First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11ß-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

Pharmacology-Guided Rule-Based Adaptive Dose Escalation in First-in-Human Studies.

First-in-human (FIH) studies typically progress through cohorts of fixed, standard size throughout the escalation scheme. This work presents and tests a pharmacology-guided rule-based adaptive dose escalation design that aims at making "best use" of participants in early clinical drug evaluation; it is paper based, not requiring real-time access to computational methods. The design minimizes the number of participants exposed to dose levels with low likelihood of being therapeutically relevant. Using criteria based on dose-limiting adverse event rate and on target exposure or target pharmacodynamics, the design increases the sample size when approaching the dose range of potential clinical relevance. The adaptive escalation design was retrospectively tested on actual data from a sample of 40 recently executed FIH studies with novel small and large molecules, and it was evaluated by simulating trials with three compounds with different therapeutic windows, i.e., representing a promising, unacceptable, and dubious profile. In retrospective evaluation of the adaptive escalation design, none of the cases overshot the actually reported top dose; one case resulted in a top dose that was within 20% under the estimated maximum tolerated dose in the original study. The median reduction of total number of participants per study was 38%. Trial simulations confirmed the retrospective evaluation, showing a similar performance of the adaptive escalation design compared with the conventional 6 + 2 design, at a reduced study size for compounds with a presumed acceptable therapeutic window. The adaptive escalation design was shown to make "best use" of participants in FIH studies without compromising safety.

A Change in Posture Significantly Affects Plasma Concentrations of Large Molecules Such as IgG Antibodies.

In several studies with monoclonal antibodies, we observed spikes in plasma concentration profiles coinciding with a change of posture of study subjects. We hypothesized that these unexpected changes were due to fluid shifts from plasma to the interstitium. The objective of this study was to investigate size and time course of the change in total immunoglobulin G (IgG) concentration after a change in posture. Thirty-two healthy subjects were enrolled. After entry in the clinic, subjects remained upright for at least 1 hour, followed by IgG sampling. Thereafter, subjects remained supine or seated (16 subjects each) for 60 minutes while IgG was sampled frequently. The within-subject day-to-day variability of IgG measured in the same position was only 2.6%. After a change in posture from standing to supine, IgG dropped rapidly in all subjects during the first 10 minutes in the supine position (9.0% decrease) and more slowly thereafter, up to a 12.3% decrease after 60 minutes. After a change in posture from standing to sitting, the decrease in IgG was more variable and modest. After 10 minutes of sitting, IgG was 3.6% lower, and after 60 minutes IgG was 7.8% lower. Changing posture causes a bias of more than 10% in plasma concentrations of total IgG. Most of the change is reached after being 15 minutes in the same position. In clinical trials in which plasma concentrations of high-molecular drugs, highly protein-bound drugs, endogenous proteins, or blood cells are assessed, standardizing posture per time point is a useful approach for reducing variability.

Structured Risk Assessment for First-in-Human Studies.

We describe a structured risk assessment and risk mitigation process that is currently used to evaluate proposed first-in human (FiH) studies. This process balances the inherent risks of an FiH study with maximal protection of subjects. Risk assessment should consider all available data, carefully identifying aspects that may lead to risk for healthy subjects. A structured risk assessment avoids omissions and promotes consistency. Such a risk assessment should be performed for Investigational Products as well as for challenge agents and study procedures. Careful risk assessment recognizes gaps of knowledge and emphasizes that FiH studies are tolerability, not toxicity, studies.

Safety in FIH Trials: A Summary of the Symposium "Fatal Drug Trial in Phase 1: Understanding Risk, Subject Safety, Timelines, and Cost".

A cross-section of clinical research professionals convened at the June 2016 Drug Information Association annual meeting in Philadelphia to discuss and critically analyze the first-in-human (FIH) clinical trial conducted by a French CRO with BIA 10-2474 (BIA) under development for pain relief by Bial-Portela & Ca., S.A., that resulted in 6 healthy volunteers hospitalized with serious adverse events, which resulted in 1 death. This paper summarizes the background, presentations, and discussion points of Symposium no. 107 in an effort to share the learnings of our symposium with others who conduct studies. Novel investigational products studied in phase 1 clinical trials propose a heightened risk of adverse events that may not be foreseeable when relying on animal studies to project outcomes in humans. Novelty of molecular structure, drug class, mechanism of action, proper dose selection, pharmacokinetics, and therapeutic window are all contributing factors that heighten risks when transitioning from animal to human trials. The potential for catastrophic events confronts every sponsor/investigator in clinical trials. Minimizing risks to subjects is an essential ethical and scientific mandate for all those involved in the clinical trials. A complex matrix of planning, conducting, and communicating preclinical and clinical observations need to be considered carefully by the Sponsor, Investigator and others during the planning, execution, and interpretation of FIH studies, in order to promote participant safety and study data integrity. Suggestions may be applied to FIH studies, which may provide a new or improved way to address complex system and prevent or mitigate situations such as what occurred with the Bial FIH trial, where seemingly a number of issues coincided in a "perfect storm" and the system failed to sound a warning or detect an issue before a life was tragically lost.