An investigational anti–interleukin-6 receptor (IL-6R) “nanobody,” vobarilizumab (Ablynx/AbbVie), has successfully completed a 12-week phase 2b monotherapy study in patients with moderate-to-severe rheumatoid arthritis (RA) who were intolerant of methotrexate or for whom continued methotrexate treatment was inappropriate. The study’s objective was to explore the efficacy and safety of various dose regimens for vobarilizumab monotherapy to guide further clinical development, and to obtain parallel descriptive information for tocilizumab (Actemra, Genentech/Roche), which also targets IL-6, in the same RA population.
A total of 251 subjects in the United States, Europe, and South America were randomly assigned to one of three blinded-dose groups of subcutaneous (SC) vobarilizumab (150 mg every four weeks [Q4W], 150 mg every two weeks [Q2W], or 225 mg Q2W) or open-label SC tocilizumab, with most of the subjects (94%) receiving once-a-week (Q1W) tocilizumab dosing. The subjects were evaluated for efficacy and safety for up to 12 weeks. Eligible subjects receiving vobarilizumab were then invited to enroll in an open-label extension study, with 91% accepting. The subjects who were not eligible to participate in the extension study or who did not elect to do so were followed for safety for an additional 12 weeks after the last dosing of vobarilizumab.
The American College of Rheumatology (ACR) efficacy results demonstrated that vobarilizumab was effective with less-frequent administration compared with tocilizumab. The ACR20 rates (the percentage of subjects with at least a 20% improvement in tender and swollen joint counts and improvements in three of five other disease-activity measures) were 73% for vobarilizumab 150 mg Q4W, 77% for vobarilizumab 150 mg Q2W, and 81% for vobarilizumab 225 mg Q2W compared with 78% for tocilizumab 162 mg Q1W or Q2W. The corresponding ACR50 rates were 44%, 37%, and 49% versus 45%, and the corresponding ACR70 rates were 16%, 24%, and 21% versus 23%.
Importantly, the disease remission rates (DAS28CRP) were 26% for vobarilizumab 150 mg Q4W, 27% for vobarilizumab 150 mg Q2W, and 41% for vobarilizumab 225 mg Q2W compared with 27% for tocilizumab. DAS28CRP is an objective RA disease activity score based on C-reactive protein (CRP); on tender and swollen joint counts of 28 defined joints; and on the patient’s global assessment of disease activity.
Treatment-emergent adverse events were similar across the various treatment groups. In the vobarilizumab groups, 2.1% of treated subjects discontinued the study drug because of adverse events compared with 6.3% of the tocilizumab group. Serious treatment-related adverse events occurred in 0.5% of vobarilizumab-treated patients compared with 3.1% of the tocilizumab group.
Vobarilizumab targets the IL-6 pathway via its receptor (IL-6R). IL-6 is a pro-inflammatory cytokine that plays a role in T-cell activation, in the production of acute-phase proteins in response to inflammation, in the induction of immunoglobulin production, and in the stimulation of osteoclast differentiation and activation. Vobarilizumab (26kD) consists of an anti–IL-6R “nanobody” linked to an anti-human serum albumin (HSA) nanobody to increase the half-life of the molecule.
Phase 1/2a proof-of-concept results with vobarilizumab were published in February 2013. This was followed by the signing of a global licensing agreement between Ablynx and AbbVie in September 2013 for the development and commercialization of vobarilizumab in RA and systemic lupus erythematosus (SLE). According to Reuters, the two companies have blockbuster hopes for vobarilizumab as an RA drug. AbbVie currently markets the top-selling RA treatment adalimumab (Humira), but it is looking for new medications to expand its portfolio to counter the impact of cut-price competition from biosimilar copies of adalimumab in the coming years.