Rilonacept
Autoinflammatory syndromes are a class of inherited diseases thought to be caused by aberrant regulation of cytokine signalling pathways1. Features of these syndromes include recurrent fevers, rash and joint pain1.
Several autoinflammatory syndromes, including familial cold autoinflammatory syndrome (FCAS) and Muckle–Wells syndrome (MWS), are associated with mutations in the gene NLRP3 (nucleotide-binding domain, leucine rich family, pyrin domain containing 3; also known as CIAS1 and NALP3)1. This gene encodes a protein called cryopyrin, which has led to the adoption of the term cryopyrin-associated periodic syndromes (CAPS) for this group of diseases1.
Attempts to treat CAPS with various anti-inflammatory drugs or immunosuppressants have generally been disappointing1, and so there is a significant need for novel therapies.
Basis of discovery
Cryopyrin is the central component of the cryopyrin inflammasome, a multiprotein complex that has an important role in innate immunity1, 2. Stimulation of the inflammasome activates caspase 1, which processes the precursor of interleukin-1
(IL-1) to its active form, leading to inflammation and immune activation (Fig. 1)1, 2.
Figure 1 | The cryopyrin inflammasome and CAPS.
Stimulation of the cryopyrin inflammasome leads to activation of caspase 1. This converts interleukin-1 (IL-1) to its active form, resulting in inflammation and activation of the immune system1, 2. Overactivity of the inflammasome owing to mutations in the gene coding for cryopyrin is thought to underlie cryopyrin-associated periodic syndromes (CAPS)1, 2. Anakinra and rilonacept block IL-1 signalling.
In 2001, it was reported that mutations in the gene encoding cryopyrin caused FCAS and MWS3. Since then, several studies have indicated that increased inflammasome activity and consequent excessive IL-1 release are important in the pathogenesis of CAPS1, 4. Such studies provided the rationale for evaluating anakinra (Kineret; Amgen), a recombinant IL-1 receptor antagonist that is approved for the treatment of rheumatoid arthritis, for treating CAPS. The efficacy of this agent in initial clinical studies5, 6 has provided strong support for IL-1 blockade as a therapeutic strategy for CAPS.
Drug properties
Rilonacept (also known as IL-1 trap) is an engineered dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human immunoglobulin G1 (IgG1)7, 8. This 'cytokine trap' blocks IL-1 signalling by acting as a soluble decoy receptor that binds to IL-1, thereby preventing its interaction with cell-surface receptors7, 8.
Clinical data
The safety and efficacy of rilonacept for the treatment of CAPS was evaluated in a randomized, double-blind, placebo-controlled trial with two parts (A and B) conducted sequentially in the same patients with FCAS and MWS8. Part A was a 6-week, randomized, double-blind, parallel-group period comparing rilonacept (160 mg weekly administered as a subcutaneous injection, after an initial loading dose of 320 mg) with placebo8. Part B followed immediately after part A and consisted of a 9-week, patient-blind period during which all subjects received rilonacept (160 mg weekly), followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on rilonacept (160 mg weekly) or to receive placebo8. Patients were then given the option to enrol in a 24-week, open-label treatment extension phase in which all patients were treated with rilonacept (160 mg weekly)8.
Patients rated five signs and symptoms of CAPS — joint pain, rash, feeling of fever/chills, eye redness/pain and fatigue — each on a scale of 0 (no severity) to 10 (very severe) using a daily diary questionnaire8. The trial evaluated the mean symptom score using the change from baseline to the end of treatment8.
In part A, patients receiving rilonacept had a larger reduction in the mean symptom score compared with placebo-treated patients (- 2.4 compared with - 0.5, respectively)8. A higher proportion of patients in the rilonacept group experienced improvement from baseline in the composite score by at least 30% (96% of patients), by at least 50% (87% of patients) and by at least 75% (70% of patients) compared with the placebo group, for which the corresponding figures were 29%, 8% and 0% of patients, respectively8.
In part B, mean symptom scores increased more in patients withdrawn to placebo compared with patients who remained on rilonacept (0.9 compared with 0.1, respectively)8.
During the open-label extension, reductions in mean symptom scores were maintained for up to 1 year8.
Indications
Rilonacept is approved by the FDA for the treatment of CAPS, including FCAS and MWS in adults and in children aged 12 years and older8.
Autoinflammatory diseases
Analysing issues in the treatment of autoinflammatory diseases is Hal M. Hoffman, M.D., Associate Professor of Medicine at the University of California San Diego, California, USA.
Recent advances in the field of inherited autoinflammatory disorders are an excellent example of translational research leading to effective targeted therapy. The identification of the genetic basis of hereditary fever disorders (CAPS, familial Mediterranean fever, hyper IgD syndrome, and tumour necrosis factor (TNF) receptor-associated periodic syndrome) has provided much needed insight into the pathophysiology of these rare inflammatory diseases. Fortunately, these advances occurred in a climate of active biologic drug discovery aimed at specific pro-inflammatory cytokines such as TNF-
and IL-1. The use of these targeted immunomodulatory drugs to treat patients with these rare genetic diseases has addressed unmet clinical needs in this patient population while also providing the opportunity to study their mechanism of action, efficacy and safety.
The greatest frustration of patients with inherited autoinflammatory disorders is the lack of physician awareness about these disorders owing to the low disease frequency in most populations. The systemic nature of these syndromes results in involvement of multiple tissues and diverse clinical presentations. Although fever is a common factor in each of these diseases, patients often seek care from a variety of specialists for symptoms such as rash, abdominal pain and joint pain, or nonspecific symptoms such as fatigue, myalgias and headache. Disease gene identification has resulted in improved diagnosis for these disorders, but a significant proportion of patients with similar clinical presentations do not have obvious mutations or are never tested. Several questions remain unanswered concerning disease pathophysiology such as the mechanism underlying the intermittent nature of episodes and the unpredictability of the development of systemic amyloidosis, the most common and severe morbidity associated with these disorders.
The recent approval of rilonacept with orphan drug status for the treatment of CAPS has had several positive effects on the future care of inherited autoinflammatory disorders. The success of rapidly bringing a drug to market has piqued the interest of other companies with compounds targeting IL-1 and related pathways, and has resulted in an increased awareness of these diseases. As a weekly injection, rilonacept provides a welcome alternative to the daily injections that are required for anakinra, a recombinant IL-1 receptor antagonist. The pivotal clinical trial for rilonacept, an adequately powered randomized, placebo-controlled design with more than 12 months of follow-up maintenance therapy using a validated clinical instrument, has raised the bar in a field characterized by small open-label case series.
However, several therapeutic challenges remain. The simple economics of modern drug development of an orphan biologic compound results in high costs. The injectable formulation may limit widespread use, as oral drugs are preferred by patients. The inherited nature of these disorders requires lifelong therapy with long-term risks still unknown. Their known genetics and pathophysiology make the inherited autoinflammatory diseases an intriguing test ground for additional IL-1-targeted therapies, and further translational studies will undoubtedly contribute to improved therapies and quality of life for these patients.