Anakinra

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Anakinra
Anakinra.png
Names
Trade namesKineret
  • Recombinant human Interleukin-1 receptor antagonist protein; syn. N2-l-methionyl-interleukin 1 receptor antagonist (human isoform x reduced)
Clinical data
Main usesRheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, Still's disease, COVID-19[1]
Side effectsPain at site of injection, upper respiratory tract infection, headache, nausea, joint pain, fever[2]
Pregnancy
category
  • AU: B1
Routes of
use
Subcutaneous
External links
AHFS/Drugs.comMonograph
US NLMAnakinra
MedlinePlusa602001
Legal
License data
Legal status
Pharmacokinetics
Bioavailability95%
MetabolismPredominantly kidney
Elimination half-life4-6 hrs
Chemical and physical data
FormulaC759H1186N208O232S10
Molar mass17257.66 g·mol−1

Anakinra, sold under the brand name Kineret, is a medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease.[1] It is also used in people with COVID-19 who require oxygen therapy.[1] It is given by injection under the skin.[1]

Common side effects include pain at the site of injection, upper respiratory tract infection, headache, nausea, joint pain, and fever.[2] Other side effects may include anaphylaxis.[2] Safety in pregnancy is unclear.[2] It is a recombinant version of the interleukin 1 receptor antagonist protein which blocks the effects of interleukin 1.[1][2]

Anakinra was approved for medical use in the United States in 2001 and Europe in 2002.[2][1] In the United Kingdom a week of medication costs the NHS about £180 as of 2021.[5] This amount in the United States costs about 1,250 USD.[6]

Medical use

It is used as a second line treatment to manage symptoms of rheumatoid arthritis after treatment with a disease-modifying antirheumatic drug (DMARD) has failed.[3][4] It can be used in combination with some DMARDs.[3][4][7]

It is used to treat anyone from infants to adults with a cryopyrin-associated periodic syndrome, including neonatal-onset multisystem inflammatory disease.[3][4]

It also appears to be effective in treating macrophage activation syndrome (MAS), a form of cytokine storm.[8]

It is used off label to treat Schnitzler's syndrome.[9]

It has been shown to help treat secondary hemophagocytic lymphohistiocytosis (HLH) especially in pediatric patients with other rheumatological disorders. [10]

It was not tested in pregnant women, but appeared to be safe in animal studies.[4]

It should not be used in people who have active infections or latent tuberculosis, who have low white blood cells counts, or who are taking TNF inhibitors.[4]

COVID19

In December of 2021, the European Medicines Agency (EMA) approved the use of anakinra to include treatment of COVID-19 in adults with pneumonia who require supplemental oxygen and are at high risk of developing severe respiratory failure (inability of the lungs to work properly).[11] High risk is based on a soluble urokinase plasminogen activator receptor (suPAR) level of greater than 6 ng per ml.[11]

In people hospitalized with COVID-19 at increased risk for respiratory failure it showed improvement after treatment.[12][13] Anakinara is undergoing multiple trials to treat COVID-19.[14] In 2021 a review and meta-analysis of 9 studies involving 1,119 cases concluded that "Available evidence shows that treatment with anakinra reduces both the need for invasive mechanical ventilation and mortality risk of hospitalized non-intubated patients with COVID-19 without increasing the risk of adverse events."[15]

Dosage

In RA it is generally used at a dose of 100 mg per day.[1]

For COVID it is used at a dose of 100 mg per day for 10 days.[1]

In children it may be used at a dose of 1 to 2 mg/kg per day.[5]

Side effects

More than ten percent of people taking Anakinra have injection site reactions, headaches, and have increased levels of cholesterol in their blood.[3] Between one and ten percent of people have severe infections, decreased white blood cells, or decreased platelets.[3] It is unclear if taking Anakinra increases the risk of getting cancer; studies are complicated by the fact that people with rheumatoid arthritis are already at higher risk of getting cancer.[3][7]

Chemistry

Anakinra is a protein that differs from the sequence of Interleukin 1 receptor antagonist by one methionine added to its N-terminus; it also differs from the human protein in that it is not glycosylated, as it is manufactured in Escherichia coli.[4]

History

It was first approved in the US in 2001[4] and the European Union in March 2002.[3][1]

In June 2018 NHS England published a Clinical Commissioning Policy: Anakinra to treat periodic fevers and autoinflammatory disorders (all ages) allowing Anakinra to be commissioned as a first-line treatment for Schnitzler's syndrome and in cases where the first-line treatment is not effective for Familial Mediterranean fever, Hyper-IgD syndrome also known as Mevalonate kinase deficiency, and TNF receptor associated periodic syndrome (TRAPS),[16] and a Clinical Commissioning Policy: Anakinra/tocilizumab for the treatment of Adult-Onset Still's Disease refractory to second-line therapy (adults), allowing Anakinra to be commissioned for Adult-onset Still's disease "as a third line treatment where patients are refractory to steroid-sparing effect DMARDs".[17]

In December 2020, Anakinra was approved by the US Food and Drug Administration for the treatment of Deficiency of the interleukin-1–receptor antagonist (DIRA), a rare autoinflammatory disease of infancy.[18] In 2021, it was announced that the Ministry of Health of the Russian Federation had approved the use of Anakinra for the treatment of CAPS.[19]

In October 2021 NHS England published Clinical Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages, allowing Anakinra to be used in the treatment of haemophagocytic lymphohistiocytosis.[20]

In October 2021 it was reported that the Iranian company PersisGen had developed "a new formulation of Anakinra", named PerkinRA.[21] The results of a clinical trial of PerkinRA had previously been reported.[22] It is marketed by Swedish Orphan Biovitrum.[3]

Research

Anakinra effectively treated meningitis caused by a rare genetic mutation in the gene NALP3 in a 67-year-old man enrolled in the Undiagnosed Diseases Network.[23] Researchers at Johns Hopkins University announced in 2019 that anakinra given to pregnant mice with Zika virus had reduced fetal deaths and birth defects.[24] In November 2019, researchers at the University of Manchester reported that Anakinra might have a use in preventing breast cancer from spreading to the bones.[25][26]

In 2021, it was reported that Anakinra appeared to reduce the neuropathic pain experienced by patients undergoing chemotherapy with vincristine, saying that "that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy".[27][28]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Kineret". Archived from the original on 21 July 2021. Retrieved 14 January 2022.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 "DailyMed - KINERET- anakinra injection, solution". dailymed.nlm.nih.gov. Archived from the original on 23 July 2021. Retrieved 14 January 2022.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "UK Anakinra label". UK Electronic Medicines Compendium. 5 October 2017. Archived from the original on 23 March 2018. Retrieved 23 March 2018.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "US Anakinra label" (PDF). FDA. May 2016. Archived (PDF) from the original on 17 February 2017. Retrieved 23 March 2018. For label updates see FDA index page for BLA 103950 Archived 2021-03-22 at the Wayback Machine
  5. 5.0 5.1 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1148. ISBN 978-0857114105.
  6. "Kineret Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 10 December 2021. Retrieved 14 January 2022.
  7. 7.0 7.1 Singh JA, Hossain A, Tanjong Ghogomu E, Kotb A, Christensen R, Mudano AS, et al. (May 2016). "Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis". The Cochrane Database of Systematic Reviews (5): CD012183. doi:10.1002/14651858.CD012183. PMC 7068903. PMID 27175934.
  8. Canna SW, Behrens EM (April 2012). "Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes". Pediatric Clinics of North America. 59 (2): 329–44. doi:10.1016/j.pcl.2012.03.002. PMC 3368378. PMID 22560573.
  9. Gusdorf L, Lipsker D (August 2017). "Schnitzler Syndrome: a Review". Current Rheumatology Reports. 19 (8): 46. doi:10.1007/s11926-017-0673-5. PMID 28718061. S2CID 13780498.
  10. Eloseily E, Weiser P, Crayne C, Haines H, Mannion M, Stoll M, et al. (September 2019). "Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis". Arthritis & Rheumatology. 72 (2): 326–34. doi:10.1002/art.41103. PMID 31513353. S2CID 202563624.
  11. 11.0 11.1 "EMA recommends approval for use of Kineret in adults with COVID-19". Archived from the original on 7 January 2022. Retrieved 14 January 2022.
  12. Kyriazopoulou, Evdoxia; Poulakou, Garyfallia; Milionis, Haralampos; Metallidis, Simeon; Adamis, Georgios; Tsiakos, Konstantinos; Fragkou, Archontoula; Rapti, Aggeliki; Damoulari, Christina; Fantoni, Massimo; Kalomenidis, Ioannis (2021-09-03). "Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial". Nature Medicine. doi:10.1038/s41591-021-01499-z. ISSN 1078-8956. Archived from the original on 2021-10-20. Retrieved 2021-11-03.
  13. "Anakinra improved survival in hospitalized COVID-19 patients". www.mdedge.com. Archived from the original on 2021-11-05. Retrieved 2021-09-09.
  14. "Anakinra in COVID-19: important considerations for clinical trials". Press release. May 2020. Archived from the original on 16 December 2021. Retrieved 5 January 2021.
  15. Barkas, Fotios; Ntekouan, Sebastian Filippas; Kosmidou, Maria; Liberopoulos, Evangelos; Liontos, Angelos; Milionis, Haralampos (2021-05-17). "Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a systematic review and meta-analysis". Rheumatology: keab447. doi:10.1093/rheumatology/keab447. PMC 8194671. PMID 33999135.
  16. NHS England (29 June 2018). Clinical Commissioning Policy: Anakinra to treat periodic fevers and autoinflammatory disorders (all ages) (PDF). Archived (PDF) from the original on 9 July 2018. Retrieved 9 July 2018.
  17. NHS England (29 June 2018). Clinical Commissioning Policy: Anakinra/tocilizumab for the treatment of Adult-Onset Still's Disease refractory to second-line therapy (adults) (PDF). Archived from the original (PDF) on 13 July 2018. Retrieved 13 July 2018.
  18. Kaufman, Michelle B. (2 February 2021). "FDA Approves New Rituximab Biosimilar & Anakinra to Treat a Rare Disease". The Rheumatologist. Archived from the original on 12 February 2021. Retrieved 4 February 2021.
  19. "Kineret approved in Russia for the treatment of CAPS". The Pharma Letter. 17 February 2021. Archived from the original on 5 November 2021. Retrieved 18 February 2021.
  20. NHS England (October 2021). Clinical Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages (PDF). Archived from the original (PDF) on 13 October 2021. Retrieved 14 October 2021.
  21. "Iran unveils homemade medicine for treating rheumatoid arthritis in children". Pars Today. 28 October 2021. Archived from the original on 16 December 2021. Retrieved 3 November 2021.
  22. "A Phase III, randomized, two armed, parallel, double blinded, active controlled non-inferiority to evaluate the efficacy and safety of PerkinRA (manufactured by Persisgen Par CO) in comparison with Kineret (Reference product, manufactured by SOBi ) in systemic Juvenile idiopathic arthritis". en.irct.ir. IRCT. Archived from the original on 2021-12-16. Retrieved 2021-11-03.
  23. Kolata G (2019-01-07). "When the Illness Is a Mystery, Patients Turn to These Detectives". The New York Times. Archived from the original on 2019-01-09. Retrieved 2019-01-09.
  24. "Rheumatoid Arthritis Drug Diminishes Zika Birth Defects in Mice". Newsroom. Johns Hopkins Medicine. 6 May 2019. Archived from the original on 23 August 2019. Retrieved 5 September 2019.
  25. "Arthritis drugs could be repurposed to help prevent breast cancer spreading to the bone, study suggests". Press release. University of Manchester. 20 November 2019. Archived from the original on 30 September 2020. Retrieved 21 November 2019.
  26. Eyre R, Alférez DG, Santiago-Gómez A, Spence K, McConnell JC, Hart C, et al. (November 2019). "Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling". Nature Communications. 10 (1): 5016. Bibcode:2019NatCo..10.5016E. doi:10.1038/s41467-019-12807-0. PMC 6825219. PMID 31676788.
  27. Starobova H, Monteleone M, Adolphe C, Batoon L, Sandrock CJ, Tay B, et al. (May 2021). "Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release". The Journal of Experimental Medicine. 218 (5): e20201452. doi:10.1084/jem.20201452. PMC 7933984. PMID 33656514.{{cite journal}}: CS1 maint: PMC embargo expired (link)
  28. "Chemotherapy with fewer side effects may be on the way". University of Queensland. 15 March 2021. Archived from the original on 15 March 2021. Retrieved 15 March 2021.

External links

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