Zenagamtide Pharmacokinetics, Safety Unaffected by Renal Impairment, Eliminating Dose Adjustments

Managing Type 2 diabetes and weight management often involves incretin-based therapies, but dosing can be complex in patients with impaired renal function due to altered drug clearance. Zenagamtide is a novel, unimolecular glucagon-like peptide-1 (GLP-1) and amylin receptor agonist in development, combining the benefits of both pathways for glycemic control and satiety. Understanding its pharmacokinetic (PK) and safety profile across varying degrees of renal impairment is crucial to ensure safe and effective dosing without the need for complex adjustments, which can be a significant barrier to treatment adherence.

This Phase 1 study enrolled 42 adults (BMI 20.0-39.9 kg/m2) categorized by baseline renal status using the CKD-EPI Collaboration creatinine equation (2021): normal function (n=14), mild, moderate, severe impairment, and end-stage renal disease (ESRD) (n=7 per impairment group). Participants received a single subcutaneous dose of zenagamtide 0.3 mg. A 4-week follow-up period assessed safety. The primary endpoint was AUC0-∞ (area under the zenagamtide plasma concentration-time curve from time zero to infinity), with Cmax (maximum observed plasma concentration) and TEAEs (treatment-emergent adverse events) as additional endpoints.

Zenagamtide's pharmacokinetic parameters showed minimal variation across renal function groups. The geometric mean of zenagamtide AUC0-∞ ranged from 520-715 h × nmol/L across all renal impairment groups, closely comparable to 543 h × nmol/L in the normal renal function group. Similarly, Cmax ranged from 2.8-3.5 nmol/L in impaired groups versus 3.2 nmol/L in the normal group. These findings indicate that renal impairment does not significantly alter zenagamtide exposure. Safety data revealed that 30 (71.4%) participants reported TEAEs. Importantly, all TEAEs were non-serious, none were severe, and the majority were mild, primarily gastrointestinal in nature. No new safety signals emerged.

Renal impairment did not appear to have a clinically relevant impact on the PK or safety profile of zenagamtide, suggesting that dose adjustment of zenagamtide is not warranted in this population.