Background/Purpose: Hyperimmunoglobulinemia
D with periodic fever syndrome (HIDS) is a recessively inherited disorder
characterized by periodic episodes of high fever, abdominal distress, joint
pain, and skin rashes.¹ Previous reports suggested interleukin
(IL)-1 blockade as a potential therapy in HIDS.^2,3 Here we report
the final results of a 36-month study assessing the efficacy and safety of the
anti-IL-1β human monoclonal antibody canakinumab
in patients with active HIDS and biallelic mevalonate
kinase (MVK) mutations.

Methods: This was an open-label single treatment arm study with a 6-month
treatment period (6mo-TP), an up-to 6-month follow-up period (6mo-FP), and a
24-month long-term treatment period (24mo-LTTP). The 6mo-TP included canakinumab administration (4 mg/kg q6w, max 300 mg,
subcutaneously), with one permissible dose up-titration to 6 mg/kg (max, 450
mg) if a flare occurred in the first 6 weeks. In the 24mo-LTTP,
patients received the same canakinumab dose
administered at the last visit of the 6mo-TP. The primary objective of the study was to assess the reduction in
frequency of flares during the 6mo-TP compared with a 6-month historical
treatment-free period. Secondary objectives were evaluated for the entire study
and included assessment of reduction in frequency of flares, changes in flare
duration, changes in physician’s global assessment (PGA) of flare severity and disease
control, changes in plasmatic inflammatory markers,
and adverse events (AEs).

Results: All enrolled patients (n=9) completed both the 6mo-TP and the
6mo-FP. Eight patients also completed the 24mo-LTTP. The median number of
flares decreased from 5 (3-12) in the historical period to 0 (0-2) during the 6mo-TP,
and persisted (0-3) until the end of the study. During the 24mo-LTTP, the
median flare duration was 3.5 days (2-8) in the first year and 8.5 days (6-11)
in the second. PGA of flare severity was “mild” to “moderate” at baseline (n=9)
and remained the same through the TP (n=2) and 6mo-FP (n= 7). Flare severity
reduced to “mild” or “minimal” and “mild” or “without signs/symptoms” in the
first (n=4) and second years (n=2) of the 24mo-LTTP, respectively. PGA disease
control scores improved in all patients from either “no” or “poor” control at
baseline to “good” or “excellent” control by Day 4, which persisted until the
end of the study. Plasma levels of C-reactive protein and serum amyloid A normalized by Day 15 and remained in normal values until
the end of the study. The most frequent AEs were infections. No deaths were
registered. No AE led to study discontinuation. Four patients experienced 14
serious AEs (mild to moderate), none considered as drug-related.

Conclusion: Canakinumab
treatment substantially reduced the frequency of flares in active HIDS and provoked
a rapid control of signs and symptoms as well as normalization of plasmatic
inflammatory markers. No unexpected safety findings were observed through the
study, and safety profile was consistent with those reported in other canakinumab studies.

References:

1.       Stoffels M, et al.Curr Opin Rheumatol. 2011;23:419-23.

2.      
Dinarello CA, et al.Semin Immunol.
2013;25:469-84.

3.       Tsitsami E, et al.Case Rep Rheumatol. 2013;2013:795027.