Safety and Efficacy of FIT039 for Verruca Vulgaris: A Placebo-Controlled, Phase I/II Randomized Controlled Trial.

TRIAL DESIGN: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. METHODS: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. RESULTS: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. CONCLUSIONS: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study.

The efficacy of a cyclin dependent kinase 9 (CDK9) inhibitor, FIT039, on verruca vulgaris: study protocol for a randomized controlled trial.

BACKGROUND: Human papilloma viruses (HPVs) infect squamous epithelial cells and form verrucous lesions, or warts. Besides the psychosocial problems caused by the disfiguring warts, a subset of HPVs can be the primary etiologic agent for malignancies such as cervical cancer. However, there is no curative antiviral therapy for HPV infection. We recently found that the viral RNA transcription of DNA viruses requires cyclin dependent kinase 9 (CDK9) in the host cells, and that FIT039, a specific inhibitor of CDK9, suppressed the proliferation of DNA viruses such as herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, human cytomegalovirus, hepatitis virus B, and HPVs. Here, we describe a protocol to evaluate the safety and antiviral effect of FIT039 on common warts in human skin. METHODS AND DESIGN: A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial was designed to evaluate the safety and efficacy of FIT039 on common warts on the extremities. A total of 44 adults with a primary diagnosis of verruca vulgaris on the extremities without serious comorbidities will be randomized into either the intervention group with an FIT039-releasing transdermal patch or a control group for a duration of 14 days. Outcomes will be assessed at baseline and postintervention. Participants will be further assessed at 2 months follow-up. The primary endpoint for efficacy is the resolution of the warts. The safety endpoint is the incidence of adverse events and adverse drug reactions. The secondary endpoints are changes in the dimensions of the wart, the cross-sectional area of the wart, and the number of clots within the area of the wart. DISCUSSION: This study is the first to assess the efficacy of FIT039 and will contribute to the development of antiviral agents that can cure refractory common warts in immunocompromised patients. TRIAL REGISTRATION: UMIN Clinical Trials, UMIN000029695 . Registered on 1 November 2017.

A Mild Case of Adult-Onset Keratosis Lichenoides Chronica Successfully Treated with Narrow-Band UVB Monotherapy.

Keratosis lichenoides chronica (KLC) is a rare keratotic disorder of unknown origin. Effective treatment has not been established yet. Here, we present adult-onset KLC, which was treated by narrow-band ultraviolet B (NB-UVB) monotherapy. Although NB-UVB was reported to be effective for pediatric-onset KLC, it has not been clear if this regimen is also useful for adult-onset type because pediatric-onset KLC is suggested to be different in nature. We assume that KLC is treatable by NB-UVB regardless of the age of the patient.

Skin-infiltrating monocytes/macrophages migrate to draining lymph nodes and produce IL-10 after contact sensitizer exposure to UV-irradiated skin.

Low-dose UVB exposure induces antigen-specific unresponsiveness to antigen(s) introduced through UV-irradiated skin (tolerance). Analysis of cytokine expression in murine draining lymph nodes (DLNs) revealed that IL-12p40 mRNA and protein expression as well as IL-12p70 protein were upregulated after application of the contact sensitizer 2,4 dinitro-1-fluorobenzene (DNFB) to normal skin. The cellular source of IL-12p40 mRNA was CD11c+ cells. By contrast, following DNFB application to UV-irradiated skin (UV+DNFB), IL-12p40 mRNA was not upregulated, and DLN IL-12p40 and p70 proteins were reduced. UVB irradiation alone did not upregulate IL-10 mRNA, but UV+DNFB upregulated IL-10 mRNA as early as 3-6 hours after DNFB application, immediately preceding a decrease of IL-12p40 mRNA from the level induced by UVB. The infiltration of F4/80+ cells into UV-irradiated skin was followed by a rapid and remarkable increase of F4/80+CD11c(-) cells in DLN 3 hours following DNFB application. FITC/DNFB skin painting and subsequent enzyme-linked immunospot assay demonstrated that flow-sorted FITC+F4/80+CD11c(-) cells from the DLN produce IL-10. Thus, monocytes/macrophages that infiltrated into the skin following UVB exposure migrate to the DLN triggered by contact sensitizers. Production of IL-10 by migrating macrophages, in conjunction with IL-12 inhibition in the DLN, likely reflects a role as mobile suppressive mediators for locally induced UV tolerance.

A phase 1, double-blind, placebo-controlled study evaluating single subcutaneous administrations of a human interleukin-12/23 monoclonal antibody in subjects with plaque psoriasis.

OBJECTIVE: To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutaneous (s.c.) administrations of a human monoclonal antibody against the p40 subunit of IL-12/23 (IL-12/23 mAb) in subjects with moderate-to-severe psoriasis. METHODS: Twenty-one subjects were enrolled sequentially into 4 dose cohorts (0.27, 0.675, 1.35, and 2.7 mg/kg) and randomized to IL-12/23 mAb or placebo in a 4:1 ratio. Laboratory/clinical parameters and pharmacokinetics were evaluated through Week 24; mRNA cytokine expression was measured in psoriatic plaques at Week 1. RESULTS: Mostly mild adverse events and no serious adverse events were reported. The pharmacokinetics (Cmax and AUC) of IL-12/23 mAb increased in an approximately dose-proportional manner. Of the 17 subjects who received IL-12/23 mAb, 13 achieved PASI 75 (compared with no placebo subjects). mRNA expression of IL-8, IL-18, and IFN-gamma in psoriatic plaques decreased in subjects with sustained Psoriasis Area and Severity Index (PASI) improvement. LIMITATIONS: Interpretation of results is limited due to the small sample size in each dose cohort. CONCLUSION: A single s.c. administration of IL-12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis.

An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis.

Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-gamma) and chemokines (IL-8, IFN-gamma-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-alpha levels and infiltrating T cells were observed in high responders (improvement in clinical score, > or =75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-alpha significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.

Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.

The balance between regulatory and effector functions is important for maintaining efficient immune responses, while avoiding autoimmunity. The inflammatory skin disease psoriasis is sustained by the ongoing activation of pathogenic effector T cells. We found that a CD4(+) T lymphocyte subpopulation in peripheral blood, phenotypically CD25(high), CTLA-4(+), Foxp3(high) (regulatory T (Treg) cells), is deficient in its suppressor activity in psoriasis. This was associated with accelerated proliferation of CD4(+) responder T cells in psoriasis, the majority of which expressed CXCR3. Nevertheless, criss-cross experiments isolated the defect to psoriatic Treg cells. To examine Treg cells in a nonlymphoid tissue of a human T cell-mediated disease, Treg cells were also analyzed and isolated from the site of inflammation, psoriatic lesional skin. At the regulatory vs effector T cells ratios calculated to be present in skin, however, the psoriatic Treg cell population demonstrated decreased suppression of effector T cells. Thus, dysfunctional blood and target tissue CD4(+)CD25(high) Treg cell activity may lead to reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo. These findings represent a critical component of human organ-specific autoimmune disease and may have important implications with regard to the possible therapeutic manipulation of Treg cells in vivo.

A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis.

The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.

Cell surface and cytokine phenotypes of skin immunocompetent cells involved in ultraviolet-induced immunosuppression.

Immunocellular migrations out of and into the skin and modulations of functional cell surface molecules on antigen-presenting cells (APCs), as well as their immunoregulatory cytokine production, are important factors involved in the mechanism of UV-induced immunosuppression and tolerance. Of particular interest here are the effects of low-dose UVB exposures that can suppress the ability of a contact sensitizer to induce contact hypersensitivity (CHS) through the site (local immunosuppression) without inducing suppression of CHS induced through skin distant to the UV exposure. Such UV-irradiated skin has many changes with respect to composition of immunocompetent cells and cytokine production. After UV exposure, Langerhans cells/dendritic cells migrate from the skin to draining lymph nodes (DLNs) as they do from contact sensitizer-applied normal skin. On the other hand, UV causes monocytic/macrophagic cells to infiltrate into the dermis and then into the epidermis; these can also be shown to be induced by contact sesitizers to migrate to DLNs. Alterations in cell surface and immunoregulatory cytokine phenotypes of the cutaneous APCs in both the skin and DLNs are critical for CHS suppression and tolerance induction. Here we describe the phenotypic changes of immunocompetent cells in UV-irradiated skin in regard to CHS suppression and tolerance and methodologies to approach this area.