1. ID DB06372
RILONACEPT
CATEGORY
Immunosuppressive Agents

2. DESCRIPTION
Rilonacept is a dimeric fusion protein consisting of portions of IL-1R and the IL-1R accessory protein linked to the Fc portion of immunoglobulin G1. Rilonacept functions as an interleukin 1 inhibitor and is used in the treatment of CAPS, also known as cryopyrin-associated periodic syndromes, including familial cold auto-inflammatory syndrome (FCAS) and Muckle-Wells Syndrome (MWS), in adults and children greater than 12 years old.
INDICATION
Rilonacept is currently used in the treatment of cryopyrin-associated periodic syndrome. In May 2012, an advisory panel for the FDA voted 11-0 against the use of Rilonacept for the treatment of gout.
PHARMACODYNAMICS
Treatment with Rilonacept resulted in decreased levels of mean C-Reactive Protein (CRP) and Serum Amyloid A (SAA). Higher levels of CRP and SAA are associated with inflammatory disease activity found in patients with Cryopyrin-Associated Periodic Syndromes.

3. MECHANISM OF ACTION
CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [Nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndtrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis are features common to all disorders. In most cases, inflammation in CAPS is associated with mutations in the NLRP-3 gene which encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist (IL-1ra) with reduced affinity. By binding IL-1, rilonacept prevents the activation of IL-1 receptors, thus reducing inflammatory responses and other effects related to an excess of IL-1.

4. HALF-LIFE = 8.6 days
PATENT
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DRUG INTERACTION
<drugbank-id>DB00051</drugbank-id> <name>Adalimumab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00092</drugbank-id> <name>Alefacept</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00026</drugbank-id> <name>Anakinra</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00098</drugbank-id> <name>Antithymocyte globulin</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00993</drugbank-id> <name>Azathioprine</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00074</drugbank-id> <name>Basiliximab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB06681</drugbank-id> <name>Belatacept</name> <description>Belatacept decreases immunosuppressive effects while rilonacept increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both. </description> <drugbank-id>DB06681</drugbank-id> <name>Belatacept</name> <description>Belatacept decreases immunosuppressive effects while rilonacept increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both. </description> <drugbank-id>DB06681</drugbank-id> <name>Belatacept</name> <description>Belatacept decreases immunosuppressive effects while rilonacept increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both. </description> <drugbank-id>DB06168</drugbank-id> <name>Canakinumab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00091</drugbank-id> <name>Cyclosporine</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00111</drugbank-id> <name>Daclizumab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00004</drugbank-id> <name>Denileukin diftitox</name> <description>decreases effects of toxoids by pharmacodynamic antagonism. </description> <drugbank-id>DB06643</drugbank-id> <name>Denosumab</name> <description>Use caution with patients on concomitant immunosuppressants or those with compromised immune systems; increased risk of serious infection. </description> <drugbank-id>DB00095</drugbank-id> <name>Efalizumab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00005</drugbank-id> <name>Etanercept</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB01590</drugbank-id> <name>Everolimus</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB05259</drugbank-id> <name>Glatiramer Acetate</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB06674</drugbank-id> <name>golimumab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB06674</drugbank-id> <name>golimumab</name> <description>Avoid combination due to the enhancement of rilonacept associated side effects. </description> <drugbank-id>DB01611</drugbank-id> <name>Hydroxychloroquine</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00065</drugbank-id> <name>Infliximab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB01097</drugbank-id> <name>Leflunomide</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00563</drugbank-id> <name>Methotrexate</name> <description>Rilonacept and methotrexate both increase immunosuppressive effects; combination may increase risk of myelosuppression. </description> <drugbank-id>DB00075</drugbank-id> <name>Muromonab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00688</drugbank-id> <name>Mycophenolate mofetil</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB06688</drugbank-id> <name>Sipuleucel-T</name> <description>decreases effectiveness of APC8015 by pharmacodynamic antagonism. </description> <drugbank-id>DB00877</drugbank-id> <name>Sirolimus</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00864</drugbank-id> <name>Tacrolimus</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB06287</drugbank-id> <name>Temsirolimus</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB01041</drugbank-id> <name>Thalidomide</name> <description>Thalidomide may increase the adverse effects of Rilonacept. Increased risk of serious infection. Concomitant therapy should be avoided. </description> <drugbank-id>DB06273</drugbank-id> <name>Tocilizumab</name> <description>results in increased immunosuppressive effects; increases the risk of infection. </description> <drugbank-id>DB00072</drugbank-id> <name>Trastuzumab</name> <description>Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. </description>

5. SEQUENCE
rilonacept|Homo sapiens||FUSION-IL1RAP-IL1R1-GAMMA-1 (IL1RAP+(Pr21-359)(1-339)+IL1R1+(Pr22-333)( )+HINGE-REGION( )+CH2( )+CH3( ))|||||||880||||MW |MW |SERCDDWGLDTMRQIQVFEDEPARIKCPLFEHFLKFNYSTAHSAGLTLIWYWTRQDRDLEEPINFRLPENRISKEKDVLWFRPTLLNDTGNYTCMLRNTTYCSKVAFPLEVVQKDSCFNSPMKLPVHKLYIEYGIQRITCPNVDGYFPSSVKPTITWYMGCYKIQNFNNVIPEGMNLSFLIALISNNGNYTCVVTYPENGRTFHLTRTLTVKVVGSPKNAVPPVIHSPNDHVVYEKEPGEELLIPCTVYFSFLMDSRNEVWWTIDGKKPDDITIDVTINESISHSRTEDETRTQILSIKKVTSEDLKRSYVCHARSAKGEVAKAAKVKQKVPAPRYTVEKCKEREEKIILVSSANEIDVRPCPLNPNEHKGTITWYKDDSKTPVSTEQASRIHQHKEKLWFVPAKVEDSGHYYCVVRNSSYCLRIKISAKFVENEPNLCYNAQAIFKQKLPVAGDGGLVCPYMEFFKNENNELPKLQWYKDCKPLLLDNIHFSGVKDRLIVMNVAEKHRGNYTCHASYTYLGKQYPITRVIEFITLEENKPTRPVIVSPANETMEVDLGSQIQLICNVTGQLSDIAYWKWNGSVIDEDDPVLGEDYYSVENPANKRRSTLITVLNISEIESRFYKHPFTCFAKNTHGIDAAYIQLIYPVTNSGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

6. TARGET
Interleukin-1 beta,Interleukin-1 alpha,Interleukin-1 receptor antagonist protein

7. Rilonacept AKA ArcalystSC
Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept has a molecular weight of approximately 251 kDa. Rilonacept is expressed in recombinant Chinese hamster ovary (CHO) cells.
DOSAGE:
Loading dose: 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites.
Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection.
Rilonacept should not be given more often than once weekly.

8. VIAL:
ARCALYST (rilonacept) is supplied in single-use, 20-mL glass vials containing a sterile, white to off-white, lyophilized powder. Each vial of ARCALYST (rilonacept) is to be reconstituted with 2.3 mL of Sterile Water for Injection. A volume of up to 2 mL can be withdrawn, which is designed to deliver 160 mg for subcutaneous administration only. The resulting solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Each vial contains 220 mg rilonacept (80 mg/ 1mL after reconstitution), histidine, arginine, polyethylene glycol 3350, sucrose, and glycine at a pH of 6.5±0.3. No preservatives are present.
ADVERSE REACTION:
Fever, chills, sore throat, flu symptoms;
easy bruising or bleeding (nosebleeds, bleeding gums);
nausea and vomiting, loss of appetite;
mouth sores; or
unusual weakness.

9. DRUG INTERACTION:
TNF-blocking agent and IL-1 blocking agent and Cytochrome P450 Substrates