2.23.1 Sifalimumab phase II trial
Sifalimumab is a fully human monoclonal antibody (immunoglobulin G1 k), which targets interferon (IFN) signalling, a pathway that has been linked to the pathogenesis of SLE. Sifalimumab neutralizes the majority of IFN-a subtypes. It met its primary endpoint of SRI (4) in phase II randomized controlled trial comparing three doses with placebo, although was not progressed to phase III studies due to the superiority of another molecule, anifrolumab [114, 382]. In a post-hoc analysis of the data from the phase II study, patients who had at least eight tender and eight swollen joints at baseline were analysed for at least 50% improvement in joint counts. In (Table 2-12) I have summarized some of the key endpoints from that paper and also calculated the difference in response rates from placebo.
Table 2-12. Post hoc analysis of joint count improvement in the sifalimumab phase II trial: N Placebo 200mg (%) Δ vs. placebo 600mg (%) Δ vs. placebo 1200mg (%) Δ vs. placebo SRI-4 431 45 58 13 57 12 60 15 BICLA 429 36 45 9 47 11 48 12 Swollen joints baseline
431 6.3 6.6 N/A 6.8 N/A 6.4 N/A
Tender joints baseline
431 10.1 10.4 N/A 8.6 N/A 9.3 N/A
50% Joints*
155 37 54 17 58 21 61 24
*50% improvement in joint counts, calculated only for patients who had at least 8 tender and swollen joints at baseline.
These would data would appear to suggest that the 50% improvement in joint counts was better able to differentiate treatment arms compared to the SRI-4 or BICLA. However, it must be noted that far fewer patients were included in the joint count endpoint as more musculoskeletal disease activity was required at baseline. Therefore, the musculoskeletal subgroup may also have responded differently to the SRI-4 and BICLA. This analysis was not presented in the paper and was, therefore, a question I sought to address in my research.
2.23.2 Anifrolumab phase II trial
The MUSE study was a multi-center, randomized, double-blind, placebo-controlled Phase IIb trial of anifrolumab, a monoclonal antibody that targets the shared interferon receptor, and therefore achieves better neutralization of interferon signalling than by targeting the various ligands for this receptor [382]. Patients with active SLE (defined as SLEDAI-2K ≥ 6 plus 1 BILAG-A boost or 2 BILAG-B relapses plus activity as seen by the physician VAS (0-3) ≥1) [47]. There was a randomization 1:1:1 to placebo, anifrolumab 300 mg or anifrolumab 1000
mg every 4 weeks. In addition, individual arms were subdivided according to the type I IFN signature. The primary endpoint was the SLE responder index (SRI, SLEDAI 2K reduction by ≥4 points, no new BILAG-A or no more than 1 new BILAG-B thrust, no worsening of ≥0.3 from the physician's perspective) combined with a reduction in the glucocorticoid dose from week 12 to week 24 to <10 mg / day, as a secondary endpoint with continuing glucocorticoid dose reduction at week 40-52 and a glucocorticoid dose of < 7.5 mg / day. Other outcomes were CLASI improvement of> 50% (if initially> 10) and> 50% reduction of swollen plus tender joints (if ever ≥8). A similar analysis to sifalimumab is presented below in Table 2-13.
Table 2-13. Post hoc analysis of joint count improvement in the anfirolumab phase II trial: n Placebo 300mg (%) Δ vs. placebo 1000mg (%) Δ vs. placebo SRI-4 305 18 34 16 29 11 BICLA 302 26 54 22 41 15 Swollen joints baseline 305 8.3 8.6 N/A 8.3 N/A Tender joints baseline 305 10.5 12.2 N/A 11.6 N/A 50% Joints* 131 49 70 21 65 16
*50% improvement in joint counts, calculated only for patients who had at least 8 tender and swollen joints at baseline. SRI-4, systemic lupus erythematosus responder index using a 4-point reduction in SLEDAI; SLE, systemic lupus erythematosus; SLEDAI-2K, systemic lupus erythematosus disease activity index, BICLA: British Isles Lupus Assessment Group-based Combined Lupus Assessment.
In this case it is somewhat less clear whether the joint count criterion differentiated treatment groups better than the BICLA. However, comparing these data with those in (Table 2-12) highlights another important point. The baseline joint counts in the two studies differed, being higher in the anifrolumab trial. Even if a threshold of eight tender and swollen joints is required before analyzing for 50% improvement, there would still be a difference in the mean baseline joint counts of patients within that subgroup. Since the criteria for the different BILAG and SLEDAI grades are based on a fixed threshold of 0, 2 or 3 joints, the degree of mismatch between a 50% improvement and BILAG and SLEDAI response will differ depending on the
baseline joint counts.
Further post-hoc analysis of arthritis parameters was published separately [383]. In this publication, the emphasis was on comparing the improvements seen in patients with or without a high interferon signature at baseline. Surprisingly, almost all the patients in the trial had active arthritis (according to SLEDAI) at baseline. The authors reported three different measures of arthritis improvement: SLEDAI-2K improvement; BILAG-2004 improvement and mean change in joint counts. Interestingly, a different conclusion regarding the predictive value of the interferon signature was drawn depending on which of the arthritis measures was used (Table 2-14).
Table 2-14: post-hoc analysis for the anifrolumab trial:
All patients IFN High IFN Low
Anifrolumab Placebo Anifrolumab Placebo Δ vs. placebo Anifrolu mab Placebo Δ vs. placebo SLEDAI response (%) 56.7 42.4 56.2 39.7 16.5 58.3 50.0 8.3 BILAG improvement (%) 69.1 49.5 66.2 47.2 19 78.3 56.5 21.8 Change mean joint count -5.5 -3.4 -4.9 -3.0 -1.9 Not given Not given -
SLEDAI: SLE Disease Activity index, BILAG: British Isles Lupus Assessment Group. IFN: interferon
2.23.3 Combined post-hoc analysis of sifalimumab and anifrolumab trials
Post-hoc analysis of the data from two 52-week studies of sifalimumab and anifrolumab. At Week 52, of the 736 patients recruited from both studies, 396 were SRI (4) responders, and 340 were non responders. They used different outcome measures to compare between the
responder and non-responder groups which included : The percentage of patients with a 7- point reduction in SLEDAI–2K; changes from baseline in clinical components of the SLEDAI– 2K and PhGA scores; percentage of patients with BILAG ‘‘A’’ or ‘‘2B’’ flares; the numbers of SLEDAI–2K organ domains with improvement; and the percentages of patients with reductions in oral corticosteroid dosage to 7.5 mg/day, 50% improvement in swollen and tender joint count, and 50% improvement in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). A greater percentage of SRI (4) responders had a 7 point reduction in SLEDAI–2K score compared with non-responders (p < 0.001). SRI (4) responders had a greater mean percentage change from baseline in clinical SLEDAI and Physician GA score than non-responders (p < 0.001). Moreover, a lower percentage of SRI (4) responders had 1 flare as measured by BILAG ‘‘A’’ or ‘‘2B’’ flare rates, in comparison to non-responders (p < 0.001), whereas the mean number of organ domains with improvement in SLEDAI–2K was greater in SRI (4) responders vs. non responders (p <0.0001). Similarly, greater percentages of SRI(4) responders achieved a reductions in oral corticosteroid dose to 7.5 mg/day (for patients who were receiving 10 mg/day oral corticosteroid at baseline), as well as 50% improvements in swollen and tender joint count, and a 50% improvement in CLASI, compared with non-responders (p < 0.001).