D3.423 - Lanadelumab treatment is effective and safe in patients with Factor XII associated cold-induced autoinflammatory syndrome: results from an open-label proof-of-concept study

Factor XII associated cold-induced autoinflammatory syndrome (FACAS) is a rare hereditary autoinflammatory disease characterized by cold-induced urticarial rash, chills, arthralgia, headache and fatigue. In FACAS, a substitution mutation in gene F12 (T859A, p.W268R) results in activation of the FXII-kallikrein-kinin pathway with signs of increased bradykinin production and local upregulation of interleukin-1β. No approved treatment is available.

We performed a phase II, exploratory, proof-of-concept, single-center, open-label, single arm interventional trial in four FACAS patients. The study comprised a run-in baseline period of 4 weeks followed by a 28-week open-label treatment phase with subcutaneous injections (kallikrein inhibitor lanadelumab 300 mg) every 2 weeks and an 8-week period of follow-up. Efficacy was assessed by changes in disease activity (patient-reported disease activity, PR-DA total score, 0-50; PR-DA subscores for urticarial rash, fatigue, chills/fever, headache, arthralgia each 0-10), inflammatory markers (C-reactive protein [CRP], serum amyloid A [SAA], erythrocyte sedimentation rate [ESR], S100A8/9) and quality of life (Dermatology Life Quality Index, DLQI; SF-36).

During treatment with lanadelumab, the clinical signs and symptoms assessed by the PR-DA total score of all patients declined from a mean value of 15.47 (SD = 5.92) at baseline (weeks -4 to -1), to a mean value of 3.60 (SD = 7.16) at weeks 9 to 12 and a mean value of 1.65 (SD = 3.30) at weeks 25 to 28. Also, all subscores reduced from baseline to week 9 to 12 and week 25 to 28. The quality of life of the patients improved, as the DLQI total score declined from a mean value of 9.00 (SD = 5.77) at week 0 (baseline), to a mean value of 0.00 (SD = 0.00) at week 12, and to a mean value of 0.25 (SD = 0.50) at week 28. SF-36 mental and physical component scores increased from baseline over time. Mean serum CRP, ESR and S100A8/9 were normal at baseline and remained normal over time. Mean serum SAA levels demonstrated only marginal changes. A total of 9 adverse events were documented, none of which were serious. All four patients completed the study.

In this open-label trial, lanadelumab treatment provided continuous symptom control and improvement of quality of life in all four patients. Lanadelumab showed a good safety profile and may be considered as a therapeutic option for FACAS patients.