Anakinra

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Anakinra
Anakinra
Structural formula

Existing structural data : PDB  1ilr , 1ilt , 1ira , 1irp , 2irt

Properties of human protein
Mass / length primary structure 153 aa; 17.26  kDa
Isoforms 4th
Identifier
Gene name IL1RN
External IDs
Drug information
ATC code L04 AC03
DrugBank DB00026
Drug class Immunosuppressants , interleukin inhibitors
Occurrence
Homology family IL-1 family
Parent taxon Euteleostomi

Anakinra is a human interleukin- 1 receptor antagonist (r-metHuIL-1ra) that is produced in Escherichia coli cells by recombinant DNA technology . Interleukin-1 (IL-1) is an inflammation- promoting messenger substance that occurs more frequently in patients with autoinflammatory , rheumatological diseases and belongs to the group of cytokines .

Clinical information

Application areas (indications)

The active ingredient is used in Europe for the treatment of rheumatoid arthritis (RA), cryopyrin-associated periodic syndrome (CAPS) and Still's syndrome including the infant form (Systemic Juvenile Idiopathic Arthritis, SJIA) and Still's syndrome in adults (Adult -Onset Still's Disease, AoSD) approved.

In rheumatoid arthritis, methotrexate can be combined with anakinra if adults do not respond adequately to methotrexate alone as part of therapy.

For CAPS, Kineret is used in patients eight months or older who weigh at least ten kilograms. To CAPS include the Familial autoinflammatory cold syndrome (FCAS, Eng. Familial cold autoinflammatory syndrome ) , the Muckle-Wells syndrome (MWS), and NOMID (Engl. Neonatal onset multisystem inflammatory disease) or CINCA (chronic infantile-neurological-cutan- articular syndrome) .

Concerning. of Still's syndrome, patients aged eight months and over and weighing at least ten kilograms, who have moderate to high disease activity with active systemic symptoms , can be treated with anakinra - as can patients in whom treatment with  nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids is impossible Improvement led. Kineret can also be used as a monotherapy or in combination with other anti-inflammatory drugs and basic therapeutic DMARDs ( disease-modifying anti-rheumatic drugs ) .

Dosage and method of administration

Treatment should be initiated and supervised by specialist physicians who have experience in the diagnosis and treatment of RA, CAPS, or Still syndrome. The dosage depends on the indication as well as the age and weight of the patient.

Use during pregnancy and breastfeeding

Anakinra has not been studied in pregnant women . The use of anakinra during pregnancy and in women of childbearing potential who does not use contraception is not recommended. It is not known whether anakinra or metabolites of anakinra are excreted in breast milk . A risk for the newborn or the unborn child cannot be excluded. The breast-feeding should be discontinued during treatment with anakinra.

Adverse effects (side effects)

In addition to data from placebo- controlled studies in patients with RA, data on adverse events in patients with CAPS and Still syndrome are available.

The frequency categories of undesirable side effects are defined according to the following convention : very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1 / 1,000, <1/100), rare (≥ 1 / 10,000, <1 / 1,000), very rare (<1 / 10,000) and not known ( frequency cannot be estimated from the available data).

The most common side effects listed are reactions at the injection site, headache or increased cholesterol level in the blood .

Common side effects are neutropenia ( treatment with Kineret should not be initiated in patients with neutropenia ( neutrophil count <1.5 × 10 9 / l)) and serious infections .

Occasional side effects are allergic reactions .

The incidence of severe side effects and infections with anakinra treatment has been shown in studies to be comparable to the incidence in the placebo group.

Pharmacodynamic properties

Mechanism of action

Anakinra neutralizes the biological activity of interleukin-1α (IL-1α) and interleukin-1β (IL-1β) by competitively inhibiting their binding to the interleukin-1 receptor type 1 (or IL1R1 for short). Interleukin-1 is a central proinflammatory cytokine that serves as a mediator of many cellular responses, including those essential in synovitis .

Pharmacodynamic effects

IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis. A correlation between plasma IL-1 concentration and disease activity has been reported. In vitro, anakinra inhibits the responses evoked by IL-1, including the induction of nitric oxide and the production of prostaglandin E 2 and / or collagenase by synovial cells, fibroblasts and chondrocytes .

In most patients with CAPS were spontaneous mutations in CIAS1 / NLRP3 - gene found. CIAS1 / NLRP3 codes for cryopyrin, a component of the inflammasome . The activated inflammasome leads to proteolytic maturation and secretion of IL-1β, which has a broad spectrum of activity, e.g. B. systemic inflammation . Untreated CAPS patients are characterized by elevated CRP -, SAA - and IL-6 - Serum levels of. Anakinra lowers the acute phase proteins - a decrease in IL-6 expression was also observed.

In addition to the various degrees of arthritis , Still syndrome is also characterized by systemic inflammatory features such as intermittent fever , rash , hepatosplenomegaly , serositis, and increased acute phase reactants, which in turn are caused by IL 1 activity. Systemically, IL-1 is known to cause the hypothalamus- controlled febrile response and promote hyperalgesia . The role of IL-1 in Still syndrome has been demonstrated ex vivo and in gene expression studies .

Clinical efficacy and safety in RA, CAPS, and Still syndrome

The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in 1,790 RA patients ≥ 18 years of age with varying degrees of disease severity.

The active ingredient is also effective and safe in CAPS patients with different degrees of disease severity. In a clinical study in 43 adult and pediatric patients (36 patients aged eight months to <18 years) with severe CAPS (NOMID / CINCA or MWS), all patients had a clinical response within ten days of starting treatment Anakinra was observed that lasted up to five years with continued drug administration.

Several published studies prove the safety and effectiveness in Still syndrome:

  • A randomized controlled trial of 24 SJIA patients treated with Kineret for up to one year.
  • A prospective , uncontrolled observational cohort study of 20 patients with newly onset SJIA. In this case, Kineret was used as the initial therapy after a lack of response to NSAIDs, but before treatment with DMARDs, systemic glucocorticoids, or other biological drugs. The treatment resulted in a normalization of body temperature in 18 out of 20 patients . After one year of follow-up, 18 of 20 patients showed a response according to the adapted ACR Pediatric 70 criteria , and 17 of 20 patients showed a response according to the adapted ACR Pediatric 90 criteria and an inactive disease status.
  • In a 24-week, multicenter, randomized, open study with 22 patients with a glucocorticoid-dependent, refractory AoSD, the safety and efficacy versus DMARD were described.

Efficacy as a first-line drug in monotherapy in juvenile Still syndrome

In a single-center, prospective study based on a treat-to-target strategy, 51 patients with newly onset systemic JIA and unsatisfactory response to non-steroidal anti-inflammatory drugs received Kineret as first-line therapy . Complete disease regression was seen in 55 percent of those affected in the first month of treatment and remission in 83 percent of patients after three months . During the three-year follow-up phase, the disease was inactive in 95 percent of the patients; after five years, 72 percent of the patients were in remission without further administration of the IL-1 receptor antagonist. This targeted therapy was shown to be highly effective, leading to early and persistent inactive disease in the majority of systemic JIA patients, greatly reducing glucocorticoid use, and preventing the development of long-term disease and therapy-related damage.

Other Information

Chemical and pharmaceutical information

Anakinra is the international non-proprietary name for the N 2– L – methionyl – 26–177 – interleukin – 1 – receptor antagonist . Anakinra is a terminal L- methionylated isoform of the human interleukin-1 receptor antagonist shortened to amino acids 26–177 and has a sequence length of 153 amino acids , the empirical formula is C 759 H 1186 N 208 O 232 S 10 and the molar mass is 17 , 26 kDa.

production

Anakinra is genetically engineered with the help of the microorganism Escherichia coli ; it was patented by Synergen in 1989.

Other diseases that can be treated with an IL-1 blockade

The use of anakinra in the following indications goes beyond the indications approved in Germany.

  • Diseases of bones, joints and muscles

Ankylosing spondylitis , erosive osteoarthritis of the hand, chronic recurrent multifocal osteomyelitis (CRMO, rheumatoid bone), traumatic knee injuries

  • Hereditary systemic autoinflammatory diseases

Familial Mediterranean Fever (FMF), TNF Receptor Associated Periodic Syndrome (TRAPS), Hyper-IgD Syndrome (HIDS), Pyogenic Arthritis, Pyoderma Gangrenosum and Acne ( PAPA Syndrome ), IL-1 Receptor Antagonist Deficiency (DIRA)

  • Systemic inflammatory diseases

Schnitzler syndrome, Behçet's disease , synovitis , acne , pustulosis, hyperostosis (SAPHO) syndrome, macrophage activation syndrome (MAS), periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA)

  • General inflammatory diseases

Gout , calcium pyrophosphate dihydrate (CPPD) crystal arthropathy (chondrocalcinosis), type 2 diabetes, hidradenitis suppurativa, pustular psoriasis, neutrophilic dermatoses, systolic heart failure, dry eyes ( sicca syndrome , keratoconjunctivitis sicca)

In several studies, anakinra is tested as an inhibitor in the upregulation of interleukin IL-1α and IL-1β as an indicator of the onset of a cytokine storm in order to suppress its consequence, a multi-organ failure. In addition to tocilizumab, the administration of the preparation is considered to be promising.

Trade names

The trade name is Kineret .

literature

Individual evidence

  1. ↑ a b Summary of the characteristics of anakinra (in German) (PDF; 757 kB), European Medicines Agency (EMA)
  2. ↑ a b c d e f g h sobi Germany: Summary of the characteristics of the drug Kineret. In: https://sobi-deutschland.de . Swedish Orphan Biovitrum AB, March 2019, accessed January 27, 2020 .
  3. ↑ a b c d e f EMA: Summary of Product Characteristics Kineret. In: https://www.ema.europa.eu/en . European Medicines Agency, August 4, 2009, accessed January 27, 2020 .
  4. ↑ EMA: Assessment Report Kineret. In: https://www.ema.europa.eu/en . European Medicines Agency, September 19, 2013, accessed January 27, 2020 .
  5. ↑ Michael H. Schiff, Gino DiVittorio, John Tesser, Roy Fleischmann, Joy Schechtman: The safety of anakinra in high-risk patients with active rheumatoid arthritis: Six-month observations of patients with comorbid conditions . In: Arthritis & Rheumatism . tape 50 , no. 6 , June 2004, ISSN  0004-3591 , p. 1752–1760 , doi : 10.1002 / art.20277 ( wiley.com [accessed February 7, 2020]).
  6. ↑ P. quarters, F. Allantaz, R. Cimaz, P. Pillet, C. Messiaen: A multicentre, randomized, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial) . In: Annals of the Rheumatic Diseases . tape 70 , no. 5 , May 1, 2011, ISSN  0003-4967 , p. 747-754 , doi : 10.1136 / ard.2010.134254 , PMID 21173013 , PMC 3070271 (free full text) - ( bmj.com [accessed February 7, 2020]).
  7. ↑ Sebastiaan J. Vastert, Wilco de Jager, Bo Jan Noordman, Dirk Holzinger, Wietse Kuis: Effectiveness of First-Line Treatment With Recombinant Interleukin-1 Receptor Antagonist in Steroid-Naive Patients With New-Onset Systemic Juvenile Idiopathic Arthritis: Results of a Prospective Cohort Study: First-Line Treatment With Recombinant IL-1Ra in New-Onset Systemic JIA . In: Arthritis & Rheumatology . tape 66 , no. 4 , April 2014, p. 1034-1043 , doi : 10.1002 / art.38296 ( wiley.com [accessed February 7, 2020]).
  8. ↑ Dan Nordström, Ann Knight, Reijo Luukkainen, Ronald van VOLLENHOVEN, Vappu Rantalaiho: Beneficial Effect of Interleukin 1 Inhibition with Anakinra in Adult-onset Still's Disease. An open, randomized, multicenter study . In: The Journal of Rheumatology . tape 39 , no. October 10 , 2012, ISSN  0315-162X , p. 2008–2011 , doi : 10.3899 / jrheum.111549 ( jrheum.org [accessed February 7, 2020]).
  9. ^ Nienke M. ter Haar, EH Pieter Dijkhuizen, Joost F. Swart, Annet Royen ‐ Kerkhof, Ayman el Idrissi: Treatment to Target Using Recombinant Interleukin ‐ 1 Receptor Antagonist as First ‐ Line Monotherapy in New ‐ Onset Systemic Juvenile Idiopathic Arthritis: Results From a five-year follow-up study . In: Arthritis & Rheumatology . tape 71 , no. 7 , July 2019, ISSN  2326-5191 , p. 1163–1173 , doi : 10.1002 / art.40865 , PMID 30848528 , PMC 6617757 (free full text).
  10. ↑ a b Entry on anakinra. In: Römpp Online . Georg Thieme Verlag, accessed on May 30, 2014.
  11. ↑ Dinarello C et al .: Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases . In: Nature Reviews Drug Discovery , 2012; 11: 633-652, doi: 10.1038 / nrd3800
  12. ↑ Andrew King, Andy Vail et al .: Anakinra in COVID-19: important considerations for clinical trials , The Lancet Rheumatology, May 21, 2020, doi: 10.1016 / S2665-9913 (20) 30160-0

Web links

  • COPE: IL1Ra COPE ( C ytokines & Cells O nline P athfinder E ncyclopedia)