Comment on: “A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-aspartate Angiotensin I in Healthy Subjects”

Des-aspartate angiotensin I (DAA-I) is a short-acting peptide molecule comprising nine amino acids, whose main role is to block angiotensin II via agonistic activity on the angiotensin AT1 receptor [1]. Lee et al. recently reported the safety, tolerability and pharmacokinetics of DAA-1 in healthy subjects who received single escalating doses of DAA-1 in an extemporaneously prepared oral formulation [2]. This study in particular assumes importance primarily because hitherto no such human clinical pharmacology data pertaining to DAA-1 have been published [2]. The safety and tolerability data gathered in this study showed no inadvertent effects and/or adverse events associated with DAA-1. However, the lack of differentiation in the single-dose pharmacokinetics of the examined three active doses in relation to placebo [2] poses a challenge in developing a cohesive clinical development plan for the advancement of DAA-1. Because of the rapid degradation of DAA-1, it was not expected that the first exogenous dose of DAA-1 at 0.08 mg/kg would show appreciable plasma levels in the human subjects [2]. Interestingly, the other two higher doses of DAA-1 (i.e., 0.7 and 1.5 mg/kg) appeared to be equally rapidly metabolized, resulting in no appreciable systemic levels of DAA-1 [2]. Perhaps one limitation of the study, as pointed out by the authors, was related to the frequency of pharmacokinetic sample time collection; perhaps, the inclusion of early time points after oral administration in a 2to 3-min interval for the first 30 min after dosing may have provided a better opportunity to pick the transient elevated levels of DAA-1 in the systemic circulation. On one hand, the development of exogenous DAA-1 is an exciting prospect from a clinical perspective, given the wide range of therapeutic interventions it could be applied to [3–5]. On the other hand, it represents an insurmountable challenge to develop DAA-1 from a clinical development perspective. The intent of this note is to provide some thoughts on developing DAA-1 as a potential drug candidate. Peptide drug delivery via the oral route is a daunting task owing to instability of peptides in the local environment of the gastrointestinal tract [6, 7]. Therefore, the lack of any DAA-1 levels above and beyond the baseline levels in the systemic circulation observed in this study is testament to the extent of the problem that needs to be overcome. The occasional spikes in the mean systemic levels of DAA-1, especially observed in later time points, were merely a reflection of the variability of the endogenously occurring DAA-1, rather than absorption from the administered DAA-1 doses [2]. In addition, none of the observed parameters such as vital signs, aldosterone levels, liver function biomarkers and renal function biomarkers showed any differences to discern a clear DAA-1 effect versus placebo effect. Overall, the single-dose data for DAA-1, although suggestive of an excellent safety/tolerability profile, have failed to provide any clues that would aid the developmental aspects of DAA-1. The key question is how would one design a multipledose escalation study of DAA-1 in humans to obtain meaningful data. What would be the starting dose and the This comment refers to the article available at doi:10.1007/s40268016-0143-y.