SPHEROX Implantation suspension Ref.[27624] Active ingredients: Autologous chondrocytes

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system
ATC code: M09AX02

Mechanism of action

Autologous chondrocyte implantation (ACI) is based on the extraction of the patient’s own chondrocytes isolated from healthy cartilage, their culture in vitro and their subsequent implantation into the cartilage defect. Spherox is cultured and implanted as three-dimensional spheroids.

Clinical efficacy

Since 2004, Spherox has been available on a named patient basis for the treatment of cartilage defects classified as Outerbridge grade 3 or 4 or ICRS grade III or IV (Outerbridge 1961, ICRS Cartilage Injury Evaluation Package 2000). Mainly, patients were treated with cartilage defects in knee.

Spherox has been analysed in a prospective, randomized, uncontrolled open-label, multicentre Phase II clinical trial including 75 patients with focal cartilage defects (ICRS grade III or IV) in the knee with a defect size of 4-10 cm². Twenty-five patients were treated with 10-30 spheroids/cm² defect, 25 with 40-70 spheroids/cm² defect and 25 with 3-7 spheroids/cm² defect. The intention-to-treat (ITT) population consisted of 73 patients. The mean patient age was 34 years (range 19 to 48 years) with a mean body mass index (BMI) of 25.2. In all three dose groups a significant improvement (α<0.05) of the KOOS (Knee Injury and Osteoarthritis Outcome Score) after 12, 24, 36, 48 and 60 months compared to before treatment could be observed. For ‘all dose groups’ the mean overall KOOS increased in the first year after treatment from 57.0 ± 15.2 to 73.4 ± 17.3 on a scale from 0 (worst) to 100 (best) and continued to increase slightly, reaching 74.6 ± 17.6 after 18 months, 73.8 ± 18.4 after two years, 77.0 ± 17.8 after three years, 77.1 ± 18.6 after four years and 76.9 ± 19.3 at final follow-up after five years. Changes within each dose group were of similar magnitude, and the three betweengroup (pairwise) analyses did not reveal any statistically significant differences between the groups. Further patient scores, e.g. the International Knee Documentation Committee (IKDC; subjective evaluation of the knee) and the Lysholm score showed after 12, 24, 36, 48 and 60 months also a significant improvement in comparison to the value before treatment. Magnetic resonance imaging (MRI) results according to the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system (0 = worst result; 100 = best result) showed an improvement within the first 60 months from 59.8 at Visit 2 (3 months after treatment) up to 75.0 points in the group of patients treated with 3-7 spheroids/cm² defect, from 64.5 at Visit 2 up to 76.4 points in the dose group of 10-30 spheroids/cm² defect, and from 64.7 at Visit 2 up to 73.6 points in the dose group of 40-70 spheroids/cm² defect.

Furthermore, a multicentre, prospective, randomised, controlled Phase III clinical trial was conducted. The objective of the study was to compare the efficacy and safety of the treatment of cartilage defects (1 to less than 4 cm²) at the femoral condyle of the knee joint with Spherox and microfracture treatment over a period of 5 years. Pivotal efficacy data were based on an interim analysis at 12 months after treatment. Additional statistical assessments were performed 24, 36, 48 and 60 months after treatment.

The treatment groups were balanced with respect to size, demography and disease background. The analysis population comprised 102 patients (41 women, 61 men) aged 37 years on average (range from 18 to 49 years) with a mean body mass index (BMI) of 25.8. Defect sizes ranged from 0.5 to 4 cm². ICRS grades were mostly IV A, followed by IIIB and IIIA (56, 22 and 10 patients respectively). None of the patients had received prior treatment with microfracture for their lesion less than one year before screening.

The assessment of the ‘overall KOOS’ for the ITT population showed that both treatments yielded a statistically significant improvement relative to baseline (day before arthroscopy). For the patients treated with Spherox the mean overall KOOS (scale of 0-100 ± SD) increased from 56.6 ± 15.4 at baseline to 81.5 ± 17.3 at 24 months after treatment. For patients treated by microfracture the mean overall KOOS increased from 51.7 ± 16.5 to 72.6 ± 19.5 after 24 months (p<0.0001 for both treatment groups). With regard to the between-group analysis, the treatment with Spherox passed the test of non-inferiority compared with microfracture (Δ of 6.1 with lower bound of CI equal to –0.4 at the 24 months assessment).

The results at later time points were consistent with these findings. At 60 months follow-up, overall KOOS was 84.5 ± 16.1 after treatment with Spherox as compared to 75.4 ± 19.6 after microfracture. The total MOCART scores 3, 12, 18, 24 until 60 months after treatment did not differ significantly between the two treatment groups. IKDC subscores as well as results from the IKDC Current Health Assessment Form and the modified Lysholm score also revealed overall improvements from baseline in both treatment groups with numerically slightly better results in the Spherox group but with no statistical significance.

Paediatric population

Spherox has been analysed in a non-interventional, open-label, multicentre surveillance study in 60 adolescent patients with closed epiphysial growth plates, aged 15 to <18 years with focal cartilage defects (ICRS grade 3 or 4) in the knee with a defect size of 0.75–12.00 cm². The mean patient age was 16.5 years (range 15 to 17 years) with a mean body mass index (BMI) of 23.9. Mean (SD) followup time, defined as the interval between the date of implantation and date of the follow-up visit as documented by the physician was 48.4 (19.5) months. The mean (SD) overall KOOS score in the paediatric population at follow-up was 75.5 (18.2). MRI results according to the MOCART scoring system (0 = worst result; 100 = best result) at follow-up was mean (SD) 74.9 (18.5) and ranged from a minimum of 30 to a maximum of 100.