Zalmoxis
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel)
Sources:EMA assessment report ↗
Species
Mouse
Longest study
3 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Immunodeficient NOD/SCID mice (GvHD xenograft models); no conventional tox species
“Two studies in two different GvHD animal models both based on the NOD/SCID system were performed to evaluate the PK and primary PD of MM-TK.”
Why that species
Product is species specific; NOD/SCID mice permit human T cell engraftment and GvHD readout
“The MM-TK DP is a species specific product and therefore standard carcinogenicity studies using rodents or non-human primates as described in the ICH guidelines are not appropriate.”
Surrogate molecule
No surrogate; human MM-TK cells in NOD/SCID mice (one model with grafted human skin)
“NOD/SCID mice subcutaneously transplanted with human skin were also used so that the direct evaluation of allogeneic GvHD response against the grafted human skin could be observed.”
Study lengthopen answer page →
Longest pivotal study
3 weeks
“Xenogenic GvHD incidence was monitored in all treated mice at week 1, 2, and 3 post-infusion”
Pivotal GLP studies
No GLP tox; two integrated PD/PK/tox NOD/SCID GvHD mouse studies (20x10^6 cells/mouse), up to ~3 weeks
“Single dose toxicity has been assessed in the immunodeficient animal models in the pharmacodynamic studies.”
Route in tox
Intravenous (mice)
“The available data indicate that the cells can end up in any tissue which is not an unexpected finding following iv administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; in vitro retroviral integration site analysis instead
“Genotoxicity studies have not been submitted.”
Carcinogenicity
Not conducted in vivo (species-specific product); in vitro clonality, integration, IL-2 dependence, RCR
“Therefore, no specific in vivo carcinogenicity studies were performed for the MM-TK to date.”
Reproductive & developmental
Not conducted; justified
“The lack of studies on reproductive and development toxicity is justified.”
Safety pharmacology
Not submitted; agreed given product type
“There are no specific studies on secondary pharmacodynamics and safety pharmacology, which is agreed considering the type of product.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
No NOAEL; GvHD occurred in mice but with lower incidence/severity than unmanipulated PBL; limited safety assessment
“Non clinical safety data obtained in two different immunedeficient animal models for Graft Versus Host disease did not indicate special hazards for humans, but allowed only a very limited safety assessment.”
Risksopen answer page →
Immune & cytokine safety
GvHD is the key immune risk; no antigenicity/immunotoxicity studies; GCV suicide gene as mitigation
“Studies on antigenicity or immunotoxicity, dependence, metabolites, impurities were not submitted”
Biodistribution & persistence
No formal biodistribution; human CD3+ cells in lymphohaematopoietic organs, GvHD target organs and skin at 3 weeks
“No formal biodistribution studies have been performed for MM-TK.”
Modality-specific risk
GvHD and oncogenic transformation (retroviral insertional mutagenesis); RCR
“it is agreed that the occurrence of GvHD and oncogenic transformation are the two main concerns associated with this product.”