Reply to Letter: Age and Sex Effects on the Single‐ and Multiple‐Dose Safety and Pharmacokinetics of the New Renin Inhibitor ACT‐178882 (2014)

We thank Drs. de Vries and Lambers Heerspink for their interest in our manuscript 1 and the points they have raised. It appears they have misunderstood the timing of the conduct of this study on the clinical development path of ACT-178882, a new renin inhibitor. The current study was only the second clinical study performed following the entry-into-humans study in which the single- and multiple-ascending dose clinical pharmacology of the compound had been elucidated 2. In this first study, only healthy young male subjects had participated, which served the objectives of an entry-into-humans study but obviously represented only a narrow population. Since the first study in hypertensive patients is usually a dose-finding study and comprises a broader population, i.e., including subjects of both sexes as well as elderly (the latter mainly constitute the target population of an antihypertensive drug), basic clinical pharmacology aspects had to be explored also in females and elderly. This sequence of studies is in accordance with regulatory guidelines of Health Authorities and Ethics Committees 3. The inherent limitations of such approach in general and in this study in particular are clearly described in the first paragraph of the Discussion: “The limitations of this study are the absence of a placebo comparator in the single-dose part of the study, the relatively short duration of treatment, and the low subject numbers. These in particular hamper the interpretation of the safety results of the present study.” We do not understand the remark of the authors of the letter that “renin inhibitors form a class of compounds lowering the blood pressure too strongly.” On the contrary, until aliskiren entered, the market development of many renin inhibitors had been discontinued because of too moderate blood pressure lowering effects, mainly due to low and variable bioavailability 4. The letter mentions that blood pressure, renal function, and RAAS biomarkers are not presented. However, effects on blood pressure are mentioned in the Results section and elaborated upon in the Discussion. With respect to renal function, our first study 2 had shown that ACT-178882 is not excreted unchanged by the kidney, suggesting that renal function does not influence the pharmacokinetics of the drug. RAAS biomarkers (active renin and plasma renin activity) were indeed not assessed in this study because of the limited sample size and the unknown relationship between these markers and the blood pressure lowering effect of renin inhibitors 5. The real proof-of-concept of this new compound can only be established by conduct of the dose-finding study referred to above. The fact that pharmacokinetics and drug exposure may change in the elderly is acknowledged and extensively discussed in the Introduction and Discussion of our manuscript. The final conclusion of our article was that dose reduction based on age is to be considered once more data is available on the therapeutic window and the dose–response relationship, again to be generated in a dose-finding study. In this context gastro-intestinal adverse events are not ignored and are actually discussed as a possible class effect of renin inhibitors. Finally the study was completely designed, evaluated, reported, and published by the authors of the manuscript. The principal investigator, who was responsible for the clinical conduct of the study by a commercial (rather than an independent) CRO had reviewed and approved the much more detailed clinical study report, which formed the basis of the manuscript. He had left the CRO which conducted the study at the time the manuscript was written. The financial disclosure is completely in line with international guidelines as well as the requirements of the journal. It is highly unusual to specify the exact number of stocks and/or options owned and even this number would be of limited value without further knowledge (e.g., when bought or granted, at which price, duration of block period, etc.).