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This is an interim analysis of the long-term effectiveness and safety of canakinumab in the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) cohort of the RELIANCE non-interventional study.
Methods
From June 2018, the RELIANCE non-interventional study enrolled paediatric (aged ≥ 2 – < 18 years) and adult patients (aged ≥ 18 years) with TRAPS who were receiving canakinumab as part of their routine medical care. Physician- and patient-reported measures of disease activity, dosing patterns and safety were evaluated at baseline and every 6 months until the end-of-study visit.
Results
A total of 21 patients with TRAPS were enrolled by the analysis cut-off date of December 2022, of which 61.9% (13/21) were paediatric patients (< 18 years) and 66.7% (14/21) were female. All patients were pre-treated with canakinumab prior to enrolment (median duration of canakinumab treatment prior to study inclusion: 1.2 years). Disease activity, evaluated by physician-reported (physician’s global assessment, disease remission, C-reactive protein, serum amyloid A) and patient-reported (disease activity, fatigue, impact on social life, autoinflammatory disease activity index diary) measures, was generally well controlled throughout the study. At baseline, the majority of patients (71.4%) were receiving the recommended starting dose (SD) of canakinumab, with a more even distribution between the < SD, SD, and > SD dosing schedules observed from month 6. No serious adverse drug reactions were reported. Patients continued to receive vaccinations during long-term treatment with canakinumab. In total, 85.7% (18/21) of patients met the Eurofever/PRINTO classification criteria for TRAPS, 42.9% (9/21) with the presence of a confirmative TNFRSF1A genotype and 42.9% (9/21) without. In total, 14.3% (3/21) of patients did not meet the classification criteria.
Conclusions
Data from this interim analysis support the long-term effectiveness and safety of canakinumab for the treatment of TRAPS.
Prior presentation: These data have been presented at the International Society of Auto-Inflammatory Diseases (ISSAID; 15–18 May 2023, Toronto, Canada; [Abstract P120], [Abstract P121]), European Alliance of Associations for Rheumatology (EULAR; 31 May–3 June 2023; Milan, Italy; [Abstract POS1573], [Abstract POS1558]), Paediatric Rheumatology European Society (PReS; 28 September–1 October 2023; Rotterdam, The Netherlands; [Abstract PT005], [Abstract PT053], [Abstract P353]) and American College of Rheumatology (ACR; 10–15 November 2023, San Diego, California; [Abstract 0275], [Abstract 0276], [Abstract 1936]) congresses.
Key Summary Points
Why carry out this study?
Although canakinumab has demonstrated efficacy as a treatment option for tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in clinical studies, there is a need for additional data on the long-term effectiveness and safety of canakinumab for the treatment of TRAPS in a real-world setting.
The objective of this interim analysis was to assess the long-term effectiveness (control of disease activity) and safety of canakinumab in the TRAPS cohort of the RELIANCE non-interventional study.
What was learned from this study?
The data from this interim analysis of the RELIANCE non-interventional study support the effectiveness of canakinumab in controlling disease activity and its long-term safety profile in patients with TRAPS.
The results demonstrate the utilization of individual dose adjustments to achieve optimal disease control in a real-world setting.
Furthermore, this study highlights the need for further research into genotype–phenotype correlation in TRAPS.
Introduction
Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disease (AID) characterized by intermittent fever, myalgia, and systemic inflammation [1]. TRAPS is actually the second most commonly diagnosed autoinflammatory syndrome in Europe, following familial Mediterranean fever (FMF), with an estimated prevalence of about one per million [2‐7]. Although the onset and/or diagnosis of TRAPS can occur at any age, it typically manifests during early childhood, displaying a broad spectrum of mild to severe symptoms, including recurrent flares of fever, extensive recurring pain such as abdominal pain, chest pain or muscle pain in the extremities (myalgia), rash, arthralgia and serositis [1, 2, 5, 8]. Patients with uncontrolled disease activity and long-term systemic inflammation are at risk of developing life-threatening complications, including amyloid A (AA) amyloidosis [1, 5, 8].
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TRAPS is caused by mutations in the TNF receptor superfamily 1A (TNFRSF1A) gene that lead to the misfolding of the TNF receptor 1 (TNFR1) protein and the consequent production of downstream pro‐inflammatory cytokines [1, 9], such as interleukin-1β (IL-1β) [10]. To date, several TNFRSF1A variants have been described, each displaying differences in sequence, pathogenicity and prevalence [8, 9, 11, 12], with the most prevalent variants being R92Q and P46L [5, 6]. There are several variants with unknown pathogenicity (variants of unknown significance [VUS]) [13] making genetic analysis an important consideration for the diagnosis and treatment of TRAPS. Several classification criteria have been proposed for TNFRSF1A variants with the aim of establishing a correlation between genotype and phenotype to ensure accurate diagnosis, optimal patient management and treatment options [14‐16].
Until recently, the primary treatment for patients with TRAPS comprised non-steroidal anti-inflammatory drugs (NSAIDs) and short-term glucocorticoids for symptomatic relief during inflammatory flares [17]. However, recent advances have seen biologic treatments (IL-1 and TNF inhibition) recommended for the long-term management of the disease using a treat-to-target approach [17]. Treatment with etanercept, a TNF inhibitor, has led to a reduction in clinical symptoms in patients with TRAPS in non-randomized controlled trials and complete remission in 50% of patients (n = 4) in observational studies, however, it is not currently approved by the European Medicines Agency (EMA) for the treatment of TRAPS [18‐22]. Canakinumab is a fully human, anti-IL-1β monoclonal antibody that blocks IL-1β signalling by selectively binding to it and is the only IL-1 inhibitor approved by the EMA and the United States of America Food and Drug Administration (FDA) for the treatment of TRAPS [23, 24]. Canakinumab is approved for the treatment of TRAPS at a starting dose of 150 mg or 2 mg/kg (for patients weighing ≥ 7.5 kg and ≤ 40 kg) every 4 weeks (q4w), with an intensified dose recommended in patients with an inadequate clinical response [23]. The pivotal, randomized, controlled Phase 3 CLUSTER study demonstrated that canakinumab is an effective and well-tolerated treatment option for achieving rapid and sustained reduction in disease activity, together with improving health-related quality of life (HRQoL) [23‐27].
The available clinical data support the benefit of canakinumab for the treatment of TRAPS [25, 26], however, given the rare and life-long nature of the disease and its potential impact on patients’ HRQoL, there is a need for additional data on long-term outcomes and genotype–phenotype correlations in this patient group.
The RELIANCE non-interventional study provides data on the effectiveness (control of disease activity) and long-term safety outcomes of canakinumab in patients with cryopyrin-associated periodic syndrome (CAPS), FMF, TRAPS, or mevalonate kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). Here, we present the results from an interim analysis of the TRAPS cohort of the RELIANCE non-interventional study with the aim of assessing the control of disease activity, dosing patterns and long-term safety with canakinumab, in addition to genotype–phenotype correlations, in this patient population in a real-world setting.
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Methods
Study Design and Patients
The RELIANCE non-interventional study is an ongoing, non-interventional, open-label, multi-center, prospective study based in Germany, evaluating the effectiveness (control of disease activity), dosing regimens and long-term safety outcomes of canakinumab. The methods for the RELIANCE non-interventional study have been previously described [28].
This non-interventional study includes paediatric (aged ≥ 2 – < 18 years) and adult patients (aged ≥ 18 years) receiving canakinumab as part of their routine medical care for clinically confirmed CAPS, FMF, TRAPS or MKD/HIDS and currently involves 23 study sites across Germany. RELIANCE was initiated in June 2018 for patients with TRAPS, with the cut-off date for this interim analysis 01 December 2022. Baseline is defined as the date of study inclusion. This non-interventional study had an enrolment period of 4.5 years and a follow-up period of between 1.5 and 6 years for patients with TRAPS, with the study end planned for December 2024. Patients were clinically and/or genetically diagnosed prior to enrolling in the study. All patients were pre-treated with canakinumab prior to study enrolment. Treatment and evaluation decisions were determined by the treating physician according to the standard of care and local clinical practice and the choice of therapy was based on the given indication, in line with the canakinumab summary of product characteristics (SmPC) and patient medical need [23].
Exclusion criteria included canakinumab for AIDs other than CAPS, FMF, TRAPS or MKD/HIDS, biologics other than canakinumab at time of inclusion, participation in an interventional clinical trial that would have an impact on routine treatment and any contraindication as per the SmPC.
Ethical Approval
The study was conducted according to the principles of the Helsinki Declaration of 1964 and its later amendments. The Ethics Committee of the Medical Faculty and the University Hospital Tübingen, as the leading ethics committee (ethical vote number: 531/2016B02), and the local ethics committees of participating institutions: The Heidelberg Ethics Committee (ethical vote number: S-509/2018), The Ethics Committee of the Philipps University Marburg (ethical vote number: 46/17), The Ethics Committee of the Albert Ludwigs University Freiburg (ethical vote number: 457/19), the Ethics Committee of the Sächsische Landesärztekammer (for Leipzig; ethical vote number: EK-BR-36/18-1), and The Ethics Committee at the Faculty of Medicine of Heinrich Heine University Düsseldorf (ethical vote number: 2017034175), Germany, approved the protocol used in this non-interventional study. All patients or their legal guardians gave written informed consent.
Dose Regimen
The recommended starting dose (SD) of canakinumab was 150 mg or 2 mg per kg of body weight for patients weighing ≥ 7.5 kg and ≤ 40 kg (2 years and older) administered subcutaneously q4w. Less than SD (< SD) was defined as < 87.5% of SD and greater than SD (> SD) was defined as > 112.5% of SD.
Data Collection
Patient characteristics, disease course, previous and concomitant treatments, as well as canakinumab treatment (dose and interval) were documented at baseline. Adjustments to canakinumab dosing regimens and safety measures (adverse events [AEs], serious adverse events [SAEs], adverse drug reactions [ADRs] and serious adverse drug reactions [SADRs]) were recorded throughout the study. An ethics committee-approved observational plan (non-interventional study protocol) defined the visit and observation schedule; all disease activity measures were evaluated at baseline and every 6 months thereafter, until the end-of-study visit or premature discontinuation, aligned with the bi-annual pattern of care most patients received. Disease activity measures included Physician Global Assessment of disease activity (PGA), physician’s assessment of disease remission, inflammatory markers (C-reactive protein [CRP] and serum amyloid A [SAA]) and patient-reported outcomes (assessment of disease activity, fatigue, impact on social life, and autoinflammatory disease activity index diary [AIDAI]). Disease remission was determined by the treating physician according to their comprehensive assessment of disease activity parameters, including PGA, physical examination and laboratory tests.
Classification of TNFRSF1A Variants
TNFRSF1A variants were classified according to the American College of Medical Genetics and Genomics (ACMG) terminology, defining five classes of pathogenicity: pathogenic, likely pathogenic, VUS, likely benign, and benign [29] and as per the Infevers and ClinVar databases [12, 30].
Statistical Analysis
All patients who received at least one dose of canakinumab and for whom at least one follow-up documentation was available were considered in the evaluation. All variables collected during the non-interventional study were evaluated and analysed using descriptive methods. Any confidence intervals (CIs) specified are purely descriptive. No alpha adjustment was made for multiple comparisons due to the exploratory nature of the evaluation. Patient discontinuation was not considered during statistical analysis, owing to the small number of patients in each disease cohort.
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For AEs, incidence rates (IRs) per 100 patient-years (PY) were reported based on the included patient population and incidence densities (number of events/sum of observation days) according to Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term for AEs, SAEs, ADRs, and SADRs. Poisson regression models were used to obtain AE incidence rates over time between age groups.
Further analyses were performed to stratify patients into three subgroups based on the Eurofever/PRINTO classification criteria [16]: patients meeting the classification criteria with the presence of a confirmative TNFRSF1A genotype (Group A); patients meeting the classification criteria without a confirmative TNFRSF1A genotype (Group B) and patients with a clinical TRAPS diagnosis without meeting the classification criteria (Group C).
Results
Demographic and Disease Characteristics
This interim analysis of the RELIANCE non-interventional study included 21 patients with TRAPS enrolled between June 2018 and December 2022. The median age of patients was 15.0 years (range 3.0–43.0 years), with the majority (61.9%; 13/21) aged < 18 years. Overall, 66.7% (14/21) of patients were female and 95.2% (20/21) were Caucasian (Table 1). Diagnosis of TRAPS was determined by the treating physician. In total, 85.7% (18/21) of patients met the Eurofever/PRINTO classification criteria for TRAPS, 42.9% (9/21) with the presence of a confirmative TNFRSF1A genotype and 42.9% (9/21) without. In total, 14.3% (3/21) of patients did not meet the classification criteria [16] (Supplementary Material Table S1). All patients were pre-treated with canakinumab prior to enrolment, with a median duration of exposure to canakinumab of 1.2 years prior to study inclusion (Table 1). At baseline, the proportion of patients rated as having absent or mild/moderate disease activity by PGA was 35.3% (6/17) and 64.7% (11/17), respectively. Median CRP level (n = 19) was 0.2 mg/dl and median SAA level (n = 18) was 0.5 mg/dl, respectively (Table 1). The patient disposition for this interim analysis is detailed in Supplementary Material Table S2.
Table 1
Demographics and baseline characteristics for the pooled TRAPS patient cohort
All patients
(N = 21)
Diagnosis, n (%)
TRAPS
21 (100.0)
Age at baseline, years
Median (Q1–Q3)
15.0 (7.0–33.0)
Age groups, n (%)
< 18 years
13 (61.9)
≥ 18 years
8 (38.1)
Sex, n (%)
Female
14 (66.7)
Ethnicity, n (%)
Caucasian
20 (95.2)
Other
1 (4.8)
TNFRSF1A variant, n (%)
PVa
9 (42.9)
VUS
9 (42.9)
Absence of a TNFRSF1A variant
2 (9.5)
Unclassified TNFRSF1A variant
1 (4.8)
Duration of canakinumab treatment, years
Prior to study inclusion, Median (Q1–Q3)
1.2 (0.5–1.8)
PGA (N = 17)
Absent
6 (35.3)
Mild/moderate
11 (64.7)
Severe
0 (0.0)
Not measured
0 (0.0)
CRP, mg/dl (N = 19)
Median (Q1–Q3)
0.2 (0.0–2.3)
SAA, mg/dl (N = 18)
Median (Q1–Q3)
0.5 (0.4–2.8)
ESR, mm/h (N = 16)
Median (Q1–Q3)
7.0 (4.0–17.0)
Due to the real-world nature of the RELIANCE non-interventional study, execution of standard of care procedures may differ between each center, resulting in some variability in data collection, in addition to, delayed or missing data yet to collect. Missing values reported within a visit/time point do not refer to the full patient cohort, but to patients who have the visit documented but no data available for the specific outcome measure. The number of patients for each parameter is indicated in the left column if lower than the total number of patients included in this interim analysis, with all (%) values based on the total number of patients with available data
aIncludes patients with pathogenic and likely pathogenic variants. CRP C-reactive protein, ESR erythrocyte sedimentation rate, PGA Physician Global Assessment of disease activity, PV pathogenic variant, SAA serum amyloid A, TNFRS1A tumor necrosis factor receptor superfamily 1A, TRAPS tumor necrosis factor receptor-associated periodic syndrome, VUS variants of unknown significance
There was an equal distribution between patients with pathogenic variants and VUS (n = 9, 42.9%, each), with the most common VUS observed in this study cohort being R92Q, with seven (33.3%) patients carrying this variant (Table 2).
Table 2
Variant status of individual patients
Patient
#
TNFRSF1A
variant
ACMG classa
Age at disease onset, years
Age at baseline, years
Duration of canakinumab treatment prior to baseline, yearsb
Canakinumab dose
PGA
CRP/SAA/ESR
(mg/dl; mg/dl; mm/h)
AIDAI score
Baseline
Month 12
Baseline
Month 12
Baseline
Month 12
Baseline
Month 12
TNFRS1A pathogenic variant
1
C29Y
Pathogenic
4
17
0
150 mg
150 mg
Mild/moderate
Absent
0.6/1.8/16.0
0.2/0.5/6.0
–
–
2
D42E
Likely pathogenic
2
14
–
4.1 mg/kg
–
–
–
8.3/55.2/–
– /–/ –
0
–
3
T50M
Pathogenic
1
14
4
150 mg
150 mg
Absent
Absent
0.0/0.2/7.0
– /–/ –
18
0
4
C70R
Pathogenic
0.2
3
1
4.5 mg/kg
4.2 mg/kg
Absent
Absent
0.1/1.2/2.0
0.1 /–/ 10.0
–
–
5
T50M
Pathogenic
9
43
2
150 mg
–
Absent
–
8.2/40.7/77.0
– /–/ –
–
–
6
C55R
Pathogenic
16
29
0
150 mg
150 mg
Mild/moderate
Severe
5.4/11.4/81.0
17.0/137.0/–
0
23
7
I170N
Likely pathogenic
15
31
3
150 mg
150 mg
Absent
Absent
2.3/2.8/18.0
1.2/1.8/–
1
0
8
Y20C
Likely pathogenic
1
33
3
150 mg
150 mg
Absent
Absent
0.2/0.2/6.0
0.8/0.3/–
2
2
9
I170N
Likely pathogenic
14
37
2
150 mg
150 mg
Absent
Absent
1.4/0.8/18.0
0.2/0.4/–
–
3
TNFRS1A VUS
10
T89A
VUS
1
4
0
4.2 mg/kg
6.0 mg/kg
Mild/moderate
Mild/moderate
– /–/ –
– /–/ –
11
0
11
R92Q
VUS
2
7
2
4.8 mg/kg
4.5 mg/kg
Mild/moderate
Absent
0.0/0.5/4.0
0.0/0.2/4.0
12
0
12
R92Q
VUS
4
33
1
150 mg
150 mg
Mild/moderate
Mild/moderate
0.0/0.4/1.0
0.0/0.3/1.0
17
–
13
R92Q
VUS
8
10
1
1.9 mg/kg
1.8 mg/kg
Mild/moderate
Mild/moderate
0.0/0.4/4.0
0.0/0.4/6.0
–
–
14
R92Q
VUS
0.5
16
3
150 mg
–
–
–
– /–/ –
– /–/ –
–
–
15
R92Q
VUS
26
38
2
150 mg
150 mg
–
–
0.0/0.5/11.0
0.1/0.5/12.0
–
–
16
N116S
VUS
30
43
1
150 mg
150 mg
Mild/moderate
Absent
0.2/0.5/–
0.0/0.3/–
33
38
17
R92Q
VUS
5
10
1
2.0 mg/kg
–
Mild/moderate
–
0.3 /–/ 4.0
– /–/ –
–
–
18
R92Q
VUS
10
10
1
150 mg
225 mg
Mild/moderate
Mild/moderate
0.0/0.4/5.0
0.1/0.5/5.0
4
0
Patients with the clinical diagnosis of TRAPS and the absence of a TNFRSF1A variant
19
S350N
Unknown
2
3
0
7.2 mg/kg
–
Mild/moderate
–
3.3/85.0/7.0
– /–/ –
–
–
20
Wild type
–
3
15
1
150 mg
150 mg
Mild/moderate
Mild/moderate
0.0/0.1/–
0.0/0.1/2.0
3
–
21
Wild type
–
1
4
1
4.0 mg/kg
3.9 mg/kg
–
–
0.3/0.1/7.0
0.3/0.2/34.0
3
31
ACMG American College of Medical Genetics and Genomics, AIDAI autoinflammatory disease activity index diary, CRP C-reactive protein, ESR erythrocyte sedimentation rate, PGA Physician Global Assessment of disease activity, SAA serum amyloid A, TNFRS1A tumor necrosis factor receptor superfamily 1A, TRAPS tumor necrosis factor receptor-associated periodic syndrome, VUS variants of unknown significance
aACMG classification of mutations according to Infevers and ClinVar databases [12, 30]
bAll patients were pre-treated with canakinumab prior to enrolment into the RELIANCE non-interventional study
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Long-Term Influence of Canakinumab on Disease Activity
Physicians’ Assessment of Disease Activity
Due to the low patient number (N = 21), the results presented should be considered a description of observed trends. Disease activity, as measured by PGA, disease remission, CRP and SAA, were generally well controlled from baseline to month 24 (Fig. 1). Most patients were reported as having absent disease activity throughout the study, except at baseline, in which the majority of patients (64.7%) were reported as having mild/moderate disease activity. Severe disease activity was reported in 7.1% (1/21) of patients at month 12 (Fig. 1a). The proportion of patients in disease remission remained > 50.0% from baseline to month 24, increasing from 57.9% at baseline to 80.0% at month 12 and falling to 58.3% at month 24 (Fig. 1b). The majority of patients remained within the normal limits of inflammatory marker levels (CRP, ≤ 0.5 mg/dl; SAA, ≤ 1.0 mg/dl) from baseline to month 18, with a slight reduction observed at month 24 (Fig. 1c, d).
Fig. 1
Physician-reported outcome measures of disease activity. a PGA, b disease remission, c CRP and d SAA for the pooled TRAPS patient cohort. CRP C-reactive protein, PGA Physician Global Assessment of disease activity, SAA serum amyloid A, TRAPS tumor necrosis factor receptor-associated periodic syndrome
Patients’ assessment of disease activity remained low throughout the study, with a slight increase observed at month 24 (median visual analogue scale [VAS] score 3.0; Supplementary Material Fig. S1a). Similarly, patient’s assessment of fatigue remained low from baseline to month 24, with a slight increase observed at month 18 and 24 (median VAS scores 4.0 and 3.0, respectively; Supplementary Material Fig. S1b). The majority of patients reported that their social life was ‘not impaired’ or ‘somewhat impaired’ throughout the study, with one patient at baseline and month 24 reporting that their social life was ‘much impaired’ (Supplementary Material Fig. S1c). Median AIDAI scores remained below the threshold of active disease (score of 9) throughout the study, except at months 2, 4 and 7, at which median scores of 14.0, 10.0 and 10.0 were reported, respectively (Supplementary Material Fig. S1d).
Canakinumab Dosing
Patients had a median duration of exposure to canakinumab of 2.5 years during the study. At baseline, the majority of patients (71.4%) were receiving SD of canakinumab, with no patients receiving < SD and 28.6% of patients receiving > SD. From month 6, a more even distribution between the < SD, SD and > SD dosing schedules was observed, which was maintained throughout the study (Fig. 2).
Fig. 2
Canakinumab dosing category for the pooled TRAPS patient cohort. The SD of canakinumab was 150 mg or 2 mg per kg of body weight for patients weighing ≥ 7.5 kg and ≤ 40 kg administered subcutaneously every 4 weeks. Less than SD (< SD) was defined as < 87.5% of SD and greater than SD (> SD) was defined as > 112.5% of SD. SD recommended starting dose, TRAPS tumor necrosis factor receptor-associated periodic syndrome
Overall, a total of 97 AEs were reported by 81.0% (17/21) of patients (IR/100PY: 185.5) at the interim analysis cut-off (Table 3). A total of nine non-study-drug-related SAEs were reported by 4.8% (1/21) of patients (IR/100PY: 17.21; Table 3) throughout the study (Supplementary Material Table S3). The most common AEs reported were SARS-CoV-2 infection (11 events reported; IR/100PY: 21.03), pyrexia (seven events reported; IR/100PY: 13.38) and nasopharyngitis (six events reported; IR/100PY: 11.47; Table S4). Patients also reported pain in extremities (two events; IR/100PY: 3.82), abdominal pain (one event; IR.100PY: 1.91) and chest pain (one event; IR/100PY: 1.91) (Supplementary Material Table S4). No SADRs were reported.
Table 3
AEs, SAEs, and SADRs for the pooled TRAPS patient cohort
All patients
(N = 21), n (%)
No. of events
IR/100PY
Any AE
17 (81.0)
97
185.5
Any non-SAE
17 (81.0)
88
168.3
Any non-treatment-related, non-SAE
13 (61.9)
61
116.6
Any non-SADR
10 (47.6)
27
51.6
Any SAE
1 (4.8)
9
17.2
Any non-treatment-related SAE
1 (4.8)
9
17.2
Any SADR
0 (0.0)
0
0.0
Any upper respiratory tract infection
1 (4.8)
3
5.7
IR/100PY = number of events multiplied by 36,525/sum of observation days (= 19,104)
Patients continued to receive vaccinations during long-term treatment with canakinumab. Patients receiving vaccinations during the 6 months prior to a documented visit are presented in Table 4. Throughout the study, 52.4% (11/21) patients received SARS-CoV-2 vaccination, 19.0% (4/21) influenza vaccination, 4.8% (1/21) diphtheria-tetanus-pertussis (dTap) vaccination and 9.5% (2/21) tick-borne encephalitis (TBE) vaccination; no patients received live-attenuated vaccinations. Of the patients who received at least one vaccination, 9.5% (2/21) experienced an AE following immunization for influenza and TBE: both were non-serious.
Table 4
Patients receiving vaccinations during the 6 months prior to documented visit in the pooled TRAPS patient cohort
Throughout the study, patients reported experiencing disease flare triggers, including cold, stress, infections, vaccinations and/or menstrual cycle hormones. At month 24, 33.3% (4/12) of patients experienced a disease flare trigger (Supplementary Material Figure S2).
Effectiveness, Dosing, and Safety of Canakinumab in Subgroups Based on the Eurofever/PRINTO Classification Criteria
The outcomes assessing the effectiveness of canakinumab in patients meeting the Eurofever/PRINTO classification criteria with the presence of a confirmative TNFRSF1A genotype (Group A); patients meeting the classification criteria without a confirmative TNFRSF1A genotype (Group B) and patients with a clinical TRAPS diagnosis without meeting the classification criteria (Group C) are presented in Figs. 3 and 4.
Fig. 3
Physician-reported outcome measures of disease activity. a PGA, b disease remission, c CRP and d SAA for patients meeting the Eurofever/PRINTO classification criteria [16] with the presence of a confirmative TNFRSF1A genotype (Group A), without a confirmative TNFRSF1A genotype (Group B) and patients with a clinical TRAPS diagnosis without meeting the classification criteria (Group C). CRP C-reactive protein, PGA Physician Global Assessment of disease activity, SAA serum amyloid A, TNFRSF1A TNF receptor superfamily 1A, TRAPS tumor necrosis factor receptor-associated periodic syndrome
Canakinumab dosing category for patients meeting the Eurofever/PRINTO classification criteria [16] with the presence of a confirmative TNFRSF1A genotype (Group A), without a confirmative TNFRSF1A genotype (Group B) and patients with a clinical TRAPS diagnosis without meeting the classification criteria (Group C). The SD of canakinumab was 150 mg or 2 mg per kg of body weight for patients weighing ≥ 7.5 kg and ≤ 40 kg administered subcutaneously every 4 weeks. Less than SD (< SD) was defined as < 87.5% of SD and greater than SD (> SD) was defined as > 112.5% of SD. SD recommended starting dose, TNFRSF1A TNF receptor superfamily 1A, TRAPS tumor necrosis factor receptor-associated periodic syndrome
In general, a greater proportion of patients in Group A were reported to have absent disease activity (as measured by PGA), throughout the study when compared with Groups B and C. One patient with severe disease activity was reported in Group A at month 12 (Fig. 3a). In Group A, > 70% of patients remained in disease remission from baseline to month 24. In Group B, 42.9% of patients were reported to be in disease remission at baseline, rising to 71.4% at month 12, then dropping to 20.0% by month 24, while all patients in Group C remained in disease remission from month 6 to month 24 (Fig. 3b). The proportion of patients with CRP levels within the normal limits was lower in Group A compared with B and C throughout the study (Fig. 3c). The proportion of patients with SAA levels within the limit of normal was lower in Groups A and C at baseline, although this was not observed after month 6 (Fig. 3d).
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At baseline, the majority of patients in all groups were receiving SD of canakinumab (A: 77.8%, B: 66.7% and C: 66.7%). Patients in Group A moved towards a more even distribution between the SD, < SD and > SD dosing groups throughout the study, whereas patients in Group B moved towards an even distribution between the SD and > SD dosing group and all patients in Group C received < SD from month 12 through to month 24 (Fig. 4).
In general, the IR/100PY for any AEs was higher in patients in Group A when compared with patients in Groups B and C (210.8 vs.161.3 and 190.2, Supplementary Material Table S5).
Discussion
The results from this interim analysis of the RELIANCE non-interventional study support the effectiveness of canakinumab in controlling disease activity and its long-term safety profile in patients with TRAPS. This finding adds further evidence to the widely accepted view that anti-IL-1 therapy is considered the most appropriate maintenance treatment in patients with TRAPS, given the lack of long-term efficacy observed with conventional treatments [5, 14].
Adequate control of disease activity, including the normalization of subclinical inflammation between disease flares, is an important factor in reducing the risk of developing long-term complications, such as AA amyloidosis, in patients with TRAPS [31]. Physician-reported outcome measures indicated well-controlled disease activity throughout this study, including the majority of patients remaining in disease remission and within the normal limits of inflammatory marker (CRP and SAA) levels from month 6. Patient-reported outcome measures, including patients’ assessment of disease activity and AIDAI scores, demonstrated well-controlled disease activity over the course of the study, highlighting the importance of both physician- and patient-reported measures of disease monitoring. Data from the Eurofever registry also supported the effectiveness of canakinumab in controlling disease activity in patients with TRAPS and higher long-term efficacy rates compared with NSAID or glucocorticoid treatment were reported [14].
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The majority of patients were receiving SD of canakinumab at baseline, which shifted towards a relatively even proportion of patients receiving < SD, SD, or > SD over the course of the study. Although the reason for dose adjustment was not collected during the study, it may be attributed to a focus on treat-to-target strategies for patients with AIDs [17, 32], or influenced by physical changes in patients, such as weight variations, which may have required dosing adjustments. It should be noted that the SD of canakinumab should follow the recommended dosing according to the SmPC/local label. The reported dosing described here was chosen by the treating physicians according to the standard of care and local clinical practice.
The long-term use of canakinumab was generally well tolerated, with no patients experiencing a SADR over the course of the study. Comparing incidence rates of AEs from this study with other real-world studies of biologics in TRAPS, no new or unexpected safety concerns were observed [3, 20, 33]. Patients were receiving vaccinations (none of which were live attenuated) throughout treatment with canakinumab, and these were not associated with any serious, drug-related reactions, although vaccinations were observed as a possible trigger for disease flares in patients. Disease flares due to vaccinations have been previously reported and are a greater concern for paediatric patients, who are more regularly exposed to vaccinations [2].
As detailed in the methods section, patients were diagnosed prior to enrolling in this non-interventional study. When evaluating this cohort against the Eurofever/PRINTO classification criteria for TRAPS [16], 85.7% (18/21) of patients met the Eurofever/PRINTO classification criteria for TRAPS, 42.9% (9/21) with the presence of a confirmative TNFRSF1A genotype and 42.9% (9/21) without. In total, 14.3% (3/21) of patients did not meet the classification criteria. In general, patients responded to canakinumab treatment regardless of fulfilling the Eurofever/PRINTO criteria.
Chronic pain is defined as pain that persists or recurs for more than 3 months and is associated with a considerable degree of emotional distress or functional impairment [34]. Chronic pain is typically reported in patients with TRAPS [5, 35] and can lead to poor HRQoL [27, 36]. In this cohort, chronic pain symptoms such as abdominal pain, chest pain, and pain in extremities were reported, in line with those observed in other patients with TRAPS [8, 35]. As chronic pain is a key symptom across both chronic pain syndromes and TRAPS, further research into the association between these conditions is warranted.
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There was an even split of patients with pathogenic variants and VUS (n = 9, each), with R92Q variants being identified as the most common, consistent with the prevalence of TNFRSF1A variants in other literature [2, 6, 14]. Recent literature suggests that patients with R92Q variants can present with a clinical phenotype more similar to patients with systemic undifferentiated recurrent fever (SURF), compared with classical TRAPS, and should therefore not be diagnosed or managed in the same way [37]. Furthermore, previous studies have observed differences in treatment response, including a smaller proportion of patients with R92Q variants achieving a complete response to canakinumab treatment when compared with classical TRAPS [26, 37]. The results from our study showed that response to canakinumab is consistent with other reported variants [14, 37]. As SURF is caused by a combination of genetic, epigenetic, and environmental factors [37], it would be essential for patients to be investigated for these aforementioned factors to ensure an accurate diagnosis.
It was observed that in general, a greater proportion of patients fulfilling the Eurofever/PRINTO criteria without a confirmative TNFRSF1A variant (Group B) received > SD canakinumab. It has been seen in other studies that patients with VUS (described as the low-penetrance variants, R92Q and P46L) may require higher doses of anti-IL-1β therapy to achieve a response [14, 37], which could also be related to the observation in this study.
Limitations should be considered when evaluating the results from this real-world observational study. No screening for somatic mosaic variants was performed during genetic analysis. The study’s scope was constrained by a relatively small patient population due to the rare nature of TRAPS, which can make the observation of trends challenging. Furthermore, data were missing for a number of patients throughout the study, leading to under-reporting of some outcome measures. The uncontrolled nature of real-world data introduces a lack of control over confounding variables, warranting caution when interpreting the results as data are not comparable to those collected pre- and post-study enrolment. Hence, while valuable for gaining insights into distinct patient cohorts, the outcomes should be regarded as an evaluation of patient’s health status over time. It should be considered that inflammatory markers, such as CRP, were only measured at 6-monthly intervals, which may not have been during disease flares. In addition, patients who did not respond to canakinumab and treatment-naïve patients were not entered into the study, which may have introduced a skewed population towards selecting patients who have a positive response to canakinumab and limit the extrapolation of results to wider populations.
Conclusions
Results from this interim analysis of the RELIANCE non-interventional study support the effectiveness and long-term safety profile of canakinumab in controlling disease activity in patients with TRAPS. Furthermore, the results add further insight into the real-world management of TRAPS, including dosing schedules and the impact of TNFRSF1A variants.
Acknowledgements
The authors would like to thank the patients and acknowledge the study assistants/nurses, including Bianca Rippberger (Freiburg) and Zahra Gholizadeh (Dresden), for their support with this study. The authors would like to thank Dr Thomas Fischer of Winicker Norimed GmbH for statistical consulting and Dr Carmen Koch-Stork of KWMedipoint for data processing.
Medical writing and Editorial Assistance
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Vernice van der Merwe and Samuel McCracken of Ashfield MedComms, an Inizio Company, and funded by Novartis Pharma AG.
Patient and Public Involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of the research.
Declarations
Conflict of Interest
Norbert Blank has received grant/research support from Novartis and Sobi; is a consultant of Novartis, Sobi, Lilly, Pfizer, AbbVie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim and Roche. Catharina Schuetz has received study support from Novartis. Markus Hufnagel has received study support from Novartis. Gerd Horneff has received grant/research support from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer and Roche and contributed to speaker’s bureau with AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer and Roche. Michael Borte has received grant/research support from Pfizer and Shire. Tilmann Kallinich received research support by Novartis. Prasad T. Oommen has received study support from Novartis. Ales Janda has received study support from Novartis. Joerg Henes has received grant/research support from Novartis, Roche, Sobi and is a Consultant of Novartis and has contributed to a speaker’s bureau with AbbVie, Chugai, Novartis, Sobi, AstraZeneca, Pfizer, BMS, GSK, Roche, Janssen, Boehringer-Ingelheim, UCB. Julia Weber-Arden was an employee of Novartis at the time of data acquisition and drafting of the manuscript and is now an employee of Fresenius Kabi at the time of publication. Michael Stock is an employee of Novartis. Jasmin B. Kuemmerle-Deschner has received grant/research support and speakers’ fees from Novartis and Sobi and is a consultant of Novartis and Sobi.
Ethical Approval
The study was conducted according to the principles of the Helsinki Declaration of 1964 and its later amendments. The Ethics Committee of the Medical Faculty and the University Hospital Tübingen, as the leading ethics committee (ethical vote number: 531/2016B02), and the local ethics committees of participating institutions: The Heidelberg Ethics Committee (ethical vote number: S-509/2018), The Ethics Committee of the Philipps University Marburg (ethical vote number: 46/17), The Ethics Committee of the Albert Ludwigs University Freiburg (ethical vote number: 457/19), the Ethics Committee of the Sächsische Landesärztekammer (for Leipzig; ethical vote number: EK-BR-36/18-1), and The Ethics Committee at the Faculty of Medicine of Heinrich Heine University Düsseldorf (ethical vote number: 2017034175), Germany, approved the protocol used in this non-interventional study. All patients or their legal guardians gave written informed consent.
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Long-term Effectiveness and Safety of Canakinumab in Patients with TRAPS: Analysis of the RELIANCE Non-Interventional Study
Verfasst von
Norbert Blank
Catharina Schuetz
Markus Hufnagel
Gerd Horneff
Michael Borte
Tilmann Kallinich
Prasad T. Oommen
Ales Janda
Joerg Henes
Julia Weber-Arden
Michael Stock
Jasmin B. Kuemmerle-Deschner
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