A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults

Abstract

Background Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study. Methods This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels. Results BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than doseproportionally. Mean half-life was short (2.4-4.9 h), and mean renal clearance was comparable in all doses (4.05-5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%-15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14deoxypoststerone) were identified and quantified. Conclusions BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).

Quinoa as Functional Food? Urinary elimination of ecdysterone after consumption of quinoa alone and in combination with spinach

“…In two participants ecdysterone was still detectable after 26 to 28 hours after one application. The half-life of ecdysterone for both intakes ranged between 2 and 5 hours, which is consistent with previous studies (Ambrosio et al, 2021; Dioh et al, 2023; Yuliandra et al, 2023). The result also indicates that the parent compound is rapidly excreted from the body.…”

“…The presence of the compounds and the metabolites in urine can be used as an indicator of doping usage. Several pharmacokinetic studies of ecdysterone have been conducted in humans, especially those related to urinary excretion (Ambrosio et al, 2021;Brandt, 2003;Dioh et al, 2023;Parr et al, 2019;Tsitsimpikou et al, 2001). After oral administration of ecdysterone, the parent compound and metabolites were excreted in urine such as 14-deoxy-ecdysterone, 2-deoxy-ecdysterone and deoxy-ecdysone (Ambrosio et al, 2021;Dioh et al, 2023;Tsitsimpikou et al, 2001).…”

Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial

“… 24 , 29 , 30 In addition, Ang-1-7's half-life in humans is approximately half an hour 31 and is shorter compared to BIO101's half-life (2.4 h–4.9 h). 32 Moreover, in contrast with BIO101, Ang-1-7 is cleaved into several peptides (Ang-1-5, Ang-1-4, and others) susceptible to evoke different biological effects. All these elements could explain the differences in efficacy of BIO101 and TXA-127 on COVID-19 respiratory symptoms and mortality.…”

BIO101 stimulates myoblast differentiation and improves muscle function in adult and old mice

“…In this context, the identification and development of drug candidates that activate MAS receptor and the protective RAAS axis is very promising. BIO101, a pharmaceutical grade formulation of 20E, is orally administrable, with a good safety profile 37 and has completed a phase 2 clinical study, with promising results on 400 m walk test in patients with sarcopenia at risk of mobility disability 38 . MAS receptor activators could constitute in the future a new class of drug for the treatment of sarcopenia and other muscle wasting diseases.…”