Phase 2b Trial Suggests Efficacy of Oral Danuglipron for Glycemic Control in T2D

Aditi R. Saxena, MD, MMSc

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New phase 2b clinical trial data suggest danuglipron, a novel, oral, small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, demonstrated an efficacy and safety profile consistent with currently available peptide agonists in adults with type 2 diabetes (T2D).¹

The analysis showed the administration of twice daily danuglipron for 16 weeks reduced glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) at all dose levels studied, as well as body weight at doses of ≥80mg, compared with placebo.

“Danuglipron was generally safe in this population, with most participants receiving metformin background therapy, with a tolerability profile consistent with the mechanism of action,” wrote the investigative team, led by Aditi R. Saxena, MD, MMSc of the internal medicine research unit at Pfizer Worldwide Research.

Current GLP-1R therapies for T2D are peptidic agonists that require subcutaneous administration, causing inconvenience for some patients and potentially reducing uptake and adherence. Semaglutide is the only GLP-1R agonist available for oral administration but requires strict fasting requirements before and after administration.² Thus, danuglipron is being investigated as an adjunct to diet and exercise to improve glycemic control in those with T2D.

Phase 1 results indicated danuglipron’s effects on reducing glycemic indexes and body weight with favorable safety and pharmacokinetic profiles in adults with T2D taking metformin.³ The phase 2b double-blind, placebo-controlled, parallel-group, 6-group randomized controlled trial was conducted for 16 weeks from July 2020 - July 2021 across 97 clinical research sites in 8 countries or regions.

Following a 2-week, single-blind, placebo, run-in period, participants were randomized to receive placebo or danuglipron target doses of 2.5, 10, 40, 80, or 120 mg twice daily with food for 16 weeks. For regimens of 40 mg or above, up to 6 weeks of the 16-week double-blind treatment period was used for dose escalation.

The primary efficacy endpoint was the change from baseline in glycated hemoglobin at week 16, while secondary endpoints included the change from baseline in HbA1c at other time points (weeks 2, 4, 6, 8, and 12), the proportion of participants achieving HbA1c ≤7%, and change from baseline in FPG and body weight at all time points. Safety was additionally monitored in the study period, including a 4-week follow-up period.

After screening 859 participants, 411 participants (mean age, 58.6 years; 209 [51%] male) were included in the analysis, with a mean HbA1c of 8.07% and a mean BMI of 32.8. Most (91%) were receiving metformin. The double-blind treatment period was completed by 316 participants (77%).

Upon analysis, all danuglipron groups were found to have statistically significant dose-responsive declines from baseline in HbA1c at week 16 compared with placebo. At Week 16, data showed the least-squares mean difference in HbA1c was -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group. A greater proportion of those receiving danuglipron compared with placebo was able to achieve the glycemic target of HbA1c <7%, with the proportion of patients generally increasing with higher danuglipron doses.

Moreover, the analysis found FPG was statistically significantly reduced at Week 16 with all danuglipron doses compared with placebo. Data showed a least-squares mean difference of -14.12 mg/dL (90% CI, -25.77 to -2.47 mg/dL) in the 2.5-mg twice daily group to -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL) in the 120-mg twice daily group. Investigators noted reductions in HbA1c and FPG were evident for all danuglipron groups as early as week 2 and continued through week 16, with some exceptions for the lowest-dose group.

Additionally, body weight was statistically reduced at week 16 compared with placebo in the 80-mg twice daily group (least-squares mean difference, -2.04 kg; 90% CI, -3.01 kg to -1.07 kg) and 120-mg twice daily group (least-squares mean difference, -4.17 kg; 90% CI, -5.15 kg to -3.18 kg). Differences were not statistically significant at lower danuglipron dose levels, but the pattern was generally evident at earlier time points.

“The weight loss seen with the higher doses of danuglipron in this study is supported by the phase 1 pharmacodynamic data for danuglipron, and the weight loss with danuglipron in the current study is of a similar magnitude to that observed in the phase 2 data for oral semaglutide and the injectable GLP-1R agonists during similar durations of dosing,” investigators wrote.

Regarding safety, 224 (55%) participants experienced a total of 538 treatment-emergent adverse events (TEAEs), with most being mild in nature (68%). As expected with the GLP-1R agonist class, the analysis showed the most reported TEAEs were gastrointestinal in nature, including nausea (7%-33% across danuglipron groups; 3% for placebo), diarrhea (4%-18%; 3% for placebo), and vomiting (0%-25%; 0% for placebo).

“In comparison with semaglutide phase 2 data, the range of proportion of participants experiencing gastrointestinal TEAEs with danuglipron was relatively similar,” investigators wrote. “Consistent with the mechanism of action, the rates of hypoglycemia was low in the current study, and there were no episodes of severe hypoglycemia.”

References

1. Saxena AR, Frias JP, Brown LS, et al. Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(5):e2314493. doi:10.1001/jamanetworkopen.2023.14493
2. Bækdal TA, Breitschaft A, Donsmark M, Maarbjerg SJ, Søndergaard FL, Borregaard J. Effect of various dosing conditions on the pharmacokinetics of oral semaglutide, a human glucagon-like peptide-1 analogue in a tablet formulation. Diabetes Ther. 2021;12(7):1915-1927. doi:10.1007/s13300-021-01078
3. Saxena AR, Gorman DN, Esquejo RM, et al. Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial. Nat Med. 2021;27(6):1079-1087. doi:10.1038/s41591-021-01391