Abstract 18934: Clinical Trial Strategies for Identifying an Evolocumab and Inclisiran Combination Regimen With Improved Safety and Efficacy Over Evolocumab Alone

    loading  Checking for direct PDF access through Ovid

Abstract

Introduction: Evolocumab monoclonal antibody trials demonstrated safety and efficacy in lowering elevated LDL cholesterol (LDL-C) to a median of 48 mg/dL. Cardiovascular events (CVE) were decreased as well (NEJM 2015, 372:1500-09). A phase II trial of inclisiran, an RNA interfering molecule, also showed safety in lowering LDL-C. (NEJM 2017, 376:1430-40). Serious adverse events (SAE) in these trials ranged from 8-11%. A clinical trial strategy is proffered to explore combined therapy using these agents, each with a different mechanism of action, to show synergism at lower, safer doses.

Methods: Published data permitted sample size estimates for a 10% and a 20% difference from the mean (48 mg/dL} following 12 weeks of evolocumab treatment, with or without inclisiran. The experimental group was defined as evolocumab with inclisiran, and the control group was standard dose evolocumab alone. The t-test for two independent variables with the following parameters was used: a type I error probability of 0.05, a power of 0.8, an allocation of 1:1, and a calculated standard deviation of 23.8.

Results: To detect a 10% difference between the experimental and control groups, 387 subjects are needed in each group. For a 20% difference, 97 experimental and controls are needed.

Conclusions: The results show that trials are feasible to determine whether combined evolocumab-inclisiran therapy is safer, and more effective, than evolocumab alone. To identify such a combination, a series of 12-week phase I trials of 20 patients would be designed beginning with 10% of the standard dose for each drug. Subsequent dose escalations using 10% dose increments would identify a candidate combination. If a SAE occurred at a certain dose combination, the previous dosing regimen without an SAE would be used for future trials. A phase II trial requires either a total of 747 or 194 total patients to detect a significant LDL-C reduction of 10 or 20% difference, respectively. Should SAE approach 5% or less, then an effective and safe evolocumab-inclisiran combination would be identified. Further phase III testing to show CVE and cardiovascular mortality improvement would be required. Discovering an improved dosing regimen would benefit those intolerant to statins.

Related Topics

    loading  Loading Related Articles