The clinical efficacy of ACTEMRA was assessed in a phase 3 multicenter, randomized, double-blind, placebo controlled study in patients with SSc (Study WA29767). A phase 2/3 multicenter, randomized, double-blind, placebo controlled study in patients with SSc (Study WA27788) provided supportive information. Study WA29767 (NCT02453256) enrolled adult patients with SSc defined by the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc, with onset of disease (first non-Raynaud symptom) of ≤ 5 years, modified Rodnan Skin Score (mRSS) of ≥ 10 and ≤ 35 at screening, elevated inflammatory markers (or platelets), and active disease based on at least one of the following: disease duration ≤ 18 months, increase in mRSS ≥ 3 units over 6 months, involvement of one new body area and an increase in mRSS of ≥ 2 over 6 months, or involvement of two new body areas within the previous 6 months, or presence of at least one tendon friction rub. Study WA27788 (NCT01532869) enrolled adult patients with SSc with onset of disease ≤ 5 years, mRSS of ≥ 15 and ≤ 40 at screening, active disease, and elevated inflammatory markers or platelets. Patients in both studies were not permitted to use biologic agents (such as TNF antagonists), alkylating agents, or cyclophosphamide. 

In Study WA29767, 212 patients were randomized in a 1:1 ratio to receive weekly SC injections of 162 mg of ACTEMRA or placebo during the 48-week, double-blinded, placebo controlled period. Rescue treatment was allowed during the treatment period after 16 weeks for >10% percent predicted FVC (ppFVC) decline or after 24 weeks for worsening skin fibrosis. The primary efficacy endpoint was change from baseline at Week 48 in mRSS. Change from baseline in FVC at Week 48 was a key secondary endpoint.

In the overall population of Study WA29767, there was not a statistically significant difference in the mean change from baseline to Week 48 in mRSS (primary endpoint) in patients receiving ACTEMRA compared to placebo (difference: -1.73; 95% CI: -3.78, 0.32). There also was not a statistically significant effect on the primary endpoint of mRSS in Study WA27788. 

In the overall population of Study WA29767, patients treated with ACTEMRA, as compared to placebo treated patients, were observed to have less decline from baseline in ppFVC and observed FVC at 48 weeks. FVC results from Study WA27788 were similar. 

Of the 212 patients who were randomized in Study WA29767, 68 patients (65%) in the ACTEMRA arm and 68 patients (64%) in the placebo arm had SSc-ILD at baseline, as confirmed by a visual read of high resolution computed tomograph (HRCT) by blinded thoracic radiologists. The mean ppFVC at baseline for patients with SSc-ILD identified by HRCT was 79.6% (median 80.5%). Post-hoc analyses were performed to evaluate results within the subgroups of patients with and without SSc-ILD.

Table 10 shows results from Study WA29767 for the changes from baseline to Week 48 in ppFVC, observed FVC, and mRSS both in the overall population and within subgroups based on SSc-ILD status at baseline. The ppFVC and observed FVC results in the overall population were primarily driven by results in the SSc-ILD subgroup. In the SSc-ILD subgroup, the differences in mean changes from baseline to Week 48 for ACTEMRA, as compared to placebo, were 6.47% and 241 mL for ppFVC and observed FVC, respectively. Figure 2 illustrates the mean change from baseline through Week 48 in observed FVC in patients with SSc-ILD.

The results of the key FVC secondary endpoints from Study WA29767 support a conclusion of effectiveness of ACTEMRA in reducing the rate of progressive loss of lung function in the study population. However, in settings where a trial does not provide evidence of an effect on the primary endpoint, the estimated magnitude of effect on other endpoints should be interpreted with caution, and comparisons to results of other products and studies may be misleading.

Figure 2 Mean Change from Baseline to Week 48 in Observed Forced Vital Capacity in SSc-ILD Patients from Study WA29767