Toxicity and Toxicokinetic Study of Subcutaneously Administered RPh201 in Minipigs

Abstract

Mastic gum extracts are widely used as herbal remedies and are being tested for several clinical indications. Nevertheless, information on their safety is limited. RPh201 is an extract of the mastic gum, formulated and stabilized in a proprietary method, which is being developed as a novel drug candidate for neurological indications. The aim of this study was to assess the systemic toxic potential of RPh201, administered twice weekly by subcutaneous injections to minipigs, after 39 weeks of administration followed by a recovery period of 6 weeks. No clinical or dose-related signs were observed, but treatment-related findings were seen at the injection sites of the high-dose animals, composed of abscesses, chronic inflammation, and subcutaneous fibrosis. Abscesses >30 mm in size, graded as marked severity, were confined to the high-dose group and were considered as adverse. Minimal-slight subcutaneous and lymph nodes abscesses seen in control, low, and intermediate doses, related to the vehicle (cottonseed oil), were not considered as adverse. Additionally, minimal-to-slight cystic spaces or vacuolation related to the vehicle were observed in the skin, lymph nodes, kidney, and lungs. These findings were considered not to be adverse. The no-observed-adverse-effect level was considered to be 12.5 mg/kg/occasion.

A First‐in‐Human Phase 1 Randomized Single and Multiple Ascending Dose Study of RPh201 in Healthy Volunteers

“…33 Abscesses >30 mm in size, graded as marked severity, were confined to the high-dose group and were considered as adverse. 34 Local injection site reactions were observed in all animals, with comparable severity and frequency in the placebo and high-dose groups. However, given the relative increase in tissue reaction in the highdose group, these changes were attributed to RPh201 administration.…”

“…At the time of phase 1, the company had a limited understanding and knowledge of the RPh201 composition and therefore was unable to integrate PK study in phase 1. PK of the 2 major ingredients, MDA and IMDA, has been demonstrated in our recent preclinical toxicology studies, and a human PK study is planned.…”

“…In vitro and in vivo animal toxicology studies of RPh201 dosed for up to 39 weeks revealed no genotoxic effects, local dermal irritation, corrosion, sensitization, adverse clinical or behavioral signs, or effects on the respiratory and central nervous systems . Abscesses >30 mm in size, graded as marked severity, were confined to the high‐dose group and were considered as adverse . Local injection site reactions were observed in all animals, with comparable severity and frequency in the placebo and high‐dose groups.…”

Delayed (21 Days) Post Stroke Treatment With RPh201, a Botany-Derived Compound, Improves Neurological Functional Recovery in a Rat Model of Embolic Stroke

“…Accumulating evidence suggests that mastic gum extracts exert potent anti-inflammatory, anti-oxidative, anti-bacterial, and anti-cancer properties in various experimental diseases ( He et al, 2006 ; Kaliora et al, 2007 ; Gholami et al, 2016 ). In vitro and in vivo animal toxicology studies performed using RPh201 for up to 39 weeks have revealed no genotoxic effects or safety concerns ( Ramot et al, 2018a , b ). Currently, clinical evaluations on the safety and therapeutic effects of RPh201 for patients with central nervous system (CNS) diseases are underway ( Cummings et al, 2019 ; Rath et al, 2019 ).…”