Anakinra

Anakinra

Clinical data
Trade names	Kineret
AHFS/Drugs.com	Monograph
MedlinePlus	a602001
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Routes of administration	Subcutaneous
ATC code	L04AC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	95%
Metabolism	predominantly renal
Biological half-life	4-6 hrs
Identifiers
IUPAC name Recombinant human Interleukin-1 receptor antagonist protein; syn. N2-l-methionyl-interleukin 1 receptor antagonist (human isoform x reduced)
CAS Number	143090-92-0 Y
DrugBank	DB00026 Y
ChemSpider	none
UNII	9013DUQ28K Y
KEGG	D02934 Y
ChEMBL	CHEMBL1201570 N
Chemical and physical data
Formula	C759H1186N208O232S10
Molar mass	17,257.6 g/mol
NY (what is this?)  (verify)

Anakinra (brand name Kineret) is a drug used to treat rheumatoid arthritis.^[1] It is an interleukin 1 (IL1) receptor antagonist. It is produced by Swedish Orphan Biovitrum.

Mechanism

Anakinra is a recombinant version of the interleukin 1 receptor antagonist (IL1-RA).^[2] Anakinra differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus ^[3] Anakinra blocks the biologic activity of naturally occurring IL-1, including inflammation and cartilage degradation associated with rheumatoid arthritis, by competitively inhibiting the binding of IL-1 to the Interleukin-1 type receptor, which is expressed in many tissues and organs. IL-1 is produced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunologic reactions. IL-1 additionally stimulates bone resorption and induces tissue damage like cartilage degradation as a result of loss of proteoglycans. In patients with rheumatoid arthritis the natural IL-1 receptor antagonist is not found in effective concentrations in synovium and synovial fluid to counteract the elevated IL-1 concentrations in these patients.

Anakinra is not considered a 'disease-modifying antirheumatic drug' (DMARD) but rather a 'biological response modifier' (BRM) because its able to selectively target the pathologic element of the disease.

Basic chemical, pharmacological data

The anakinra molecule is a recombinant, non-glycosylated version of human IL-1RA (RA for receptor antagonist) prepared from cultures of genetically modified Escherichia coli using recombinant DNA technology. It consists of 153 amino acids and has a molecular weight of 17,257.6 g/mol (approx. 17.3 kilodaltons) and differs from native human IL-1RA in that it has the addition of a single methionine residue on its amino terminus.

Anakinra had an absolute bioavailability of 95% for healthy adults (n = 11) after a 70 mg subcutaneous bolus injection. Peak plasma concentrations of anakinra generally occurred 3 to 7 hours after s.c. administration of clinically relevant doses (1 to 2 mg/kg: n = 18) for patients with rheumatoid arthritis. The terminal half-life ranged from 4 to 6 hours. After daily s.c. dosing for up to 24 weeks, no unexpected accumulations of anakinra were observed in the plasma samples of rheumatoid arthritis patients.

Commercial and marketing

This drug is sold under the tradename "Kineret" and is produced by the pharmaceutical company Amgen. Since 15 December 2008, Swedish Orphan Biovitrum AB is the global market authorisation holder for Kineret on the indication adult rheumatoid arthritis. It is delivered as injection concentrate containing 100 mg each single dose.

Indications

Anakinra is indicated for the management of signs and symptoms of rheumatoid arthritis and to inhibit the progression of structural damage associated with the disease in adults with moderately to severely active disease who have had an absence of clinical improvement of symptoms or inadequate response in therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs). It is used as monotherapeutic agent or in combination with DMARDs. Anakinra should not be used in combination with anti-TNF agents such as etanercept (Enbrel), infliximab (Remicade) or adalimumab (Humira). First EU approval 8 March 2002 :^[4]

Anakinra showed moderate but statistically significant therapeutic efficacy; in most studies methotrexate was administered concomitantly. In the methotrexate plus anakinra group 38% of 250 patients reached an improvement/relief of symptoms of at least 20% within 24 weeks. In the control group of 251 patients under methotrexate treatment alone response was seen in 22% only. The clinical response was measured according to ACR-criteria (20, 50, and 70).

There are no direct studies comparing anakinra with TNF-α inhibitors, but indirect data suggests that anakinra may be inferior to TNF-α inhibitors. However a review of the literature has suggested that TNF-α inhibitors may be superior then anakinra.^[5] In a study with infliximab plus methotrexate 50% of all patients had significant remission (according to at least ACR 20 criteria) after a 30-week treatment period.

Anakinra may have applications for treating lupus nephritis.^[6] Inflammatory reactions caused by anti-dsDNA complexes with extracellular DNA in the glomerular basement membrane cause macrophage IL-1 release onto neighbouring mesangial cell IL-1 receptors.^[7]

Contraindications and precautions

Contraindications:

• Hypersensitivity to anakinra, other E. coli derived proteins, or to any other ingredient (absolute contraindication).
• Preexisting malignant diseases (e.g., solid cancers, leukemia): absolutely contraindicated (anakinra may worsen already existing malignancies).
• Patients with neutropenia due to any reason : absolutely contraindicated. Neutrophil counts should be obtained before initiating therapy and regularly thereafter (see recommended laboratory tests).
• Severely impaired renal function (creatinine clearance less than 30 ml/minute): absolutely contraindicated.
• Preexisting active tuberculosis (disease may be worsened – see side-effects).
• Concomitant application of live-virus vaccines (see Interactions).
• Lactation: it is unknown if anakinra is distributed into human milk. Nursing mothers should either discontinue the drug or breast-feeding, taking into account the importance of the drug to the mother.

Precautions:

• Geriatric patients (over 65 yrs of age): risk of infections is increased.
• Asthma: increased risk of severe infections.
• Women of childbearing potential should use effective contraception methods.
• Pregnancy: animal studies showed no adverse effects. Human data is not available. The drug should be applied to pregnant women only if clearly indicated.
• Mild to moderately impaired renal function: caution.

Side-effects

Side-effects

• Gastrointestinal tract : Frequently, nausea (8%), diarrhea (7%), unspecific abdominal pain (5%).
• Gastrointestinal tract : elevated liver transaminases
• Allergy : Rare cases of allergic reactions including severe anaphylaxis have been noticed. If necessary, the usual symptomatic therapy with corticosteroids, epinephrine, antihistamines and intravenous fluid correction should be initiated as soon as possible. Rare cases of allergic skin rash have also been seen.
• Respiratory tract : Frequently, infections of upper respiratory tract (13%), sinusitis (7%), flu-like syndrome (6%), Infrequently, pneumonia and tuberculosis.
• Skin : Frequently ecchymoses, infrequently skin mycosis, lupus erythematosus-like syndrome, urticaria, and isolated cases of melanoma (see malignancies).
• Immune system : Frequently, infections (40%, severe in 2%). Infrequently, production of antibodies with neutralizing activity.
• Blood and blood forming organs : Frequently, decrease in neutrophil counts (8% under anakinra, placebo 2%), infrequent significant neutropenia (0.4% under anakinra), moderate eosinophilia, moderately low platelet count, and malignant lymphomas (0.12 cases/100 patient years) (see malignancies).
• Musculoskeletal system : Infrequently seen are arthritic symptoms, arthritic symptoms associated with inflammation, bony infections.
• Pain, inflammation, and erythema at injection sites : Very frequently (70% of patients), usually during first 4 weeks of therapy, reversible within 1 to 2 weeks. These reactions are reasons why many patients discontinue therapy.

Recommended laboratory tests

In patients receiving anakinra a decrease in neutrophil counts may be found. In the placebo-controlled studies 8% of patients receiving anakinra had decreases in neutrophil counts of at least 1 World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Anakinra-treated patients experienced defined neutropenia (ANC < 1 x 109/L) in 0.4%.

Neutrophil counts should be assessed prior to initiating anakinra treatment, and while receiving anakinra, monthly for 3 months, and thereafter quarterly for a period up to 1 year.

Malignancies

Among 5,300 rheumatoid arthritis patients treated with anakinra in clinical trials for a mean of 15 months (approximately 6,400 patient years of treatment), 8 cases of lymphomas were observed resulting in a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population. However, the observed incidence of lymphomas in patients with rheumatoid arthritis is considerably higher than in the normal population, and may be even higher in those with high disease activity.

Additionally, 37 solid tumors of different origination have been found. Of these, the number of 3 melanomas reported in study 4 is significant (1 case expected), but the clear association to anakinra therapy remains unclear.

The Cochrane Collaboration (www.cochrane.org) is an independent body which produces systematic literature reviews to a high academic standard. The Cochrane review entitled, ‘Anakinra for rheumatoid arthritis’ (Mertens and Singh, 2009; http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005121/pdf_standard_fs.html) evaluates the clinical effectiveness and safety of anakinra in adult patients with rheumatoid arthritis, using data from 2876 patients, from five trials which constituted in total 781 randomized to placebo and 2065 to anakinra. The authors conclude, “There were no statistically significant differences noted in most safety outcomes with treatment with anakinra versus placebo - including number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). Injection site reactions were significantly increased, occurring in 1235/1729 (71%) versus 204/729 (28%) of patients treated with anakinra versus placebo, respectively”. These injection site reactions last for no more than four months and are not serious. Each of the trials reviewed measured prevalence of malignancies and found no evidence that these are increased amongst patients taking anakinra.

Interactions

TNF-blocking agents

An increased incidence of serious infections and an increased risk of neutropenia have been seen when anakinra and etanercept were used concomitantly in patients with rheumatoid arthritis. Similar interactions can be anticipated for the combination therapy of anakinra together with other agents blocking TNF (alpha) (e.g., adalimumab, infliximab). Therefore, combined drug therapy with anakinra and any TNF-blocking agent is not recommended and should be avoided. Moreover, in a 24-week clinical study a regime with anakinra and etanercept did not provide any additional benefit to the patients.

Methotrexate

Methotrexate has been coadministered with anakinra in quite extended clinical studies. Neither specific drug interactions nor increased toxicity of anakinra and/or methotrexate have been noticed. In animal models (rats) studying the effects of both drugs when coadminstered, no effects on clearing of both drugs form plasma or on the respective toxicologic properties have been seen. Therefore, the concomitant use of both disease modifiers in patients with rheumatoid arthritis can be regarded as safe.

Vaccines

Live-virus vaccines should not be given to patients during anakinra treatment. Information is not available, if anakinra would affect the rate of secondary transmission of vaccine virus (e.g., measles or poliomyelitis viruses) following administration of a live virus vaccine or regarding any other effect of vaccination on patients receiving the drug. Due to the fact that anakinra decreases the immune response to antigens in general, vaccine efficacy may be reduced in patients receiving anakinra.

Dosage regimen

The usual dosage is 100 mg subcutaneously once a day. Dose reduction to 100 mg subcutaneously every other day should be considered in patients with severe renal impairment, if these are treated in exceptional cases (see contraindications and precautions). No additional benefits of doses exceeding 100 mg daily have been seen.

Duration of treatment

In the pre-clinical and clinical studies the usual duration of therapy was 24 weeks. It is possible to extend therapy to 48 weeks in patients with satisfying remission after 24 weeks to maintain clinically evident improvements. Under continued therapy anakinra has been shown to slow progression of disease over a period of at least 12 month evidenced by X-ray studies or other clinical examinations. Some experience with 48 to 60 weeks (15 months) treatment duration has already been gained and no evidence has been seen regarding additional toxicity.

Possible future indications

Due to the specific mechanism of action of anakinra, a possible efficiency may be anticipated in patients with inflammatory joint diseases such as psoriatic arthritis, and spondylarthritis. Possibly, anakinra may even benefit patients with destructive osteoarthritis in inflammatory phases. Clinical studies have not been initiated so far regarding these diseases. Currently, the use of anakinra in these patients is therefore not recommended.

Anakinra may be effective in pediatric patients with juvenile rheumatoid arthritis (JRA), also known as Juvenile Idiopathic Arthritis (JIA) or Still's Disease.^[8]

A 2005 article published in Arthritis & Rheumatism reported rapid improvement in four patients with Adult-Onset Still's Disease who were treated with Anakinra.^[9] Authors of a 2012 review article published in the International Journal of Inflammation concluded that "a growing number of evidences supports the utilisation of anakinra in Adult-Onset Still's Disease".^[10]

On April 12, 2007 an article in the New England Journal of Medicine discussed the possibility of using anakinra for treatment of type 2 diabetes.^[11] A few studies have looked at the effectiveness of anakinra in some familial periodic fever syndromes.

On May 2, 2008 an article in the review Science discussed the possibility of using anakinra for treatment of asbestosis. "Since Anakinra (IL-1ra) is efficiently used in the clinical treatment of autoinflammatory syndromes as well as gout patients, the present study suggests a potential use of Anakinra in order to slow down progression of asbestosis, silicosis and possibly other inflammatory lung diseases." ^[12] There is anecdotal evidence suggesting that IL-1 inhibitors may indeed be effective in gouty arthritis,and this approach is currently under study.^[13]

In 2008, an article in the European Journal of Pediatrics discussed treatment of colchicine-resistant Familial Mediterranean Fever with anakinra.^[14]

In July 2012, the University of Manchester scientists have demonstrated the effectiveness of the drug Anakinra (IL-1Ra), which is already used for rheumatoid arthritis in experimental studies of stroke: MRI scans revealed that the rats that were given IL-1Ra (Anakinra) up to three hours after the stroke, had only about half the brain damage of the placebo group. (http://medicalxpress.com/news/2012-07-treatments-reality.html)

On July 23, 2012 an article in the journal Annals of Neurology reported anakinra may be useful in epilepsy. The article stated that "anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown." (http://onlinelibrary.wiley.com/doi/10.1002/ana.23567/abstract)

The Nijmegen ME/CFS centre is starting a RCT to study the effects of Anakinra treatment in 46 female ME/CFS patients.

References

External links

• Kineret homepage
• http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/tumorrisiko.html (on the risk of cancerogenity (in German))
• http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/ausblicke-moegliche-zukuenftige-anwendungen-von-anakinra-kineret.html (same site on future indications)
• http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/anakinra-kineret-in-der-kinderrheumatologie.html (same site on possible pediatric indications)