https://orcid.org/0000-0003-0704-1916
Abstract
To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency during the open label extension (weeks 41–113) of the randomized controlled CLUSTER trial.
During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was evaluated every 8 weeks using physician global assessment and counting the number of flares. Concentrations of CRP and serum amyloid A protein were measured. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analysed separately in three subgroups of patients receiving a cumulative dose of less than <35 mg/kg, ≥35 to <70 mg/kg or ≥70 mg/kg.
Of the 74 patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. Low physician global assessment scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/l, while median serum amyloid A concentrations remained only slightly above the normal range of 10 mg/l. The study showed no new or unexpected adverse events.
Canakinumab proved effective to control disease activity and prevent flares in mevalonate kinase deficiency during the 72-week study period. No new safety concerns were reported.
NCT02059291. https://clinicaltrials.gov.
This study underlines the efficacy of canakinumab as a long-term therapy for patients with mevalonate kinase deficiency.
Individual dose adjustments can be important to optimise the therapeutic effect of canakinumab.
No new or unexpected adverse events of canakinumab were reported during the 72-week study period.
Introduction
Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome characterized by fever and generalized inflammation. Patients with MKD may experience fever, gastrointestinal complaints, skin rash, mucosal ulcers, lymphadenopathy, myalgia and arthralgia. In many patients there is a strongly elevated serum immunoglobulin D, giving rise to the alternative name hyper IgD syndrome. Very severely affected patients can also present with dysmorphic features, neurological manifestations, ocular manifestations and pre- and postnatal growth retardation. This extremely rare phenotype of MKD is known as mevalonic aciduria [1–3].
Mutations in the mevalonate kinase (MVK) gene are the cause of MKD [4, 5]. MVK is an essential enzyme in the mevalonate pathway, which produces cholesterol and non-sterol isoprenoids. In MKD patients, the MVK activity is reduced [6]. Recently, this biochemical defect was associated with an uncontrolled activation of the MEFV-gene product, Pyrin, which in turn results in Caspase-1 mediated IL-1β release. IL-1β is a strong inducer of fever and inflammation [7]. This confirms a major role for IL-1 β in the pathophysiology of MKD and provides a target for therapies.
The treatment of MKD had until recently not been based on strong evidence. Mildly affected patients have been managed with non-steroidal anti-inflammatory drugs or corticosteroids given during attacks. More severely affected patients appear to have benefitted from biological treatments, such as the short-term IL-1 antagonist anakinra or the TNF-α antagonist etanercept [8–13]. Recently, evidence-based therapy has become possible. Results up to week 40 of the phase III CLUSTER trial (NCT02059291) demonstrated that canakinumab, a fully human anti−IL-1β monoclonal antibody, was effective in controlling inflammation and preventing flares in patients with MKD [14]. We now report the results from the last part of this study, epoch 4, a 72-week period of open-label treatment designed to study the long-term efficacy and safety of canakinumab in patients with MKD.
Patients and methods
Study design
The CLUSTER study (NCT02059291, https://clinicaltrials.gov/) was designed to evaluate the safety and efficacy of canakinumab in three genetic autoinflammatory diseases, namely MVK deficiency, colchicine-resistant familial Mediterranean fever and the tumour necrosis factor associated periodic syndrome. As previously reported, the study consisted of three cohorts, one for each disease, and all cohorts followed the same study design. The more detailed inclusion and exclusion criteria have been described in a previous article [14]. The study was split into four epochs: a screening period up to 12 weeks (Epoch 1), a randomized double-blind, placebo-controlled period of 16 weeks (Epoch 2), a randomized withdrawal, open-label period of 24 weeks (Epoch 3). Epoch 4 was an open-label treatment period of 72 weeks.
In the present article, we report the results of MKD patients in Epoch 4 (weeks 41–113 of the trial). In Epoch 3, part of the patients had been randomized to receive placebo every 8 weeks (q8w) or canakinumab 150 mg, while the other patients were treated with canakinumab 150 mg or 300 mg every 4 weeks (q4w). Patients who suffered from a flare, which was defined as a physician global assessment (PGA) >2 or CRP >30 mg/l were able to start with canakinumab or increase the dose up to a maximum of 300 mg q4w. Hence, patients received either placebo q8w, canakinumab 150 mg (q4w or q8w) or canakinumab 300 mg (q4w or q8w). The use of other biologicals was prohibited, while NSAIDS and corticosteroids were allowed.
All patients who completed Epoch 3 continued to receive the same canakinumab dose at the start of Epoch 4. Patients who entered Epoch 4 on placebo did not receive canakinumab unless they experienced a flare. Then treatment with 150 mg q8w was started. A stepwise dose increase was maintained if patients experienced a flare. Importantly, down-titration was not allowed in Epoch 4.
Doses were adjusted according to body weight in patients under 40 kg. These received canakinumab 2 mg/kg (instead of canakinumab 150 mg) or canakinumab 4 mg/kg (instead of canakinumab 300 mg).
Thirty-three centres in 13 countries participated in this part of the study. Independent ethical committee approval for enrolling patients was granted in accordance with local requirements. The institutional review board or ethical committee of each centre approved this study. Written informed consent was obtained from patients or their parents/legal guardians according to local ethical regulations.
Objectives
The objectives for Epoch 4 were to evaluate the long-term safety and tolerability of canakinumab and to assess the efficacy regarding the number of flares, the PGA and the analysis of biochemic markers [CRP and serum amyloid A (SAA) serum levels].
Patients
The detailed inclusion criteria for patients have been described previously [14]. Patients were included if there was a genetic or enzymatic diagnosis confirming MKD and if they reported at least three fever episodes in the 6 months prior to enrollment.
Assessments
Visits to the hospital to evaluate the safety and efficacy were planned every 8 weeks. The investigator performed the PGA of disease activity. PGA was assessed by the presence of fever or symptoms associated with MKD (lymphadenopathy, aphthous ulcers and/or abdominal pain). Serum levels of CRP and SAA were analysed at local and central laboratories. A PGA >2 or a CRP >30mg/l was considered to be a new flare.
The safety was evaluated by gathering all adverse events with their severity. Besides regular monitoring of haematology, blood chemistry (including creatinine clearance), vital signs and body weight was performed.
Statistical analysis
The safety set of Epoch 4 was used for all analyses. This set consisted of all patients who received treatment and had >1 post baseline assessment. Safety and efficacy analyses were performed in three groups according to the cumulative dose adjusted by weight. Patients were divided into groups who received a cumulative dose <35 mg/kg, a cumulative dose ≥35 to <70 mg/kg or a cumulative dose ≥70mg/kg.
Descriptive statistics were used to describe the baseline characteristics and demographic features, but also PGA score, CRP, SAA and the number of flares during Epoch 4. Adverse events are presented using exposure adjusted event rates.
Median values between dose in mg/kg and body weight or age were compared using the Kruskal–Wallis test. The Fisher exact test was used to assess the association between dose regimens and body weight or age. P-values presented in this analysis are nominal, no correction for multiple testing were made.
Results
Patient disposition and baseline characteristics
Of the 74 MKD patients who were included in the CLUSTER trial, 66 entered Epoch 4. Patients had discontinued during Epoch 2 and 3 due to adverse events, a lack of efficacy or due to their own decision. The patient distribution among the dose regimens is shown in Fig. 1. One patient (1.5 %) discontinued due to his own decision. Patients had experienced fever episodes frequently with a median of 12 episodes per year when entering the study. Overall, 18 patients received a cumulative dose <35 mg/kg and 30 ≥ 35 to <70 mg/kg, while 18 patients received a cumulative dose of ≥70mg/kg.
Patient flow diagram showing treatment regiments at the beginning and the end of Epoch 4
n: number of patients; q4w: every 4 weeks; q8: every 8 weeks.
All demographic and disease characteristics are listed in Table 1. The median age at baseline was 11.5. Half of the included patients (n = 33; 50%) were below 12 years of age on entry, while 15 patients (23%) were between 12 and 18 years. Thirty-four patients (52%) had a body weight <40 kg and did receive a weight-adjusted dose as mentioned in the methods section.
Baseline demographic and disease characteristics
| Characteristics | Patients (n = 66) |
|---|---|
| Median age in years (Q1, Q3) | 11.5 (6–19) |
| Male, n (%) | 28 (42.4%) |
| Caucasian ethnicity, n (%) | 59 (89.4%) |
| Median duration of disease in years | 9.76 (5.33–16.52) |
| Median number of flares per year (Q1, Q3) | 12 (10–20) |
| MVK genotype, n (%) | |
| p.V377I/p.V377I | 14 (21.2%) |
| p.V377I/p.I268T | 13 (19.7%) |
| p.V377I/other mutation than p. V377I | 24 (36.4%) |
| Other mutations | 15 (22.7%) |
| CRP in mg/L (Q1, Q3) | 113.5 (69.4–242.7) |
| SAA in mg/L (Q1, Q3) | 2061 (600–4387) |
| PGA score (disease activity), n (%) | |
| 0 None | 0 (0%) |
| 1 Minimal | 0 (0%) |
| 2 Mild | 16 (24.2%) |
| 3 Moderate | 40 (60.6%) |
| 4 Severe | 10 (15.2%) |
| Prior use of anakinra | 11 (16.7%) |
| Prior use of other biologicals | 3 (4.5%) |
| Characteristics | Patients (n = 66) |
|---|---|
| Median age in years (Q1, Q3) | 11.5 (6–19) |
| Male, n (%) | 28 (42.4%) |
| Caucasian ethnicity, n (%) | 59 (89.4%) |
| Median duration of disease in years | 9.76 (5.33–16.52) |
| Median number of flares per year (Q1, Q3) | 12 (10–20) |
| MVK genotype, n (%) | |
| p.V377I/p.V377I | 14 (21.2%) |
| p.V377I/p.I268T | 13 (19.7%) |
| p.V377I/other mutation than p. V377I | 24 (36.4%) |
| Other mutations | 15 (22.7%) |
| CRP in mg/L (Q1, Q3) | 113.5 (69.4–242.7) |
| SAA in mg/L (Q1, Q3) | 2061 (600–4387) |
| PGA score (disease activity), n (%) | |
| 0 None | 0 (0%) |
| 1 Minimal | 0 (0%) |
| 2 Mild | 16 (24.2%) |
| 3 Moderate | 40 (60.6%) |
| 4 Severe | 10 (15.2%) |
| Prior use of anakinra | 11 (16.7%) |
| Prior use of other biologicals | 3 (4.5%) |
MVK: mevalonate kinase.
Baseline demographic and disease characteristics
| Characteristics | Patients (n = 66) |
|---|---|
| Median age in years (Q1, Q3) | 11.5 (6–19) |
| Male, n (%) | 28 (42.4%) |
| Caucasian ethnicity, n (%) | 59 (89.4%) |
| Median duration of disease in years | 9.76 (5.33–16.52) |
| Median number of flares per year (Q1, Q3) | 12 (10–20) |
| MVK genotype, n (%) | |
| p.V377I/p.V377I | 14 (21.2%) |
| p.V377I/p.I268T | 13 (19.7%) |
| p.V377I/other mutation than p. V377I | 24 (36.4%) |
| Other mutations | 15 (22.7%) |
| CRP in mg/L (Q1, Q3) | 113.5 (69.4–242.7) |
| SAA in mg/L (Q1, Q3) | 2061 (600–4387) |
| PGA score (disease activity), n (%) | |
| 0 None | 0 (0%) |
| 1 Minimal | 0 (0%) |
| 2 Mild | 16 (24.2%) |
| 3 Moderate | 40 (60.6%) |
| 4 Severe | 10 (15.2%) |
| Prior use of anakinra | 11 (16.7%) |
| Prior use of other biologicals | 3 (4.5%) |
| Characteristics | Patients (n = 66) |
|---|---|
| Median age in years (Q1, Q3) | 11.5 (6–19) |
| Male, n (%) | 28 (42.4%) |
| Caucasian ethnicity, n (%) | 59 (89.4%) |
| Median duration of disease in years | 9.76 (5.33–16.52) |
| Median number of flares per year (Q1, Q3) | 12 (10–20) |
| MVK genotype, n (%) | |
| p.V377I/p.V377I | 14 (21.2%) |
| p.V377I/p.I268T | 13 (19.7%) |
| p.V377I/other mutation than p. V377I | 24 (36.4%) |
| Other mutations | 15 (22.7%) |
| CRP in mg/L (Q1, Q3) | 113.5 (69.4–242.7) |
| SAA in mg/L (Q1, Q3) | 2061 (600–4387) |
| PGA score (disease activity), n (%) | |
| 0 None | 0 (0%) |
| 1 Minimal | 0 (0%) |
| 2 Mild | 16 (24.2%) |
| 3 Moderate | 40 (60.6%) |
| 4 Severe | 10 (15.2%) |
| Prior use of anakinra | 11 (16.7%) |
| Prior use of other biologicals | 3 (4.5%) |
MVK: mevalonate kinase.
Disease control
At the begin of the CLUSTER study, patients had a median flare frequency of 12 episodes per year. At the end of Epoch 4, the median flare frequency was 0 (Q1–Q3 0–0.72). Forty-two patients (64%) did not experience any flare during Epoch 4, while another 13 patients (20%) suffered from one flare. Eleven patients (17%) reported two or three flares.
At the start of the CLUSTER trial (Epoch 1) all patients had mild to severe disease activity according to PGA score. Low PGA scores were seen at the end of the study for all groups with >90% reporting none or a minimal disease activity. PGA scores were similar in the three groups, which might indicate that a good clinical response might be obtained by increasing the dose (Fig. 2).
Disease activity as measured by physician’s global assessment over time according to the cumulative dose adjusted by weight in mg/kg
<35: cumulative dose of <35 mg/kg (n = 18); ≥35 to<70: cumulative dose of ≥35 to<70 mg/kg (n = 30); ≥70: cumulative dose of ≥70 mg (n = 18). (A) Disease activity at baseline. (B) Disease activity at the start of Epoch 4. (C) Disease activity at the end of Epoch 4. One patient belonging to the ≥35 to<70 mg/kg group discontinued early. No available disease activity for this patient at week 113.
As described in the methods section, the dose of canakinumab could be up-titrated to achieve a good clinical response. Fig. 3A shows the different dose regimens and the proportion of patients that received them. The flow-chart of different dose regimens is shown in Fig. 1. At the start of Epoch 4, 19 patients (29%) were receiving the lowest dose regimen (150 mg q8) and in 12 (18%) this dose was sufficient to control the disease throughout Epoch 4. Another 20 patients (30%) received intermediate doses (150 mg q4 and 300 mg q8) at the end of the study. However, the highest regimen (300 mg q4) was required in 32 patients (49%) at the end of Epoch 4, while this regimen was only used to treat 18 patients (27%) at the start. One patient who started on 150 mg q4 discontinued while being on 300 mg q4.
Dosing regimens
(A) Dosing regimens for all patients (n = 66) at the start and end of Epoch 4. (B) Dosing regimens at study end according to body weight at baseline. (C) Dosing regimens at study end according to age at baseline. One patient belonging to the groups >40 kg and ≥18 years discontinued early while being on 300 mg q4.
Patients with a body weight ≤40 kg received a weight-adjusted dose. At the end of Epoch 4 the median dose in patients ≤40 kg was 7.93 mg/kg and 5.29 in patients >40 kg (P-value 0.69, not significant). This trend is also seen in Fig. 3B which shows that 20 patients (59%) with a body weight ≤40 kg received the highest dose regimen (300 mg q4), while the same regimen was only used in 12 patients (38%) with a body weight >40 kg (P-value 0.403, not significant). Besides, Fig. 3C shows that patients younger than 12 years received the highest dose regimen of 300 mg q4 significantly more often (P-value 0.027).
CRP and SAA analyses
Canakinumab had already been proven to lead to a rapid decrease of CRP levels during Epoch 2. CRP levels were well controlled throughout Epoch 4. The median CRP levels during Epoch 4 were mostly below <10mg/l for all groups (Fig. 4). Median CRP levels seemed slightly lower in patients receiving the highest cumulative dose (≥70 mg/kg).
CRP and SAA levels in MKD patients over time
(A) Median CRP levels. The x-axis represents the weeks when CRP levels were measured during baseline and Epoch 4. The y-axis represents a logarithmic scale in mg/L. The dotted line indicates the upper limit of the normal range. (B) Median SAA levels. The x-axis represents the weeks when SAA levels were measured during baseline and Epoch 4. The y-axis represents a logarithmic scale in mg/L. The dotted line indicates the upper limit of the normal range. One patient belonging to the group ≥35 to<70 mg/kg discontinued early and is not included at timepoint 105 and 113.
SAA levels decreased steeply after starting treatment with canakinumab. The median SAA levels remained stable throughout Epoch 4 for all cumulative groups, but slightly above the upper limit of normal of <10mg/l. The median SAA level at the end of the study for the whole group was 16 mg/l (Q1–Q3 635) and was below or equal to 20 mg/l for all cumulative groups. However, at some points throughout Epoch 4 median SAA levels were elevated, mostly in the cumulative group receiving a dose <35 mg/kg. The highest median value was 48 mg/l and occurred in the ≥70 mg/kg group.
Adverse events
At study conclusion, the median duration of exposure to canakinumab or placebo from the begin of Epoch 4 was 507 days.
The total exposure during Epoch 4 was 92 patient years. The exposure-adjusted rate of adverse events was 10.3 per patient year (Table 2). This appeared to be higher in the ≥35 to <70 mg/kg (11.9) and the ≥70mg/kg (11.0) compared with the <35 mg/kg group (6.85). Some common adverse events, such as abdominal pain, diarrhoea and aphthous ulcers were probably linked to flares of MKD episodes. Infections were the most frequently reported organ class. Twenty-eight serious adverse events were reported in 14 patients. Three of these 28 serious adverse events were MKD flares, although some other serious adverse events might also have been caused by MKD flares. Eleven serious infections were reported in nine patients [pneumonia (n = 3), one each: anal abscess, appendicitis, bronchitis, herpesvirus infection, influenza, orchitis, pyelonephritis and tonsillitis]. During the study no complications related to amyloidosis, and no deaths were reported.
Exposure-adjusted incidence of adverse events per patient years, and total number of adverse events in Epoch 4
| Cumulative dose <35 mg/kg (n = 18) Expa: 9159 pt days Event rate (n) | Cumulative dose ≥35 to <70 mg/kg (n= 30) Expa: 15336 pt days Event rate (n) | Cumulative ≥70 mg/kg (n = 18) Expa: 9238 pt days Event rate (n) | Total (n = 66) Expa: 33733 pt days Event rate (n) | |
|---|---|---|---|---|
| Total adverse events | 6.85(172) | 11.9 (501) | 11.0 (278) | 10.3 (951) |
| Infections | 2.23 (56) | 2.83 (119) | 3.04 (77) | 2.73 (252) |
| Most common adverse eventsb | ||||
| Pyrexia | 0.44 (11) | 2.00 (84) | 1.38 (35) | 1.41 (130) |
| MKDc | 0.72 (18) | 1.00 (42) | 0.55 (14) | 0.80 (74) |
| Headache | 0.16 (4) | 0.71 (30) | 0.55 (14) | 0.52 (48) |
| Aphthous ulcer | 0.00 0 | 0.43 (18) | 0.32 (8) | 0.28 (26) |
| Viral upper respiratory tract infection | 0.28 (7) | 0.12 (5) | 0.51 (13) | 0.27 (25) |
| Influenza | 0.32 (8) | 0.17 (7) | 0.28 (7) | 0.24 (22) |
| Cough | 0.16 (4) | 0.26 (11) | 0.24 (6) | 0.23 (21) |
| Oropharyngeal pain | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Diarrhea | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Abdominal pain | 0.16 (4) | 0.31 (13) | 0.12 (3) | 0.22 (20) |
| Upper respiratory tract infection | 0.20 (5) | 0.24 (10) | 0.20 (5) | 0.22 (20) |
| Lymphadenopathy | 0.16 (4) | 0.10 (4) | 0.36 (9) | 0.18 (17) |
| Serious adverse events | 0.28 (7) | 0.29 (12) | 0.36 (9) | 0.30 (28) |
| Serious infections | 0.16 (4) | 0.10 (4) | 0.12 (3) | 0.12 (11) |
| Cumulative dose <35 mg/kg (n = 18) Expa: 9159 pt days Event rate (n) | Cumulative dose ≥35 to <70 mg/kg (n= 30) Expa: 15336 pt days Event rate (n) | Cumulative ≥70 mg/kg (n = 18) Expa: 9238 pt days Event rate (n) | Total (n = 66) Expa: 33733 pt days Event rate (n) | |
|---|---|---|---|---|
| Total adverse events | 6.85(172) | 11.9 (501) | 11.0 (278) | 10.3 (951) |
| Infections | 2.23 (56) | 2.83 (119) | 3.04 (77) | 2.73 (252) |
| Most common adverse eventsb | ||||
| Pyrexia | 0.44 (11) | 2.00 (84) | 1.38 (35) | 1.41 (130) |
| MKDc | 0.72 (18) | 1.00 (42) | 0.55 (14) | 0.80 (74) |
| Headache | 0.16 (4) | 0.71 (30) | 0.55 (14) | 0.52 (48) |
| Aphthous ulcer | 0.00 0 | 0.43 (18) | 0.32 (8) | 0.28 (26) |
| Viral upper respiratory tract infection | 0.28 (7) | 0.12 (5) | 0.51 (13) | 0.27 (25) |
| Influenza | 0.32 (8) | 0.17 (7) | 0.28 (7) | 0.24 (22) |
| Cough | 0.16 (4) | 0.26 (11) | 0.24 (6) | 0.23 (21) |
| Oropharyngeal pain | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Diarrhea | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Abdominal pain | 0.16 (4) | 0.31 (13) | 0.12 (3) | 0.22 (20) |
| Upper respiratory tract infection | 0.20 (5) | 0.24 (10) | 0.20 (5) | 0.22 (20) |
| Lymphadenopathy | 0.16 (4) | 0.10 (4) | 0.36 (9) | 0.18 (17) |
| Serious adverse events | 0.28 (7) | 0.29 (12) | 0.36 (9) | 0.30 (28) |
| Serious infections | 0.16 (4) | 0.10 (4) | 0.12 (3) | 0.12 (11) |
Exp: exposure to canakinumab in each patient group, in patient-days.
Adverse events occurring >15% of the patients are mentioned in this table.
MKD: Some cases of MKD flares were reported as adverse events using this preferred term.
MKD: mevalonate kinase deficiency.
Exposure-adjusted incidence of adverse events per patient years, and total number of adverse events in Epoch 4
| Cumulative dose <35 mg/kg (n = 18) Expa: 9159 pt days Event rate (n) | Cumulative dose ≥35 to <70 mg/kg (n= 30) Expa: 15336 pt days Event rate (n) | Cumulative ≥70 mg/kg (n = 18) Expa: 9238 pt days Event rate (n) | Total (n = 66) Expa: 33733 pt days Event rate (n) | |
|---|---|---|---|---|
| Total adverse events | 6.85(172) | 11.9 (501) | 11.0 (278) | 10.3 (951) |
| Infections | 2.23 (56) | 2.83 (119) | 3.04 (77) | 2.73 (252) |
| Most common adverse eventsb | ||||
| Pyrexia | 0.44 (11) | 2.00 (84) | 1.38 (35) | 1.41 (130) |
| MKDc | 0.72 (18) | 1.00 (42) | 0.55 (14) | 0.80 (74) |
| Headache | 0.16 (4) | 0.71 (30) | 0.55 (14) | 0.52 (48) |
| Aphthous ulcer | 0.00 0 | 0.43 (18) | 0.32 (8) | 0.28 (26) |
| Viral upper respiratory tract infection | 0.28 (7) | 0.12 (5) | 0.51 (13) | 0.27 (25) |
| Influenza | 0.32 (8) | 0.17 (7) | 0.28 (7) | 0.24 (22) |
| Cough | 0.16 (4) | 0.26 (11) | 0.24 (6) | 0.23 (21) |
| Oropharyngeal pain | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Diarrhea | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Abdominal pain | 0.16 (4) | 0.31 (13) | 0.12 (3) | 0.22 (20) |
| Upper respiratory tract infection | 0.20 (5) | 0.24 (10) | 0.20 (5) | 0.22 (20) |
| Lymphadenopathy | 0.16 (4) | 0.10 (4) | 0.36 (9) | 0.18 (17) |
| Serious adverse events | 0.28 (7) | 0.29 (12) | 0.36 (9) | 0.30 (28) |
| Serious infections | 0.16 (4) | 0.10 (4) | 0.12 (3) | 0.12 (11) |
| Cumulative dose <35 mg/kg (n = 18) Expa: 9159 pt days Event rate (n) | Cumulative dose ≥35 to <70 mg/kg (n= 30) Expa: 15336 pt days Event rate (n) | Cumulative ≥70 mg/kg (n = 18) Expa: 9238 pt days Event rate (n) | Total (n = 66) Expa: 33733 pt days Event rate (n) | |
|---|---|---|---|---|
| Total adverse events | 6.85(172) | 11.9 (501) | 11.0 (278) | 10.3 (951) |
| Infections | 2.23 (56) | 2.83 (119) | 3.04 (77) | 2.73 (252) |
| Most common adverse eventsb | ||||
| Pyrexia | 0.44 (11) | 2.00 (84) | 1.38 (35) | 1.41 (130) |
| MKDc | 0.72 (18) | 1.00 (42) | 0.55 (14) | 0.80 (74) |
| Headache | 0.16 (4) | 0.71 (30) | 0.55 (14) | 0.52 (48) |
| Aphthous ulcer | 0.00 0 | 0.43 (18) | 0.32 (8) | 0.28 (26) |
| Viral upper respiratory tract infection | 0.28 (7) | 0.12 (5) | 0.51 (13) | 0.27 (25) |
| Influenza | 0.32 (8) | 0.17 (7) | 0.28 (7) | 0.24 (22) |
| Cough | 0.16 (4) | 0.26 (11) | 0.24 (6) | 0.23 (21) |
| Oropharyngeal pain | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Diarrhea | 0.12 (3) | 0.19 (8) | 0.40 (10) | 0.23 (21) |
| Abdominal pain | 0.16 (4) | 0.31 (13) | 0.12 (3) | 0.22 (20) |
| Upper respiratory tract infection | 0.20 (5) | 0.24 (10) | 0.20 (5) | 0.22 (20) |
| Lymphadenopathy | 0.16 (4) | 0.10 (4) | 0.36 (9) | 0.18 (17) |
| Serious adverse events | 0.28 (7) | 0.29 (12) | 0.36 (9) | 0.30 (28) |
| Serious infections | 0.16 (4) | 0.10 (4) | 0.12 (3) | 0.12 (11) |
Exp: exposure to canakinumab in each patient group, in patient-days.
Adverse events occurring >15% of the patients are mentioned in this table.
MKD: Some cases of MKD flares were reported as adverse events using this preferred term.
MKD: mevalonate kinase deficiency.
Discussion
Canakinumab has already been proven to effectively control MKD in a previous report on Epoch 2 of the CLUSTER study [14]. In the present study, we report the long-term safety and efficacy of canakinumab in MKD patients from week 41 of treatment. During the 72-week study period of Epoch 4, treatment with canakinumab continued to be effective in controlling the disease. The median flare rate was 0 with 83% of the patients experiencing 0 or 1 flare during this period compared with a median flare rate of 12 before enrollment in the study.
Different dose regimens were used to control the disease and patients with a body weight <40 kg received a weight-adjusted dose. Younger patients needed a higher dose regimen significantly more often. Besides, there was a trend showing that patients with a body weight <40 kg also received a higher dosing regimen. This might be explained by the phenotype of MKD getting milder as patients grow older. However, higher dose requirements of IL-1 blockade in young children have been noted in diseases other than MKD. This observation suggests that younger patients might require higher doses, and this should be taken into account when treating these patients. The demonstration of a need for higher doses in children emphasizes the importance of including children in clinical trials.
Importantly, dose adjustments were required in a substantial number of patients. The phenomenon of higher dose requirements over time has been observed in other auto-inflammatory diseases, such as in FMF [15]. There is no explanation for this phenomenon yet. There are as yet no indications that this is due to the formation of antibodies against canakinumab.
Median CRP levels were well controlled and remained low for all cumulative groups throughout Epoch 4. SAA levels were low, but not entirely normal. Long-term follow up will determine whether the degree of disease control is sufficient to prevent AA amyloidosis. Furthermore, this study showed no unexpected safety findings with most adverse events classified as mild.
Canakinumab appears to be a highly effective therapeutic option to control the inflammatory phenotype of MKD when the disease cannot be satisfactorily controlled with more widely available drugs, like NSAIDs, corticosteroids or the short-term acting IL-1 antagonist anakinra.
The present study comes with a number of inherent limitations. The study design, the open-label nature of this part of the study, might have biased the clinical outcomes. Dose reduction was not allowed during the study, potentially raising the median final dose. Other limitations are the small number of patients and the lack of a control group. Furthermore, a detailed patient reported outcome measure, such as the Auto-Inflammatory Diseases Activity Index might have yielded better information on disease activity compared with the PGA score.
In conclusion, we have described that continuous treatment with canakinumab, with doses varying from 150 mg q8 to 300 mg q4, is effective to control disease activity, in patients with active MKD.
Acknowledgements
The authors thank all additional investigators for their participation in the study: Sara Muria, Rosa Merino, Maria Alessio, Jasmin Kummerle Deschner, Alberto Tommasini, Sinisa Savic, Pierre Quartier, Richard Mouy, Michaela Semeraro, Candize Meyzer, Jordi Anton, Michel Moutschen, Alina Boteanu, Isabelle Kone-Paut, Takahiro Yasumi, Bernard Lauwerys, Seza Özen, Elisabeth Weissbarth-Riedel, Romina Gallizzi, Lori Tucker, Alexandre Belot, Raffaele Manna, Gerd Horneff, Paul Brogan, Marco Cattalini, Helen Lachmann and Ilonka Orban.
Funding: This work was supported by Novartis Pharma AG.
Disclosure statement: I.C. does not report personal fees or grants except personal consulting fees outside of work presented from GlaxoSmithKline, Novartis and Clementia. Speaker Bureau from Roche, Abbvie, Novartis and Sobi. J.F. received consultancy fees from Novartis and SOBI.
The other authors declare no conflicts of interest.
Data availability statement
The data underlying this article will be shared on reasonable request to the corresponding author.
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