Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers

Abstract

This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).

Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies

“…In a further safety and pharmacokinetic study conducted in monkeys, SAL200 was well tolerated and did not cause any adverse effects when injected as a single dose (up to 80 mg/kg body weight) or as multiple doses, up to 40 mg/kg per day (138). Most recently, SAL200 became the first endolysin-based drug applied to humans by intravenous infusion as part of a phase 1 clinical trial (140). Single ascending doses (up to 10 mg/kg) were applied to healthy male volunteers, and pharmacokinetics, pharmacodynamics, and tolerance of the drug candidate were evaluated.…”

“…This endolysin differs from LysK in only 3 amino acids; however, it was claimed by those authors to exhibit higher activity against multiple S. aureus strains than LysK (139). SAL-1 is the first endolysin that has been intravenously administered to humans (140), which is discussed in more detail below.…”

Phage Lytic Protein LysRODI Prevents Staphylococcal Mastitis in Mice

“…A pipeline portfolio recently published in The Lancet Infectious Diseases, highlighted endolysin-based antimicrobials as the compounds with the greatest potential to be used as novel therapeutics (Czaplewski et al, 2016). Indeed, there is evidence that many phage lytic proteins (enzybiotics) are effective in animal models of infection (Schmelcher et al, 2015a) and also clinical phase I trials have been completed without the observation of adverse effects (Jun et al, 2017). Phage lytic proteins have also been proposed as potential disinfectants for the food industry (Gutierrez et al, 2016) due to their rapid bactericidal action and biodegradability.…”

Phages of life – the path to pharma

“…The success of phage therapy ultimately depends on optimal dose, timing, formulation and administration, with pharmacokinetics and pharmacodynamics characterized for each phage or phage cocktail. To date, only a few clinical trials have evaluated the potential of phage or phage‐based therapies in humans (Rhoads et al ., ; Wright et al ., ; Sarker and Brüssow, ; Jun et al, ). There is significant interest in the outcomes of ‘Phagoburn’ (http://www.phagoburn.eu), a European Union‐funded research and development trial assessing the safety, effectiveness and pharmacodynamics of two therapeutic phage cocktails for burn wounds infected by Escherichia coli and Pseudomonas aeruginosa .…”