Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden
Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors
ATC code: L04AC03
Anakinra neutralises the biologic activity of interleukin-1α (IL-1α) and interleukin-1β (IL-1β) by competitively inhibiting their binding to interleukin-1 type I receptor (IL-1RI). Interleukin-1 (IL-1) is a pivotal pro-inflammatory cytokine mediating many cellular responses including those important in synovial inflammation.
IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis, and a correlation has been reported between IL-1 concentrations in the plasma and the activity of the disease. Anakinra inhibits responses elicited by IL-1 in vitro, including the induction of nitric oxide and prostaglandin E2 and/or collagenase production by synovial cells, fibroblasts, and chondrocytes.
In COVID-19 patients, progression from lower respiratory tract infection (LRTI) to severe respiratory failure (SRF) is dependent on the early release of IL-1α from virally infected lung epithelial cells, which in turn stimulates further cytokine production including IL-1β from alveolar macrophages.
Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with CAPS. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has a broad range of effects including systemic inflammation. Untreated CAPS patients are characterized by increased CRP, SAA and IL-6 relative to normal serum levels. Administration of Kineret results in a decrease in the acute phase reactants and a decrease in IL-6 expression level has been observed. Decreased acute phase protein levels are noted within the first weeks of treatment.
In patients with FMF, mutation of the MEFV gene encoding for pyrin is leading to malfunctioning and overproduction of interleukin-1β (IL-1β) in the FMF inflammasome. Untreated FMF is characterized by increased CRP and SAA. Administration of Kineret results in a decrease in acute phase reactants (e.g. CRP and SAA).
Still’s disease, in addition to various degrees of arthritis, is characterised by systemic inflammatory features such as spiking fever, skin rash, hepatosplenomegaly, serositis, and increased acute phase reactants driven by IL-1 activity. Systemically, IL-1 is known to cause the hypothalamic fever response and promote hyperalgesia. The role of IL-1 in the pathogenesis of Still’s disease has been demonstrated by ex vivo and gene expression studies.
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.
A clinical response to anakinra generally appeared within 2 weeks of initiation of treatment and was sustained with continued administration of anakinra. Maximal clinical response was generally seen within 12 weeks after starting treatment.
Combined anakinra and methotrexate treatment demonstrates a statistically and clinically significant reduction in the severity of the signs and symptoms of RA in patients who have had an inadequate response to methotrexate alone (38% vs. 22% responders as measured by ACR20 criteria). Significant improvements are seen in the pain, tender joint count, physical function (HAQ score), acute phase reactants and in the patient’s and physician’s global assessment.
X-ray examinations have been undertaken in one clinical study with anakinra. These have shown no deleterious effect on joint cartilage.
Clinical efficacy and safety in COVID-19 The safety and efficacy of Kineret was evaluated in patients with COVID-19 pneumonia ≥ 18 years of age with a risk of developing severe respiratory failure in a randomized double-blind placebo- controlled study. The patient population enrolled into the SAVE-MORE study was hospitalized with confirmed COVID-19 pneumonia (LRTI radiologically confirmed by chest X-ray or CT) and was considered to be at risk of developing SRF, determined by an elevation in suPAR (≥ 6 ng/ml). Patients had suPAR level ≥ 6 ng/ml measured by the suPARnostic Quick Triage kit. These patients had not yet progressed to SRF (i.e., exclusion criteria were: pO2/FiO2 ratio less than 150 mmHg or the requirement of mechanical ventilation, NIV, or ECMO). The majority of patients received low- or high-flow supplementary oxygen at screening (81.6%). The study enrolled 606 patients and efficacy analysis was performed in the intention-to-treat (ITT) population comprising of 594 patients of whom 189 patients were randomized to the placebo+SoC arm and 405 patients to the anakinra+SoC arm. The majority of the patients (91.4%) had severe COVID-19 pneumonia and 8.6 % of patients had moderate COVID-19 pneumonia at start of treatment. 85.9% of patients received dexamethasone. The mean (SD) duration of Kineret treatment was 8.4 (2.1) days. The primary endpoint of the study was the comparative 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment by Day 28. The 11-point WHO CPS provides a measure of illness severity across a range from 0 (not infected); 1-3 (mild disease), 4-5 (hospitalized – moderate disease), 6-9 (hospitalized – severe disease with increasing degrees of NIV, MV and ECMO) to 10 (dead). Of the patients randomised in the SAVE-MORE study 8.6% had a baseline WHO-CPS of 4; 84.7% had a baseline WHO-CPS of 5 and 6.7% had a baseline WHO-CPS of 6.
In patients treated with Kineret for up to 10 days a significant improvement of the clinical status according to the WHO-CPS was demonstrated by Day 28 compared to placebo (OR: 0.36 [95% CI 0.26 to 0.50] P<0.001). Improvement of the patients' clinical status was seen by Day 14. The treatment benefit of Kineret was supported by increase in the number of patients fully recovered and reduction in the number of patients who progressed to severe respiratory failure or death compared to placebo. No new safety signals or safety concerns were observed from the use of Kineret for treatment of COVID-19.
The safety and efficacy of Kineret have been demonstrated in CAPS patients with varying degrees of disease severity. In a clinical study including 43 adult and paediatric patients (36 patients aged 8 months to <18 years) with severe CAPS (NOMID/CINCA and MWS), a clinical response to anakinra was seen within 10 days after initiation of treatment in all patients and was sustained for up to 5 years with the continued administration of Kineret.
Kineret treatment significantly decreases the manifestations of CAPS, including a reduction in frequently occurring symptoms as fever, rash, joint pain, headache, fatigue, and eye redness. A rapid and sustained decrease in the levels of the inflammatory biomarkers; serum amyloid A (SAA), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and a normalization of inflammatory hematological changes are seen. In the severe form of CAPS, long-term treatment improves the systemic inflammatory organ manifestations of the eye, inner ear, and CNS. Hearing and visual acuity did not deteriorate further during anakinra treatment.
Analysis of treatment-emergent AEs classified by presence of CIAS1 mutation showed that there were no major differences between the CIAS1 and non-CIAS1 groups in overall AE reporting rates, 7.4 and 9.2, respectively. Similar rates were obtained for the groups on the SOC level, except for eye disorders with 55 AEs (rate 0.5), whereof 35 ocular hyperemia (which could also be a symptom of CAPS) in the CIAS1 group, and 4 AEs in the non-CIAS1 group (rate 0.1).
The safety and efficacy of Kineret in the treatment of patients with colchicine resistant FMF has been demonstrated in a randomized, double-blind, and placebo-controlled published study with a treatment period of 4 months. Primary efficacy outcomes were number of attacks per month, and number of patients with a mean of <1 attack per month. 25 patients with colchicine resistant FMF were enrolled; 12 randomized to receive Kineret and 13 to receive placebo. The mean number of attacks per patient per month was significantly lower in those receiving Kineret (1.7) compared to placebo (3.5). The number of patients with <1 attack per month was significantly higher in the Kineret group; 6 patients, compared to none in the placebo group.
Additional published data in patients with FMF, intolerant to colchicine or with colchicine resistant FMF, demonstrate that the clinical effect of Kineret is evident in both clinical symptoms of attacks as well as in reduced levels of inflammatory markers, such as CRP and SAA. In the published studies the safety profile of anakinra in patients with FMF was generally similar to that in other indications.
The efficacy and safety of Kineret for the treatment of Still’s disease (SJIA and AOSD) were evaluated in a randomized double-blind placebo-controlled multi-center study of 11 patients (aged 1 to 51 years) treated for 12 weeks, whereof 6 patients received Kineret. Kineret was efficacious in the treatment of Still’s disease as demonstrated by superiority to placebo in the primary endpoint ACR30 response with absence of fever at Week 2 (p-value = 0.0022). The demonstrated efficacy of Kineret in ACR30, ACR50, ACR70 and ACR90 responses at Week 2 were sustained throughout the 12 weeks treatment period. No relevant unexpected safety findings were observed in the study, and the results were in line with the known safety profile of Kineret.
The safety and efficacy have been demonstrated in a published randomized controlled study in 24 SJIA patients treated with Kineret for up to 1 year. After a 1-month blinded phase, 8 of 12 patients in the Kineret treated group were identified as modified ACRpedi30 responders compared to 1 of 12 in the placebo group. At the same time point, 7 of 12 in the Kineret treated group were classified as ACRpedi50 and 5 of 12 as ACRpedi70 responders compared to none in the placebo group. 16 patients completed the subsequent open label phase and among 7 responders at month 12, 6 had stopped glucocorticoid treatment and 5 of them had inactive disease.
In a published prospective, uncontrolled, observational cohort study of 20 patients with new-onset SJIA Kineret was used as initial therapy after failure to respond to NSAIDs, but before the use of DMARDs, systemic glucocorticoids, or other biologic agents. Treatment with Kineret resulted in normalization of body temperature in 18 of 20 patients. At 1 year follow-up, 18 of 20 patients showed at least an adapted ACRpedi 70 response, and 17 of 20 patients reached an adapted ACRpedi 90 response as well as inactive disease.
A non-interventional safety study in 306 paediatric patients with Still’s disease confirmed the long- term safety profile of Kineret without any new safety findings. Approximately half (46.1%) of the patients were continuously treated with Kineret for at least 1 year, and 28.1% for at least 2 years. The pattern and frequency of AEs, including SAEs, were in line with the known safety profile of Kineret. In general, the rate of AEs was highest during the first 6 months of treatment and considerably lower during later time periods. There were no deaths during Kineret treatment. Few patients discontinued due to AEs. The main reason for Kineret discontinuation was inefficacy however, the second most common reason for discontinuation was disease remission. Long-term treatment with Kineret in SJIA patients was well tolerated, with no overall increase in incidence rate of AEs, including Macrophage activation syndrome (MAS), over time.
The safety and efficacy of Kineret versus DMARD have been reported in a published 24-week multicenter, randomized, open-label study of 22 patients with glucocorticoid-dependent refractory AOSD. At Week 24, 6 of 12 patients on Kineret were in remission versus 2 of 10 patients on DMARDs. During an open-label extension phase, switching or add-on treatment with the comparator drug was possible if improvement did not occur within 24 weeks. 17 patients completed the open-label extension phase (Week 52), of which 7 of 14 Kineret-treated patients, and 2 of 3 patients on DMARDs, were in remission at that time point.
Additional published data in Still’s disease indicate that Kineret induces a rapid resolution of systemic features such as fever, rash, and elevation of acute phase reactants. Glucocorticoid doses can in many cases be reduced after initiation of Kineret therapy.
Overall, the efficacy and safety profile of Kineret is comparable in adult and paediatric patients with CAPS or Still’s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with Kineret in one or more subsets of the paediatric population in CAPS and RA (JIA) (see section 4.2 for information on paediatric use).
Kineret was studied in a single randomized, blinded multi-center study in 86 patients with polyarticular course JIA (ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Kineret for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for paediatric use in JIA.
See section 4.8.
The absolute bioavailability of anakinra after a 70 mg subcutaneous bolus injection in healthy subjects (n=11) is 95%. The absorption process is the rate-limiting factor for the disappearance of anakinra from the plasma after subcutaneous injection. In subjects with RA, maximum plasma concentrations of anakinra occurred at 3 to 7 hours after subcutaneous administration of anakinra at clinically relevant doses (1 to 2 mg/kg; n=18). The plasma concentration decreased with no discernible distribution phase and the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of anakinra was observed after daily subcutaneous doses for up to 24 weeks. Mean (SD) estimates of clearance (CL/F) and volume of distribution (Vd/F) by population analysis of data from two PK studies in 35 RA patients were 105(27) ml/min and 18.5(11) l, respectively. Human and animal data demonstrated that the kidney is the major organ responsible for elimination of anakinra. The clearance of anakinra in RA patients increased with increasing creatinine clearance.
The influence of demographic covariates on the pharmacokinetics of anakinra was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of anakinra at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated anakinra clearance increased with increasing creatinine clearance and body weight. Population pharmacokinetic analysis demonstrated that the mean plasma clearance value after subcutaneous bolus administration was approximately 14% higher in men than in women and approximately 10% higher in subjects <65 years than in subjects ≥65 years. However, after adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance. No dose adjustment is required based on age or gender.
In general the pharmacokinetics in CAPS patients is similar to that in RA patients. In CAPS patients approximate dose linearity with a slight tendency to higher than proportional increase has been noted. Pharmacokinetic data in children <4 years are lacking, but clinical experience is available from 8 months of age, and when started at the recommended daily dose of 1-2 mg/kg, no safety concerns have been identified. Pharmacokinetic data are lacking in older CAPS patients. Distribution into the cerebrospinal fluid has been demonstrated.
The median steady-state dose-normalized anakinra concentration in SJIA patients (aged 3 to 17 years) over 28 weeks was comparable to that observed in RA patients.
A study including 12 patients with hepatic dysfunction (Child-Pugh Class B) given a single 1mg/kg intravenous dose has been performed. Pharmacokinetic parameters were not substantially different from healthy volunteers, other than a decrease in clearance of approximately 30% in comparison with data from a study with healthy volunteers. A corresponding decrease in creatinine clearance was seen in the hepatic failure population. Accordingly, the decrease in clearance is most likely explained by a decrease in renal function in this population. These data support that no dose adjustment is required for patients with hepatic dysfunction of Child-Pugh Class B. See section 4.2.
The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance <30 ml/min), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal dialysis. These data support that no dose adjustment is needed for patients with mild renal impairment (CLcr 50 to 80 ml/minute). See section 4.2.
Anakinra had no observed effect on the fertility, early development, embryo-foetal development, or peri- and postnatal development in the rat at doses up to 100 times the human dose (2 mg/kg/day). No effects on embryo-foetal development in the rabbit were observed at doses 100 times the human dose.
In a standard battery of tests designed to identify hazards with respect to DNA, anakinra did not induce bacterial or mammalian cell gene mutations. Neither did anakinra increase the incidence of chromosomal abnormalities or micronuclei in bone marrow cells in mice. Long-term studies have not been performed to evaluate the carcinogenic potential of anakinra. Data from mice over expressing IL-1ra and IL-1ra mutant knock-out mice, did not indicate an increased risk of tumour development.
A formal toxicologic and toxicokinetic interaction study in rats revealed no evidence that Kineret alters the toxicologic or pharmacokinetic profile of methotrexate.
Juvenile rats treated at doses up to 100 times the human dose from day 7 postparturition up to adolescence did not show any signs of adverse effects of the treatment.
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