Lantidra
donislecel
Species
no relevantMonkeyRatMouse
Longest study
none
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
No studies with product; literature only (diabetic mice, rats, NHP, pigs)
“No nonclinical studies were conducted with LANTIDRA.”
Why that species
Published diabetic rodent and NHP islet transplant models used to support activity, liver distribution and need for immunosuppression
“The findings of these studies support inclusion of immunosuppression as a critical component for successful islet engraftment and survival following transplant in diabetic animals.”
Surrogate molecule
Yes: literature studies with animal allogeneic/syngeneic islets (no studies with clinical product)
“Pancreatic islets were isolated from C57BL/6 or BALB/C mice (9 weeks old, 20-22 g).”
Species: general tox
None; no toxicology studies with the product (published islet allograft literature cited)
“No toxicology studies with LANTIDRA were conducted.”
Species: DART
Not conducted
“No DART studies with LANTIDRA were conducted.”
Species: carcinogenicity
Not conducted; publications in diabetic rats with intraportal islet transplants cited
“No carcinogenicity/tumorigenicity studies with LANITDRA were conducted. The applicant cited two publications that examined the potential for hepatic carcinogenicity following intraportal transplantation of allogeneic islets in diabetic rats.”
Surrogate used in
Yes: all supporting data from published studies of animal allogeneic/syngeneic islets in diabetic mice, rats and NHPs
“The applicant included references to published studies evaluating the biological activity as well as the hepatic distribution and safety of transplanted allogeneic or syngeneic islets in combination with various immunosuppressive agents in diabetic rodent (mice, rats) and nonhuman primate models.”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“No toxicology studies with LANTIDRA were conducted.”
Pivotal GLP studies
None; publications on intraportal islet allograft safety (e.g., diabetic mouse liver morphology study) cited instead
“The applicant provided publications assessing the overall safety of islet allografts following intraportal transplantation in Module 4 of the BLA.”
Route in tox
Intraportal (hepatic portal vein) transplantation in published models
“were transplanted with 400 allogeneic islets via the portal vein.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genotoxicity studies with LANTIDRA were conducted.”
Carcinogenicity
Not conducted; literature hepatic tumors in rats with low islet numbers, risk considered low
“Thus, the carcinogenic risk of LANTIDRA in transplanted patients is considered low.”
Reproductive & developmental
Not conducted
“No DART studies with LANTIDRA were conducted.”
Safety pharmacology
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.
Genotox: Ames
Not conducted
“No genotoxicity studies with LANTIDRA were conducted.”
Genotox: in vitro mammalian
Not conducted
“No genotoxicity studies with LANTIDRA were conducted.”
Genotox: in vivo
Not conducted
“No genotoxicity studies with LANTIDRA were conducted.”
Carcinogenicity model
Not conducted; literature: low-number intraportal islet grafts in diabetic rats caused liver tumors, high numbers did not; risk judged low
“This combination of islet number, hyperinsulinism, and hyperglycemia resulted in liver tumors. Transplantation of high numbers of islets did not result in hepatic neoplasms.”
Carcinogenicity timing
Not conducted; published rat islet-transplant literature cited instead
“No carcinogenicity/tumorigenicity studies with LANITDRA were conducted. The applicant cited two publications that examined the potential for hepatic carcinogenicity following intraportal transplantation of allogeneic islets in diabetic rats.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with LANTIDRA were conducted.”
First doseopen answer page →
First-in-human starting dose
No nonclinical basis; target 10,000 EIN/kg from prior Edmonton Protocol clinical experience
“In both UIH-001 & UIH-002 studies a target islet dose of 10,000 EIN/kg was proposed based on the findings of previous experience with Edmonton Protocol for allogeneic islet transplantation.”
NOAEL / key findings
No NOAEL; literature mouse intraportal allografts: emboli, thrombosis, focal liver necrosis without immunosuppression
“These findings were observed on Day 1, progressed to necrotic regions surrounded by multifocal leucocyte infiltrates by Day 3, with progressive mononuclear leukocyte infiltration of the colonized islets (from peri-islet to intra-islet), leading to islet destruction by Days 9-14.”
Risksopen answer page →
Immune & cytokine safety
Allograft rejection without immunosuppression in mice; clinical HLA sensitization (donor-specific antibodies) risk
“These data suggest that an immunosuppression regimen is necessary for islet survival post-transplant and provide overall support for use of the (revised) Edmonton Protocol with intraportal transplantation of LANTIDRA in the target patient population.”
Biodistribution & persistence
Literature pig PET: labeled islets heterogeneously in liver, no extrahepatic accumulation
“The distribution of the 18F-FDG-labeled islet cells in the liver was found to be heterogeneous. No accumulation of radioactivity was detected in non-hepatic tissues.”
Modality-specific risk
Intraportal liver toxicity (thrombosis, necrosis), immunosuppression need, hormonal hepatocarcinogenesis
“This combination of islet number, hyperinsulinism, and hyperglycemia resulted in liver tumors.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
HLA sensitization: 21% (6/28) transitioned from PRA <20% to ≥20% after transplant
“For the combined UIH-001 & 002, 6 out of 28 (21%) patients tested transitioned from panel-reactive antibodies (PRA Class I, Class II, or both) <20% at baseline to ≥ 20 % following islet transplant.”
Label warnings
- Risks from Concomitant Immunosuppression
- Procedural Complications
- Increased Risk of Islet Graft Rejection
- Transmission of Donor-Derived Infections
- Panel Reactive Antibodies (PRA)
Infections
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 nonclinical basis; target 10,000 EIN/kg from prior Edmonton Protocol clinical experience
“In both UIH-001 & UIH-002 studies a target islet dose of 10,000 EIN/kg was proposed based on the findings of previous experience with Edmonton Protocol for allogeneic islet transplantation.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no toxicology studies conducted; published literature instead)
“No toxicology studies with LANTIDRA were conducted. The applicant provided publications assessing the overall safety of islet allografts following intraportal transplantation in Module 4 of the BLA.”
Pivotal GLP studies
None; publications on intraportal islet allograft safety (e.g., diabetic mouse liver morphology study) cited instead
“The applicant provided publications assessing the overall safety of islet allografts following intraportal transplantation in Module 4 of the BLA.”
DART package
Species: DART
Not conducted
“No DART studies with LANTIDRA were conducted.”
Reproductive & developmental
Not conducted
“No DART studies with LANTIDRA were conducted.”
PPND / ePPND: when
Not conducted: no DART studies
“No DART studies with LANTIDRA were conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted; publications in diabetic rats with intraportal islet transplants cited
“No carcinogenicity/tumorigenicity studies with LANITDRA were conducted. The applicant cited two publications that examined the potential for hepatic carcinogenicity following intraportal transplantation of allogeneic islets in diabetic rats.”
Carcinogenicity model
Not conducted; literature: low-number intraportal islet grafts in diabetic rats caused liver tumors, high numbers did not; risk judged low
“This combination of islet number, hyperinsulinism, and hyperglycemia resulted in liver tumors. Transplantation of high numbers of islets did not result in hepatic neoplasms.”
Carcinogenicity timing
Not conducted; published rat islet-transplant literature cited instead
“No carcinogenicity/tumorigenicity studies with LANITDRA were conducted. The applicant cited two publications that examined the potential for hepatic carcinogenicity following intraportal transplantation of allogeneic islets in diabetic rats.”
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; literature mouse intraportal allografts: emboli, thrombosis, focal liver necrosis without immunosuppression
“These findings were observed on Day 1, progressed to necrotic regions surrounded by multifocal leucocyte infiltrates by Day 3, with progressive mononuclear leukocyte infiltration of the colonized islets (from peri-islet to intra-islet), leading to islet destruction by Days 9-14.”
Efficacy evidenceopen answer page →
Efficacy evidence
Literature only: animal allogeneic/syngeneic islets with immunosuppressants in diabetic mice, rats and NHPs; no studies with the product
“Instead, the applicant referenced multiple publications and one manuscript in the BLA submission that evaluated biological activity, local (liver) distribution, and the local (liver) safety of transplanted allogeneic or syngeneic islets in combination with various immunosuppressive agents in diabetic rodent (mice, rats) and nonhuman primate (NHP) models.”
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
Published literature gave overall support for mechanism of action and need for immunosuppression; supports approval
“Review of the nonclinical studies in the published literature provided overall support for the purported mechanism of action of LANTIDRA and the need for an immunosuppressive regimen. The nonclinical data support approval of the license application.”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
No nonclinical studies with the product; published islet-transplant literature in rodents and monkeys relied on instead
Why: Published literature supports mechanism of action and need for immunosuppression · Weight of evidence
“No nonclinical studies were conducted with LANTIDRA. Instead, the applicant referenced multiple publications and one manuscript in the BLA submission that evaluated biological activity, local (liver) distribution, and the local (liver) safety of transplanted allogeneic or syngeneic islets in combination with various immunosuppressive agents in diabetic rodent (mice, rats) and nonhuman primate (NHP) models.”
“Review of the nonclinical studies in the published literature provided overall support for the purported mechanism of action of LANTIDRA and the need for an immunosuppressive regimen.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; literature hepatic tumours in rats given low islet numbers judged low risk
Why: Tumours only with low islet numbers; translation of rodent data to the clinic not well understood · Weight of evidence
“Transplantation of high numbers of islets did not result in hepatic neoplasms. Per the proposed label, the recommended minimum clinical dose level for the target population is 4000-5000 EIN/kg.”
“In addition, the translation of these rodent data (rodent donors and recipients) to the clinical scenario is not well understood. Thus, the carcinogenic risk of LANTIDRA in transplanted patients is considered low.”
DARTVerdict not stated
No genotoxicity or developmental and reproductive toxicity studies
“No genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with LANTIDRA.”
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