Status – BLA approved in Feb. 2008; approved in EU in Oct. 2009

Organizations involved:

Regeneron Pharmaceuticals, Inc. – Manuf.; R&D; Tech.; World mark.

Cross ref.: See also Kineret from Amgen, another IL-1 inhibitor.

Description: Arcalyst is a lyophilized (freeze-dried) formulation of IL-1 Trap (rilonacept), a recombinant dimeric fusion single-chain antibody-like or immunoadhesin glycoprotein expressed by unspecified transformed mammalian cells consisting of two linked human IL-1 cytokine receptor extracellular domains - the interleukin-1 (IL-1) type I receptor (IL-1RI) and the IL-1 receptor accessory protein (AcP) - linked in-line to the Fc (constant; framework, not immunogen-binding) portion of human immunogloblulin G1 (IgG1); expressed in transformed Chinese hamster ovary (CHO) cells. Rilonacept is a dimeric glycoprotein with a protein molecular weight of 201.21 kDa, has 27 disulfide bridges, and a calculated molecular formula of C9030H13932N2400O2670S74, with ~25% glycosylation (polysacchide polymers attachment) to give a total molecular weight of 251 kDa.

Arcalyst is packaged in single-use 20-mL glass vials containing 220 mg of rilonacept as a lyophilized powder for reconstitution. Each vial is to reconstituted with 2.3 mL of SterileWater for Injection. A volume of up to 2 mL can be withdrawn, which is designed to deliver 160 mg for subcutaneous administration. Reconstituted Arcalyst is a viscous, clear, colorless to pale yellow, essentially free from particulates, 80 mg/mL solution. Each vial contains 20 mg rilonacept (80 mg/ 1mL after reconstitution), histidine, arginine, polyethylene glycol 3350 (PEG-3350), sucrose, and glycine at a pH of 6.5±0.3. Vials are stored under refrigeration, and the expiration date is marked on each vial. The vials contain no preservatives.

IL-1 Trap is designed to attach to and neutralize the activity of interleukin-1 (IL-1) in the blood stream before IL-1 can attach to cell-surface receptors and generate signals that can trigger disease activity in body tissue. Once bound to IL-1 Trap, IL-1 cannot bind to cell surface receptors and the IL-1 Trap–IL-1 complex is excreted from the body.

Nomenclature: Interleukin-1 trap, rDNA [BIO]; Arcalyst [TR]; rilonacept [USAN; INN]; Interleukin 1 receptor accessory protein (human extracellular domain fragment) fusion protein with type I interleukin 1 receptor (human extracellular domain fragment) fusion protein with immunoglobulin G1 (human Fc fragment), homodimer [CAS]; [653-glycine][human interleukin-1 receptor accessory protein-(1-339)-peptide (extracellular domain fragment) fusion protein with human type I interleukin-1 receptor-(5-316)-peptide (extracellular domain fragment) fusion protein with human immunoglobulin G1-(229 C-terminal residues)-peptide (Fc fragment)] dimer [CAS]; [653-glycine][human interleukin-1 receptor accessory protein-(1-339)-peptide (extracellular domain fragment) fusion protein with human type 1 interleukin-1 receptor-(5-316)-peptide (extracellular domain fragment) fusion protein with human immunoglobulin G1-(229 C-terminal residues)-peptide (Fc fragment)], (659-659’:662-662’)-bisdisulfide dimer [CAS]; [653-glycine][human interleukin-1 receptor accessory protein-(1-339)-peptide (extracellular domain fragment) fusion protein with human type 1 interleukin-1 receptor-(5-316)-peptide (extracellular domain fragment) fusion protein with human immunoglobulin G1-(229 C-terminal residues)-peptide (Fc fragment)], (659-659’:662-662’)-bisdisulfide dimer [CAS]; 501081-76-1 [CAS RN]; IL-1 Trap, recombinant [SY]

Biological.: “Traps,” as developed by Regeneron, are composed of fusions between two distinct cytokine receptor components and a portion of an antibody molecule called the “Fc region”, resulting in the generation of cytokine blockers with markedly increased affinity over that offered by single component agents. In simplistic terms, two cytokine-binding receptors have been swapped into or substituted for the immunogen-binding portions of the two arms of an antibody/immunoglobulin molecule. In this respect, IL-1 Trap appears to qualify as an immunoadhesin, i.e., recombinant fusion proteins combining certain structural features of antibodies with high-affinity cell surface receptors (and seems to be covered by the associated dominant patent held by Genentech).

IL-1 is a pluripotent cytokine responsible for normal physiological roles ranging from the induction of vascular permeability and fever during sepsis to the increased secretion of additional cytokines in autoimmune diseases. Other roles of IL-1 include production and release of prostaglandins, pituitary hormones, and collagenases. IL-1 also stimulates the immune system to boost production of lymphocytes. A balance exists between the beneficial and harmful effects of IL-1. It can negatively impact the vascular, endocrine, connective tissue, immune, haematopoietic, and central nervous systems, making it an important therapeutic target in a number of pathological conditions including rheumatoid arthritis, atherosclerosis, diabetes mellitus type I, inflammatory bowel disease and other autoimmune disorders, Alzheimer’s disease, leukaemia, and solid tumors

Three proteins comprise the IL-1 family, two of which are agonists, IL-1alpha and IL-1beta; the third is IL-1 receptor antagonist (IL-1ra). IL-1alpha and IL-1beta are derived from different genes but are functionally similar, and both bind to the same cellular receptor. Although they exhibit similar biological activities, IL-1alpha and IL-1beta differ in the manner in which they are processed and secreted. IL-1alpha is localized in the cytosol or cell membrane and is believed to regulate the intracellular environment. IL-1beta is first cleaved by interleukin-1beta-converting enzyme (ICE) to its mature active form and then secreted extracellularly. Patients with infectious or inflammatory conditions exhibit elevated plasma concentrations of IL-1beta but not IL-1alpha, suggesting a systemic role of IL-1beta.

There are two IL-1 receptors, the biologically active IL-1 receptor type I (IL-1RI) and the IL-1 receptor type II (IL-1RII). Both are members of the immunoglobulin superfamily and contain structurally similar IL-1 binding sites. IL-1RI is expressed on most cell types, preferentially binds IL-1alpha, and is responsible for the signal transduction of IL-1. IL-1RIIacts as an antagonist. Found within B lymphocytes, neutrophils, and monocytes, IL-1RII preferentially binds IL-1beta and contains a shorter cytoplasmic segment. This decreases its signal transduction ability, attenuating the response to IL-1. Due to these antagonistic effects, IL-1RII is referred to as a decoy IL-1 receptor, resulting in its potential as a therapeutic agent (see the Kineret entry). Upon binding of IL-1 to either receptor type, the IL-1R accessory protein (IL-1RAcP) is recruited to the complex. The IL-1RAcP facilitates signal transduction via the recruitment of kinases and activator and intracellular proteins. Without IL-1RAcP, IL-1 remains capable of binding IL-1RI, but signal transduction is unable to occur. This mechanism affects the efficacy of therapeutics that attempt to prevent the IL-1 and IL-1RI interaction.

Rilonacept incorporates in a single molecule the extracellular domains of both receptor components required for IL-1 signaling: IL-1RI and AcP. Because rilonacept contains two receptor components, each with picomolar affinity, IL-1 Trap molecule is expected to be a more efficient inhibitor in vivo of IL-1 than anakinra (IL-1 receptor antagonist; Kineret from Amgen; see related entry). In in vitro experiments measuring the relative efficacies (IC50) of IL-trap and IL-1ra in the presence of IL-1beta (4 pM), the IC50 of IL-1 trap vs. IL-1ra were 2 pM and 70 pM, respectively.

IL-1 Trap may be useful for treatment of a number of diseases and disorders in which IL-1 may play an important role, including cancers, a spectrum of rare diseases called cryopyrin-associated periodic syndromes (CAPS), and other diseases associated with inflammation. A number of studies have shown that high interleukin-1 (IL-1) concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype.

Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas. Patients with IL-1 producing tumors generally have bad prognoses. Prolonged inflammatory cytokine exposure has the potential to promote tumor growth through the induction of angiogenesis, DNA damage, and other events favorable to tumor invasion and metastases. The exact mechanisms by which IL-1 promotes tumor growth remain unclear. The protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNF-alpha, and TGF-beta.

Companies.: Rilonacept and Trap technology were developed by Regeneron Pharmaceuticals Inc. Regeneron will exclusively manufacture and market Rilonacept.

FDA class: Biologic BLA

Appprovals: Date = 20080227; BLA no. 125249

Indications: [full text of the "Indications and USAGE" section of product insert/labeling]:

ARCALYST (rilonacept) is an interleukin-1 blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome

(MWS) in adults and children 12 and older.

Status: On June 8, 2007, Regeneron completed its rolling/fast track BLA submission for Arcalyst with FDA seeking approval of Rilonacept for the long-term treatment of cryopyrin-associated periodic syndromes (CAPS), . This followed completion of analysis of a 24-week open-label extension trial (see the Trials section below). The FDA had earlier granted Orphan Drug and Fast Track designations to the BLA for the treatment of CAPS. On Aug. 8, 2007, FDA accepted the BLA filing and granted it priority review status (target approval decision in 6 months).

On Feb. 27, 2008, FDA approved Arcalyst with orphan designation for the long term treatment of two Cryopyrin-Associated Periodic Syndromes (CAPS) disorders: Familial Cold Auto-Inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). Rilonacept was launched in the U.S. on March 25, 2008.

On Oct. 27, 2009, Arcalyst received marketing authorization in the European Union for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS) with severe symptoms, including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS), in adults and children aged 12 years and older. Marketing authorization for rilonacept was granted by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) under exceptional circumstances. Approval in the E.U. under exceptional circumstances is permissible for products for which a company can demonstrate that comprehensive data cannot be provided, for example because of the rarity of the condition. Each year, Regeneron will need to provide the EMEA with any new information that may become available for review.

In May 2012, an FDA advisory panel voted unanimously (11-0) against recommending Arcalyst receive approval for the prevention of gout flare-ups when patients start uric acid-lowering therapy, basedon concerns over a lack of data to support its use in this setting. FDA reviewers had noted Arcalyst's potential to boost the risk of infections and malignancies, and questioned whether data from the 16-week trial submitted in the application was sufficient to determine safety. In late June, FDA formally refused to grant approval for this expanded indication.

In Aug. 2012, FDA issued a complete response letter (CRL) for the sBLA for Arcalyst for subcutaneous use for the prevention of gout flares in patients initiating uric acid-lowering therapy. The agency has requested additional clinical data, "as well as additional chemistry, manufacturing and controls information related to a proposed new dosage form". Tech. transfer: The product insert for Arclyst claims coverage by U.S. 6,927,044, 6,472,179, 5,844,099 and pending patents.

Regeneron has received patents covering aspects of Rilonacept including U.S. 6,927,044, “IL-1 receptor based cytokine traps,” expiring, May 19, 2019, a descendent of U.S. 6,472,179, “Receptor based antagonists and methods of making and using.” The exemplary claim (no. 1) is “An isolated nucleic acid molecule encoding a fusion polypeptide capable of binding a cytokine to form a nonfunctional complex comprising: a) a nucleotide sequence encoding a first fusion polypeptide component comprising the amino acid sequence of the cytokine binding portion of the extracellular domain of the specificity determining component of a receptor for the cytokine; b) a nucleotide sequence encoding a second fusion polypeptide component comprising the amino acid sequence of the cytokine binding portion of the extracellular domain of the signal transducing component of a receptor for the cytokine; and c) a nucleotide sequence encoding a third fusion polypeptide component comprising the amino acid sequence of a multimerizing component, wherein the receptor of a) can be the same or different from the receptor of b).” Further claims include coverage for use of IL-1 receptor sequences and the “multimerizing component” preferentially being the Fc portion of immunoglobulin. The “specificity determining component” of a cytokine’s receptor refers to the component or subunit of a receptor responsible for determining the cellular target of the cytokine. The “signal transducing component” of the cytokine’s receptor refers to the component or subunit of a receptor which is not the specificity determining component and which does not bind or weakly binds the cytokine in the absence of the specificity determining component, and may participate in cytokine signaling.

Patent applications related to Arcalyst assigned to Regeneron (as of Jan. 2013) include U.S. 20090156492, " Methods of Using IL-1 Antagonists to Treat Autoinflammatory Disease," concerning treatment of Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), familial mediterranean fever (FMF), and systemic onset juvenile rheumatoid arthritis (Still's Disease).

EP 1750746 A1, "METHODS OF USING IL-1 ANTAGONISTS TO TREAT AUTOINFLAMMATORY DISEASE." with relevant uses claimed, if granted, will expire in 2025. Other EP filings pending (in Jan. 2013) include EP2311871, "IL-1 antagonist stable liquid formulation," which would expire in 2025; EP2356151 "HIGH AFFINITY HUMAN ANTIBODIES TO HUMAN IL-4 RECEPTOR" which would expire in 2029; EP2069403, "HIGH AFFINITY HUMAN ANTIBODIES TO HUMAN IL-4 RECEPTOR," which would expire in 2027; and EP1778723, "IL-1 ANTAGONIST FORMULATIONS, expiring 2025.

Rilonacept may come under Genentech immunoadhesin (cellular receptor-antibody framework fusion proteins) patent portfolio, including U.S. patents 5,116,964; 5,428,130; 5,455,165; and 5,514,382. These patents have been licensed for Enbrel (a tumor necrosis factor receptor–IgG fusion protein) and Amevive (alelacept; a leukocyte function-associated antigen-3–IgG fusion protein). See related entries. Regeneron has not disclosed whether it has or will take a license from Genentech.

Trials: In Oct. 2006, positive results were reported from the pivotal Phase III clinical program designed to provide two separate demonstrations of efficacy for the IL-1 Trap within a single group of adult patients with cryopyrin-associated periodic syndromes (CAPS). This involved two studies (Part A and Part B). Both studies met their primary endpoints (Part A: p < 0.0001 and Part B: p < 0.001). Both the Part A and Part B studies achieved statistical significance in all of their pre-specified secondary and exploratory endpoints. The primary endpoint of both was the change in disease activity, measured using a composite symptom score composed of a daily evaluation of fever/chills, rash, fatigue, joint pain, and eye redness/pain. The first study (Part A) was a double-blind and placebo-controlled 6-week trial, in which patients randomized to receive IL-1 Trap had an ~85% reduction in their mean symptom score compared to an ~13% reduction in patients treated with placebo (p<0.0001). Following a 9-week interval during which all patients received IL-1 Trap, a “randomized withdrawal” study (Part B) was performed, in which the same patients were re-randomized to either switch to placebo or continue treatment with the IL-1 Trap in a double-blind manner. During this withdrawal period, patients who switched to placebo had a five-fold increase in their mean symptom score, compared with those remaining on the IL-1 Trap who had no significant change (p= .0002).

Preliminary analysis of safety data from both studies indicated that there were no drug-related serious adverse events. Injection site reactions and upper respiratory tract infections, all mild to moderate in nature, occurred more frequently in patients while on IL-1 Trap than on placebo. In these two studies, IL-1 Trap appeared to be well tolerated; 46 of 47 randomized patients completed the Part A study, and 44 of 45 randomized patients completed the Part B study. As of early 2007, a 24-week open-label extension phase was ongoing.

Regeneron has been studying higher doses of the IL-1 Trap in different diseases after a Phase II trial using lower doses in subjects with rheumatoid arthritis failed to achieve its primary efficacy endpoint.

Three clinical trials have evaluated rilonacept in adult subjects with rheumatoid arthritis (RA); two Phase 1 studies involving 137 subjects, and one Phase II trial involving 201 subjects. Rilonacept was generally well tolerated. The most frequently reported adverse event was injection-site reaction, and most of the reported adverse events were mild to moderate in intensity. No serious adverse events were thought to be drug-related, and there was no evidence of increased infectious events above control.

Based on preclinical evidence that IL-1 appears to play a critical role in gout, Regeneron initiated a proof of concept study of IL-1 Trap in gout in the first quarter of 2007. The company is also planning to initiate exploratory proof of concept studies of IL-1 Trap in other indications:. Ultimately, IL-1 Trap might be useful for various cancers.

In Sept. 2008, results were reported from a Phase II trial of IL-1 Trap in addition to allopurinol for treatment of gout. This lowered uric acid levels and produced a statistically significant reduction versus placebo in the incidence of gout flares. In this 83-patient, double-blind, placebo-controlled study, the mean number of flares per patient over the first 12 weeks of urate-lowering therapy was 0.79 with placebo and 0.15 with Rilonacept (p=0.0011), an 81 percent reduction. This was the primary endpoint of the study. All secondary endpoints also were met with statistical significance. Regeneron plans to initiate a Phase III trial program early in 2009 with Rilonacept in the prevention of gout flares in patients initiating urate-lowering drug therapy.

In June 2010, Regeneron reported that a Phase III study in gout patients initiating allopurinol therapy to lower their uric acid levels showed that ARCALYST (rilonacept) prevented gout attacks, as measured by the primary endpoint of the number of gout flares per patient over the 16 week treatment period. Patients who received ARCALYST at a weekly, self-administered, subcutaneous dose of 160 milligrams (mg) had an 80% decrease in mean number of gout flares compared to the placebo group over the 16 week treatment period (0.21 flares vs. 1.06 flares, p<0.0001) Patients who received ARCALYST at a weekly dose of 80 mg had a 73% decrease compared to the placebo group (0.29 flares vs. 1.06 flares, p<0.0001).

Disease: Cryopyrin-associated periodic syndromes (CAPS) is a spectrum of rare inherited inflammatory conditions, including Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID). CAPS are caused by a range of mutations in the gene CIAS1 (also known as NALP3) which encodes cryopyrincryopyrin, which regulates release of IL-1beta. The development of an effective therapy for these syndromes is remarkable since the genetic basis of these conditions was only first identified in 2001.

CAPS is caused by a single gene mutation that leads to overproduction of interleukin-1 beta (IL-1ß), which causes sustained inflammation and tissue damage. Symptoms, such as debilitating fatigue, rash, fever, headaches, joint pain and conjunctivitis, can be present from birth or infancy, and can occur daily throughout patients' lives. Long-term consequences may be serious and potentially fatal, including deafness, bone and joint deformities, central nervous system damage leading to visual loss, and amyloidosis resulting in renal failure and early death.

CAPS disorders are rare (ultra-orphan), with only an estimated several hundred patients in treatment and a few thousand diagnosed patients. These syndromes are characterized by spontaneous systemic inflammation and are considered autoinflammatory disorders. A novel feature of these conditions (particularly FCAS and MWS) is that exposure to mild degrees of cold temperature can provoke a major inflammatory episode that occurs within hours, termed cryopyrin (“icy-fire”). Currently, there are no therapeutics approved for the treatment of CAPS.

Medical: For adult patients 18 yrs and older, treatment is initiated with a loading dose of 320 mg delivered as two, 2-mL, subcutaneous injections of 160 mg on the same day at two different sites. This is continued with once weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection. For pediatric patients aged 12 to 17 years, treatment is initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2mL, continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. If the initial dose is given as two injections, they should be given on the same day at two different sites.

IL-1 blockade may interfere with the immune response to infections.

Market: Total 2009 sales were $20 million, and $10.7 million in 2008.

Rilonacept, with its novel mechanism, may have difficulty gaining market share, with most physicians and even many patients more familiar with tumor necrosis (TNF) inhibitors being useful for treatment of inflammatory disorders, and competition (including off-label) from Kineret and upcoming IL-1 inhhibitors, including small molecule drugs. For example, Eli Lilly and Novartis are each developing antibodies to IL-1 and Amgen is developing an antibody to the IL-1 receptor.

Arcalyst is distributed in the U.S. through two specialty pharmacies, which will directly mail patients Arcalyst and the supplies needed for self-injection. The pharmacies also provide access to self-injection training and adherence counseling to patients who need those services.

Competition: Ilaris, an IL-1beta monoclonal antibody (see relate entry), now competes with Arcalyst for CAPS indications:.