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

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 cohortVaccination

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)Long-Term Influence of Canakinumab on Disease ActivityPhysicians’ 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

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

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 12Canakinumab 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

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