) or placebo for 26 weeks. The primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints included weight loss; the proportion of patients achieving HbA1c of <7%; change in fasting glucose glevel; and safety and tolerability.

"We found that over 26 weeks, all three doses of semaglutide had statistically significant HbA1c reductions compared to placebo," reported Aroda, discussing the on-treatment results.

"Those reductions were on average 1.5% in the 14-mg dose (final HbA1c, 6.4%), 1.3% in the 7-mg dose (final HbA1c, 6.6%), and 0.8% on the 3-mg dose (final HbA1c, 7.0%), compared to a 0.1% reduction on placebo."

With respect to weight loss, Aroda pointed out that the results had not reached a plateau at the point of data cutoff. At week 26, patients in the high-dose group showed a mean drop of 4.3 kg, which was the only result that was significant compared with mean loss of 1.6 kg in the placebo group.

As seen with injectable GLP-1 receptor agonists, the main problem with respect to tolerability was gastrointestinal effects, with an increase in nausea in the oral semaglutide groups, particularly in the highest-dose group, at 16%, compared to 5.6% with placebo. There was less at the lower doses.

"This nausea dissipated as the weeks went by," reported Aroda.

PIONEER-2, -4, and -7 Trials

Other studies are running out to 52 weeks in the phase 3 program of oral semaglutide. The company announced topline results of the PIONEER-2 study in May, which found that patients treated with 14-mg oral semaglutide daily achieved a significant reduction in HbA1c of 1.4% at 26 weeks and 1.3% at 52 weeks, compared to reductions of 0.9% and 0.8% with 25 mg of the SGLT-2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) at the same time points. Weight loss with oral semaglutide was significantly greater compared to empagliflozin at the 52-week time point.

On June 20, the company also announced topline results of the PIONEER-4 phase 3 trial, which compared oral semaglutide to 1.8-mg liraglutide and placebo, and PIONEER 7, which compared oral semaglutide to sitagliptin 100 mg. Oral semaglutide reduced HbA1c to a greater extent than the comparator agents in both trials.

Aroda is a consultant for Adocia, AstraZeneca, Novo Nordisk, and Sanofi and has received research support from AstraZeneca/BMS, Calibra, Eisai, Janssen, Novo Nordisk, Sanofi, Theracos. Nair has disclosed no relevant financial relationships. Wilding worked for Novo Nordisk on the SUSTAIN 6 study and the semaglutide obesity program.

American Diabetes Association 2018 Scientific Sessions. June 25, 2018; Orlando, Florida. Abstract 2-LB.

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