Results of a phase 3 trial show that treatment with rilonacept (Arcalyst), a drug already approved to treat inflammatory disease, both resolved acute episodes of recurrent pericarditis and prevented further recurrence.
The agent acts as an interleukin-1α and interleukin-1β cytokine trap, reducing inflammation. It is already approved by the US Food and Drug Administration (FDA) to treat a group of rare inherited inflammatory diseases called cryopyrin-associated periodic syndromes (CAPS).
“In RHAPSODY, in these symptomatic pericarditis patients failing standard-of-care colchicine and steroids, we showed there was a very robust treatment response to rilonacept,” Allan Klein, MD, director of the Center for the Diagnosis and Treatment of Pericardial Diseases at Cleveland Clinic, Cleveland, Ohio, told theheart.org | Medscape Cardiology.
There was “rapid resolution” of the acute episode even after the first dose of rilonacept, and the relative risk for recurrence was reduced by 96%, “which is quite dramatic,” Klein said. Patients were able to be weaned off standard-of-care treatments, including steroids, and reported improved quality of life. With treatment, patients experienced none or minimal pericarditis pain for 98% of trial days, he added.
“These data could represent a paradigm shift in that rilonacept not only provided a steroid-sparing option to half of the study population who were on steroids at study entry but potentially obviated the need for initiation of steroids in patients who were experiencing a recurrence despite colchicine,” Klein concluded.
Results of the Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis, a Pivotal Symptomatology and Outcomes Study (RHAPSODY) trial were presented at the American Heart Association 2020 Scientific Sessions virtual meeting and were published online November 16 in The New England Journal of Medicine. The co–principal investigator was Massimo Imazio, MD, AOU Città della Salute e della Scienza di Torino, Turin, Italy.
Athena Poppas, MD, president of the American College of Cardiology, called the results “exciting.”
“This should change practice, so I find it to be quite exciting, and also confirming the hypothesis of the importance of interleukin-1 in particular as a primary mediator of this disorder,” Poppas said in an interview.
Pericarditis is an “unusual condition, but a particularly challenging condition because we haven’t had any great therapies for this in the past, and it can be quite debilitating for patients,” she noted. Most of the drugs currently used for nonspecific immune suppression can have significant side effects, although the recent addition of colchicine as treatment of this condition “was a great step forward,” she said.
The current findings with rilonacept “were quite impressive by their efficacy and relative tolerability,” she said. “I think the caveat remains the safety profile with respect to longer-term use or in higher-risk groups ― older patients in particular ― with upper respiratory infection, and the increase in the LDL and triglyceride levels will need to be watched.
“I’m thinking in particular the postpericardotomy group, which, again, is a small proportion of their group ― I think it was 15%. They have coronary disease, so you’d have to sort of weigh the pros and cons of that,” Poppas added.
Recurrent pericarditis is a chronic, often debilitating disease frequently affecting younger people. It occurs subsequent to viral illness or cardiac procedures, such as valve surgery or ablation, Klein said. “It sets off an inflammatory process and takes months to years to treat.” Of those with a first episode, 15% to 30% will experience recurrence despite treatment with colchicine, the authors write.
There is no FDA-approved therapy, but anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and, more recently, colchicine have been used. “Among the limited therapeutic options, glucocorticoids are of particular concern because of nonspecific immunosuppression and because of the risk of serious adverse events associated with long-term use,” they note.
The researchers postulate that interleukin-1 (IL-1) plays a major role, Klein said. IL-1α and IL-1β cause pericardial inflammation in a self-perpetuating cycle. Rilonacept acts to trap both IL-1α and IL-1β, stopping the cycle. A previous phase 2 trial of rilonacept showed evidence of resolution of pericardial inflammation.
RHAPSODY was a phase 3, multicenter, double-blind, “randomized-withdrawal” trial of rilonacept vs placebo in patients with acute symptoms of recurrent pericarditis and systemic inflammation. The trial was conducted in Australia, Israel, Italy, and the United States.
Eligible patients were adults and adolescents (≥12 years of age) who had experienced at least a second recurrence. They had previously met 2015 European Society of Cardiology criteria for pericarditis at least once, despite treatment with NSAIDs, colchicine, or glucocorticoids in any combination. They were required to have a pain scale score of at least 4 of 10, as well as inflammation, with a C-reactive protein (CRP) level of at least 1 mg/dL within 7 days of the first administration of rilonacept.
Patients initially underwent a run-in period of 12 weeks, during which time rilonacept treatment was begun and other medications were tapered and discontinued. Rilonacept was given subcutaneously as a loading dose of 320 mg (or 4.4 mg/kg for those younger than 18 years), followed by weekly maintenance doses of 160 mg (or 2.2 mg/kg).
Those who had a clinical response to treatment, defined as a CRP level of <0.5 mg/dL and weekly mean daily pain rating scale score of ≤2, indicating minimal or no pain, were then randomly assigned in a 1:1 ratio to continue treatment or receive placebo in a double-blind, event driven, randomized-withdrawal period.
In all, 86 patients entered the run-in phase; during this period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of CRP was 7 days, the researchers note. All patients who received steroids at baseline successfully tapered off and transitioned to monotherapy with rilonacept within 8 weeks, Klein noted.
A total of 79 patients (92%) completed the run-in. Of the responders, 61 were randomly assigned. The primary efficacy endpoint was the time to first adjudicated pericarditis recurrence. Patients experiencing recurrence could be given open-label rilonacept bailout and remain in the study, Klein noted. Safety was also assessed.
“During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated,” the researchers note in their NEJM report.
Median time to first adjudicated recurrence in the placebo group was 8.6 weeks after randomization (95% CI, 4.0 – 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 – 0.18; P < .0001 by log-rank test).
Pericarditis recurred during this period in 2 of 30 patients (7%) treated with rilonacept and in 23 of 31 patients (74%) who received placebo.
“This corresponds to a 96% reduction in the risk of a recurrent pericarditis event,” Klein said during his presentation. “Of note, there were no reported recurrences for the remainder of randomized-withdrawal period in patients receiving bailout rilonacept.”
All three major secondary endpoints at week 16 were “highly statistically significant” in favor of treatment, he noted. “Four times as many rilonacept recipients maintained clinical response compared to placebo recipients. From the patient quality-of-life perspective, 81% of patients receiving rilonacept report absence or minimal pericarditis symptoms compared to 25% of placebo recipients.”
Reports from the patients indicate that those who received rilonacept were pain free or had minimal pain on 98% of trial days; those who received placebo had minimal or no pain on 46% of trial days.
Adverse events seen with treatment were consistent with the known side effect profile of rilonacept in CAPS, Klein said. There were no serious drug-related adverse events and no deaths.
The most common adverse events were injection site reactions (34%), all of which were of mild or moderate severity; and upper respiratory tract infections, which occurred in seven patients (23%), all of which were again mild or of moderate severity.
During the run-in phase, four patients discontinued treatment because of adverse events, which included alopecia, extrinsic allergic alveolitis, erythema, and systemic allergic reaction (hypersensitivity).
The researchers also reported that LDL cholesterol levels were higher at week 24 with rilonacept before bailout than placebo (124.8 mg/dL vs 111.7 mg/dL). Similarly, triglyceride levels were higher in the treated group before bailout vs placebo (198 mg/dL vs 96.7 mg/dL). These increases in lipid level have been “reported elsewhere,” they note in the NEJM report.
The long-term extension period is ongoing, Klein noted.
The discussant for the RHAPSODY trial presentation during the session was Brendan M. Everett, MD, MPH, associate professor of medicine at Harvard Medical School, Boston, Massachusetts. He congratulated the researchers on conducting this study in a “challenging area of cardiology that is of great clinical importance to many patients.”
He pointed out that the data from the run-in period suggest a clinical benefit with rilonacept, although they are uncontrolled and “thus difficult ― at least for me ― to interpret,” Everett said. Also, because about 8% of patients who didn’t respond to treatment weren’t randomly assigned, “the results presented may not apply to all patients with recurrent pericarditis,” he said.
“Nonetheless, it appears that rilonacept is remarkably beneficial for those patients who can tolerate it, and one wonders whether or not it’s best suited to replace corticosteroids as second-line therapy in the management of pericarditis,” Everett added.
“If that is the case, its efficacy and safety need to be directly compared to corticosteroids, both in the short term, as was the case in this trial, and potentially over the long term as well,” he said. Corticosteroids are known to have “important adverse effects and it would be important to compare those to those of rilonacept.
“Thus, 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.
Rilonacept has FDA orphan drug designation for the treatment of pericarditis and breakthrough therapy designation for recurrent pericarditis, the Kiniksa website notes.
Kiniksa licensed rilonacept from Regeneron in 2017 for evaluation “in diseases believed to be mediated by both IL-1α and IL-1β, including recurrent pericarditis,” the company says.
“The Biologic License Application (BLA) for CAPS will transfer to Kiniksa, and the company plans to submit a Supplemental Biologic License Application (sBLA) with the FDA in recurrent pericarditis by the end of 2020,” the company adds. “Upon receipt of FDA approval for rilonacept in recurrent pericarditis, Kiniksa would assume the sales and distribution of rilonacept for the approved indications in the United States and will evenly split profits on sales with Regeneron.”
The RHAPSODY study was funded by Kiniksa Pharmaceuticals. Klein reports honoraria (modest) from Sobi, Wolters Kluwer, Elsevier, and Pfizer and a research grant (modest) from Kiniksa. Some coauthors are employees of Kiniksa. Everett and Poppas have disclosed no relevant financial relationships.
American Heart Association (AHA) Scientific Sessions 2020: Abstract LBS 7. Presented November 16, 2020.
N Engl J Med. Published online November 16, 2020. Abstract