The efficacy and safety of ILARIS for the treatment of TRAPS, HIDS/MKD, and FMF was demonstrated in a 4-Part study (TRAPS, HIDS/MKD, and FMF Study 1) (NCT02059291) consisting of three separate, disease cohorts (TRAPS, HIDS/MKD, and FMF) which enrolled 185 patients aged greater than 28 days. Patients in each cohort entered a 12-week screening period (Part 1) during which they were evaluated for the onset of disease flare. Patients aged 2 to 76 years were then randomized at flare onset into a 16-week double-blind, placebo-controlled treatment period (Part 2) where they received either 150 mg ILARIS (2 mg/kg for patients weighing less than or equal to 40 kg) subcutaneously or placebo every 4 weeks. Part 3 and Part 4 of this study are ongoing.

Randomized patients in Part 2 treated with ILARIS whose disease flare did not resolve, or who had persistent disease activity from Day 8 up to Day 14 (Physician’s Global Assessment [PGA] greater than or equal to 2 or C-reactive Protein [CRP] greater than 10 mg/L and no reduction by at least 40% from baseline) received an additional dose of 150 mg (or 2 mg/kg for patients weighing less than or equal to 40 kg). Patients treated with ILARIS whose disease flare did not resolve, or who had persistent disease activity from Day 15 up to Day 28 (PGA greater than or equal to 2 or CRP greater than 10 mg/L and no reduction by at least 70% from baseline), also received an additional dose of 150 mg (or 2 mg/kg for patients weighing less than or equal to 40 kg). On or after Day 29, patients treated with ILARIS in Part 2 with PGA greater than or equal to 2 and CRP greater than or equal to 30 mg/L were also up-titrated. All up-titrated patients remained at the increased dose of 300 mg (or 4 mg/kg for patients weighing less than or equal to 40 kg) every 4 weeks.

The primary efficacy endpoint of the randomized, 16-week treatment period (Part 2) was the proportion of complete responders within each cohort as defined by patients who had resolution of their index disease flare at Day 15 and did not experience a new disease flare during the remainder of the 16-week treatment period. Resolution of the index disease flare (initial flare at the time of the randomization) was defined at the Day 15 visit as a PGA Disease Activity score less than 2 (“minimal or no disease”) and C-reactive Protein (CRP) within normal range (less than or equal to 10 mg/L) or reduction greater than or equal to 70% from baseline. The key signs and symptoms assessed in the PGA for each condition were the following: TRAPS: abdominal pain, skin rash, musculoskeletal pain, eye manifestations; HIDS/MKD: abdominal pain; lymphadenopathy, aphthous ulcers; FMF: abdominal pain, skin rash, chest pain, arthralgia/arthritis. A new flare was defined as a PGA score greater than or equal to 2 (“mild, moderate, or severe disease”) and CRP greater to or equal than 30 mg/L. In the 16-week treatment period (Part 2), patients who needed dose escalation, who crossed over from placebo to ILARIS, or who discontinued from the study due to any reason prior to Week 16 were considered as non-responders.

Patients randomized in the TRAPS cohort (N = 46) were aged 2 to 76 years (median age at baseline: 15.5 years) and of this population, 57.8% did not have fever at baseline. Randomized TRAPS patients were those with chronic or recurrent disease activity defined as 6 flares per year (median number of flares per year: 9.0) with PGA greater than or equal to 2 and CRP greater than 10 mg/L (median CRP at baseline: 112.5 mg/L). In the TRAPS cohort, 11/22 (50.0%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 21/24 (87.5%) patients randomized to placebo crossed over to ILARIS.

Patients randomized in the HIDS/MKD cohort (N = 72) were aged 2 to 47 years (median age at baseline: 11.0 years) and of this population, 41.7% did not have fever at baseline. Randomized HIDS/MKD patients were those with a confirmed diagnosis of HIDS according to known genetic MVK/enzymatic (MKD) findings, and documented prior history of greater than or equal to 3 febrile acute flares within a 6-month period (median number of flares per year: 12.0) when not receiving prophylactic treatment and during the study, had active HIDS flares defined as PGA greater than or equal to 2 and CRP greater than 10 mg/L (median CRP at baseline: 113.5 mg/L). In the HIDS/MKD cohort, 19/37 (51.4%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 31/35 (88.6%) patients randomized to placebo crossed over to ILARIS.

Patients randomized in the FMF cohort (N = 63) were aged 2 to 69 years (median age at baseline: 18.0 years) and of this population, 76.2% did not have fever at baseline. Randomized FMF patients were those with documented active disease despite colchicine therapy or documented intolerance to effective doses of colchicine. Patients had active disease defined as at least one flare per month (median number of flares per year: 18.0) and CRP greater than 10 mg/L (median CRP at baseline: 94.0 mg/L). Patients were allowed to continue their stable dose of colchicine without change. Of the 63 randomized patients, 55 (87.3%) were taking concomitant colchicine therapy on or after randomization. In the FMF cohort, 10/31 (32.3%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 27/32 (84.4%) patients randomized to placebo crossed over to ILARIS.

For the primary efficacy endpoint, ILARIS was superior to placebo in the proportion of TRAPS, HIDS/MKD, and FMF patients who resolved their index disease flare at Day 15 and had no new flare over the 16 weeks of treatment from the time of the resolution of the index flare (see Table 5).

At Day 15, a higher proportion of ILARIS-treated patients compared to placebo-treated patients experienced resolution of their index flare in all disease cohorts (see Table 6).

There was supportive evidence of efficacy for ILARIS at Day 15, as compared to placebo, for the components of the primary endpoint, CRP and PGA Disease Activity score, as well as for the secondary endpoint SAA level (see Table 7).