Tocilizumab fails to reach primary endpoint in JIA-associated uveitis
Tocilizumab failed to meet its primary endpoint of treatment response in patients with uveitis associated with juvenile idiopathic arthritis, according to phase 2 trial findings published in The Lancet Rheumatology.
“Children with moderate to severe uveitis can be refractory to methotrexate,” Athimalaipet V. Ramanan, FRCP, of the University of Bristol, in the United Kingdom, and colleagues wrote. “In such patients, monoclonal TNF inhibitors, including adalimumab, are often effective. However, 30% to 40% of patients are refractory to both methotrexate and TNF inhibitors and are therefore at great risk of significant ocular complications and blindness.”
“In patients with severe disease that does not respond to methotrexate and anti-TNF drugs, strong evidence supports the approach of targeting interleukin-6 (IL-6) in the disease pathogenesis,” they added. “Therefore, a phase 2 trial of the potential efficacy, safety, and tolerability of the IL-6 receptor inhibitor tocilizumab was done.”
To analyze the efficacy and safety of tocilizumab (Actemra, Genentech) among patients with JIA-associated uveitis who are refractory to methotrexate and TNF inhibitors, Ramanan and colleagues conducted the phase 2 APTITUDE trial. The researchers recruited participants aged 2 years to 18 years with active JIA-associated uveitis from seven tertiary hospitals throughout the United Kingdom between Dec. 3, 2015, and March 9, 2018. Twenty-two individuals met the inclusion criteria. All participants had been receiving a stable dose of methotrexate for at least 12 weeks, and had not responded to a TNF inhibitor.
Patients weighing 30 kg or more received 162 mg of subcutaneous tocilizumab every 2 weeks for a total 24 weeks. Those weighing less than 30 kg received 162 mg every 3 weeks for 24 weeks.
The primary outcome was treatment response, defined as a two-step decrease, or decrease to zero, in inflammation from baseline based on anterior chamber cells at week 12. The researchers analyzed adverse events up to 30 calendar days after treatment cessation.
Twenty-one of the 22 enrolled participants received treatment after one patient was found ineligible and withdrawn. Seven of those 21 participants responded to treatment, for a median unbiased estimate of proportion of 34% (95% CI, 25-57). Seventeen participants discontinued tocilizumab, while four completed 24 weeks of treatment and 12 weeks of follow-up. The investigators wrote that safety results were consistent with tocilizumab’s known profile.
“Subcutaneous tocilizumab did not meet its primary endpoint in this Simon design study,” Ramanan and colleagues wrote. “Efficacy signals for juvenile idiopathic arthritis uveitis were noted, including reduction of macular edema, as reported in previous studies, but not at a sufficient level to warrant a phase 3 study. There might be merit in studying intravenous formulations of tocilizumab in a select predefined population of patients.”
“For patients with refractory uveitis not responsive to anti-TNF drugs, other therapeutic approaches have been reported anecdotally, including checking for antidrug antibodies, weekly adalimumab abatacept, and JAK-kinase inhibitors,” they added. “Tocilizumab might provide a valuable adjunctive therapeutic option for children with uveitis refractory to anti-TNF, particularly as adalimumab is the only evidence-based and licensed therapy. Although our study did not meet its primary endpoint, this is, to our knowledge, the only prospective study of tocilizumab.” – by Jason Laday
Disclosure: Ramanan reports grants from Versus Arthritis during the conduct of the study, as well as personal fees from AbbVie, Roche, UCB, Lilly and Sobi outside of the study. Please see the study for all other authors’ relevant financial disclosures.