MACI
autologous cultured chondrocytes on porcine collagen membrane
Species
RabbitOther
Longest study
53 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit and horse, with analogous MACI (species-matched autologous cells on ACI-Maix)
“Studies conducted in horses and rabbits compared ACI-Maix or empty defects to analogous products consisting of ACI-Maix seeded with rabbit or horse cells.”
Why that species
Critical-sized knee/stifle defect models in load-bearing species; no further rationale stated
“Implantation of MACI secured with a commercially available fibrin sealant resulted in improved repair of critical-sized defects in the knee/stifle”
Surrogate molecule
Yes: analogous product using rabbit or horse autologous chondrocytes on the same membrane
“The products consisted of the same membrane as MACI with rabbit or horse cells, respectively.”
Species: general tox
Horse (definitive combined pharm/tox study) and rabbit, using analogous product with species' own cells
“Studies conducted in horses and rabbits compared ACI-Maix or empty defects to analogous products consisting of ACI-Maix seeded with rabbit or horse cells.”
Species: DART
Not conducted; local knee administration with minimal systemic entry
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically.”
Species: carcinogenicity
Not conducted
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies.”
Surrogate used in
Yes: all animal studies used analogous products (same membrane seeded with rabbit or horse cells)
“The products consisted of the same membrane as MACI with rabbit or horse cells, respectively.”
Study lengthopen answer page →
Longest pivotal study
53 weeks
“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417)”
Pivotal GLP studies
Combined GLP-type pharm/tox 53-week equine study (27 horses, stifle trochlear defect implant); 12- and 24-week rabbit studies
“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417) to evaluate the safety and the activity of MACI”
Route in tox
Surgical implantation into cartilage defect (intra-articular, fibrin sealant fixed)
“Implantation is performed using sterile surgical techniques and requires both the preparation of the defect bed and the application of fibrin sealant”
Skipped studiesopen answer page →
Genotoxicity
Not conducted on cells; four studies on collagen membrane were non-mutagenic
“Four studies ( in vitro and in vivo ) were conducted to assess the genotoxic potential of the collagen membrane.”
Carcinogenicity
Not conducted (avascular local site, differentiated cells, no systemic distribution)
“Studies to evaluate the carcinogenicity or impairment of fertility potential of MACI have not been performed.”
Reproductive & developmental
Not conducted (local administration, minimal systemic entry, mature autologous cells)
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically.”
Safety pharmacology
Not conducted
“No safety pharmacology studies were conducted.”
Genotox: Ames
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: in vitro mammalian
Chondrocyte expansion did not change karyotype in vitro; negative
“In vitro studies have shown that the expansion process for chondrocytes does not induce changes to the cellular karyotype.”
Genotox: in vivo
Collagen membrane: four in vitro and in vivo genotoxicity studies non-mutagenic (assays not named)
“Four studies ( in vitro and in vivo ) were conducted to assess the genotoxic potential of the collagen membrane. The results from these studies demonstrated that the collagen membrane was non-mutagenic.”
Carcinogenicity model
Not conducted; no tumors in the one-year horse study
“No tumors were detected in the one-year animal study, thus indicating that tumor formation is unlikely.”
Carcinogenicity timing
Not required: local implantation site, no systemic distribution, membrane not genotoxic
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were conducted.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of MACI don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; no significant safety signals; mild transient inflammation, mild early lameness in horses recovered by 53 weeks (FDA pharmacology/toxicology review, p. 3)
NOAEL / key findings
No NOAEL; no significant safety signals; mild transient inflammation, mild early lameness in horses recovered by 53 weeks
“There were no significant safety signals identified in the animals.”
Risksopen answer page →
Immune & cytokine safety
Inflammation likely due to defect creation and possible immune response to porcine membrane
“Inflammation was present in all knees, likely due to defect creation and possible immune response to the porcine membrane.”
Biodistribution & persistence
No systemic distribution of MACI, membrane or chondrocytes to lymph nodes or tissues in horses; membrane persisted to 53 weeks
“There was no indication of systemic adverse reactions or systemic distribution of MACI, ACI-Maix, or the seeded chondrocytes.”
Modality-specific risk
Local inflammation, graft failure/delamination, membrane persistence; tumorigenicity judged unlikely
“No tumors were detected in the one-year animal study, thus indicating that tumor formation is unlikely.”
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
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.
Label warnings
- Malignancy
- Transmissible Infectious Diseases
- Presurgical Assessment of Comorbidities
- Product Sterility
Secondary malignancy
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Outside the United States: all clinical studies ex-US (countries not named)
“Note: No IND(s) is associated with this file. All clinical studies were conducted outside of the United States (OUS).”
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
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of MACI don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; no significant safety signals; mild transient inflammation, mild early lameness in horses recovered by 53 weeks (FDA pharmacology/toxicology review, p. 3)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single implantation); longest study 53-week horse implant study
“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417) to evaluate the safety and the activity of MACI”
Pivotal GLP studies
Combined GLP-type pharm/tox 53-week equine study (27 horses, stifle trochlear defect implant); 12- and 24-week rabbit studies
“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417) to evaluate the safety and the activity of MACI”
DART package
Species: DART
Not conducted; local knee administration with minimal systemic entry
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically.”
Reproductive & developmental
Not conducted (local administration, minimal systemic entry, mature autologous cells)
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically.”
PPND / ePPND: when
Not conducted: local knee implantation, no systemic distribution
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
Carcinogenicity
Species: carcinogenicity
Not conducted
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies.”
Carcinogenicity model
Not conducted; no tumors in the one-year horse study
“No tumors were detected in the one-year animal study, thus indicating that tumor formation is unlikely.”
Carcinogenicity timing
Not required: local implantation site, no systemic distribution, membrane not genotoxic
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
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; no significant safety signals; mild transient inflammation, mild early lameness in horses recovered by 53 weeks
“There were no significant safety signals identified in the animals.”
Efficacy evidenceopen answer page →
Efficacy evidence
Analogous MACI (animal cells on same membrane) in critical-sized knee/stifle cartilage defects in rabbits and horses: improved repair vs membrane alone or empty defect
“Collectively, the rabbit and equine studies indicate that implantation of MACI secured with a commercially available fibrin sealant resulted in improved repair of critical-sized defects in the knee/stifle, compared to implanted membrane alone or empty defect.”
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
Horse study showed MACI can repair cartilage defects with some biomechanical gains, but repair not identical to native cartilage
“this study demonstrated that implantation with MACI is capable of repairing cartilage defects. Improved results were observed in some biomechanical testing outcomes over implanted ACI-Maix membrane alone or no agent (empty defect). However, he also noted that biomechanical properties and repair with MACI are not identical to native cartilage.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity/tumorigenicity studies
Why: Local implantation site, no systemic distribution, membrane not genotoxic · Pharmacology or kinetics · Weight of evidence
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration, and the lack of genotoxicity or mutagenicity observed for the ACI-Maix membrane in biocompatibility tests.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Local knee administration with minimal systemic entry; autologous, terminally differentiated cells · Pharmacology or kinetics · Low-risk modality
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically. As MACI is derived from autologous, mature, terminally differentiated cells, the concern for potential DART, as well as adverse effects on lactation, are mitigated.”
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
OtherVerdict not stated
Pivotal safety and activity studies used analogous products (rabbit or horse cells on the same membrane); combined pharmacology-toxicology horse study
“Studies conducted in horses and rabbits compared ACI-Maix or empty defects to analogous products consisting of ACI-Maix seeded with rabbit or horse cells.”
GLPCriticised but acceptedBeyond the letter
Non-GLP in vitro fibrin glue toxicity study poorly designed and reported; only summary information provided
Why: Study not critical given the other nonclinical and clinical data · Weight of evidence · Human data
“This in vitro study to assess the toxicity of various fibrin glues/sealants on human chondrocytes was poorly designed, conducted, and reported. Thus, this reviewer is not able to independently verify the study sponsor’s conclusion.”
“Only summary information from this study was provided. However, since this study is not critical for determining the safety and activity of MACI in the context of the other non-clinical and clinical data submitted, a complete study report was not requested.”
Similar precedents
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