Rilonacept shows therapeutic potential for recurrent pericarditis

In patients with recurrent pericarditis (RP), the interleukin (IL)-1α and IL-1β cytokine trap rilonacept significantly reduced the risk of recurrence, with rapid resolution of episodes, the RHAPSODY* trial has shown.

“Rilonacept monotherapy reduced RP event risk by 96 percent vs placebo … [and] provided rapid and sustained reductions in pain and CRP** as soon as after the first dose,” noted Dr Allan Klein from the Cleveland Clinic Foundation, Ohio, US. “The management of RP with targeted monotherapy such as rilonacept could offer an alternative therapeutic option for patients.”

RP is characterized by chronic pericardial inflammation that substantially impairs physical function. [Heart 2004;90:1364-1368; Mayo Clin Proc 2010;85:572-593] While there are therapeutic options for RP, these are limited, and none are FDA-approved. Up to 30 percent of initial episodes will recur despite colchicine treatment, and long-term glucocorticoid use entails serious adverse event (AE) risks and nonspecific immunosuppression. [Eur Heart J 2015;36:2921-2964; Ann Intern Med 2011;155: 409-414]

“IL-1 has been implicated in the pathophysiology of RP and is a viable target for intervention in patients [with] systemic inflammation (eg, elevated CRP levels),” said the researchers. In a phase II trial, rilonacept demonstrated early evidence of pericarditis resolution. [Circulation 2019;140(Suppl 1):abstract 12851]

A phase III trial was conducted comprising 86 adults (mean age 44.7 years, 57 percent female) with acute symptomatic RP and systemic inflammation who failed standard background therapy (BT)***. They initially entered a 12-week^# run-in phase, wherein subcutaneous rilonacept was given (320 mg loading dose then 160 mg weekly) while BT was being discontinued. The randomized-withdrawal (RW) phase ensued thereafter, wherein clinical responders (n=61) were randomized 1:1 to continue rilonacept or receive placebo. [AHA 2020, session LBS.07; N Engl J Med 2020;doi:10.1056/NEJMoa2027892]

Run-in phase

At week 1, mean baseline pain score dropped from 4.5 to 1.6, reflecting rapid resolution of the acute pericarditis episode after the first dose. The reduction was sustained throughout this phase, reaching a score of 0.46 by week 12. Mean baseline CRP level also dropped from 3.7 to 0.30 mg/dL at week 1, which was also sustained until week 12 (0.24 mg/dL).

Median time to pain resolution/near-resolution was 5 days, median time to CRP level normalization was 7 days, and median time to prespecified treatment response was 5 days. Four patients discontinued rilonacept owing to AEs.

RW phase

The two incidences of recurrence in the rilonacept arm were deemed “too few”, hence the ‘not estimable’ median time to first adjudicated recurrence. With placebo, 23 recurrence events were observed, with a median time to recurrence of 8.6 weeks (hazard ratio, 0.04; p<0.001).

Among those who reported recurrence, bailout rilonacept was given to all placebo recipients and one of the two rilonacept-treated patients; following which, no recurrence was reported.

At week 16, all major secondary efficacy endpoints were achieved: significantly more rilonacept recipients had sustained clinical response (81 percent vs 20 percent) and no/minimal symptoms (81 percent vs 25 percent). The number of days with no/minimal pain was also greater with rilonacept vs placebo (least squares mean, 98 percent vs 46 percent; p<0.001 for all).

Four serious AEs were reported, but none were treatment-related. The most common AEs associated with rilonacept were injection-site reactions and upper respiratory tract infections, all of which were mild or moderate in severity.

IL-1 pathway inhibition

Despite the relatively small sample, the effect size was “large and significant”, noted the researchers. And while the RW analysis limited the findings to clinical responders, 77 participants from the overall cohort had the prespecified treatment response deemed necessary for randomization. “[This implies] that the findings may be applicable to many patients with RP.”

“[Taken together,] the resolution of acute episodes and prevention of subsequent episodes during rilonacept monotherapy support the hypotheses that IL-1 is an important mediator of RP in patients who have evidence of systemic inflammation,” they said. “[The findings suggest] that targeted inhibition of the IL-1 pathway is sufficient for the treatment and prevention of pericarditis episodes.”

The long-term extension phase of RHAPSODY is underway.