Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease

Abstract

Background: Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals.

Methods: We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period.

Results: Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1β plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1β plasma levels.

Conclusion: We demonstrated that IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1β inhibition is warranted.

Trial registration: ClinicalTrials.gov NCT01267994.

Funding: NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.

Figures

Figure 3. Hearing thresholds (PTA and WRS) relative to IL-1β plasma levels in a phase I/II trial of anakinra for corticosteroid-resistant AIED (NCT01267994).

At visit 1, anakinra (daily subcutaneous injectable medication) was instituted (↑) for the next 84 days, after which therapy was discontinued (↓). Interval audiograms were obtained at visits 2 (day 28), 3 (day 56), and 4 (day 84). The 180-day post-treatment observational period is shown in visits 5 (day 114), 6 (day 174), and 7 (day 264). The left axis shows PTA, plotted inversely, similar to an audiogram (lower numbers correspond to better hearing); solid lines denote active ears (blue, left; red, right), and dashed lines denote inactive ears. Numeric values show WRS for the active ear (blue, left; red, right), with a best possible score of 100. The right axis shows IL-1β plasma values (green). In some patients, after visit 4, anakinra treatment was reinstated for an additional 28 days (denoted by arrows) because of a decline in hearing. Institution of steroid therapy in patient LIJ-07 is denoted by a red arrow.

Figure 2. Best hearing improvement observed while on anakinra therapy.

PTA improvement (A) and WRS improvement (B) during the 84-day drug period were both significantly higher in anakinra responders (n = 7) versus nonresponders (n = 3) (P = 0.02 for both, Mann-Whitney test). The result was also compared with the historic improvement with corticosteroid therapy (Standard of care) previously reported by Niparko et al. (1).

Figure 1. CONSORT flow diagram.

For enrollment, all patients must have been treated with a 28-day course of prednisone and have experienced no clinical improvement, as assessed by PTA and WRS. All patients that met enrollment criteria were allocated to receive the intervention (n = 13). Of the 13 subjects, 1 never received anakinra. Of the 12 patients that received anakinra, 2 were unable to complete the initial 28 days of therapy, leaving 10 subjects evaluable for the efficacy assessment.