IV-18 Lei Ma

Efpeglenatide dose selection for a phase 3 study in type 2 diabetes mellitus (T2DM) patients: pharmacokinetics and pharmacodynamics (PK/PD) modeling, network meta-analysis and clinical trial simulation

Lei Ma, Qi Tang, Dimple Patel, Veyrat-Follet Christine, Zhaoling Meng

Sanofi

Objectives: 

Efpeglenatide (efpeg) is a glucagon like peptide -1 receptor agonist (GLP-1 RA) being developed for the treatment of type 2 diabetes mellitus (T2DM). The primary objectives of this analysis were to: assess efficacy of different efpeg doses based on an established longitudinal exposure-response (E-R) model between efpeg and changes in glycated hemoglobin A1c (HbA1c) with selected covariates; compare with competing GLP-1 RAs and perform clinical trial simulations (CTS) to evaluate the probability of success (POS) of a head-to-head trial and guide efpeg dose selection and comparator selection for the trial.

Methods: 

Efpeg pharmacokinetic (PK) and efficacy (HbA1c) data were obtained from 5 clinical studies (1 Phase 1b and 4 Phase 2) in T2DM and obesity populations with treatment duration ranging from 8 to 22 weeks. A sequential population PK/PD model for HbA1c was developed using nonlinear mixed effects modeling program, NONMEM (version 7.3). Relevant covariates, such as baseline HbA1c, body weight, age, sex, race and obesity were also evaluated. Based on the established E-R model, stochastic simulations were performed to illustrate the impact of various efpeg dosing regimens on the change from baseline HbA1c (%) difference from placebo in subjects with T2DM and obesity. Network meta-analysis was used to synthesize competitive intelligence while CTS were used to evaluate the POS of phase 3 head-to-head study by leveraging meta-analysis results. 

Results: 

The indirect response model incorporating an exponential plateau non-drug effect adequately characterized the longitudinal HbA1c data in subjects with T2DM or non-diabetic overweight to obese subjects. The final HbA1c E-R model included the following statistically significant covariates: baseline HbA1c on maximum decrease in log HbA1c due to treatment effects (Imax), first-order rate constant describing the temporal delay between drug concentration and subsequent changes in HbA1c (kout) and maximum placebo effect; female sex on Imax; and obese subjects on kout. The efpeg concentration that results in 50% of the maximal drug effect (IC50) was estimated to be 165 ng/mL. For example, the average predicted efpeg concentration (Cavg) for a 4 mg once a week (qw) dosing regimen at steady-state in T2DM patients is 581 ng/mL. At this concentration, 78% of the maximal percentage reduction in HbA1c is achieved. 

CTS were performed using the final PK/PD model to evaluate the POS of efpeg treatments against potential comparators. The head to head trial includes four arms (n = 300/arm) with one placebo arm, two efpeg arms (4 mg and 6 mg, qw) and one comparator arm Dulaglutide (dula) 1.5 mg or Semaglutide (sema) 1 mg (both qw). The treatment duration is 30 week. The dropout rate is assumed to be 15% and 10% for placebo and efpeg groups, respectively. Treatment effects for comparators on HbA1c were based on AWARD trials 1, 5 and 61-3, SUSTAIN trials 1, 3, 6 and 74-7, LEAD 28 and DURATION 19. A network model was used to leverage information from multiple clinical trials to increase precision of the estimated effects of competitors and reduce the biases. The comparison between efpeg and sema is estimated through two routes: 1) efpeg→placebo→sema and 2) efpeg→lira→placebo→sema.   Liraglutide (lira) data have two contributions to the analysis: 1) help to benchmark lira effect for comparison between lira and efpeg and 2) placebo arm helps to estimate placebo effect more precisely. CTS suggested that:

  • 6 mg efpeg has high chances to be superior to dula on HbA1c (POS = 88%)
  • 6 mg efpeg has comparable performance to sema on HbA1c (POS = 76% to show non-inferiority). 
  • 4 mg efpeg has high chances to be non-inferior to dula on HbA1c (POS = 99%) 

Conclusions: 

  • The indirect response model incorporating an exponential plateau non-drug effect adequately characterized the longitudinal HbA1c data in subjects with T2DM or non-diabetic overweight/obese subjects.
  • The magnitude of the non-drug effect was dependent on the baseline HbA1c value such that a larger maximum decrease in HbA1c was predicted for subjects with higher baseline HbA1c.
  • Upon repeated dosing, the large majority of the maximum effect on HbA1c attributed to efpeg exposure was predicted to be obtained by approximately 12 weeks.
  • Based on CTS, 6 mg/qw efpeg would have high POS to demonstrate superiority against dula (88%) and non-inferiority against sema (76%) on HbA1c in a head-to-head trial.

References:
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Reference: PAGE 27 (2018) Abstr 8632 [www.page-meeting.org/?abstract=8632]

Poster: Drug/Disease Modelling - Other Topics