Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Vericel Denmark ApS, Amaliegade 10, DK-1256 Copenhagen K, Denmark
Pharmacotherapeutic group: Other Medicines for Disorders of the Musculo-Skeletal system
ATC code: M09AX02
Clinical pharmacology studies have not been conducted on MACI. Current clinical and nonclinical evidence suggests that delivery of autologous chondrocytes on the collagen membrane promotes proliferation and re-differentiation of seeded cells, and may result in synthesis of hyaline-like cartilage repair tissue.
MACI has been investigated in a parallel, randomised, open-label trial in 144 patients with Outerbridge Grade III or IV focal cartilage defects of the knee of 3-20 cm² (median 4 cm²). Seventy-two patients received MACI, and 72 were treated with microfracture. The median age of patients was 34 to 35 years (age range: 18 to 54), and the mean body mass index was 26. The majority of patients had undergone at least 1 prior orthopaedic knee surgery. MACI was superior compared to microfracture regarding the improvement of pain and function according to the KOOS scale (Knee Injury and Osteoarthritis Outcome Score). See responder rates in Table 1 below.
Four patients were treatment failures in the microfracture treatment arm, versus one in the MACI treatment arm. There were no significant differences observed in the structural markers of cartilage repair between both treatments, as assessed by International Cartilage Repair Society (ICRS) II overall assessment histology scores of biopsies, and MRI defect fill scores.
Table 1. KOOS Response Rate*: Full Analysis Set:
| n (%) | MACI N=72 | Microfracture N=72 | p-value |
|---|---|---|---|
| Visit 10 (Week 104) Stratified by centre | |||
| Responded | 63 (87.50) | 49 (68.06) | 0.016 |
| Not Responded | 9 (12.50) | 20 (27.78) | |
| Missing | 0 | 3 (4.17) | |
| Visit 10 (Week 104) Unstratified | |||
| Responded | 62 (86.11) | 48 (66.67) | 0.011 |
| Not Responded | 7 (9.72) | 18 (25.00) | |
| Missing | 3 (4.17) | 6 (8.33) | |
* KOOS Response Rate: Responder is defined as an improvement of the Knee Injury and Osteoarthritis Outcome Score from baseline of minimal 10 points of a scale of 100.
The European Medicines Agency has deferred the obligation to submit the results of studies with MACI in paediatric patients from the closure of the femoral epiphyseal growth plate to less than 18 years of age. See section 4.2 for information on paediatric use.
Typical clinical pharmacokinetic (ADME) studies have not been performed on MACI. The pharmacokinetic behaviour of MACI is related to the resorption of the collagen membrane, a proteolytic process performed by cells in the vicinity of the defects. The membrane is resorbed over the months following implantation.
Non-clinical data based on implantation of MACI in rabbits and horses did not reveal any special hazard for humans.
Non-clinical in vitro investigations have shown that the collagen membrane is non-cytotoxic, nonmutagenic, non-reactive (short- and long-term implantation), non-sensitising, a negligible irritant, and non-toxic (acute systemic).
A rabbit study demonstrated that at 3 months post-implantation, minimal numbers of inflammatory cells were present in the vicinity of the defect, with variable chondrogenesis. In a horse study, signs of a minor inflammatory response, characterised by a slight increase in synovial fluid volume and a mild lymphoid accumulation in the synovium, were observed at 3 months. By 6 months, these signals had subsided, resulting in a normal synovial appearance. There were no indications of gross inflammatory
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