Gan & Lee Pharmaceuticals announced positive clinical results from two Phase I trials of its novel once-weekly insulin analog, GZR4, at the 60th Annual Meeting of the European Association for the Study of Diabetes (EASD 2024). The trials, involving healthy subjects and patients with Type 2 diabetes mellitus (T2DM), demonstrated GZR4's potential for stable glycemic control with a favorable safety profile, offering a promising alternative to daily insulin injections. These findings could address challenges related to treatment adherence and initiation of insulin therapy in T2DM management.
Phase Ia Study: Safety and Tolerability in Healthy Subjects
The Phase Ia study was a placebo-controlled, active-comparator-controlled, single-center, single-dose, randomized, dose-escalation study. It evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GZR4 in healthy adult male participants. Participants received subcutaneous injections of GZR4 (1, 3, 6, or 12 nmol/kg), placebo, or insulin degludec (IDeg) at 0.4 U/kg (2.4 nmol/kg). A 24-hour glucose clamp procedure was conducted to assess glucose-lowering effects.
The results indicated that GZR4 was well-tolerated, with no serious adverse events (SAEs) or discontinuations due to adverse events. The glucose infusion rate (GIR) on day 7 was approximately 80% of that on day 2 in subjects receiving 12 nmol/kg GZR4, suggesting a sustained glucose-lowering effect for one week. Furthermore, the glucose-lowering effect of GZR4 at 6 nmol/kg was comparable to that of 0.4 U/kg IDeg, implying GZR4's potency is approximately 2.5-fold greater than IDeg on a molar concentration basis.
Phase Ib Study: Efficacy and Safety in T2DM Patients
The Phase Ib trial was a randomized, open-label, active-controlled, multi-center, dose-escalation study. Thirty-six patients with T2DM previously treated with basal insulin were randomized (3:1) to receive once-weekly GZR4 (6, 8, or 12 nmol/kg) or once-daily IDeg (equal to pre-enrolment daily basal insulin dosage) for 6 weeks.
PK results showed dose-dependent increases in GZR4's maximum plasma concentration (Cmax), with a time to maximum concentration (Tmax) of approximately 32 hours and a half-life of 135 hours at steady state. PD data indicated dose-dependent reductions in fasting blood glucose (FBG) at week 6, with GZR4 outperforming the IDeg group (-1.77 ± 0.20, -2.03 ± 0.66, and -2.75 ± 0.71 mmol/L for GZR4 in 6, 8, and 12 nmol/kg groups, respectively, versus -1.12 ± 0.36 mmol/L for IDeg). The 6 nmol/kg GZR4 group demonstrated a reduction in HbA1c of 0.76 ± 0.14%, compared to a reduction of 0.13 ± 0.21% in the IDeg group.
GZR4 demonstrated good safety and tolerability in T2DM patients, with no serious adverse events reported. The most frequent adverse event was hypoglycemia, but no severe hypoglycemia occurred.
Ongoing Phase II Study
Gan & Lee is also conducting a multicenter, randomized, open-label, parallel-control, treat-to-target phase 2 study in T2DM patients with inadequate glycemic control on oral antidiabetic drugs. This study, involving 179 participants, compares once-weekly GZR4 with once-daily insulin degludec. Preliminary results are promising and further validate the Phase I findings.
Implications for Diabetes Management
"A significant number of patients with Type 2 diabetes mellitus are experiencing delays in initiating insulin therapy and exhibit poor long-term adherence to treatment," said Dr. Gan Zhong-ru, Chairman of Gan & Lee Pharmaceuticals. "The introduction of weekly insulin preparations has the potential to significantly improve the aforementioned challenges. The completed Phase I trials confirmed GZR4's ability to provide stable glycemic control for a full week with a single dose, along with favorable safety and tolerability profiles. In addition, GZR4 is expected to reduce the weekly dosage of insulin required reaching the glycemic target, thereby reducing the possible risk of hypoglycaemia. We look forward to continuing to explore the clinical benefits of GZR4 in future trials."
