Introduction & Objectives
Systemic sclerosis (SSc) is a rare, multi-system, autoimmune disease of unknown origin characterized by chronic inflammation, fibrosis and small vessel damage in involved tissues. Activation of the innate immune system is a key component in disease pathogenesis in SSc. Immunosuppressive drugs, such as mycophenolate, methotrexate, glucocorticoids, cyclophosphamide and azathioprine are used for overall disease control or treatment of skin or interstitial lung disease in diffuse cutaneous SSc (dcSSc). However, imunosuppressive drugs may have only modest efficacy, with poor tolerability, and cause toxicities, such as cytopenias and infection. Further, glucocorticoid use can provoke renal crisis. Hematopoietic stem cell transplantation can provide benefit in severe, early dcSSc, but carries substantial treatment-related morbidity and mortality in the first few years after treatment. A major need for treatments that are more effective and safe enough to treat a broad spectrum of individuals with dcSSc remains.
Spiera et al. assessed the safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis (dcSSc).
Lenabasum is a synthetic, orally administered agonist of cannabinoid receptor 2 (CB2) that modulates the endocannabinoid system to activate the resolution phase of innate immune responses. Lenabasum improves skin and lung inflammation and fibrosis when administered prophylactically or therapeutically in animal models of SSc. It reduces transforming growth factor β (TGFβ) and collagen production by isolated SSc fibroblasts, limiting fibrosis in an inflammation-independent animal model of SSc. Lenabasum is therefore a rational candidate for treatment of SSc.
The hypothesis of this study was that lenabasum would provide clinical benefit by triggering pathways that resolve adverse innate immune responses and ameliorate ongoing fibrotic processes.
A randomized, double-blind, placebo-controlled, phase 2 study was conducted at 9 SSc clinics in the US. Adults with dcSSc of six or fewer 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 four weeks, followed by 20 mg twice daily for eight weeks. Safety and efficacy were assessed at weeks 4, 8, 12 and 16.
Adverse events (AEs) occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious AEs related to lenabasum. Compared with placebo, lenabasum treatment was associated with greater improvement in ACR 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, vs. 0.00 in the placebo group, at week 16 (P=0.07 by two-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).