Background/Purpose: Familial Mediterranean fever (FMF), Hyper IgD Syndrome (HIDS)/mevalonate kinase deficiency (MKD) and TNF-receptor associated periodic syndrome (TRAPS) are monogenic auto-inflammatory diseases caused by mutations in the MEFV, MVK and TNFRSF1A genes, respectively.¹ We analyzed responses to canakinumab (CAN), a fully human anti-IL-1β monoclonal antibody, in the pivotal, controlled CLUSTER trial in patients with colchicine-resistant FMF (crFMF), HIDS/MKD and TRAPS, according to MEFV, MVK and TNFRSF1A genes.

Methods: Inclusion criteria were: age ≥2 years with a baseline flare, fulfillment of Tel Hashomer criteria, at least one known MEFV exon 10 gene mutation, ≥1 documented flare/month on colchicine (crFMF); genetic or enzymatic diagnosis of HIDS/MKD and ≥3 documented flares in 6 months (HIDS/MKD); TNFRSF1A gene mutation and chronic or recurrent (>6 flares/year) disease (TRAPS). The study design has been reported previously.² Overall, 63 crFMF, 72 HIDS/MKD, and 46 TRAPS patients were randomized 1:1, to receive CAN 150 mg or placebo q4w. Patients (pts) were eligible for blinded escape until Day 29 if the baseline flare did not resolve and received 1 add-on injection of CAN 150 mg. We analyzed the proportion of patients showing complete response (resolution of the baseline flare and no new flare until Week 16) from those pts initially randomized to CAN (31 crFMF, 37 HIDS/MKD, 22 TRAPS).

Results: The primary outcome of complete response was achieved by more pts randomized to CAN than to placebo (p<0.001 for each disease cohort).² Among the crFMF pts randomized to CAN, no significant difference in complete response were observed between 25 pts homozygous for M694V and six pts heterozygous for exon 10 mutations (Table). In HIDS/MKD pts, the proportion of CAN responders was higher in pts carrying at least one V377I mutation, compared to those carrying other mutations. Most of the TRAPS pts with classic pathogenic mutations achieved complete response.

Table. Proportion of patients randomized to canakinumab attaining the primary outcome at week 16 according to the genotypes

¹ p<0.05 versus patients with Non V377I/non V377I and patients with 1 mutation associated with mevalonic aciduria

² p<0.001 versus patients with R92Q or P46L

Conclusion: Homozygous and heterozygous patients with crFMF showed no difference in CAN responses. Among HIDS/MKD pts, the proportion of CAN responders was higher among those carrying at least one V377I mutation. Among TRAPS pts, all pts carrying mutations associated with classical TRAPS responded to CAN; the poor response rate of pts carrying R92Q or P46L variants shows that the disease associated with these variants differs from classic TRAPS, not only in clinical features, but also in the role that IL-1β production plays in the pathogenesis.

1. De Jesus AA, et al. Clin immunol (Orlando, FL) 2013; 147(3):155-174.
2. De Benedetti F, et al. Ann Rheum Dis 2016;75:615-616.

Study Number: NCT02059291

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-phenotypes-impacting-efficacy-and-safety-of-canakinumab-in-patients-with-colchicine-resistant-fmf-traps-and-hidsmkd-results-from-cluster-study/