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.