Sustained Pericarditis Recurrence Risk Reduction With Long-Term Rilonacept

Abstract

Background: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment.

Methods and results: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P<0.0001).

Conclusions: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Keywords: autoinflammatory disease; interleukin‐1; recurrent pericarditis; rilonacept.

Figure 1. RHAPSODY design.

Patients who completed the randomized‐withdrawal period while on study drug and were clinically stable were eligible to continue treatment with rilonacept (160 mg subcutaneously self‐ or caregiver‐administered once weekly) in the open‐label, long‐term extension. Patients still in the run‐in when the event‐driven randomized‐withdrawal period ended and who had achieved the defined clinical‐response criteria were transitioned directly into the long‐term extension. *Duration of the RI period was concealed from patients to blind them to randomization timing. LTE indicates long‐term extension; RHAPSODY, Rilonacept Inhibition of Interleukin‐1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study; RI, run‐in; RW, randomized‐withdrawal; and SC, subcutaneous.

Figure 2. Patient disposition during long‐term extension of phase 3 RHAPSODY.*

Of the 74 eligible patients who were enrolled in the open‐label, long‐term extension of RHAPSODY, 69 patients completed this phase of the study. *Patient disposition data for RHAPSODY study periods before long‐term extension have been published. ^†Investigator decision to discontinue patient due to serious adverse events of acute endocarditis. ^‡44 US patients either transitioned to rilonacept after US Food and Drug Administration approval (n=32; completed subsequent 6‐week safety follow‐up) or discontinued treatment (n=12; completed subsequent 6‐week safety follow‐up); 25 non‐US (Australia, Israel, Italy) patients remained on open‐label rilonacept until long‐term extension closure (completed subsequent 6‐week safety follow‐up). FDA indicates Food and Drug Administration; and RHAPSODY, Rilonacept Inhibition of Interleukin‐1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study.

Figure 3. Treatment response after 18‐month decision milestone.

Pericarditis recurrence risk was reduced among patients who continued rilonacept treatment after the 18‐month decision milestone compared with patients who suspended treatment and remained under observation (rescue allowed) (hazard ratio, 0.02; P<0.0001). *The patient with a recurrence at 23.4 weeks had interrupted rilonacept treatment approximately 4 weeks prior for elective cardiac surgery.