Topline Data for Oral Semaglutide in PIONEER 6 CV Outcomes Trial

November 26, 2018

An oral form of the glucagon-like peptide 1 (GLP-1) agonist, semaglutide, in development for the treatment of type 2 diabetes, has shown a reduction in cardiovascular and all-cause mortality in the PIONEER 6 cardiovascular outcomes trial, but did not significantly reduce the overall composite primary endpoint of major adverse cardiovascular events (MACE).

Semaglutide is already approved as a once-weekly subcutaneous injection in doses of 0.5 mg and 1 mg for the treatment of type 2 diabetes, known as Ozempic (Novo Nordisk), in the United States, European Union, Canada, and Japan.

The injectable formulation showed a significant reduction in MACE in the SUSTAIN-6 cardiovascular outcomes trial compared with placebo in patients with type 2 diabetes at high cardiovascular risk, as reported by Medscape Medical News in 2016.

Now also formulated as the first oral GLP-1 agonist to approach the market, "Novo Nordisk expects to file oral semaglutide for regulatory review in the US and EU in the first half of 2019," the company said in its press release announcing the PIONEER-6 results on November 23.

A US Food and Drug Administration (FDA) panel recently voted to retain cardiovascular outcomes studies for new type 2 diabetes drugs as a condition of US marketing. The original 2008 FDA guidance arose out of concerns about cardiovascular harm arising from older studies of type 2 diabetes medications.

But thus far, none of the eight completed mandated cardiovascular outcomes trials have identified excess CV risk from the drugs in question, and a number have actually shown benefit.

PIONEER-6: Significant Reduction in Death but Not MACE Overall

The PIONEER clinical trials for oral semaglutide is a global development program with enrollment of 8845 people with type 2 diabetes across 10 clinical trials all completed in 2018, Novo Nordisk notes.

PIONEER 1, the first of these trials to report which was presented as a poster at the American Diabetes Association (ADA) 2018 Scientific Sessions in June, compared one of three once-daily doses of oral semaglutide (3, 7, or 14 mg) with placebo in just over 700 drug-naive patients with type 2 diabetes.

Those treated with semaglutide monotherapy for 26 weeks showed a significant lowering of HbA1c by an average of 1.5% in the group that received the highest dose. Weight loss was also significant in this group, at a mean of 4.3 kg by study end.

It is this highest dose — 14 mg/day — that was tested in the PIONEER 6 trial, which compared the cardiovascular safety of oral semaglutide with placebo, both in addition to standard of care, in 3183 adults with type 2 diabetes at high risk of cardiovascular events.

As a cardiovascular outcomes safety trial, PIONEER 6 achieved its primary endpoint, demonstrating noninferiority of MACE with oral semaglutide compared with placebo, both in addition to standard of care.

The results are based on the accumulated occurrence of 137 MACE, with a median follow-up of 16 months, making this one of the shortest cardiovascular outcomes trials of a type 2 diabetes drug, with a low number of enrollees compared with other similar trials and a low number of cardiovascular events.

The MACE primary endpoint was a composite outcome of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, and had a hazard ratio (HR) of 0.79 in favor of oral semaglutide compared with placebo, although this 21% reduction did not reach statistical significance.

The MACE results were driven by a significant reduction in cardiovascular death of 51% (HR, 0.49; P = .03) in favor of oral semaglutide, while nonfatal myocardial infarction (HR, 1.18) was not significantly different, nor was nonfatal stroke (HR, 0.74). Both of these endpoints were broadly similarly distributed between the oral semaglutide and placebo groups.

In addition, a significant reduction in all-cause mortality of 49% (HR, 0.51; P = .008) in favor of oral semaglutide was observed.    

Talks With FDA on Combining CV Data for Oral and SC Semaglutide

"We are very encouraged that PIONEER 6 demonstrated cardiovascular safety as well as a significant reduction in both cardiovascular and all-cause mortality following oral semaglutide treatment in people with type 2 diabetes at high cardiovascular risk," said Mads Krogsgaard Thomsen, PhD, executive vice president and chief science officer of Novo Nordisk, in the company release.

The improvements in secondary endpoints including HbA1c, body weight, and blood pressure were similar to results reported throughout the PIONEER program for oral semaglutide, says Novo Nordisk.

Furthermore, the safety profile of oral semaglutide in PIONEER 6 "was consistent with the established safety profile observed in previous PIONEER clinical trials."

Novo Nordisk notes that since the US approval of Ozempic (once-weekly injectable semaglutide) a year ago, it has "engaged in a constructive dialogue with the US FDA on minimizing the need for additional separate large cardiovascular outcomes trials to obtain a cardiovascular indication for semaglutide in different formulations."

Following the results of the PIONEER 6 trial, Novo Nordisk is now "evaluating the potential to obtain a cardiovascular indication for Ozempic based on the already obtained clinical data from the cardiovascular outcome trial SUSTAIN 6 in combination with the cardiovascular outcome trial PIONEER 6 with oral semaglutide. Novo Nordisk will continue these discussions with the FDA."

Other recently reported top-line results from a trial with another GLP-1 agonist, once-weekly subcutaneous dulaglutide (Trulicity, Lilly), were seemingly more impressive.

In the REWIND trial, dulaglutide 1.5 mg SC per week significantly reduced the risk of MACE compared with placebo when added to standard of care in type 2 diabetes in the unique scenario where the majority of patients did not have established cardiovascular disease at baseline.

Full details of the REWIND study will be reported at the American Diabetes Association Scientific Sessions in San Francisco in 2019.

Follow Lisa Nainggolan on Twitter:  @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

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