Almost Complete Victory Over Recurrent Pericarditis
Arcalyst (rilonacept) has become the first drug indicated for the treatment of recurrent pericarditis and reduction in risk of its recurrence in adults and children 12 years and older.
The expansion of Arcalyst’s list of indications has been approved by the U.S. Food and Drug Administration (FDA) in March 2021.
Arcalyst made its debut in February 2008, when it received FDA approval for the therapy of rare genetic diseases in children and adults — cryopyrin-associated periodic syndromes (CAPS) such as familial cold auto-inflammatory syndrome (FCAS) [also known as familial cold urticaria (FCU)], muckle-wells syndrome (MWS). In December 2020, Arcalyst learned how to maintain remission status of deficiency of interleukin-1 receptor antagonist (DIRA) in children and adults.
In the European Union, Arcalyst appeared in October 2009: rilonacept was authorized for the treatment of FCAS/FCU, MWS, neonatal-onset multisystem inflammatory disease (NOMID) [also known as chronic infantile neurological cutaneous and articular syndrome (CINCA)]. In October 2012, the marketing authorization for Arcalyst was withdrawn — by the manufacturer voluntarily for commercial reasons.
Arcalyst was developed by Regeneron Pharmaceuticals, which transferred the license to market it to Bermuda-based Kiniksa Pharmaceuticals in September 2017.
What Is Recurrent Pericarditis?
Pericarditis is an inflammatory disease of the pericardial sac (pericardium) of mostly idiopathic nature. Other causes include: infections, metabolic disorders, myocardial infarction, autoimmune pathologies, myocardial damage after medical procedures, neoplasms, and drug exposure.
The clinical diagnosis of recurrent pericarditis is made with another episode of the disease after an asymptomatic period of at least 4-6 weeks. After the first episode of acute pericarditis, 15-30% of patients experience at least one recurrence, and up to half of these patients experience subsequent recurrences. This prevalence is higher among patients with elevated levels of C-reactive protein and when treated with corticosteroids with the exception of colchicine. Yes, corticosteroids do relieve symptoms very quickly, but they carry a high risk of serious side effects by providing nonspecific immunosuppression.
After at least two relapses, up to 40% of patients experience new episodes of pericarditis, requiring months or even years of treatment. The chronic and debilitating course of the disease seriously impairs quality of life: largely due to the extensive negative impact on the patient’s physical abilities, general well-being, and work performance. Patients have to go to the hospital, attend emergency rooms, and experience continuous chest pain and a condition of anxiety.
Current approaches to treating recurrent pericarditis involve prescribing symptomatic medications such as aspirin, nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids. In severe cases of treatment-refractory pericarditis (among 10% of patients), immunosuppressants are used: anakinra, canakinumab, azathioprine, intravenous immunoglobulins, methotrexate, mycophenolate mofetil.
Nevertheless, no approved specific treatment for recurrent pericarditis has existed to date.
Arcalyst: Efficacy and Safety of Treatment of Recurrent Pericarditis with Rilonacept
The RHAPSODY (NCT03737110) phase 3 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) enrolled patients (n=86) aged 12 years and older with a diagnosis of recurrent pericarditis.
Among the main inclusion criteria for the trial: at least three episodes of pericarditis during screening; stable doses (if received) of nonsteroidal anti-inflammatory drugs, colchicine, corticosteroids (in any combination) for at least 3 days before the first dose of rilonacept.
During the 12-week run-in period, participants received injections of rilonacept weekly (160 mg after a loading dose of 320 mg) with a concomitant withdrawal of all other background medications. Patients who responded to treatment (n=61) (pain severity ≤ 2.0 on the 11-point numeric rating scale [NRS] and C-reactive protein [CPR] levels ≤ 0.5 mg/dL) proceeded to the next step, comparing rilonacept monotherapy with placebo.
The rilonacept group demonstrated an exit to the primary endpoint set by time to first pericarditis recurrence: over the follow-up period of 50 weeks, no median of this time was recorded due to too few disease recurrences (recurrence in 7% of subjects; n=2/30) — versus 8.6 weeks (95% CI: 4.0–11.7) in the placebo group (recurrence in 74% of patients; n=23/31).
Administration of rilonacept provided a 96% relative risk reduction in pericarditis recurrence: hazard ratio (HR) 0.04 (95% CI: 0.01–0.18); p<0.001.
After 16 weeks, 81% of patients receiving rilonacept maintained a clinical response — vs. 20% in the control group (p=0.0002). The proportion of subjects with no or minimal pericarditis symptoms according to the 7-point Patient Global Impression of Pericarditis Severity (PGIPS) was 81% — vs. 25% (p=0.0006). The proportion of days with no or minimal pain was 98% — vs. 46% (p<0.0001).
Importantly, rilonacept monotherapy allowed complete discontinuation of corticosteroids and colchicine, and this occurred relatively quickly after a median of 7.9 weeks.
The safety profile of rilonacept was characterized by acceptable tolerability. The vast majority of adverse reactions were mild to moderate in severity. The most common adverse events included: infectious and infestations (in 40% of subjects), upper respiratory tract infections (23%), and injection site reactions (20%).
Arcalyst: Mechanism of Action of Rilonacept in Recurrent Pericarditis
The pathophysiology of recurrent pericarditis has not been fully clarified but is more likely an interaction between environmental triggers and the innate and adaptive immune system. Patients with recurrent pericarditis have an abnormal inflammatory response, which may be related to both autoimmune and autoinflammatory processes. Studies have shown that members of the interleukin-1 (IL-1) cytokine family, which are important mediators of innate immunity and local and systemic inflammation, are positioned as key components in the pathogenesis of recurrent pericarditis.
Thus, in addition to inflammatory cytokines such as interleukin-6 (IL-6), interleukin 1 alpha (IL-1α) and interleukin 1 beta (IL-1β) are responsible for the promotion and progression of inflammation in pericarditis. Tissue damage caused by increased production of IL-1α and IL-1β stimulates their additional synthesis, thereby creating an endless loop of pericardial inflammation with its transformation into a chronic disease. Preformed IL-1α released by damaged and inflamed pericardial cells activates the NLRP3 inflammasome, which enhances the inflammatory response by producing IL-1β.
Rilonacept (rilonacept) is an IL-1α and IL-1β inhibitor. The drug compound, being a dimeric fusion protein, consists of the ligand-binding domains of the extracellular sites of the interleukin-1 receptor accessory protein (IL-1RAcP) and interleukin 1 receptor type 1 (IL1R1) attached to the Fc region of human immunoglobulin G1 (IgG1). Rilonacept works as a trap for IL-1α and IL-1β, binding and neutralizing them: it prevents IL-1α and IL-1β from interacting with IL1R1, resulting in suppression of the latter’s activity.
Treatment of Recurrent Pericarditis: Market Landscape
Currently, only rilonacept has proven therapeutic efficacy against recurrent pericarditis. However, drugs similar in the mechanism of action have broadly comparable efficacy and safety profiles.
For example, Kineret (anakinra), a recombinant non-glycosylated homologue of the interleukin 1 receptor antagonist (IL1RN), which, acting as a competitive inhibitor of IL-1 binding to IL1R1, blocks the biological activity of IL-1α and IL-1β and has long been used to treat recurrent pericarditis.
Kineret, developed by Sobi (Swedish Orphan Biovitrum), is approved in the therapy of moderate-to-severe rheumatoid arthritis in active form and NOMID.
Ilaris (canakinumab), a human monoclonal antibody that binds IL-1β and thereby neutralizes its activity by blocking the interaction of IL-1β with IL-1 receptors, is also prescribed off-label for recurrent pericarditis. Canakinumab does not affect IL-1α and IL1RN.
Ilaris, which is backed by Novartis, is approved in the therapy of periodic fever syndromes (PFS) which include CAPS (MWS, NOMID/CINCA, FCAS/FCU); tumor necrosis factor receptor-associated periodic syndrome (TRAPS); hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD); familial mediterranean fever (FMF). Ilaris is used for Still’s disease, including adult-onset Still’s Disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA). Ilaris is also used in the therapy of gouty arthritis.
Rilonacept, anakinra, and canakinumab are all prescribed subcutaneously, and while rilonacept requires weekly injections, anakinra refers to a daily dose, and canakinumab is given once a month.
No reliable evidence has yet been offered that selective IL-1β antagonism is more effective and safer than non-selective IL-1α and IL-1β antagonism. However, it is believed that dual blockade may be useful in severe cases of recurrent pericarditis.
Arcalyst: Rilonacept’s Prospects
The United States market is understandably the most lucrative in the world for any pharmaceutical business. Kiniksa estimates that there are approximately 40,000 patients with recurrent pericarditis in the U.S., although those eligible for therapy with rilonacept are fewer — about 14,000. These are patients whose disease is either refractory to existing symptomatic drugs, is experiencing multiple relapses, or is dependent on corticosteroids.
The only direct competitor to rilonacept is RPH-104, a fusion protein being developed by Russian R-Pharm that selectively binds and inactivates IL-1β. RPH-104 is now in phase 2/3 (randomized, double-blind, placebo-controlled) clinical trial CL04018068 (NCT04692766) among a modest number (n=25) of patients with idiopathic recurrent pericarditis.
Arcalyst (rilonacept). Prescribing information. U.S. [PDF]
Kiniksa Pharmaceuticals. FDA approval of Arcalyst (rilonacept) for recurrent pericarditis. March 18, 2021. [PDF]
Kiniksa Pharmaceuticals. Corporate presentation. March 2021. [PDF]
RHAPSODY: rationale for and design of a pivotal phase 3 trial to assess efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β trap, in patients with recurrent pericarditis. Am Heart J. 2020 Oct;228:81-90. [source]
Phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis. N Engl J Med. 2021 Jan 7;384(1):31-41. [source]