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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.

Introduction: Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation. Methods: At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE. An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension. Results: Baseline and 18MDM CMRs were available for 13 patients. Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM while on treatment are provided in Figure . CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2). Conclusions: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.

Abstract Aims In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence. Methods and results RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE (n = 9), patients with moderate or severe pericardial LGE (n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence. Conclusions Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered. ClinicalTrials.gov Identifier NCT03737110

Abstract Background Recurrent pericarditis (RP) patients report that painful, debilitating flares negatively impact their health-related quality of life (HRQoL). RHAPSODY, the Phase 3 trial of rilonacept (IL-1α/IL-1β cytokine trap), included a daily pain diary and patient-reported outcome SF-36v2 to measure HRQoL throughout the trial. Purpose The purpose of this research is to evaluate the effect of rilonacept on HRQoL in relation to changes in pain for RP patients who have a recurrence. Methods RHAPSODY enrolled 86 patients with acute symptomatic RP to receive weekly rilonacept for a 12-week run-in (RI) period and randomized 61 patients (1:1) to receive placebo (n=31) or continue rilonacept (n=30) for the event-driven randomized-withdrawal (RW) period. Patients on placebo who experienced a qualifying recurrence during RW (return of pericarditis pain and increase in C-reactive protein) were rescued with bailout rilonacept. Patients reported daily pericarditis pain electronically, using a 0–10 numeric rating scale (NRS), and completed the SF-36v2 at study visits prior to clinician interaction. Scores from RI Baseline (BL), RI Week 12 (RW BL), Recurrence visit, and RW up to Week 24 (or end of study; EOS) were evaluated for patients who experienced recurrence in RW. Analyses exclude one patient randomized to placebo who had a recurrence after Week 24 of the RW period. Results Analyses focused on the 22 of 30 patients (73%) in the placebo group who experienced a recurrence before Week 24 of RW (median time from RW BL to recurrence: 8.6 weeks). During RI, daily pain scores decreased while on rilonacept (Cohen's effect size [ES] d=−2.0), and SF-36v2 scores improved, with scores at RI BL (Fig. 1 red line) below the general population average of 50 and near or above average at RI Week 12 (Fig. 1 blue line); ES were all large (d&gt;0.8), ranging from 0.917 (Mental Component Summary) to 2.021 (Bodily Pain). At recurrence, pain scores increased (d=6.5; Fig. 2) and SF-36v2 scores were below the population average (Fig. 1 orange line), with largest reductions between RI Week 12 (RW BL) and recurrence for Bodily Pain (−13.4) and Physical Component Summary (−10.6). Following rilonacept bailout, average pain decreased (d=−2.1; Fig. 2), and by RW Week 24/EOS, SF-36v2 scores returned to similar levels as at the end of the RI period (Fig. 1 green line). Conclusion Impaired RI BL SF-36v2 scores indicate negative impact of RP on HRQOL in RP patients. While receiving rilonacept, HRQoL scores improved to near or above population averages, in conjunction with patient-reported pain. After discontinuing rilonacept during RW, HRQoL scores worsened at recurrence and improved upon receipt of bail-out rilonacept, similar to pain. These results provide support for the broader benefit of rilonacept treatment beyond pain, when administered on top of conventional therapies and as mono-therapy, providing evidence of its potential to improve HRQoL in this patient population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Kiniksa Pharmaceuticals, Ltd.