Ryoncil
remestemcel-L
Species
MonkeyRatPig
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat, baboon and pig using species-specific surrogate ceMSC
“The nonclinical program utilized multiple surrogate animal-derived ceMSC manufactured similarly to the clinical product.”
Why that species
Species-matched allogeneic MSC model allogeneic administration and recipient immune interaction
“This approach was taken to model administration of allogeneic ceMSCs in humans and evaluate the interactions between the cell product and recipient immune system.”
Surrogate molecule
Yes: rat, baboon, pig and dog culture-expanded MSC made similarly to remestemcel-L
“Nonclinical studies were conducted using human bone marrow-derived ceMSC and surrogate animal-derived ceMSC produced using an early manufacturing process.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A six-month GLP study in baboons was performed using labeled allogeneic baboon ceMSC to evaluate the safety and immunogenicity following IV administration of 5x106 cells/kg on Day 1”
Pivotal GLP studies
GLP rat single-dose IV (x2), 90-day rat repeat-dose IV (13 doses), 6-month baboon single IV; GLP rat pulmonary and pig cardiac safety pharm
“In a GLP repeat dose toxicity study, rats received 2x106 , 10x106 or 20x106 rat ceMSC/kg administered in a 5mL/kg dosing volume by tail vein injection over a two-minute period”
Route in tox
Intravenous (tail vein, femoral/jugular catheter, saphenous vein)
“Remestemcel-L is administered intravenously.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not warranted)
“Genotoxicity, carcinogenicity and reproductive and developmental toxicity studies were not performed for remestemcel-L.”
Carcinogenicity
Not conducted; 6-week nude mouse tumorigenicity study showed no tumors
“There was no evidence of neoplastic tissue formation attributable to ceMSC over the six-week duration of the study.”
Reproductive & developmental
Not conducted (not warranted)
“Genotoxicity, carcinogenicity and reproductive and developmental toxicity studies were not performed for remestemcel-L.”
Safety pharmacology
GLP rat pulmonary function study (high mortality at >=16x10^6 cells/kg) and pig cardiac study (no effects)
“A GLP safety pharmacology study evaluating pulmonary function in rats was conducted with single IV administration of rat-derived ceMSC”
First doseopen answer page →
First-in-human starting dose
No formal dose-finding; 2x10^6 cells/kg clinical dose from earlier clinical/expanded access experience, not nonclinically derived
“No formal pharmacokinetic, clinical dose finding, or dose regimen optimization studies have been performed during the development of RYONCIL for treatment of aGvHD in pediatrics.”
NOAEL / key findings
No NOAEL; rat mortality at >=10-15x10^6 cells/kg with pulmonary thrombi; baboon 5x10^6 cells/kg no toxicity
“Dose levels of 15x106 cells/kg and higher resulted in increased mortality shortly after dosing, associated with shallowed breathing, impaired righting reflex, and pale discolored skin.”
Risksopen answer page →
Immune & cytokine safety
Low-level alloantibody formation in baboons; in vitro ceMSC suppress T cells and shift cytokines (IFNg, IL-10 up, TNFa down)
“Low level alloantibody formation in ceMSC-administered animals was observed.”
Biodistribution & persistence
Rat ceMSC in lung within 1 h, then liver, kidney, spleen by 24 h, still detected at 240 h
“Cells were initially detected in the lung within the first hour following cell administration, followed by distribution to the liver, kidney and spleen within the first 24 hours”
Modality-specific risk
Infusion-related pulmonary toxicity, cell aggregation/thromboembolism, immunogenicity; tumorigenicity
“The specific cause of death was undetermined based on the lack of histopathology findings, but possible cell aggregation was noted.”