Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study

Fisher, BA; Mariette, X; Papas, A; Grader-Beck, T; Bootsma, H; Ng, WF; van Daele, PLA; Finzel, S; Noaiseh, G; Elgueta, S; Hermann, J; McCoy, SS; Akpek, E; Bookman, A; Sopala, M; Montecchi-Palmer, M; Luo, WL; Scheurer, C; Hueber, W; TWINSS study group

doi:10.1016/s0140-6736(24)01211-x

Sjögren's disease & overlap diseases

Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study

LancetPublished 31 Jul 2024Randomised controlled trial

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Authors' conclusion

The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24.

Study context

Population: Adults with SjD fulfilling ACR/EULAR 2016 criteria; cohort 1: EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥5 and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥5; cohort 2: ESSDAI <5, ESSPRI (dryness or fatigue) ≥5 and Impact of Dry Eye on Everyday Life score ≥30460 screened
Participants: 44 / 43 / 43 / 43 / 50 / 50

Comparison: Subcutaneous iscalimab (anti-CD40) 150 mg, 300 mg or 600 mg vs placebo (cohort 1); iscalimab 600 mg vs placebo (cohort 2)
Iscalimab 150 mg (cohort 1)n = 44
Iscalimab 300 mg (cohort 1)n = 43
Iscalimab 600 mg (cohort 1)n = 43
Placebo (cohort 1)n = 43reference
Iscalimab 600 mg (cohort 2)n = 50
Placebo (cohort 2)n = 50reference
Primary endpoint: Cohort 1: dose-response of iscalimab on change in ESSDAI from baseline (Multiple Comparison Procedure-Modelling (MCP-Mod)); cohort 2: effect of iscalimab 600 mg on ESSPRI
Follow-up: Week 24

Methodological detailsdouble-blind, placebo-controlled, phase 2b, dose-ranging, multicentre (71 sites, 23 countries), two cohorts

Double-blind
Placebo-controlled
Phase 2b
Dose-ranging
Multicentre (71 sites, 23 countries)
Two cohorts

Primary result

As reported in the abstract

Cohort 1: placebo-adjusted change in ESSDAI from baseline

Each group vs placebo (cohort 1)LS mean difference (95% CI)P value

Iscalimab 150 mg (cohort 1)

−3.0(−4.9 to −1.1)

P = 0.0025

Iscalimab 600 mg (cohort 1)

−2.9(−4.9 to −1.0)

P = 0.0037

Significant dose-response relationship in one of four models (Linlog model): one-sided p=0.0041

Further findings

Outcome	← Lower with iscalimab 600 mg (cohort 2) ←→ Higher with iscalimab 600 mg (cohort 2) →	LS mean change from baseline (points) (95% CI)	P value
Co-primary, cohort 2: placebo-adjusted change in ESSPRI from baseline · week 24Iscalimab 600 mg (cohort 2)vs Placebo (cohort 2)Trend towards improvement	−2−101	−0.57 (−1.30 to 0.15)	P = 0.12
	−2−101Difference, points (linear scale)

Deaths · 24 weeks

No deaths occurred

Safety

Outcome	Values
Serious adverse events, cohort 1 · 24 weeks	Placebo (cohort 1) 2% · Iscalimab 150 mg (cohort 1) 2% · Iscalimab 300 mg (cohort 1) 7% · Iscalimab 600 mg (cohort 1) 9%
Serious adverse events, cohort 2 · 24 weeks	Iscalimab 600 mg (cohort 2) 4% · Placebo (cohort 2) 4%

Serious adverse events, cohort 1: 9 patients in cohort 1

Original publication

Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study. Lancet. Published 31 July 2024. doi:10.1016/s0140-6736(24)01211-x

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