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.”
Species: general tox
Rat (90-day repeat-dose IV) using species-specific rat ceMSC
“In a 90-day GLP repeat dose toxicity study, rats received 2×106, 10×106 or 20×106 rat ceMSC/kg administered in a 5mL/kg dosing volume by tail vein injection over a two-minute period”
Species: DART
Not conducted (not warranted based on product characteristics and safety profile)
“Genotoxicity, carcinogenicity and reproductive and developmental toxicity studies were not performed for remestemcel-L. These studies are not warranted based on the product characteristics and safety profile.”
Species: carcinogenicity
No carcinogenicity study; athymic mouse tumorigenicity study with human ceMSC (six weeks)
“In a tumorigenicity study in athymic mice, administration of human ceMSC from five separate donors was evaluated at dose levels up to 50x106 cells/kg. There was no evidence of neoplastic tissue formation attributable to ceMSC over the six-week duration of the study.”
Surrogate used in
Yes: animal-derived ceMSC (rat, baboon, pig) manufactured similarly to the clinical product for safety pharmacology and toxicity
“The nonclinical program utilized multiple surrogate animal-derived ceMSC manufactured similarly to the clinical product.”
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.”
Instead of genotoxicity
Not applicable: cells not genetically modified
“Genotoxicity, carcinogenicity and reproductive and developmental toxicity studies were not performed for remestemcel-L.”
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”
Genotox: Ames
Not conducted
“No genotoxicity studies were conducted.”
Genotox: in vitro mammalian
Not conducted
“No genotoxicity studies were conducted.”
Genotox: in vivo
Not conducted
“No genotoxicity studies were conducted.”
Carcinogenicity model
Six-week tumorigenicity study in athymic mice, human ceMSC up to 50x10^6 cells/kg: no neoplastic tissue
“In a tumorigenicity study in athymic mice, administration of human ceMSC from five separate donors was evaluated at dose levels up to 50x106 cells/kg. There was no evidence of neoplastic tissue formation attributable to ceMSC over the six-week duration of the study.”
Carcinogenicity timing
Not required: not warranted based on product characteristics and safety profile
“Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies were not performed for RYONCIL. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Pig cardiac safety pharmacology study (single IV allogeneic pig ceMSC): no product-related effects on cardiac function
“A cardiac safety pharmacology study in pigs was conducted with single IV infusion of 1x106 and 10x106 allogeneic pig ceMSC/kg using a catheter at a constant rate of 2-3 mL/min. No product-related effects on cardiac function were observed.”
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.”
Anti-drug antibodies: animals
Low-level alloantibody formation in baboons given allogeneic baboon ceMSC; no toxicities
“No toxicities were observed in the study and there were no significant effects of ceMSC on immune cell subsets. Low level alloantibody formation in ceMSC-administered animals was observed.”
Anti-drug antibodies: patients
Not characterized; potential anti-donor (ADA) or anti-HLA antibodies noted
“Since RYONCIL is an allogenic product, there is a potential for development of anti-drug (donor) antibodies (ADA) or anti-HLA antibodies. Humoral immune response was not characterized in pediatric patients.”
Label warnings
- Hypersensitivity and Acute Infusion Reactions
- Transmission of Infectious Agents
- Ectopic Tissue Formation
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week (90-day) rat IV GLP study, 13 doses; recovery phase not stated
“In a 90-day GLP repeat dose toxicity study, rats received 2×106, 10×106 or 20×106 rat ceMSC/kg administered in a 5mL/kg dosing volume by tail vein injection over a two-minute period twice per week for 4 weeks and weekly thereafter for a total of 13 dose administrations.”
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”
DART package
Species: DART
Not conducted (not warranted based on product characteristics and safety profile)
“Genotoxicity, carcinogenicity and reproductive and developmental toxicity studies were not performed for remestemcel-L. These studies are not warranted based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted (not warranted)
“Genotoxicity, carcinogenicity and reproductive and developmental toxicity studies were not performed for remestemcel-L.”
PPND / ePPND: when
Not conducted: not warranted based on product characteristics and safety profile
“Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies were not performed for RYONCIL. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
No carcinogenicity study; athymic mouse tumorigenicity study with human ceMSC (six weeks)
“In a tumorigenicity study in athymic mice, administration of human ceMSC from five separate donors was evaluated at dose levels up to 50x106 cells/kg. There was no evidence of neoplastic tissue formation attributable to ceMSC over the six-week duration of the study.”
Carcinogenicity model
Six-week tumorigenicity study in athymic mice, human ceMSC up to 50x10^6 cells/kg: no neoplastic tissue
“In a tumorigenicity study in athymic mice, administration of human ceMSC from five separate donors was evaluated at dose levels up to 50x106 cells/kg. There was no evidence of neoplastic tissue formation attributable to ceMSC over the six-week duration of the study.”
Carcinogenicity timing
Not required: not warranted based on product characteristics and safety profile
“Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies were not performed for RYONCIL. These studies are not warranted based on the product characteristics and safety profile.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human ceMSC co-cultured with allogeneic immune cells (T cell suppression, cytokine modulation); no animal GVHD model
“In vitro studies characterizing the effects of bone marrow-derived ceMSC in co-culture with allogeneic immune cells demonstrated that ceMSC suppressed alloreactive T cell proliferation and can modify the cytokine secretion profile of various immune cells in culture.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
Limited support: studies used early-process human ceMSC and surrogate animal ceMSC
“Nonclinical studies were conducted using human bone marrow-derived culture-expanded MSC (ceMSC) and surrogate animal-derived ceMSC produced using an early manufacturing process. As a result, the completed nonclinical studies provide limited support for RYONCIL.”
Test articleopen answer page →
Test article vs clinical lot
Human bone marrow ceMSC and surrogate animal-derived ceMSC, made with an early manufacturing process. Bridging: Not bridged; reviewers concluded the studies provide limited support for RYONCIL
“Nonclinical studies were conducted using human bone marrow-derived culture-expanded MSC (ceMSC) and surrogate animal-derived ceMSC produced using an early manufacturing process. As a result, the completed nonclinical studies provide limited support for RYONCIL.”
Genetically modified?
Expanded allogeneic human bone marrow mesenchymal stromal cells; not genetically modified
“Remestemcel-L is comprised of expanded allogeneic human bone marrow-derived mesenchymal stromal cells.”
First approval
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
Nonclinical studies used surrogate animal-derived MSC and human MSC from an early manufacturing process, not the commercial product
“Nonclinical studies were conducted using human bone marrow-derived culture-expanded MSC (ceMSC) and surrogate animal-derived ceMSC produced using an early manufacturing process. As a result, the completed nonclinical studies provide limited support for RYONCIL.”
“Based on review of the nonclinical data in this BLA submission (STN #125706), there are no nonclinical deficiencies identified in the pharmacology/toxicology studies.”
OtherAcceptedBeyond the letter
No genotoxicity, carcinogenicity, or reproductive and developmental toxicity studies
Why: Not warranted given product characteristics and safety profile · Low-risk modality · Other reason
“Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies were not performed for RYONCIL. These studies are not warranted based on the product characteristics and safety profile.”
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