New monoclonal antibodies currently in advanced stages of development that target interleukin-17 (IL-17) or its receptor include secukinumab and ixekizumab. Those that target IL-12/23 include ustekinumab and guselkumab.1-3
Emerging monoclonal antibodies that target IL-17 or IL-12/23
Secukinumab (AIN457) is a monoclonal antibody targeting IL-17A that is being developed by Novartis. Secukinumab is formulated for subcutaneous (SC) administration and is a fully human monoclonal antibody. The significance of this is that, unlike monoclonal antibodies that are derived from animals such as mice, fully human antibodies have less risk for certain side effects. In Phase 2 studies conducted in patients with moderate to severe RA, secukinumab has resulted in significantly greater rates of ACR20 responses and reductions in 28-joint disease activity scores (DAS28) versus placebo, with rates of side effects slightly higher than placebo.4 Long-term results from one Phase 2 study suggest that these significant responses are durable.5 Three Phase 3 studies and one long-term extension study of secukinumab are currently ongoing and scheduled for completion through 2018.
Phase 2 and 3 RA program for secukinumab
- Secukinumab + MTX versus placebo + MTX in patients with inadequate response to MTX
- Secukinumab + MTX in patients with inadequate response to, or were intolerant of, one or more TNF-α inhibitors
- Secukinumab in patients with inadequate response to, or were intolerant of, one or more TNF-α inhibitors
- Sarilumab versus abatacept (Orencia) in patients with inadequate response to, or were intolerant of, one or more TNF-α inhibitor
- 4-year extension of core Phase 3 study
*Projected enrollment. MTX=methotrexate; TNF-α=tissue necrosis factor-alpha.
Ixekizumab (LY2439821) is a humanized monoclonal antibody that targets IL-17A. Ixekizumab, which is formulated for SC administration, is being developed by Eli Lilly and Company and is currently in Phase 2 development.1
In 2012, results from a Phase 2 study were reported. The study was conducted in 448 patients with RA who comprised two populations, patients who had not received biologic disease-modifying anti-rheumatic drug (DMARD) treatment (this group included 270 patients) and patients who had received an anti-TNF-α agent and had an inadequate response (this group included 178 patients).2,6
Patients were randomized to a range of doses of ixekizumab + conventional DMARD treatment or placebo + DMARD treatment. At week 12, among patients who were anti-TNF-α naive, ixekizumab at all doses resulted in higher rates of ACR20 responses versus placebo. However, the 30 mg dose was the only one that resulted in a significantly higher rate of ACR20 responses versus placebo (70% versus 35%, respectively; P<0.05). In patients who had an inadequate response to prior anti-TNF-α treatment, both ixekizumab doses produced ACR20 response rates of about 40% at week 12, compared with just over 20% with placebo (both P<0.05). Ixekizumab also resulted in greater reductions in 28-symptom disease activity scores (DAS28) versus placebo, as well as greater decreases in C-reactive protein (CRP) levels. The most common side effects with ixekizumab included upper respiratory tract and urinary tract infections, hypersensitivity (allergic) reactions, injection site pain, and headache, none of which were seen in greater than 10% of patients.2,6
Ustekinumab and guselkumab
Ustekinumab (Stelara) is a monoclonal antibody targeting IL-12/23 being developed by Centocor and guselkumab (CNTO 1959) is a fully human IL-23–targeted monoclonal antibody under development by Janssen. Both drugs are formulated for SC administration. Stelara and guselkumab are currently being compared in combination with methotrexate in an ongoing Phase 2 study (the study has completed recruitment) in patients with active moderate to severe RA who have had inadequate response to methotrexate.2