Adding RoActemra (tocilizumab) to methotrexate failed to show effectiveness in children and adolescents with treatment-resistant uveitis — inflammation of the eye — associated with juvenile idiopathic arthritis (JIA), a Phase 2 clinical trial shows.
Although one third of the participants showed significant reductions in uveitis, the number of responders to RoActemra (known as Actemra in the U.S.) did not reach the predefined minimum needed to support the launch of a Phase 3 clinical trial.
Based on the positive responses, the researchers noted that combining RoActemra with methotrexate still may be a potential therapeutic option for some patients with JIA-associated uveitis resistant to methotrexate alone and to TNF inhibitors.
The trial’s results, “Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial,” were published in the journal The Lancet Rheumatology.
Uveitis is an inflammatory condition that causes swelling and destruction of the eye tissues, particularly the middle layer of the eye, called the uvea. It is the most frequent and severe extra-articular complication associated with JIA.
Treatment of JIA-associated uveitis typically includes first-line methotrexate (an immunosuppressive and anti-inflammatory therapy), followed by second-line TNF inhibitors — which block the activity of an inflammatory molecule – such as adalimumab (sold as Humira, among others).
However, 30–40% of patients do not respond to both methotrexate and TNF inhibitors and for that reason are they are at great risk of significant eye problems and blindness.
RoActemra (marketed by Roche) is an approved therapy for the systemic and polyarticular forms of JIA. It works by blocking the signals of the interleukin-6 protein, which has been shown to play a significant role in JIA.
While several studies have suggested that this treatment is beneficial in people with JIA resistant to methotrexate and TNF inhibitors, its effects in JIA-associated uveitis remain undetermined.
To clarify this, the University Hospitals Bristol NHS Foundation Trust in collaboration with Arthritis Research UK (now known as Versus Arthritis), initiated a Phase 2 clinical trial, called APTITUDE (ISRCTN95363507; EudraCT 2015-001323-23). It was designed to evaluate RoActemra’s safety and effectiveness in pediatric patients (ages 5–17) with active JIA-associated uveitis, and who failed treatment with both methotrexate and TNF inhibitors.
Participants were recruited at seven tertiary hospitals across the U.K. RoActemra was given to 21 patients, average age 12.3, who had been receiving a stable dose of methotrexate for at least 12 weeks (with no adequate response) and had not responded to previous adalimumab treatment.
A 162 mg dose of RoActemra was injected subcutaneously (under the skin) every two weeks to patients weighing at least 30 kilograms (66 pounds), and every three weeks to those weighing less than 30 kg, for a total of 24 weeks. After that, patients were followed for 12 more weeks. Participants continued their methotrexate treatment regimen during the trial.
The trial’s main goal was to assess whether adding RoActemra to methotrexate would lead to a response — classified as a two-grade reduction in the number of inflammatory cells in the eye’s anterior chamber — at week 12. According to the team’s criteria, progression to a Phase 3 trial would be justified if such response would be seen in more than seven of the 21 patients.
Secondary goals included safety and tolerability measures, as well as other effectiveness assessments.
Results showed that only four patients completed the initial 24 weeks of treatment. At week 12, seven patients (33%) had responded to treatment, meaning that the trial failed to meet its primary goal. Three additional patients achieved partial responses (one-grade reduction) at week 24.
Also, three of the four participants with macular edema — a common complication of uveitis — had it resolved after RoActemra treatment.
No significant improvements were observed in other effectiveness measures.
RoActemra’s safety profile was consistent with that reported in previous trials. Skin reactions in the injection site (38%) and headaches (24%) were the most common adverse side effects, and no serious side effects occurred.
Researchers said the study had some limitations, including the small number of patients, a potentially short treatment period set for the primary goal, and the presence of an overall moderate-to-severe disease — since substantial immunosuppressive therapy failed to lower inflammation in most patients.
“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,” the researchers wrote.
“Tocilizumab [RoActemra] might provide a valuable adjunctive therapeutic option for children with uveitis refractory to [TNF inhibitors], particularly as adalimumab is the only evidence-based and licensed therapy,” they added.
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