An interleukin-1α and interleukin-1β cytokine trap worked for the treatment and prevention of recurrent pericarditis, according to RHAPSODY investigators.
Patients on at least their second bout of pericarditis were enrolled in a 12-week run-in period in which rilonacept (Arcalyst) was initiated and background medications discontinued. Those who showed a clinical response to rilonacept entered the randomized-withdrawal period in which they were split between continued rilonacept monotherapy or placebo.
It took a median 8.6 weeks for the placebo group to have their first pericarditis recurrence, whereas events were too rare for this to be calculated in the rilonacept arm (HR 0.04, 95% CI 0.01-0.18). Sixteen weeks into the randomized-withdrawal period, the incidence of pericarditis recurrence was 7% with rilonacept versus 74% with placebo, reported Allan Klein, MD, of Cleveland Clinic, and colleagues.
The RHAPSODY results were presented at the American Heart Association (AHA) virtual meeting. The full study wast published in the New England Journal of Medicine. Topline trial results were announced by Kiniksa Pharmaceuticals last June.
“Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo,” the authors concluded. “The results of this trial suggest that patients treated with rilonacept may be able to discontinue colchicine and glucocorticoids.”
Study results were consistent regardless of previous glucocorticoid use.
“Is rilonacept best suited to replace corticosteroids as second-line therapy in the management of recurrent pericarditis? If so, its efficacy and safety needs to be directly compared to corticosteroids,” commented AHA session discussant Brendan Everett, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
Rilonacept blocks interleukin-1 signaling, which is thought to be a mediator of recurrent pericarditis. The drug is FDA approved for the treatment of cryopyrin-associated periodic syndromes, a group of rare, inherited, autoinflammatory conditions.
Klein’s group noted that the two pericarditis recurrence events in the rilonacept group were associated with temporary interruptions of the trial-drug regimen: one interruption was due to poor adherence to the regimen, and the other was due to myalgia that was subsequently resolved.
The run-in period saw four patients experience adverse events, most commonly injection-site reactions and upper respiratory tract infections, leading to discontinuation of rilonacept therapy.
Non-fasting LDL cholesterol level was higher on rilonacept than placebo (average 124.8 vs 111.7 mg/dL), as were non-fasting triglycerides (198.0 vs 96.7mg/dL).
These increases may be “problematic, especially in a vulnerable population,” said Sanjay Kaul, MD, of Cedars Sinai Medical Center in Los Angeles, who was not involved with RHAPSODY.
Other issues that need to be addressed further include cost and longer-term safety, particularly for people with autoimmune disorders such as lupus, commented C. Noel Bairey Merz, MD, also of Cedars Sinai.
Rilonacept received FDA breakthrough therapy designation to rilonacept for recurrent pericarditis in 2019 and orphan drug designation in 2020.
“Pending FDA approval, best practice and likely future guideline advisement is to use the therapy in accordance with the clinical trial,” Bairey Merz told MedPage Today.
“Overall, promising data, but in my opinion the benefit is likely overestimated and risk likely underestimated,” according to Kaul, who noted that FDA had denied approval of rilonacept for gout in 2012 due to a safety signal of increased risk of malignancy.
RHAPSODY was a phase III trial that included 86 patients with recurrent pericarditis who reported acute symptoms on a pain scale, and had signs of systemic inflammation (CRP levels at least 1 mg/dL), despite treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or oral glucocorticoids.
They first entered the run-in period consisting of a 1-week stabilization period, a 9-week period to wean from background therapy for pericarditis, and a 2-week period of rilonacept monotherapy. The first dose of rilonacept was followed by resolution of pain a median of 5 days later; median time to normalization of CRP was 7 days.
The next step was randomization to continued rilonacept monotherapy or matching placebo. Eligible individuals were those who met the clinical response criteria of CRP levels ≤0.5 mg/dL, weekly reports of no or minimal pain on rilonacept monotherapy, and lack of pericarditis recurrence.
Of the 86 participants, 61 completed the run-in period and were randomized before enrollment was stopped because the investigators accrued enough primary endpoint events for their main analysis. Half the patients were followed through 24 weeks after the run-in period.
Rilonacept was administered subcutaneously once a week. Median duration of rilonacept treatment (including the run-in period) was 9 months.
The two study arms had an average 98.7% adherence to their assigned regimens.
“Data from the run-in period suggest a clinical benefit of rilonacept but are uncontrolled and thus difficult to interpret,” commented Everett.
“However, 79 of the 86 patients who entered the run-in period had the prespecified clinical response that was considered to be necessary in order for them to undergo randomization, which suggests that the findings may be applicable to many patients with recurrent pericarditis,” Klein and colleagues maintained.
Nevertheless, limiting treatment exposure to responders might have led to overestimation of rilonacept’s benefit, Kaul commented.
RHAPSODY investigators also acknowledged their relatively small sample and the study’s limited generalizability to pericarditis patients without elevated inflammation markers.
A long-term extension study is ongoing, they said.
“With some important caveats and remaining clinical questions, rilonacept seems likely to provide an important therapeutic advance for patients with a challenging clinical disease,” Everett concluded.
COVID-19 infection can be complicated by myopericarditis and pericardial effusion with tamponade requiring drainage, a case study reported.
Last Updated November 17, 2020
RHAPSODY was funded by Kiniksa Pharmaceuticals. A co-author is a company employee.
Bairey Merz disclosed relevant relationships with Abbott, Sanofi, and iRhythm.
Everett disclosed support from the National Heart, Lung, and Blood Institute.
Kaul disclosed no relevant relationships with industry.
Klein disclosed relevant relationships with Kiniksa, Sobi, and Pfizer.