VML 295 (LY-293111), a novel LTB4 antagonist, is not effective in the prevention of relapse in psoriasis

Abstract

Leukotriene B4 (LTB4) receptor antagonists have been the subject of several studies in the treatment of inflammatory diseases, including psoriasis. A novel oral LTB4 antagonist, VML 295 (LY-293111) has recently been developed and has a pronounced effect on epidermal inflammatory parameters. However, oral treatment of psoriasis for 4 weeks did not result in a decrease in disease severity. The present study was performed in order to investigate whether prolonged treatment with VML 295 up to 8 weeks has a beneficial effect on the overall severity of psoriasis. Moreover, we studied to what extent VML 295 is able to prevent relapse in psoriasis. In the present study, 35 patients with stable chronic plaque psoriasis were included. A representative plaque of at least 16 cm2 was initially treated with clobetasol-17-propionate lotion under hydrocolloid occlusion in all patients. Clearance was achieved within 6 weeks in 31 patients. After clearance, the patients were randomized to treatment and received oral VML 295 capsules 200 mg twice daily or placebo for 8 weeks. Twenty-five patients completed the study. The psoriasis area and severity index (PASI) was assessed before treatment, at clearance, and on days 15, 29, 43 and 5 7 of the treatment period. Biopsies were taken from the treated lesion before treatment, after clearance and at relapse, and cells were analysed by flow cytometry with markers for differentiation (keratin 10), inflammation (vimentin), and proliferation (DNA content). After 8 weeks of treatment, 14 of 15 VML 295-treated patients had relapsed and 11 of 16 placebo-treated patients had relapsed. A total of six patients were withdrawn. The time to relapse and the number of relapsed patients was not significantly different comparing the treatment groups. There was no significant difference in PASI scores between VML 295-treated patients and placebo-treated patients after 8 weeks of treatment. Flow cytometric parameters for differentiation, inflammation and proliferation did not show significant differences between VML 295- and placebo-treated patients. We conclude that oral VML 295 (LY-293111) is not effective in preventing relapse in psoriasis, either clinically or at the cellular level, and that in our group of patients VML 295 had no beneficial effect on overall psoriasis severity. Moreover, we conclude that further development of LTB4 modulating drugs for the treatment of psoriasis is not indicated.

20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4-mediated responses of human neutrophils and eosinophils

“…As such, LTB 4 blockade was seen as a promising anti‐inflammatory strategy. However, clinical trials involving LTB 4 modifiers failed to diminish chronic inflammation, and often failed to reduce neutrophil or eosinophil numbers in asthma, rheumatoid arthritis and other diseases . This indicated that LTB 4 was not a critical pro‐inflammatory effector in humans.…”

Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis

“…However, a randomized, controlled trial of another BLT1 antagonist, VML295, in patients with psoriasis did not alleviate the psoriasis severity (48). Although the clinical utility of BLT1 antagonists for psoriasis still remains controversial, the involvement of LTB 4 in the pathogenesis of psoriasis was strongly suspected by the abundance of LTB 4 in human psoriatic skin and the fact that topical application of LTB 4 on the skin induces flare and epidermal hyperproliferation in humans (8).…”

A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours

“…Starting doses LY293111 has been tested in healthy volunteers and patients at doses up to 200 mg BID [8]. The most common adverse event observed was diarrhea.…”

“…LY293111 affects human neutrophils by inducing chemotaxis, aggregation, calcium mobilization, superoxide production and upregulation of the CD11b/CD18 adhesion receptor. This drug was initially developed and clinically investigated as a treatment of inflammatory diseases including asthma, inflammatory bowel disease and psoriasis but unfortunately despite a very favorable toxicity profile it had an absence of clinically significant efficacy in these diseases [8,9].…”