First Oral GLP-1 Agonist Showcased while Approval Pending

Results of 3 pivotal clinical trials on the safety and efficacy of oral semaglultide, the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist (RA) to be considered for FDA approval to treat type 2 diabetes (T2DM), were presented at the American Diabetes Association (ADA) Scientific Sessions meeting in San Francisco, CA, June 7-11.

The studies, under the umbrella of the PIONEER (Peptide InnOvatioN for Early DiabEtes Treatment) program, found oral semaglutide: 

•  Superior to the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin for A1c lowering and weight loss (PIONEER 7)

•  Neutral in relation to renal function in patients with moderate kidney disease (PIONEER 5)

•  Superior to placebo in A1c reduction and weight loss as an add-on to insulin, with or without metformin; insulin dose was also reduced (PIONEER 8)

Earlier this year, Novo Nordisk submitted 2 new drug applications (NDAs) to the FDA for oral semaglutide, one seeking approval for the agent as an adjunct to diet and exercise to improve glycemic control in adults with T2DM, the other petitioning for an indication to reduce risk of major adverse cardiovascular events (MACE) such as heart attack, stroke, or death in adults with T2DM and established cardiovascular disease (CVD).

These filings, too, are based on the PIONEER clinical trial series, a program involving over 8,000 people with T2DM in 10 global clinical trials.

Next: PIONEER 7 evaluates flexible dosing

PIONEER 7 -- John Buse, MD, PhD, Professor of Medicine, Director of the Diabetes Care Center, and Chief of Endocrinology at the University of North Carolina School of Medicine, Chapel Hill, North Carolina, presented results from PIONEER 7, a randomized, open-label trial that compared oral semaglutide to the oral DPP-4 inhibitor, sitagliptin (Januvia).¹ All participants had T2DM uncontrolled on 1 to 2 oral glucose-lowering drugs.

Oral semaglutide was administered in a once-daily adjustable dose (based on A1c and tolerability) of 3, 7, or 14 mg (n=253) and sitagliptin was administered at a dose of 100 mg daily (n=251). The primary study endpoint at week 52 was A1c <7.0%, and the secondary endpoint was weight change.

Buse reported that oral semaglutide was superior to sitagliptin for both the primary and secondary endpoints, and that semaglutide was associated with a significantly greater reduction in A1c at week 52. Fewer patients on oral semaglutide needed rescue medication (3% vs 16%). 

Although adverse events and trial discontinuation were more common with oral semaglutide (78% vs 69% and 9% vs 3%, respectively), Buse noted that most events were mild to moderate or transient nausea, and that most of the discontinuations were due to gastrointestinal complaint.

“Flexible dose adjustment with oral semaglutide provided superior glycemic control and weight loss at week 52 vs sitagliptin, and was well tolerated with safety consistent with the GLP-1 RA class,” Buse concluded.

Next: PIONEER 5 focuses on renal impairment

PIONEER 5 -- The results of PIONEER 5, a placebo-controlled assessment of oral semaglutide in patients with T2DM and moderate renal impairment, were presented by Ofri Mosenzon, MD, MSc, Professor of Internal Medicine at Hadassah Hebrew University Hospital, Jerusalem, Israel.²

Study participants had an estimated glomerular filtration rate (eGFR) of 30-59 mL/min/1.73m² and had been receiving 1 to 2 glucose-lowering agents, which could include basal insulin. The primary study endpoint, change in A1c, and secondary endpoint, change in body weight, were assessed at week 26.

Mosenzon reported oral semaglutide superior to, and statistically significantly better than placebo in reducing A1c and body weight, with more patients reaching targets for those measures and for composite targets. She noted that fewer patients on oral semaglutide required rescue medication (4% vs 10%). There was no change in eGFR in either group at follow-up.

“In conclusion, in patients with T2D and moderate renal impairment, oral semaglutide provided superior glycemic control and body weight loss compared to placebo at 26 weeks,” Mosenzon indicated.  “[Semaglutide] did not appear to affect renal function, and was well tolerated, in line with the population and GLP-1RA class.

Next: PIONEER 8 looks at semaglutide as add-on to insulin

PIONEER 8 -- Bernard Zinman, MD, Director of the Leadership Sinai Center for Diabetes, Mount Sinai Hospital and Professor of Medicine, University of Toronto, Toronto, Onatario, Canada, presented results of the PIONEER 8 trial of oral semaglutide as an add-on to insulin.³

Participants had T2DM uncontrolled on insulin with and without metformin and were randomized to receive oral semaglutide 3 mg (n=184), 7 mg (n=182), 14 mg (N=181) or placebo (N=184) in double-blind format for 52 weeks. The primary outcome measure was change in A1c and secondary measure was change in body weight as measured at week 26.

Oral semaglutide was superior to placebo in reducing both measures at week 26, and statistically significantly greater dose-dependent reductions in A1c and body weight were achieved at week 26 and 52. In addition, total insulin dose was significantly reduced from baseline with active drug with the 7 mg and 14 mg doses compared to placebo at weeks 26 and 52.

“As add-on to insulin with or with metformin, oral semaglutide had superior A1c and body weight reductions versus placebo at week 26,” Zinman summarized.  “It also reduced insulin use by week 52 and was well tolerated without significantly increasing hypoglycemia rate.”

Buse commented on the value of the findings from these and other trials of the PIONEER program, and the prospects for the oral form of semaglutide. 

“The GLP-1 receptor agonists are arguably the most powerful glucose-lowering and weight-lowering medications that we have.  In a number of trials, it’s been shown that these drugs seem to reduce the risk of heart attack, stroke, and in some cases, cardiovascular death,” Buse observed. “However, there are some people who are reluctant to take the medication because it’s currently only available as an injection, which is a barrier to using this otherwise good class of drugs.”

Buse noted the pending NDAs for this first GLP-1 RA for oral administration, and commented that it “potentially could be approved and available by the end of the year or early next year.”

“If the drug is approved, because it is administered orally, it has the potential to be more frequently used early in the course of the disease, and perhaps will become the preferred agent in the class,” Buse opined.

References
1. Buse JB, Bode BW, Cho YM, et al. Effect and safety of flexible dose adjustment with oral semaglutide vs sitagliptin in Type 2 diabetes: PIONEER 7. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 983-P.

2. Mosenzon O, Rosenlund S, Eriksson JW, et al. Oral semaglutide vs placebo in patients with Type 2 diabetes and moderate renal impairment: PIONEER 5. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 1004-P.

3. Zinman B, Aroda VR, Buse JB, et al. Oral semaglutide as add-on to insulin in T2D: Pioneer 8. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 985-P.