CD40-CD154 blockade pivotal in Sjögren’s syndrome treatment?
The novel nondepleting, anti-CD40 monoclonal antibody iscalimab showed preliminary signs of efficacy in patients with primary Sjögren’s syndrome (SjS), a study has shown.
Treatment for primary SjS is limited to symptomatic care and no systemic therapies have shown efficacy, noted the researchers. “[Evidence] suggest that CD40-CD154 interactions might be involved in the pathology of primary SjS. However … no clinical evidence supports a pivotal role for this pathway in [this setting]. If this costimulatory pathway were to be involved, blockade in patients with clinically active primary SjS might provide therapeutic benefit,” they added.
Forty-four participants initially underwent a 12-week double-blind phase followed by a 12-week open-label phase where all participants received iscalimab. In the double-blind phase, participants were randomized 2:1 to receive either subcutaneous (SC) iscalimab 3 mg/kg or placebo (cohort 1; n=12) or intravenous (IV) iscalimab 10 mg/kg or placebo (cohort 2; n=32) at weeks 0, 2, 4, and 8. An 8-week follow up ensued thereafter. [Lancet Rheumatol 2020;2:PE142-E152]
Infused, higher dose steps up
Despite the lack of significant between-group difference in ESSDAI scores in cohort 1, in cohort 2, four infusions of iscalimab led to a mean reduction in ESSDAI score vs placebo (-5.21 points; pone-sided=0.009), which reflects reduction in disease activity.
The open-label phase saw sustained ESSDAI score reductions – particularly among those who initiated with iscalimab – at week 14 (-3.85 points; pone-sided=0.038), week 16 (-2.57 points; pone-sided=0.049), and week 20 (-3.77 points; pone-sided=0.015). Placebo recipients who switched to active treatment did manifest improvements at week 12. These reductions further highlight the efficacy of the infused, higher-dose iscalimab, said the researchers.
Post hoc analysis reinforced these results, given the 6.1-point reduction in clinical ESSDAI (ie, ESSDAI without biological domain) with IV iscalimab vs placebo at week 12.
SC iscalimab led to mean trough plasma concentrations <10 μg/mL which was substantially lower than expected. [Am J Transplant 2019;doi:10.1111/ajt.15661] On the contrary, the mean trough plasma concentrations of >100 μg/mL in cohort 2 were deemed sufficient for suppressing germinal centre development and inhibition of T-cell-dependent antigen responses in nonhuman primates, thus suggesting a dose-response relationship for iscalimab. [Am J Transplant 2018;18:2895-2904; Toxicol Sci 2018;166:192-202]
All cohort 1 patients reported at least one mild/moderate adverse event (AE), while in cohort 2, AEs were reported by 52 percent and 64 percent of iscalimab and placebo recipients, respectively. The most frequent AE in both cohorts was upper respiratory tract infection. No major safety signals were reported in both cohorts during the open-label phase.
The absence of injection site reactions, cytopenias, or thromboembolic events, which have been observed with biologicals targeting CD154, further imply that iscalimab was well-tolerated. [Arthritis Rheum 2003;48:719-727]
CD40 blockade: beyond B-cell depletion
Although the B-cell–depleting drug rituximab has been used in some SjS cases, its therapeutic benefit apparently varies. [Arthritis Rheumatol 2017;69:1440-1450] “Therefore, CD40 blockade with iscalimab could have additional effects beyond targeting B-cell hyperreactivity in primary SjS, possibly due to involvement of CD40-expressing non-B cell types in primary SjS pathology,” explained the researchers. This theory is supported by a study showing a drop in macrophage count following CD40-CD154 blockade in mice. [Ann Rheum Dis 2019;78:974-978]
Taken together, the findings reflected clinically meaningful reduction in disease activity with this new investigational drug and highlighted the pivotal role of CD40-CD154 interactions in this setting, said the researchers. “[Our findings suggest that] CD40-CD154 signalling is a key pathway associated with the underlying pathology of primary SjS.”
These findings are important given the increased risk of lymphoma associated with the progressive immune-mediated dysfunctions tied to SjS. [N Engl J Med 2018;378:931-939] However, given the small sample size, short duration, and lack of statistical significance in some efficacy findings, larger trials with longer durations are warranted to ascertain the therapeutic potential of CD40 blockade in this setting, noted the researchers.
It should also be noted that despite the improvement observed in the articular domain of ESSDAI, this was also the most severely affected at baseline. “[F]urther study of tender and swollen joint counts and the disease activity score using 28 joint counts [is thus warranted] to understand the importance of this domain in driving ESSDAI improvements,” they added.