presentation about Drugs that act on interleukin 1 ( Anakinra , Canakinumab and Rilonacept ) and their role in the treatment of variety of conditions.

2. Introduction
• The cytokines interleukin 1 (IL1) are produced acutely as part of host defence in
response to microbial infection, inflammation, and tissue injury 1 .
• Overexpression of these cytokines, however, has been implicated in the
pathogenesis of several human diseases—notably, rheumatoid arthritis (RA) and
other chronic inflammatory disorders, including Crohn’s disease. Accordingly,
agents capable of blocking these cytokines have been sought for their potential
clinical use . 2
• IL1 produces a variety of biological actions that appear conserved across species.
Systemic injection of recombinant IL1 elicits fever, increased slow wave sleep,
anorexia, hypotension, leucopenia, and thrombocytopenia. IL1 stimulates the
hypothalamic-pituitary-adrenal axis, leading to production of adrenocorticotrophic
hormone, growth hormone, vasopressin, and somatostatin. 3

3. • IL-1 production is induced in response to inflammatory stimuli and mediates various physiological
responses including inflammatory and immunological responses.
• IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid
loss of proteoglycans, as well as stimulation of bone resorption.
• The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from rheumatoid
arthritis (RA) patients are not sufficient to compete with the elevated amount of locally produced
IL-1. 3
Types of IL-1 :
• IL-1α is a “dual-function cytokine”, which means it plays a role in the nucleus by
affecting transcription, apart from its extracellular receptor-mediated effects as a classical cytokine.
In this group also belongs IL-33. 4
• Interleukin 1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous
mediator, mononuclear cell factor, lymphocyte activating factor and other names, is
a cytokine protein that in humans is encoded by the IL1B gene. 5

4. Anakinra ( Kineret )

5. Anakinra
• Anakinra blocks the biological activity of interleukin-1 (IL-1) by competitively inhibiting
IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide
variety of tissues and organs. 5
• The Anakinra molecule is a non glycosylated version of human IL-1 receptor antagonist
(IL-1RA) prepared from cultures of genetically modified E.Coli, using recombinant DNA
Technology . It differs from native human IL-1 RA in that it has the addition of a single
methionine residue on its amino terminus . 6
Kinetics :
• Anakinra has an absolute bioavailability of 95% for healthy adults after subcutaneous
injection. Peak plasma concentration of Anakinra generally occurred 3 to 7 hours after
subcutaneous administration of clinically relevant doses for patients with Rheumatoid
arthritis. The terminal t 1/2 ranged from 4 to 6 hours.

6.  Therapeutic use & adverse effects :
• Rheumatoid arthritis : Anakinra was approved by the US Food and Drug Administration and the European Commission for
the treatment of patients with Rheumatoid arthritis in 2001 8
• Cryopyrin-Associated Periodic Syndrome ( FDA approved )
• Juvenile idiopathic arthritis ( orphan drug )
• Adult-onset Still's disease ( orphan drug )
 Adverse effects :
• injection site reactions
• recurrent infections
• possibly pulmonary infections with history of asthma / COPD
• possible risk of malignancy
• A decrease in neutrophil count may be found. 8
 Preparation & Dosage :
• Anakinra - 100 mg, pre-filled syringes for subcutaneous administration.
• The usual dosage is 100 mg subcutaneously once a day.
• Duration of therapy is usually 24 weeks.

7. Canakinumab ( Ilaris )

8. Canakinumab
• Canakinumab is a fully human monoclonal antibody targeting IL-1b that has an expanding list of
clinical indications. IL-1b is aproinflammatory cytokine that plays a key role during inflammation
and is implicated in acute and chronic autoimmune diseases10.
• It is synthesized as a precursor peptide(pro-IL-1b) that undergoes proteolytic cleavage and
excretion into the extracellular space. Once secreted, IL-1b acts on target cells through the IL-1RI
receptor. Dysregulated IL-1b secretion is observed in several autoimmune diseases, specifically in
autoinflammatory diseases, and the clinical manifestations can be significantly relieved by IL-1b
blockade
Mode of action :
• Canakinumab is a high affinity, fully human monoclonal antihuman IL-1b antibody of the IgG1/k
isotype. It was generated using a transgenic mouse strain capable of producing human IgGκ
monoclonal antibodies. Upon binding to canakinumab, the antibody-IL-1b complex is unable to
attach to the cell surface receptor therefore interrupting IL-1b-dependent signaling.

9. Kinetics :
• In human studies, canakinumab has a half-life between 21 and 30 days. The pharmacokinetic (PK) parameters
of canakinumab were determined in asthma, RA, psoriatic and CAPS patients. peak serum concentration
(Cmax of 16 + 3.5 μg/ml) in approximately 7 days. Half-life is long (mean: 26 days) after single sc.
administration. The absolute bioavailability is estimated to be 70%. 13.
Indications :
• Cryopyrin-Associated Periodic Syndrome ( FDA approved )
• Tumor Necrosis Factor Receptor-Associated Periodic Syndrome ( FDA approved )
• Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency ( FDA approved )
• Familial Mediterranean Fever ( FDA approved )
Adverse Effects :
• Bronchitis , Diarrhea, Gastroenteritis, Headache, Influenza, Musculoskeletal pain, Nasopharyngitis, Nausea,
Pharyngitis, Rhinitis ,Weight increase and Vertigo .
Dosage Forms & Strengths :
• powder for injection
• 180mg/vial (150mg/mL after reconstitution)

10. Rilonacept (Arcalyst )

11. Rilonacept (Arcalyst )
• Rilonacept blocks IL-1 signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its
interaction with cell–surface receptors, thereby reducing the inflammatory process.
Kinetics :
• For CAPS patients receiving 160 mg of rilonacept weekly for up to 48 weeks, steady state was reached
in six weeks. Average trough levels were 24 mcg/mL, and the circulation half-life in vivo was 8.6 days.
Indications :
• Cryopyrin Associated Periodic Syndrome :
Rilonacept was given an "orphan drug" status by the United States Food and Drug Administration and is
used 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

12.  Adverse effects :
 >10%
• Injection site reactions (48%)
• Infections (34-48%)
• Upper respiratory tract infections (26%)
 1-10%
• Cough (9%)
• Hypoesthesia (9%)
• Sinusitis (9%)
 <1%
• Hypersensitivity reaction
• Neutropenia
 Dosing :
• powder for injection
• 220mg/vial

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