FormalPara Key Summary Points

Why carry out this study?

Although canakinumab has demonstrated efficacy as a long-term treatment option for mevalonate kinase deficiency/hyperimmunoglobulin-D syndrome (MKD/HIDS) in clinical studies, there is a need for further data on the long-term safety and effectiveness of canakinumab for the treatment of MKD/HIDS in the real-world setting

The aim of this study was to assess the long-term safety and effectiveness (control of disease activity) of canakinumab in patients with MKD/HIDS in clinical routine through an interim analysis of data from the RELIANCE registry

What was learned from the study?

This interim analysis of data from the RELIANCE registry supports the long-term safety profile of canakinumab as well as its effectiveness at controlling disease activity over time in patients with MKD/HIDS under clinical routine conditions

The results add further insight into the types of MKD/HIDS genotypes and phenotypes observed in this patient population

The results also demonstrate the impact of individual dose adjustments on achieving improvement of disease control and health-related quality of life in the real-world setting

Introduction

Mevalonate kinase deficiency (MKD) encompasses a spectrum of very rare inherited autoinflammatory diseases (AIDs), including hyperimmunoglobulin-D syndrome (HIDS) and mevalonic aciduria (MVA), characterised by fever and systemic inflammation [1,2,3,4]. HIDS is a less severe phenotype, whereas MVA is a more severe phenotype with clinical features such as intrauterine growth retardation and neurological involvement [3, 5]. The estimated prevalence of MKD/HIDS in Germany is 6.2/1,000,000 (patients aged ≤ 16 years), with the estimated prevalence in Eastern and Central Europe 1.3/1,000,000 (patients aged 0–19 years). However, as many patients remain undiagnosed, these are likely to be underestimates [3, 6, 7]. MKD/HIDS is caused by recessive mutations in the mevalonate kinase (MVK) gene, leading to reduced MVK enzyme activity [8]. As an essential enzyme in the mevalonate pathway, the extent of MVK enzyme activity is associated with the severity of MKD [8]. Amongst other effects, this leads to the induction of the pyrin inflammasome (via uncontrolled activation of pyrin), resulting in caspase-1-mediated release of interleukin (IL)-1β, a strong inducer of fever and inflammation [1,2,3, 9]. The most frequently observed MVK mutations are V377I and I268T. To date, the number of genotype-phenotype associations described in patients with MKD/HIDS is very limited [2, 3, 10].

Most patients with MKD/HIDS develop symptoms at a young age (between 0 and 5 years of age), involving recurrent flares of fever, cervical lymphadenopathy, splenomegaly, abdominal pain with vomiting and diarrhoea, skin rash, myalgia, arthralgia and headaches, and patients with uncontrolled disease activity are at risk of developing long-term complications, including amyloid A (AA) amyloidosis, macrophage activation syndrome (MAS), joint contractures and abdominal adhesions [1,2,3, 11]. Disease flares often occur spontaneously in a repeating pattern (every 4–6 weeks), although events such as periods of stress, infections and vaccinations have been linked to disease flares [3, 8].

Current treatment recommendations for MKD/HIDS aim to support the early and rapid control of disease activity, prevention of disease and treatment-related damage, and the enabling of participation in daily activities and improvement of health-related quality of life (HRQoL) [12,13,14]. Until recently, the primary treatment for patients with MKD/HIDS comprised non-steroidal anti-inflammatory drugs (NSAIDs) and short-term glucocorticoids for symptomatic relief during inflammatory flares; however, biologic treatments (IL-1, IL-6 and tumour necrosis factor [TNF] inhibition) are now also recommended for the long-term management of the disease, using a treat-to-target approach [12,13,14,15].

Canakinumab is a fully human, anti-IL-1β monoclonal antibody that selectively binds to IL-1β, blocking its signalling [1, 16,17,18,19]. It is approved by the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) as a biologic therapy in adults, adolescents and children aged ≥ 2 years with MKD/HIDS at starting dose of 150 mg or 2 mg/kg (for patients weighing ≤ 40 kg) every 4 weeks (q4w), with an intensified dose recommended in patients with an inadequate clinical response [17]. The pivotal, randomised, controlled Phase 3 CLUSTER study demonstrated that canakinumab is an effective and well-tolerated long-term treatment option for achieving rapid and sustained reductions in disease activity alongside improving HRQoL in patients with MKD/HIDS. Clinical and real-world data support the benefit of canakinumab for the treatment of MKD/HIDS [1, 6, 16, 20]; however, given the life-long nature of the disease, and potential impact on patients’ quality of life, there is a need for further data on the long-term safety and effectiveness of canakinumab in these patients. Furthermore, the rare nature of MKD/HIDS necessitates further research in the therapy area, including factors such as the types of MVK mutations and how they impact disease phenotypes and the impact of long-term IL-1 inhibition on the vaccination of patients [21].

The RELIANCE registry provides data on the long-term safety outcomes and effectiveness (control of disease activity) of canakinumab in patients with cryopyrin-associated autoinflammatory syndromes (CAPS), familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS) or MKD/HIDS. Here, we present the patient-level results from an interim analysis of the MKD/HIDS cohort of the RELIANCE registry, aiming to assess the long-term safety and control of disease activity with canakinumab in this patient population.

Methods

Study Design and Patients

The RELIANCE registry is an on-going, non-interventional, open-label, multi-centre, prospective study based in Germany, evaluating the long-term safety outcomes, dosing regimens and effectiveness (control of disease activity) of canakinumab. The methods for the RELIANCE registry have been described previously [22].

The registry currently involves 23 study sites across Germany and includes paediatric (aged ≥ 2 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. The registry was initiated in June 2018 for patients with MKD/HIDS, with an enrolment period of 4.5 years and a follow-up period of between 1.5 years and 7 years, with study end planned for December 2024. For this interim analysis, a data cut-off of 27 February 2024, with a filter for data collected prior to 1 December 2022, was used. Patients were diagnosed prior to enrolling in the registry and a genetic diagnosis of MKD/HIDS was documented in all patients in this cohort. A retrospective analysis was performed to determine whether the patients in this cohort fulfilled the Eurofever/PRINTO clinical classification criteria for MKD [23] based on the variables collected during the registry. Patients that had a confirmatory MVK genotype, alongside at least one symptom among gastrointestinal symptoms, cervical lymphadenitis or aphthous stomatitis prior to inclusion, or during the study, were classified as fulfilling the criteria.

Treatment and evaluation decisions were determined by the treating physician according to standard of care and local clinical practice, and the choice of therapy was based on the given indication, in line with the summary of product characteristics (SmPC) and patient medical need [17].

Exclusion criteria included treatment with canakinumab for AIDs other than CAPS, FMF, TRAPS or MKD/HIDS, treatment with biologics other than canakinumab at time of inclusion and for the duration of the study, participation in an interventional clinical trial which would have an impact on routine treatment and any contraindication as per the SmPC.

The study was conducted according to the principles of the Declaration of Helsinki. The Ethics Committee of the Medical Faculty and the University Hospital Tübingen, as the leading ethics committee, and the local ethics committees of participating institutions, approved the protocol used in this registry. 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/kg of body weight for patients weighing ≤ 40 kg 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, non-autoinflammatory-related medical history, previous biologic therapy use and canakinumab treatment (dose and interval) were collected 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. All disease activity measures, including physician’s global assessment of disease activity (PGA), physician’s assessment of disease remission, inflammatory markers (C-reactive protein [CRP], serum amyloid A [SAA] and erythrocyte sedimentation rate [ESR]), and patient-reported outcomes (assessment of disease activity, fatigue, impacted social life, and autoinflammatory disease activity index diary [AIDAI]) were evaluated at baseline and every 6 months thereafter, until the end-of-study visit or premature discontinuation, in line with the bi-annual pattern of care most patients received. PGA was scored on a 5-point visual analogue scale (VAS), i.e., absent, minimal, mild, moderate or severe, comprising of the following key signs and symptoms: lymphadenopathy, aphtous ulcers and abdominal pain. Remission was determined by the treating physician according to their comprehensive assessment of disease activity parameters including PGA, physical examination and laboratory tests.

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 registry were evaluated and analysed using descriptive methods. Any confidence intervals specified are purely descriptive. Due to the exploratory nature of the evaluation, no alpha adjustment was made for multiple comparisons. Patient discontinuation was not considered during statistical analysis because of the small number of patients in each disease cohort.

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 terms for AEs, SAEs, ADRs and SADRs. Poisson regression models were used to obtain AE IRs over time between age groups.

Results

Demographic and Disease Characteristics

This interim analysis of the RELIANCE registry included data from a total of eight patients with MKD/HIDS enrolled between June 2018 and December 2022 (Table 1).

Table 1 Demographics and baseline characteristics for the pooled patient cohort
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The median (range) age of patients was 8.0 (2.0–39.0) years with five (62.5%) patients < 18 years old. In total, five (62.5%) patients were female and seven (87.5%) were white. All patients in this cohort had a genetically confirmed diagnosis of MKD/HIDS. The V377I mutation was present in six (75.0%) patients and I268T mutation in two (25.0%) patients. At baseline (study inclusion), the proportion of patients rated as having absent, mild/moderate or severe disease activity by PGA was 37.5%, 50.0% and 12.5%, respectively. Median CRP level was 0.2 mg/dl, median SAA level was 0.6 mg/dl and ESR was 10.0 mm/h (Table 1).

None of the patients discontinued the study by the cut-off date of this interim analysis. All patients in this cohort had prior exposure to canakinumab at baseline and five (n = 7; 71.4%) patients were previously treated with anakinra. Median duration of exposure to canakinumab was 3.8 years (including treatment prior to and during the study, Table 1).

Safety Profile of Long-Term Canakinumab

Overall, a total of 48 AEs were reported by 7 (87.5%) patients (IR/100PY: 218.1) at the interim analysis cut-off (Table 2). The most common AEs reported were pyrexia (six events reported; IR/100PY: 27.3) and nasopharyngitis (four events reported; IR/100PY: 18.2). One case of COVID-19 was reported (non-serious, IR/100PY: 4.5; Table S1). A total of two SAEs were reported by one (12.5%) patient (IR/100PY: 9.1), including one fall and one concussion (Table 2; Table S1). Non-SADRs were reported in five patients; these included, amongst others, leukopenia, neutropenia and S100 protein increase (n = 2 each; Table S1). No SADRs were reported.

Table 2 AEs, SAEs, SADRs for the pooled patient cohort
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Vaccination

Patients were receiving vaccinations throughout the study period, with 42.9% of patients reported as receiving a vaccination (within the last 6 months prior to documented visit) at months 6 and 18 (Table 3). Throughout the study, two (25.0%) patients received diphtheria-tetanus-pertussis (DTaP) vaccination, two (25.0%) received influenza vaccination, one (12.5%) received pneumococcal vaccination, one (12.5%) received meningococcal vaccination and one (12.5%) received COVID-19 vaccination; no patients received live-attenuated vaccinations. Of the patients who received at least one vaccination, two (25.0%) experienced an AE following immunisation for COVID-19 or DTaP: both were non-serious and not study drug-related (Table S1). Throughout the study, patients reported experiencing disease flare triggers, including cold, stress, infections, vaccinations and/or menstrual cycle hormones. Of the seven patients with data available at month 6, the majority (57.1%) experienced a disease flare trigger (Figure S1).

Table 3 Patients receiving vaccinations during the 6 months prior to documented visit (pooled patient cohort)
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Long-Term Influence of Canakinumab on Disease Activity

Physicians’ Assessment of Disease Activity

Due to the low patient number (N = 8), the results presented should be considered a description of observed trends. Disease activity (as measured by PGA, disease remission, CRP, SAA and ESR) was generally well controlled over the course of the study for the pooled patient cohort (Fig. 1). Most patients were reported as having either absent or mild/moderate disease activity over time, with severe disease activity in one (12.5%) patient at baseline and one (12.5%) patient at month 12 (Fig. 1a). The proportion of patients in disease remission remained ≥ 50.0% from baseline to month 24 (Fig. 1b). Median inflammatory marker levels (CRP, SAA and ESR) remained within the limits of normal (CRP, ≤ 0.5 mg/dl; SAA, ≤ 1.0 mg/dl; ESR, ≤ 15.0–20.0 mm/h) throughout the study (Fig. 1c–e). Most patients (≥ 50%) had CRP, SAA and ESR levels within the limits of normal throughout the study, except for CRP levels at month 6, in which 42.9% of patients had CRP levels ≤ 0.5 mg/dl (Figure S2).

Fig. 1
Fig. 1Fig. 1Fig. 1
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Physician-reported outcome measures of disease activity a PGA, b disease remission, c CRP, d SAA and e ESR for the pooled patient cohort and individual patients. CRP C-reactive protein, ESR erythrocyte sedimentation rate, MKD/HIDS mevalonate kinase deficiency/hyperimmunoglobulin-D syndrome, PGA physician’s global assessment, SAA serum amyloid A

At a patient level, Patient 2 experienced a spike in CRP levels at month 18 following COVID-19 vaccination (89.0 mg/dl; not classified as clinically relevant), with all other physician-reported outcome measures remaining within normal range; the patient also remained in disease remission until month 24 (Fig. 1). Patient 4 had a higher disease activity at baseline (PGA: severe; CRP: 0.4 mg/dl; SAA: 1.6 mg/dl; ESR: 16.0 mm/h) compared with the other patients in this cohort, which was seen to reduce over the course of the study (Fig. 1). Patient 7 had increased disease activity at month 12 (PGA: severe; CRP: 3.2 mg/dl), which was reduced by month 18 with the patient achieving disease remission (Fig. 1).

Patients’ Assessment of Disease Activity

Patient-reported outcome measures highlighted that disease activity was well controlled over the course of the study for the pooled patient cohort (Fig. 2). Median AIDAI scores remained below the cut-off score of 9.0 for active disease for most of the study, with one score > 9.0 observed between the baseline and month 6 visit (Fig. 2a). Median VAS scores for patients’ assessment of disease activity remained at 0.0 for the majority of the study, increasing to 2.0 at month 6 and then returning to 0.0 for the following visits (Fig. 2b). A reduction in patients’ assessment of fatigue (median VAS scores 2.5–1.0) and impact on social life (33.3% reporting ‘much impaired’ to 0.0% reporting ‘much impaired’) was observed from baseline to month 12, which was maintained throughout the study (Fig. 2c, d).

Fig. 2
Fig. 2Fig. 2
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Patient-reported outcome measures of disease activity: a AIDAI,* b disease activity, c fatigue and d impact on social life for the pooled patient cohort and individual patients. AIDAI autoinflammatory disease activity index diary, MKD/HIDS mevalonate kinase deficiency/hyperimmunoglobulin-D syndrome, VAS visual analogue scale. *AIDAI scores are collected on a monthly basis. The AIDAI scores presented are for the month preceding the study visit, i.e., values for month 6 are for the month preceding the visit (month 5)

At a patient level, the AIDAI scores for Patient 1 increased throughout the study from 0.0 to 20.0 at baseline and month 12. The AIDAI scores available for Patient 4 remained above the threshold for active disease throughout the study (baseline: 39.0; month 6: 21.0) and a reduction of AIDAI scores from 18.0 to 0.0 at baseline and month 6 was observed for Patient 6. Most patients reported low VAS scores for patients’ assessment of disease activity throughout the study (Fig. 2b). VAS scores for patients’ assessment of fatigue were generally higher than for other patient-reported outcome measures, with 4/8 (50.0%) patients reporting VAS scores ≥ 2.0 for the larger part of the study (Fig. 2c). At baseline, Patients 4 and 5 reported that their social life was ‘much impaired’. At month 6, Patient 5 reported social life as ‘not impaired’; month 6 data are not available for Patient 4 (Fig. 2d). Conversely, Patient 2 reported their social life was ‘not impaired’ at baseline and ‘much impaired’ at month 6, returning to ‘not impaired’ at month 12 (Fig. 2d).

Impact of Mutation Status

All eight (100.0%) patients had a genetically confirmed MKD/HIDS diagnosis. All patients had different MVK mutations, with V377I mutations being the most common in this cohort (6/8 patients, 75.0%; Table 4). All variants were identified as pathogenic or likely pathogenic. In total, two (25.0%) patients had homozygous, one (12.5%) patient had heterozygous and five (62.5%) patients had compound heterozygous MVK mutations (Table 4). Irrespectively of the underlying mutation, all patients had generally well-controlled disease activity over the course of the study while receiving canakinumab. It was observed that the two patients with I268T mutations received a diagnosis of MKD/HIDS in adulthood (22 years old) (Table 4).

Table 4 Individual patient mutation status with outcome measures at baseline and month 12
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Canakinumab Dosing

At baseline, most patients were receiving > SD canakinumab, with this trend being observed throughout the study (Fig. 3). At month 12, four (66.7%) patients were receiving > SD canakinumab, with one patient receiving < SD and one patient receiving SD. At a patient level, Patient 2 increased canakinumab dose from SD (150 mg) to > SD (300 mg) at month 12, which was then returned to SD at month 18. Patient 6 received < SD and Patients 1, 3, 4, 5 and 7 all received > SD throughout the study, although Patient 3 increased the dose from 3.7 mg/kg to 6.3 mg/kg and Patient 5 increased the dose from 5.6 mg/kg to 8.1 mg/kg from month 6 to month 12, respectively (Fig. 3).

Fig. 3
Fig. 3
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Canakinumab dosing category for the pooled patient cohort and individual patients, q4w every four weeks, SD recommended starting dose. Patients highlighted in grey are aged ≥ 18 years; patient ages are listed in Table 4. The SD of canakinumab was 150 mg or 2 mg per kg of body weight for patients weighing ≤ 40 kg 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. No dosage was documented at month 6 in Patient 7; therefore, an average dose was used when assigning < SD, SD or > SD for this patient at month 6

Discussion

Data from this interim analysis of the RELIANCE registry support the long-term safety profile of canakinumab and its effectiveness at controlling disease activity in patients with MKD/HIDS. The long-term use of canakinumab was generally well tolerated, with no patients experiencing an SADR over the course of the study. Only one case of COVID-19 was reported, which was non-serious, and the patient fully recovered. When comparing the IRs of AEs from this study with other real-world studies of biologics in MKD/HIDS, no new or unexpected safety concerns were reported [6, 15, 24, 25]. Although not reported in this cohort, it should be noted that MAS can present as a serious complication of MKD/HIDS. In a recent case-based review, recurrent MAS was observed as a complication in paediatric patients with HIDS, which was successfully controlled with corticosteroids and anti-IL-1 therapies [26]. Furthermore, most patients were receiving > SD of canakinumab from baseline of this study, which was well tolerated and not associated with an increased rate of SAEs. Patients were receiving vaccinations 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.

Adequate control of disease activity, including the normalisation of subclinical inflammation between disease flares, is an important factor in reducing the risk of developing long-term complications [1,2,3, 13]. The results from this interim analysis demonstrate that disease activity, as measured by physician- and patient-reported outcome measures, was generally well controlled over time, with most patients remaining in disease remission, and inflammatory markers (CRP, SAA and ESR) remaining within the limit of normal, throughout the 24-month study period. Notably, some patients were considered to be in remission, despite having mild/moderate disease activity as measured by PGA. A possible explanation for this observation may be that disease remission was determined by the treating physician and did not include absent disease activity as a criterion, similar to PGA. This observation is in line with findings from two recent studies in other AIDs (CAPS, FMF and TRAPS), which found that disease activity as measured by PGA was in discordance with inflammatory markers [27, 28]. Interestingly, analysing the patient-level data for this cohort further highlights the complexity of symptoms experienced by patients with MKD/HIDS, emphasising that symptoms such as fatigue can persist despite a patient being in disease remission. This observation may reflect the psychological burden of a chronic disease and its subjective consequences for the patients, which may not be identified by physicians.

As MKD/HIDS is a rare AID with a broad range of clinical manifestations, alongside being widely underdiagnosed, genetic screening for MVK mutations is an important factor in ensuring early diagnosis and optimum disease management and allowing for genotype-phenotype associations to be identified [3]. In this study, all eight (100.0%) patients had genetically confirmed MKD/HIDS, with the MVK V337I variant being identified as the most common, consistent with the prevalence of MVK variants in the literature [2, 29]. The two patients with I268T variants were diagnosed in adulthood, although no clear genotype-phenotype associations were identified. These results show that patients with the variants observed in this MKD/HIDS cohort responded well to long-term treatment with canakinumab. When retrospectively evaluating this cohort against the Eurofever/PRINTO clinical classification criteria for MKD [23], most patients (n = 7, 87.5%) fulfilled these criteria.

As mentioned, most patients were receiving > SD canakinumab throughout the study period. Patient-level data allow identification of patients who experienced an increase in disease activity during the study (e.g., Patient 3 at month 12, patient-reported disease activity [VAS score 8.0]; CRP 0.5 mg/dl) and the corresponding dose adjustment of canakinumab (3.7 mg/kg to 6.3 mg/kg), resulting in a reduction in disease activity by month 18 (patient-reported disease activity [VAS score 0.0]; CRP 0.0 mg/dl). Furthermore, it was observed that Patient 6 received < SD canakinumab throughout the study while remaining in disease remission. These results reinforce the importance of individual treat-to-target strategies in the management of MKD/HIDS, in which dose adjustments and/or changes in therapy are recommended in response to patients not achieving treatment targets or changes in disease activity. Notably, the canakinumab dose should follow the recommended dosing according to the SmPC/local label. The reported dosing described here was chosen by the treating physicians.

As with every real-world observational study, limitations should be considered when evaluating the results from this interim analysis. Given the rare nature of MKD/HIDS, the small patient population makes it challenging to observe trends and draw clear conclusions. Furthermore, data were missing for a number of patients throughout the study, leading to under-reporting of some outcome measures. Data collection from real-world disease registries are not controlled or conducted in a randomised fashion, meaning data are not comparable with those collected pre- and post-registry enrolment. Therefore, although useful for gaining insights into specific patient populations, results should be considered as an assessment of patient health condition over time. As all patients were receiving canakinumab treatment at the start of the study, there is potential that the patient population may be skewed towards selecting patients that have a positive response to canakinumab (i.e., patients that did not respond to canakinumab prior to enrolment were switched to another treatment and were therefore not included). Consequently, the assessment of the effectiveness of canakinumab is limited to the long-term maintenance of disease control. In addition, some variables were not collected as part of the study, including the reason for dose increase of canakinumab and impact of the COVID-19 pandemic on patients (e.g., missing visits, impact on social life).

Conclusions

Data from this interim analysis of the RELIANCE registry, the longest running real-world canakinumab registry, support the long-term safety profile of canakinumab and its ability to control disease activity in the treatment of MKD/HIDS. Furthermore, the results add further insight into the management of MKD/HIDS, a rare monogenic AID with limited literature available in the field.