Research Presented on 4 Proposed Etanercept Biosimilars

Four presentations on Monday at the 2017 American College of Rheumatology’s (ACR) Annual Meeting in San Diego, California, covered research comparing reference etanercept to 4 proposed biosimilars: SB4, LBEC0101, CHS-0214, and GP2015.

Anti-Drug Antibodies and Injection Site Reactions

Significantly fewer patients taking the etanercept biosimilar SB4 developed anti-drug antibodies (ADAs) or experienced injection site reaction (ISRs) compared with those taking reference etanercept, according to the results of a phase 3, randomized, double-blind study of patients with moderate to severe rheumatoid arthritis (RA) who received either SB4 or reference etanercept with background methotrexate for 52 weeks.¹ Efficacy was comparable between SB4 and reference etanercept in patients without detectable ADAs and in patients who did not experience ISR, Jiri Vencovsky, MD, and colleagues reported.

The study was carried out in 595 patients (299 received SB4; 296 received reference etanercept). At week 24, ADAs and ISRs were reported as follows:

ADAs

SB4: 2 patients were ADA-positive, 297 patients were ADA-negative

Reference: 39 patients were ADA-positive, 257 patients were ADA negative

ISRs

SB4: 9 patients had ISRs, 290 patients had no ISRs

Reference: 48 patients had ISRs, 249 patients had no ISRs

Due to the low incidence of ADA in the SB4 treatment group, the impact of ADAs on efficacy could not be evaluated. Within the reference group, there was a trend toward increased efficacy in patients without detectable ADAs compared with patients with ADAs. In both the SB4 and reference groups, patients without ISRs tended to have higher efficacy than patients with ISRs.

There was no reported correlation between the presence of ADAs and ISRs.

Efficacy of LBEC0101 Equivalent to Reference Etanercept

The clinical efficacy of the proposed etanercept biosimilar LBEC0101 was equivalent to that of reference etanercept, was well tolerated, and had a comparable safety profile to the reference, according to a phase 3 trial in patients with active RA inadequately responding to methotrexate.²

Hiroaki Matsuno, MD, and colleagues followed 374 patients for 52 weeks in the multicenter, randomized, double-blind, parallel-group reference-product controlled study conducted in Japan and Korea. Patients with active RA for 6 months or more who had inadequate response to methotrexate were randomly assigned to receive weekly doses of LBEC0101 (n = 187) or the reference (n = 187) administered subcutaneously for 52 weeks. The primary efficacy endpoint was:

• Mean change from baseline in disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24
• Efficacy, safety, and immunogenicity outcomes were assessed up to week 52

Mean changes from baseline in DAS28-ESR score at week 24 in the per-protocol set were —3.009 in the LBEC0101 group and –2.859 in the reference group. The estimated treatment difference in change from baseline to week 24 in DAS28-ESR between the 2 groups was –0.150 (95% confidence interval [CI], –0.3768-0.0775), completely within the pre-specified equivalence margin of –0.6 to 0.6, indicating that equivalence in efficacy between LBEC0101 and the reference was proven.

The secondary endpoint, measuring changes in RA symptoms on the ACR20 scale at week 24, was similar between the 2 groups. Incidence of AEs up to week 52 was comparable except for ISR, which was reported in 34.3% of patients in the reference group and 10.2% of the LBEC0101 group. ADAs developed in 1.6% and 9.6% of patients in the LBEC0101 and reference groups, respectively, up to 52 weeks.

CHS-0214 Well Tolerated, Efficacious in Extension Study

The majority of patients in an open-label safety extension study of the proposed etanercept biosimilar CHS-0214 maintained an efficacious response to treatment with the biosimilar and tolerated the treatment well, with no increase in treatment-emergent AEs (TEAEs) with ongoing drug exposure, according to Ingrid Louw, MD, and colleagues.³ No new safety signals were identified in these patients with an average of 80 weeks of treatment, the researchers noted.

The extension study was conducted in 359 patients (225 with RA, 134 with psoriasis [PsO]) who had completed 48 weeks of a prior CHS-0214 equivalence trial and had an additional mean duration of treatment of 31.45 weeks of open-label CHS-0214.

Durable response was achieved in 87.5% of RA patients and 90.1% of PsO patients at the data cut-off date. Loss of efficacy was a factor in study discontinuation for 5 patients. TEAEs were reported in 60.5% of patients; serious AEs (SAEs) were reported in 3.9%; and 4 patients (1.1%) had a TEAE leading to study drug discontinuation.

Phase 3 Study Shows Equivalence of GP2015 to Reference

The proposed etanercept biosimilar GP2015 demonstrated equivalent efficacy to the reference in patients with RA who had an inadequate response to methotrexate, and the overall safety profile of the biosimilar was comparable to the reference, according to the 24-week results of the phase 3 EQUIRA study, reported by Arthur Kavanaugh, MD, and colleagues.⁴

Adult patients with active RA who had an inadequate clinical response to methotrexate were randomized 1:1 to self-administer GP2015 (n = 170) or the reference (n = 156) subcutaneously once weekly for 24 weeks. All patients continued to receive concomitant methotrexate at a stable dose throughout the study and folic acid.

The primary endpoint was change from baseline in DAS28-CRP at week 24. In the per-protocol set, GP2015 was found to be equivalent to the reference in change from baseline to week 24 in DAS28-CRP (95% CI within the pre-specified equivalence margin of -0.6 to 0.6). At week 24 the ACR 20/50/70 response rates and the mean change from baseline in DAS28-CRP scores were comparable between GP2015 and reference groups.

In the GP2015 versus reference groups (safety set), TEAEs occurred in 43.5% versus 49.5% of patients, respectively; serious AEs occurred in 0.5% versus 3.2% of patients, respectively; and 1 patient died in the reference group. ISRs, as a part of all AEs, were reported in 7.0% of the GP2015 group and 17.9% of the reference group. Using a very sensitive assay, very low titers of ADAs were transiently detected; however, at week 24 none of the patients had significant levels detected.

References

1. Vencovsky J, Emery P, Keystone EC, Ghil J, Cheong SY, Hong E. Impact of anti-drug antibody and injection site reaction on efficacy: 24-week results from a phase III study comparing SB4 (etanercept biosimilar) with reference etanercept in patients with rheumatoid arthritis. Presented at the American College of Rheumatology 2017 meeting, November 6, 2017; San Diego, California. Abstract 1470. http://acrabstracts.org/abstract/impact-of- anti-drug-antibody-and-injection-site-reaction-on-efficacy-24-week-results-from-a-phase-iii- study-comparing-sb4-etanercept-biosimilar-with-reference-etanercept-in-patients-with-rheumatoid/

2. Matsuno H, Tomomitsu M, Hagino A, Shin S, Lee J, Song YW. A Phase III, multicenter, double-blind, randomized, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate. Presented at the American College of Rheumatology 2017 meeting, November 6, 2017; San Diego, California. Abstract 2441. http://acrabstracts.org/abstract/a-phase-iii-multicenter-double-blind-randomized-parallel-group-study-to-evaluate-the-similarities-between-lbec0101-and-etanercept-reference-product-in-terms-of-efficacy-and-safety-in-patients-with/

3. Louw I, Kivitz AJ, Takeuchi T, et al. The long-term safety and durability of response of CHS-0214, a proposed biosimilar to etanercept: an open-label safety extension study. Presented at the American College of Rheumatology 2017 meeting, November 6, 2017; San Diego, California. Abstract 2492. http://acrabstracts.org/abstract/the-long-term-safety-and-durability-of-response-of-chs-0214-a-proposed-biosimilar-to-etanercept-an-open-label-safety-extension-study/

4. Kavanaugh A, Allanore Y, Kucharz EJ, Babic G. Etanercept biosimilar GP2015 has equivalent efficacy and safety to etanercept originator in patients with moderate to severe rheumatoid arthritis: the Phase 3 EQUIRA study. Presented at the American College of Rheumatology 2017 meeting, November 6, 2017; San Diego, California. Abstract 2797. http://acrabstracts.org/abstract/etanercept-biosimilar-gp2015-has-equivalent-efficacy-and-safety-to-etanercept-originator-in-patients-with-moderate-to-severe-rheumatoid-arthritis-the-phase-3-equira-study/