Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist

Abstract

Background: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years).

Methods: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months.

Results: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported.

Conclusion: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections.

Trial registration: ClinicalTrials.gov NCT01801449.

Funding: NIH, NIAMS, and NIAID.

Keywords: Clinical Trials; Immunology.

Conflict of interest statement

Conflict of interest: R. Goldbach-Mansky has received study support under a Cooperative Research and Development Agreement from Regeneron, SOBI, Novartis, and E. Lilly. G.A. Montealegre Sanchez has received study support under a Cooperative Research and Development Agreement from Regeneron and E. Lilly.

Figures

Figure 1. Study design.

(A) Length of time in months (minimum to maximum) patients were untreated. During this time they acquired the organ damage listed in Table 1. (B) Length of time in months patients were treated with the recombinant IL-1 receptor anakinra and prior to enrollment into the open-label study. (C) Open-label study overview. Anakinra was discontinued prior to initiation of the study. Loading dose of rilonacept was given at 4.4 mg/kg/wk, followed by a maintenance dose of 2.2 mg/kg/wk. Patients were seen every 1 to 3 months for the first 6 months of the initial phase and then every 6 months for the duration of the study. The length of the open-label study was 2 years.

Figure 2. Clinical and laboratory responses in patients with deficiency of IL-1 receptor antagonist treated with rilonacept.

(A) Diary scores, Childhood Health Assessment Questionnaires (CHAQ) scores, and Pediatric Quality of Life (PedsQL) assessments were obtained at the baseline visit and after 3, 6, 12, 18, and 24 months on rilonacept (n = 6). § denotes that the diary score was 0 at baseline. The diary, CHAQ, and PedsQL scores did not significantly change from baseline. The transient elevation on the diary score at 3 months reflects the presence of micropustules in keratinized skin areas (i.e., elbow and knees). (B) C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) were compared between the pretreatment period, the anakinra treatment period, and the visits after initiation of rilonacept (baseline visit and after 3, 6, 12, 18, and 24 months). (C) White blood cells count (WBC), hemoglobin (Hb), and platelet count changes pretreatment, on anakinra, and on the respective rilonacept visits (baseline and after 3, 6, 12, 18, and 24 months) were compared. Comparisons among pretreatment, on anakinra, and respective rilonacept visits were made using paired t tests (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). Dots represent individual patients, and lines show the mean ± SD. Asterisks over values at test points indicate comparisons between pretreatment and anakinra as well as pretreatment and rilonacept. Asterisks over lines indicate comparisons between anakinra versus rilonacept.

Figure 3. Linear growth on IL-1–blocking treatment is shown for each patient enrolled.

Historical data from prior to the initiation of rilonacept (red arrowhead indicates start of rilonacept) were collected and graphed. The inset in each graph shows height obtained between 0 and 36 months of age. The yellow arrowhead in the inset denotes initiation of anakinra treatment; in the big graph, the yellow arrowhead indicates reinitiation of anakinra treatment after completion of the rilonacept study. The graph shows heights collected from the ages of 2 years until the end of rilonacept treatment (2 years of treatment). Patient 5 remains on rilonacept after the trial (the end of rilonacept study indicated by the black arrowhead). Midparental height (percentiles) are indicated in the top left corner of each graph. P1, patient 1; P2, patient 2; P3, patient 3; P4, patient 4; P5, patient 5; P6, patient 6.

Figure 4. Dual-energy X-ray absorptiometry.

Mean Z scores of anteroposterior lumbar spine were used for comparisons. Prior to treatment with anakinra, two patients had osteoporosis, and another two had osteopenia documented within the first year of anakinra initiation. Z scores normalized after treatment with anakinra from –2.52 ± 1.51 to –0.08 ± 1.23 (P < 0.05). Z scores continued to be normal after 12 months of treatment with rilonacept (mean Z score –0.12 ± 1.26) (P < 0.05 versus pretreatment period). Comparisons between pretreatment, on anakinra, and respective rilonacept visits were made using paired t tests (*P < 0.05). Dots represent individual patients, and lines show the mean ± SD.