Canakinumab Research Articles

IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab

Background and aimShort-term mortality in alcohol-related hepatitis (AH) is high and no current therapy results in durable benefit. A role for IL-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. MethodsParticipants with biopsy-confirmed AH and discriminant function ≥32 but MELD ≤27 were randomly allocated 1:1 to receive either CAN 3mg/kg or placebo (PBO). Liver biopsies were taken before, and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analysed by modified Intention-To-Treat (mITT). ResultsFifty-seven participants were randomised: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data was evaluable from 48 participants. In CAN-treated participants, 14/24 (58%) demonstrated histological improvement compared to 10/24 (42%) in the PBO group (p=0.25). There was no improvement in prognostic scores of liver function. Four of the 55 participants (7%) died within 90 days; 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post-hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (p=0.04). ConclusionCAN therapy in severe AH participants with MELD≤27 did not alter biochemical or clinical outcomes compared to PBO. Non-significant histological improvements did not translate into clinical benefit.

Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

Efficacy of canakinumab in patients with Still's disease across different lines of biologic therapy: real-life data from the International AIDA Network Registry for Still's Disease.

The effectiveness of canakinumab may change according to the different times it is used after Still's disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment. Patients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still's disease. Seventy-seven (51 females and 26 males) patients with Still's disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent. No statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response (p =0.62), partial response (p =0.61), treatment failure (p >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy (p =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use (p =0.34), daily glucocorticoid dosage (p =0.47), or concomitant methotrexate dosage (p =0.43) at the last assessment during CAN treatment. Canakinumab has proved to be effective in patients with Still's disease, regardless of its line of biologic treatment.

LBA4 CANOPY-N: A phase II study of canakinumab (CAN) or pembrolizumab (PEM), alone or in combination, as neoadjuvant therapy in patients (pts) with resectable stage Ib–IIIa non-small cell lung cancer (NSCLC)

CAN is a monoclonal antibody that inhibits proinflammatory IL-1β–driven pathways that may play a role in tumor growth in early-stage NSCLC. Preclinical data suggest targeting IL-1β could decrease inflammation and immunosuppression in the tumor microenvironment (TME).

LBA49 CANOPY-A: Phase III study of canakinumab (CAN) as adjuvant therapy in patients (pts) with completely resected non-small cell lung cancer (NSCLC)

CAN is a high-affinity anti-IL–1β antibody that was superior to placebo (PBO) at preventing cardiac adverse events (AEs) in the CANTOS study. In an exploratory analysis of CANTOS, CAN was associated with significant reductions in NSCLC incidence and mortality, suggesting that CAN inhibition of the IL-1β pathway may have reduced the rate of progression, invasiveness, and metastatic spread of lung cancers undiagnosed at trial entry. Here, we show efficacy and safety of CAN as adjuvant therapy vs PBO in pts with completely resected NSCLC.

OP0042 LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF) - INTERIM ANALYSIS OF THE RELIANCE REGISTRY

BackgroundFamilial Mediterranean Fever (FMF) is a chronic disease characterized by recurrent attacks of fever as well as serositis and bears the risk of serious complications (e. g. amyloidosis). Treatment of FMF according to EULAR aims to control acute attacks and subclinical inflammation as well as to improve patient´s quality of life1. Clinical data indicate that the inhibition of interleukin-1β with canakinumab (CAN) is effective in controlling and preventing flares in FMF patients2.ObjectivesThe present study explores the long-term efficacy and safety of canakinumab in routine clinical practice conditions in pediatric (age ≥2 years) and adult FMF patients.MethodsRELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a 3-year follow-up period. Patients with clinically confirmed FMF diagnosis who routinely receive canakinumab are enrolled in order to evaluate effectiveness and safety of canakinumab. Disease activity and remission by physicians´ assessment, disease activity, fatigue and impact on social life by patients’ assessment, inflammatory markers and AIDAI (Auto-Inflammatory Diseases Activity Index) score were recorded at baseline and assessed at 6-monthly intervals within the 3-year observation period of the study.ResultsThis interim analysis of FMF patients (N=74) enrolled by December 2021 includes baseline as well as 6- to 24-month data. Mean age in this cohort was 25 years (2−61 years) and the proportion of female patients was 51 % (N=38). At baseline, median duration of prior CAN treatment was 1.0 years (0−6 years).At month 24, physician ratings report around 63% of patients in disease remission and patient-reported disease activity (mean PPA) decreased from moderate (3.0) to low (2.6) during the observation period. Other disease activity parameters also decreased (Table 1). A total of 18 serious adverse events were reported, of which 2 (1 case of tonsillectomy and 1 case of tachycardia) were classified as drug - related.Table 1.Baseline characteristics and 4th interim analysis data of patients with FMFBaseline12 months24 monthsNumber of patients, N744624Number (%) of patients with days absent from work/school during last 6 months6 (8)11 (24)9 (38)Number (%) of patients in disease remission (physician assessment)22 (45)23 (72)12 (63)Patient’s assessment of current disease activity; 0–10, median (min; max)2.0 (0; 10)2.0 (0; 7)2.0 (0; 10)Patient’s assessment of current fatigue; 0–10, median (min; max)5.0 (0; 10)2.0 (0; 10)4.0 (0; 10)Number (%) of patients without impairment of social life by the disease27 (50)28 (80)8 (67)CRP (mg/dl) | SAA (mg/dl) | ESR (mm/h); median0.2 | 0.7 | 8.00.2 | 0.5 | 4.00.2 | 0.7 | 6.0Number (%) of patients with disease-related symptomsprior to inclusion into the study | at baseline12 months24 monthsFever68 (93) | 14 (29)8 (25)3 (16)Abdominal pain67 (92) | 20 (41)10 (31)4 (21)Thoracic pain45 (62) | 5 (10)3 (9)1 (5)Headache34 (47) | 11 (22)7 (22)5 (26)Myalgia23 (32) | 6 (12)4 (13)2 (11)Arthralgia/arthritis39 (54) | 16 (33)9 (28)5 (26)Dermal symptoms (urticarial, maculopapulose)15 (21) | 5 (10)3 (9)0 (0)SAENumber of eventsIncidence rate# per 100 patient yearsAll types of SAE1814.03SADR21.56Incidence rate = number of events * 36,525 / sum of observation days (=46,848).CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; n. a., not annotated; SAA, serum amyloid A; SADR, serious adverse drug reaction; SAE, serious adverse events.ConclusionInterim data of FMF patients from the RELIANCE study, the longest running real-life canakinumab registry confirm efficacy and safety of long-term canakinumab treatment.

Abstracts from the ISSAID 2021 Periodic Congress

Abstracts from the ISSAID 2021 Periodic Congress

The feasibility of withdrawing canakinumab in paediatric colchicine-resistant familial Mediterranean fever patients.

To determine the feasibility of withdrawing canakinumab (CAN) in a large cohort of paediatric patients with colchicine-resistant familial Mediterranean fever (crFMF). This retrospective observational cohort study included paediatric crFMF patients that received CAN treatment for ≥6 months. Patient data were recorded at treatment onset (baseline), and at 1, 3, 6, 12, 18, and 24 months after initiation of treatment. The study included 114 patients that were followed-up for 2736 person-months. During the 24-month follow-up period, the CAN dose interval remained unchanged in 44 patients. The dose interval was extended in 58 patients within a median 6 months (range: 3-18 months) of treatment initiation. In all, 4 of these 58 patients had a new attack of crFMF after the dose interval was extended. CAN was withdrawn in 12 patients (in 5 at month 12 month and in 7 at month 18), of which 2 had a new attack within 3 months of withdrawal. In these 2 patients CAN was re-initiated with a dose interval of 8 weeks. The remaining 10 patients in which CAN was withdrawn did not report any symptoms throughout the remainder of the 24-month follow-up period. The median attack-free period in those treated with CAN was 669 d (95% CI: 644-696). The present findings show that it may be feasible to withdraw CAN or extend its dose interval in paediatric crFMF patients. Based on the present findings, we think that as the quantity of real-life data increases, standard CAN protocols may be developed.

1194MO Canakinumab (CAN) + docetaxel (DTX) for the second- or third-line (2/3L) treatment of advanced non-small cell lung cancer (NSCLC): CANOPY-2 phase III results

In patients (pts) with advanced NSCLC who progress after platinum-doublet chemotherapy (PDC) and immune checkpoint inhibitor therapy, treatment options are limited; DTX is most commonly used in this setting. Preclinical data with CAN, a selective interleukin-1β inhibitor, plus DTX showed greater tumor growth reduction than DTX alone and decreased immunosuppressive cell infiltration in the tumor microenvironment.

Canakinumab

Canakinumab

POS1310 CANAKINUMAB IS A RESCUE TREATMENT FOR MACROPHAGE ACTIVATION SYNDROME IN PATIENTS WITH SYSTEMIC ONSET JUVENILE IDIOPATHIC ARTHRITIS: SINGLE CENTER EXPERIENCE

Background:Macrophage activation syndrome (MAS) is a severe life-threatening complication of the systemic-onset juvenile idiopathic arthritis (soJIA). The treatment options included high-dose of the corticosteroids (CS), cyclosporine A (CsA), intravenous immunoglobulin (IVIG) and biologics, predominantly IL-1 antagonist – anakinra. In Russia anakinra has not approved yet, so canakinumab (CAN) is a single anti-IL-1 option, available in Russia.Objectives:To evaluate the safety and efficacy of canakinumab in patients with severe MAS in soJIA, who failed the previous treatment.Methods:In the retrospective case series study were included 9 soJIA patients (4 boys and 5 girls) with severe MAS, resistant to combination of high-dose CS, IVIG and CsA.Results:All patients had a MAS during the onset of JIA. The main clinical features of disease onset included: fever 9 (100%), active arthritis 5 (56%), pleuritis 7 (78%), pericarditis – 5 (56%), peritonitis 2 (22%), rash 6 (67%), hepatomegaly 9 (100%), splenomegaly 9 (100%), lymphadenopathy 7 (78%), bleeding 4 (44%), CNS involvement – 3 (33%). Initial treatment included high doses CS 8 (89%), oral CS 9 (100%), methotrexate 5 (56%), tocilizumab 4 (44%), and canakinumab 5 (56%), CsA 4 (44%), IVIG 6 (67%). TCZ was discontinued due to infusion reaction (n=2), TCZ inefficacy (n=3) and presence of MAS in all patients (n=5). In children whom TCZ was switched on CAN we used the standard dose of CAN 4 mg/kg, but if MAS occurred on the CAN we temporally increased the doses since 8 to 25 mg/kg (300 mg). In all cases MAS episodes were successfully resolved during CAN treatment. In 5 (56%) MAS had repeated course during the CAN which lead to temporally increasing the doses of CAN (pt3, pt5, pt8, pt 9) or required to increase immunosupression with abatacept or tofacitinib. Three patients with repeated MAS developed interstitial lung disease (ILD). Two patients who successfully resolved MAS after CAN had relapses of arthritis and switched CAN to TCZ.IDSexJIA onset, yRepeated MASInitial biologicMAS on CANExperience of increased CAN dosesOutcomesCurrent treatment1F7.7NTCZNNRemissionCAN2F11.5NCANNNsoJIA flare, ILDTCZ3F7.9YCANYYRemissionCAN4F3.4NTCZNYRemission, ILDCAN, CS, MMF5M0.8YTCZYYRemission, ILDCAN, abatacept, CsA, CS6M14.2YCANNNRemissionTCZ7M1.1YCANNNRemissionN8М1.3NCANYYRemissionCAN every 12 months9F9.1NTCZYYMinimal disease activityCAN, tofacitinibFootnotes: CAN – canakinumab, CS – corticosteroids, CsA – cyclosporine A, ID – identification, ILD – interstitial lung disease, F – females, M – males, N- no, TCZ – tocilizumab, Y – yes.Conclusion:Canakinumab is an effective rescue treatment either soJIA either MAS. In patients with MAS developed on CAN required the temporal increasing of the doses.Funding statement:This work was supported by the Russian Foundation for Basic Research (grant № 18-515-57001).Disclosure of Interests:None declared

POS1379 LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF) - INTERIM ANALYSIS OF THE RELIANCE REGISTRY

Background:Familial Mediterranean Fever (FMF) is characterized by recurrent attacks of fever and serositis as well as elevated inflammatory markers. FMF treatment goals according to EULAR are to control acute attacks and subclinical inflammation and to improve patients´ quality of life1. In a phase 3 pivotal study (CLUSTER study), FMF patients treated with the interleukin-1β inhibitor canakinumab met all these goals2.Objectives:The present study explores the long-term efficacy and safety of canakinumab (CAN) in routine clinical practice in pediatric (age ≥2 years) and adult FMF patients.Methods:RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a three-year follow-up period. Patients with clinically confirmed diagnosis of FMF who routinely receive CAN were enrolled in order to evaluate effectiveness and safety of CAN under standard clinical practice conditions. Disease activity and remission by physicians´ assessment, disease activity, fatigue and impact on social life by patients’ assessment, inflammatory markers and AIDAI (Auto-Inflammatory Diseases Activity Index) score were recorded at baseline and were assessed at 6-monthly intervals within the three-year observation period of the study.Results:This interim analysis of FMF patients (N=54) enrolled by December 2020 includes baseline as well as 6-, 12- and 18-month data. Mean age in this cohort was 25 years (4−56 years) and the proportion of female patients was 46 % (N=25). At baseline, median duration of prior CAN treatment was 2.0 years (0−6 years).While physician ratings report around 62% of patients in disease remission, 52% with absent and 34% with mild-moderate disease activity, patient-reported disease activity decreased from moderate (PPA 3.0) to low (PPA 2.0) during the observation period. A decrease was observed regarding disease activity parameters, in particular in patients without prior CAN therapy (Table 1, Figure 1). A total of 11 serious adverse events was reported, of which one case of tonsillectomy was classified as drug-related.Conclusion:Interim data of FMF patients from the RELIANCE study, the longest running real-life CAN registry, confirm efficacy and safety of long-term CAN treatment.

Canakinumab

Canakinumab

Experiences with IL-1 blockade in systemic juvenile idiopathic arthritis \u2013 data from the German AID-registry

BackgroundSystemic juvenile idiopathic arthritis (sJIA) is a complex disease with dysregulation of the innate immune system driven by cytokines. A major role is ascribed to interleukin-1β (IL-1β), supporting the autoinflammatory character of the disease and offering an effective blocking mechanism for treatment. Here we present clinical practice data from the German AID-registry for patients treated with IL-1 inhibition (IL-1i).MethodsIn 2009 a clinical and research consortium (AID-Net) was established, including an online AID-registry. Patients with documented sJIA diagnosis were identified. Data for this retrospective IL-1i study were recorded by 17 centers. Response to treatment was evaluated according to Wallace criteria and additionally by an own classifying clinical response system.ResultsIn 6 years, 202 patients with confirmed sJIA were recorded in the AID-registry. Out of these, 111 children received therapy with Anakinra (ANA) (n = 84, 39 f) and/or Canakinumab (CANA) (n = 27, 15 f) at a median age of 8.7 y (range 0.6–19.1). During the first 12 months 75/111 (ANA 55, CANA 20) patients were evaluated according to Wallace criteria (achievement of inactive disease 28/55 and 17/20, remission over 6 months under medication 13/55 and 7/20 cases). Over the whole period of time, clinical response was preserved in the majority of patients (ANA 54/80, CANA 20/27). Arthritis mostly persisted in polyarticular (PA) courses. During treatment with IL-1i concomitant medication could be tapered in about 15%. IL-1i was discontinued in 59/111 patients. 45 (15) adverse events (AE)s in ANA (CANA) treated patients (19.7 (26.6) AE/100 ANA (CANA) exposure years, 95%CI: 14.4–26.4 (14.9–43.9)) were reported.ConclusionIn a large cohort of sJIA patients from Germany, we can confirm an overall favorable clinical response to both available IL-1 blocking agents. IL-1i was well tolerated with acceptable safety and effectiveness in a real-life clinical setting.

Canakinumab

Canakinumab

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network.

Background:This study aims at describing the therapeutic outcome of patients carrying the R92Q variant in the TNFRSF1A gene treated with anakinra (ANA) or canakinumab (CAN) and identifying any factors predictive of complete response to IL-1 inhibition.Methods:Clinical data of patients treated with ANA or CAN for recurrent inflammatory attacks due to the presence of the R92Q variant were retrospectively collected and analysed.Results:Data about 20 treatment courses with IL-1 inhibitors (16 with ANA and 4 with CAN) from 19 patients were collected. Mean age at disease onset was 20.2 ± 14.8 years. In 5 cases (26%) the R92Q variant was found in a family member affected by recurrent fever. The therapeutic response was complete in 13(68%) and partial in 2 patients (11%); treatment failure was observed in 4 cases (21%). Median AIDAI decreased from 10 (interquartile range [IQR] = 28) to 0 (IQR = 1) at the 12-month follow-up visit (p < 0.001). Mean ESR and median CRP dropped respectively from 40.8 ± 24.8 to 9.1 ± 4.5 mm/h (p < 0.001) and from 3.0 (IQR = 1.9) to 0.3 (IQR = 0.3) mg/dl (p < 0.001) after 12 months of treatment. A steroid-sparing effect was observed from the third month of treatment (p < 0.01). Thirteen patients (65%) were still on treatment at the last follow-up visit (median duration of treatment 17 (IQR = 38) months). The presence of R92Q mutation in a symptomatic relative (p = 0.022), the relapsing remitting disease course (p < 0.001) and the presence of migratory erythematous skin rashes during fever attacks (p = 0.005) were associated with complete efficacy of IL-1 inhibitors.Conclusions:R92Q patients showed a favourable response to ANA and CAN, particularly when the mutation segregated in a family member and when a relapsing-remitting disease course or TNF-α receptor-associated periodic syndrome (TRAPS) typical skin rash were observed. In the subgroup of patients not taking advantage of IL-1 blockage different molecular mechanisms underlying the autoinflammatory picture are likely to exist.

Canakinumab

Canakinumab

Canakinumab

Canakinumab

Canakinumab

Canakinumab

Canakinumab

Canakinumab