A biosimilar of etanercept, LBEC0101 posesses an equivalent properties to etanercept (ETN-RP) in terms of clinical efficacy and safety.

Etanercept is a bio-pharmaceutical product obtained through the recombinant DNA technology. It consists of disulfide bond-linked chain of fusion protein and is mainly used for the treatment of autoimmune disorder. It works by interfering with tumor necrosis factor (TNF) and acts as a TNF inhibitor which is major contributor in the inflammatory disorders like rheumatoid arthritis (RA) and psoriasis. Etanercept acts by inhibiting the TNF-α receptors by binding with the TNF receptor and blocking its interaction with the cell surface. In Japan and Korea etanercept is named as ETN-RP which is approved drug for the treatment of various inflammatory disorders like RA, psoriatic arthritis, and axial spondyloarthritis. LBEC0101 is a biosimilar product to ETN-RP. The similarities between these two products with respect to its structural and functional properties and biological activities has been demonstrated by in vitro and in vivo studies such as a TNF-α binding affinity study. Moreover, for the clinical development of LBEC0101, a phase I pharmacokinetic (PK) study on healthy male volunteers was conducted and showed equivalent result to ETN-RP. The present study compared the efficacy and safety of LBEC0101 and ETN-RP as an ancillary therapy to methotrexate (MTX) in patients with active RA and has poor responses to previous MTX treatment.

Rationale behind the research:

The biologicals used for the tretment of RA are highly expensive e.g. ENT-RP approx. cost is £204 721

Therefore, this study used a biosimilar named as LBEC0101 which shown to have similar outcomes as of ENT-RP

Objective:

To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active RA despite MXT treatment.

Study outcomes measures:

Primary Endpoints: Change from the baseline DAS28-ESR at week 24

Secondary Endpoints:

• Efficacy: The changes from baseline in DAS28-ESR at weeks 12 and 52 and ACR20 response rates at weeks 12, 24 and 52. Other efficacy endpoints included ACR50, ACR70 and European League Against Rheumatism (EULAR) response rates based on the DAS28-ESR at weeks 12, 24 and 52.
• Safety: Safety endpoints included incidence of adverse events (AEs) and serious adverse events (SAEs) up to week 54.
• Pharmacokinetics: Serum trough concentrations (Ctrough) of ETN at weeks 12, 24 and 52 were analyzed by a validated immunofluorescence assay using Gyrolab platform.
• Immunogenicity: Anti-drug antibodies (ADAs) and neutralizing antibodies at weeks 0, 12, 24 and 52 were analyzed by validated electro chemiluminescent immunoassay using Meso Scale Discovery platform

Time period:

Efficacy: Baseline, week 12, week 24, week 52

Study Outcomes 

• LS mean change from baseline in DAS28-ESR at week 24: The least squares mean changes from baseline in DAS28-ESR at week 24, the primary efficacy endpoint, were −3.01 (95% CI −3.198 to −2.820) in the LBEC0101 group and −2.86 (95% CI −3.051 to −2.667) in the ETN-RP group (figure 1)

Figure 1A: DAS28-ESR change from baseline (PPS-24w and FAS). 

• Mean±SD of DAS28-ESR at baseline, week 12, week 24 and week 52 : The mean DAS28-ESR rapidly declined up to week 12 and almost plateaued after week 24 in both groups (Figure 1B).

Figure 1B:  Mean±SD of DAS28-ESR at baseline, week 12, week 24 and week 52 

• American College of Rheumatology: ACR20 response rates, the secondary efficacy endpoint, were 93.3% in the LBEC0101 group and 86.7% in the ETN-RP group at week 24. The between-group difference in ACR20 (95% CI) was 6.6% (0.2 to 13.1) in the PPS-24w (Figure 2A). The ACR50 and ACR70 response rates also showed similar trends to the ACR20 response rate (Figure 2B,C)

Figure 2. ACR20 response rates (A). The between-group difference in ACR20. (B,C) The ACR50 and ACR70 response rates.

• EULAR Response: Figure 4 shows more than 90% of patients achieved a moderate to good EULAR response at weeks 12, 24 and 52, and after week 24, less than 5% of patients remained as non-responders in both groups.

Figure 4: EULAR response at weeks 12 and 24 (PPS-24w) and at week 52 (PPS-52w)

• Safety: Almost about 93% patients developed AEs in both the groups, but most of them were mild in severity. In both LBEC0101 and ETN-RP groups, 31 and 20 patients reported SAEs respectively, including three deaths in LBEC0101 and one death in ETN-RP group.  The incidence of SAEs in the LBEC0101 group (16.6%) was higher than that in the ETN-RP group (10.7%), but the incidence of SAEs was same in both the groups (7.0%).  There was no difference in the incidence of infection between the groups (LBEC0101 54.5% vs ETN-RP 54.5%), about three patients in each group suffered with interstitial lung disease and one patient in the LBEC0101 group diagnosed with sepsis. Only a fewer patients reported injection site reactions and to a lesser frequency in LBEC0101 group as compared to ETN-RP group (LBEC0101 10.2% (19 patients, 77 events) vs ETN-RP 34.2% (64 patients, 438 events)). Early occurrence of most of these events was seen (before week 12), and were mild in severity in both the groups. Four patients were diagnosed with malignacies in the ETN-RP group and heart failure occurred in one patient (0.5%) in the LBEC0101 group. Neurological events, active tuberculosis and occurrences of HBV reactivation was absent in both the groups.
  
  

In conclusion, LBEC0101 was shown to be equivalent to ETN-RP in terms of clinical efficacy and safety. The study results were found to be more consistent than previous clinical studies on ETN-RP. ACR20 response rates of the LBEC0101 were quiet similar to ETN-RP. The safety profile of LBEC0101 was also comparable to ETN-RP; however, fewer injection site reactions and ADAs were observed in the LBEC0101 group.