A placebo-controlled clinical trial across multiple centers in China concluded that the rituximab biosimilar HLX01 with methotrexate in biologic-naïve patients with moderate-to-severe active rheumatoid arthritis (RA), and inadequate responses to methotrexate alone, was superior to placebo in clinical outcomes with a comparable safety profile.

Methotrexate, a disease-modifying anti-rheumatic drug, is a first-line treatment for RA. However, up to 40% of patients with RA may not respond sufficiently to methotrexate, according to the authors. For those patients, current guidelines recommend adding biologics.

Rituximab is an antibody targeting the CD20 antigen on the surface of B lymphocytes, approved by the US FDA and European Medicines Agency for adult patients with RA with inadequate response or intolerance to anti-tumor necrosis factor (TNF) alpha biologics. The authors cited studies demonstrating superior efficacy of rituximab plus methotrexate over placebo in patients who are refractory to anti-TNF therapy, and in biologic-naïve patients who responded poorly to methotrexate alone. The authors also said rituximab may present advantages over TNF inhibitors, including less frequent dosing and a lower rate of discontinuation.

HLX01 is Currently Approved for NHL and CLL—But Not RA – in China

The authors said that no rituximab product has yet been approved in China to treat RA. The rituximab biosimilar HLX01 (Shanghai Henlius Biotech) has shown biosimilarity in in-vitro studies of physical and biochemical properties, pharmacokinetic, and pharmacodynamic studies in healthy patients, and clinical efficacy and safety studies in patients with RA and diffuse large B-cell lymphoma. HLX01 has been approved as China’s first rituximab biosimilar and is indicated for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, the same indications as the reference product. The investigators commented that approval of HLX01 for treatment of RA in China “would expand therapeutic options for Chinese patients.”

The trial consisted of a placebo-controlled phase followed by an extension during which all patients received the biosimilar. A total of 275 patients across 40 centers in China were randomized to placebo (n = 183) or biosimilar (n = 92) groups. Patients received infusions of the placebo or biosimilar on the first days of weeks 1 and 3. On the first days of weeks 24 and 26, patients in both groups who continued the study received the biosimilar. All patients received methotrexate throughout the study.

The primary efficacy endpoint, the American College of Rheumatology (ACR) 20 response rate, a disease activity assessment based on multiple variables, was evaluated at week 24. Secondary efficacy endpoints, safety, immunogenicity, pharmacokinetics, and pharmacodynamics were assessed up to week 48.

HLX01 Superior to Placebo at 24 Weeks With More Improvement During Extension Phase

At week 24, the ACR20 response rate was 61% in the biosimilar group, compared to 36% in the placebo group, with an odds ratio of 2.8 (95% CI, 1.6-4.6; P < .001). After week 24, the authors said, the ACR20 response rate was “at similar or higher levels than that at week 24” in the patients who continued treatment with the biosimilar. In those patients who switched from placebo to HLX01 at week 24, “the response rate progressively increased,” they wrote.

Greater decreases in measures of disease activity (DAS28-CRP and DAS28-ESR) were observed in the HLX01 group compared to the placebo group, and after week 24, when all patients were treated with HLX01, these measures continued to decrease in both groups. Pain, physical function, and physical and mental health indicators also “improved to a greater extent in the HLX01 group than in the placebo group,” up to week 24 “and all showed a continuous improvement thereafter in the two groups,” the authors said.

Regarding immunogenicity, the percentage of patients positive for anti-drug antibodies (ADA) after baseline “was very low.” ADAs were detected in 11 (6.0%) and 3 (3.3%) patients receiving HLX01 and placebo before week 24, and in 7 (3.8%) and 8 (8.8%) of those who continued taking the biosimilar and switched to the biosimilar from placebo after week 24.

Most patients (83% receiving HLX01 and 80% receiving placebo) reported at least 1 treatment-emergent adverse event (TEAE) up to week 24, most of which were grade 1 or 2 in severity. Serious TEAEs were similar between groups, affecting 6.6% of those in the biosimilar group and 7.6% in the placebo group.

More TEAEs leading to discontinuation of treatment (7.1% and 4.3%, respectively) and AEs of special interest (5.5% and 2.2%, respectively) occurred in the HLX01 group compared to the placebo group. The most common AEs of special interest were immediate hypersensitivity reactions (1.6% and 0 in the biosimilar and placebo groups, respectively) and infective pneumonia (1.1% and 0, respectively). The authors said that incidence of serious infections was “comparable” between groups, with 2.2% of patients in each group experiencing serious infection.

Study Adds to the “Limited Evidence” on Rituximab in Chinese Patients with RA

The authors concluded that 2 infusions of HLX01 were superior to placebo in improving ACR20 response rates and other disease activity measures, and that “this response was sustained by a second course of HLX01 treatment, following which improvements in disease activity persisted over 48 weeks.”They added that the incidence of TEAEs was comparable in the two groups, and that their findings support the use of HLX01 as an add-on to methotrexate in Chinese patients with moderate-to-severe RA.

The authors noted that their study was not designed as a bioequivalence study because no rituximab product has yet been approved for the treatment of RA in China, and also because there is limited evidence on rituximab therapy in Chinese patients with RA. Although their study did not directly compare the rituximab biosimilar to an anti-TNF biologic, they commented, “the ACR20 response rate at week 24 in patients treated with HLX01 was comparable to those treated with TNF inhibitors (ranging from 47.8 to 75.7%) in previously reported clinical studies.”

Reference

Zeng X, Liu J, Liu X, et al; Efficacy and safety of HLX01 in patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy: a phase 3 study. Arthritis Res Ther. 2022;24(1):136. doi:10.1186/s13075-022-02821-x

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