Safety and Efficacy of Lenabasum in a Phase II, Randomized, Placebo-Controlled Trial in Adults With Systemic Sclerosis

Abstract

Objective: To assess the safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis (dcSSc).

Methods: A randomized, double-blind, placebo-controlled, phase II study was conducted at 9 SSc clinics in the US. Adults with dcSSc of ≤6 years' duration who were receiving stable standard-of-care treatment were randomized to receive lenabasum (n = 27) or placebo (n = 15). Lenabasum doses were 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, followed by 20 mg twice daily for 8 weeks. Safety and efficacy were assessed at weeks 4, 8, 12, and 16.

Results: Adverse events (AEs) occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious AEs related to lenabasum. Compared to placebo, lenabasum treatment was associated with greater improvement in the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score and other efficacy outcome measures that assessed overall disease, skin involvement, and patient-reported function. The median CRISS score increased in the lenabasum group during the study, reaching 0.33, versus 0.00 in the placebo group, at week 16 (P = 0.07 by 2-sided mixed-effects model repeated-measures analysis). Gene expression in inflammation and fibrosis pathways was reduced, and inflammation and fibrosis were improved on histologic evaluation of skin biopsy specimens, in the lenabasum group compared to the placebo group (all P ≤ 0.05).

Conclusion: Despite a short trial duration in a small number of patients in this phase II study in dcSSc, our findings indicate that lenabasum improves efficacy outcomes and underlying disease pathology with a favorable safety profile.

Figure 1

Effects of lenabasum on overall disease in patients with systemic sclerosis (SSc). A, American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score at the indicated weeks in patients with SSc treated with lenabasum (blue) or placebo (orange). CRISS score was not determined at baseline. Data are shown as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. Lines outside the boxes represent the minimum and maximum values. Circles indicate individual patients (some values overlap). B, Change from baseline in patient global assessment of overall health (PtGA) related to SSc in patients receiving lenabasum (blue) or placebo (orange). Values are the mean ± SEM. The mean ± SD baseline score was 5 ± 2.8 in the placebo group and 5 ± 2.3 in the lenabasum group. C, Change from baseline in physician global assessment of overall health (MDGA) related to SSc in patients receiving lenabasum (blue) or placebo (orange). Values are the mean ± SEM. The mean ± SD baseline score was 5 ± 2.1 in the placebo group and 5 ± 1.8 in the lenabasum group. Missing data were imputed using the last observation carried forward method. For CRISS score at week 16, patient global assessment at week 8, and physician global assessment at week 8, P ≤ 0.05 by 1‐sided mixed‐effects model repeated‐measures (MMRM) analysis and P ≤ 0.10 by 2‐sided MMRM analysis. For CRISS score at week 8 and patient global assessment at week 12, P ≤ 0.10 by 1‐sided MMRM analysis and P ≤ 0.15 by 2‐sided MMRM analysis.

Figure 2

Effects of lenabasum on skin involvement in patients with SSc. A, Change from baseline in modified Rodnan skin thickness score (MRSS) in patients with SSc treated with lenabasum (blue) or placebo (orange). The mean ± SD baseline score was 26 ± 11.1 in the placebo group and 24 ± 10.4 in the lenabasum group. B, Change from baseline in Scleroderma Skin Patient‐Reported Outcome (SSPRO) in patients with SSc treated with lenabasum (blue) or placebo (orange). The mean ± SD baseline score was 83 ± 32.6 in the placebo group and 73 ± 27.3 in the lenabasum group. C, Change from baseline in 5‐D itch score in patients with SSc treated with lenabasum (blue) or placebo (orange). The mean ± SD baseline score was 12.9 ± 5.3 in the placebo group and 10.7 ± 4.4 in the lenabasum group. Values are the mean ± SEM. Missing data were imputed using the last observation carried forward method. For SSPRO at week 12, P ≤ 0.005 by 1‐sided MMRM analysis and P ≤ 0.01 by 2‐sided MMRM analysis. For SSPRO at week 4 and 5‐D itch score at week 12, P ≤ 0.05 by 1‐sided MMRM analysis and P ≤ 0.10 by 2‐sided MMRM analysis. For MRSS at week 16, P ≤ 0.10 by 1‐sided MMRM analysis and P ≤ 0.50 by 2‐sided MMRM analysis. See Figure 1 for other definitions.

Figure 3

Effects of lenabasum on patient‐reported function in patients with SSc. A, Change from baseline in Health Assessment Questionnaire (HAQ) disability index (DI) in patients with SSc treated with lenabasum (blue) or placebo (orange). The mean ± SD baseline score was 1.5 ± 0.79 in the placebo group and 1.1 ± 0.80 in the lenabasum group. B, Change from baseline in Patient‐Reported Outcomes Measurement Information System 29‐item general health profile (PROMIS‐29) physical function score in patients with SSc treated with lenabasum (blue) or placebo (orange). The mean ± SD baseline score was 38 ± 7.2 in the placebo group and 43 ± 8.5 in the lenabasum group. C, Change from baseline in PROMIS‐29 social role score in patients with SSc treated with lenabasum (blue) or placebo (orange). The mean ± SD baseline score was 41 ± 7.3 in the placebo group and 46 ± 8.59 in the lenabasum group. Values are the mean ± SEM. Missing data were imputed using the last observation carried forward method. For HAQ DI at week 8, P ≤ 0.005 by 1‐sided MMRM analysis and P ≤ 0.01 by 2‐sided MMRM analysis. For HAQ DI at week 12, P ≤ 0.01 by 1‐sided MMRM analysis and P ≤ 0.05 by 2‐sided MMRM analysis. For HAQ DI at week 4 and PROMIS‐29 physical function score at week 12, P ≤ 0.05 by 1‐sided MMRM analysis and P ≤ 0.10 by 2‐sided MMRM analysis. See Figure 1 for other definitions.

Figure 4

Gene expression, inflammation, and fibrosis in skin biopsy specimens from patients with systemic sclerosis (SSc) treated with lenabasum or placebo. A–D, Gene set centroids for paired biopsy specimens from baseline and week 12. Centroids for each subject were generated by averaging expression values of all genes from the inflammatory response gene set (A and B) and extracellular matrix organization gene set (C and D) separately for baseline and week 12 samples from subjects treated with lenabasum (A and C) or placebo (B and D). P = 0.0002 in A, P = 0.48 in B, P < 0.0001 in C, and P = 0.31 in D, for baseline versus posttreatment, by paired t‐test. E, Change from baseline in inflammation and fibrosis in paired skin biopsy specimens from patients with SSc treated with placebo (n = 13) or lenabasum (n = 23). Values are the number (%) of patients with paired skin biopsy specimens that showed improvement (green), were stable (yellow), or had worsened (orange) at week 12 compared to baseline.