Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study.

BACKGROUND: Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediator production. OBJECTIVE: Assess apremilast efficacy and safety in moderate to severe plaque psoriasis. METHODS: Phase II, 12-week, multicenter, double-blind, placebo-controlled, parallel-group, dose-comparison study of 259 subjects randomized 1 : 1 : 1 to placebo, apremilast 20 mg QD or apremilast 20 mg BID. RESULTS: More subjects receiving apremilast 20 mg BID achieved ≥ 75% reduction in Psoriasis Area and Severity Index (PASI-75) vs. placebo (24.4% vs. 10.3%; P = 0.023). A similar proportion of subjects receiving apremilast 20 mg QD and placebo achieved PASI-75 at week 12 [9/87 (10.3%, each group)]. Mean per cent reduction in PASI from baseline was 17.4% for placebo, 30.3% for apremilast 20 mg QD (P = 0.021 vs. placebo) and 52.1% for apremilast 20 mg BID (P < 0.001). Apremilast 20 mg BID significantly decreased mean body surface area involvement vs. placebo (30.8% vs. 3.2%; P < 0.001). The most common adverse events were headache, nasopharyngitis, diarrhoea and nausea. Most events (> 90%) were mild to moderate and did not lead to study discontinuation. Serious adverse events occurred in four placebo subjects (panic attack, hospitalization for rehabilitation, hospitalization for alcoholism, worsening psoriasis), one receiving apremilast 20 mg QD (knee surgery) and in one receiving apremilast 20 mg BID (worsening psoriasis). The panic attack was considered treatment-related; both cases of worsening psoriasis occurred after medication discontinuation. No deaths or opportunistic infections were reported. CONCLUSION: Apremilast 20 mg BID for 12 weeks was effective and well tolerated in subjects with moderate to severe plaque psoriasis.

An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast.

OBJECTIVE: To evaluate the clinical and biological activity of apremilast in patients with severe plaque-type psoriasis. RESEARCH DESIGN AND METHODS: Apremilast, a phosphodiesterase-4 inhibitor, inhibits in vitro activity of multiple inflammatory factors implicated in the pathogenesis of psoriasis. Patients received 20 mg apremilast orally for 29 days. Immunohistological analysis was conducted on lesional-skin biopsies for psoriasis-associated inflammatory markers. Lipopolysaccharide-stimulated tumor necrosis factor-alpha levels were evaluated in blood. Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment, and Body Surface Area were used to monitor disease severity. RESULTS: There were 19 patients enrolled in this study, of whom 17 completed the study. Epidermal thickness was reduced by a mean of 20.5% from baseline to day 29. Among the responders, T cells were reduced by 28.8% and 42.6% in the dermis and epidermis, respectively. Similarly, CD11c cells were reduced by 18.5% and 40.2% in the dermis and epidermis, respectively. Fourteen of the 19 (73.7%) patients demonstrated an improvement in their PASI scores. LIMITATIONS: This was a small, single-arm, open-label pilot study; therefore there was neither a placebo nor a comparison group. CONCLUSION: Apremilast demonstrated biological activity and improved psoriasis clinical efficacy scores in patients with severe plaque-type psoriasis. The majority of adverse events were mild in nature. Two adverse events (fatigue and dizziness) were judged by the investigator to be moderate and related to apremilast. In addition, there were no clinically-relevant abnormal laboratory test results in subjects treated with apremilast for 29 days.

Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab).

BACKGROUND AND OBJECTIVE: There seems to be a strong causal relationship between allergy and the origins of asthma. Susceptibility to both is determined by a combination of genetics and environment acting through a complex network of cytokines. Nearly 90% of affected children have positive skin tests indicating the presence of specific immunoglobulin E (IgE), with sensitivity to house dust mite, Alternaria, cockroach, cat, and dog most closely linked to the disease. Greater exposure to house dust mite during infancy leads to earlier onset of wheezing, and elevated serum IgE levels correlate with the appearance of asthma symptoms. Specific IgE binds to high-affinity (FcepsilonRI) receptors on mast cells and basophils. The IgE-mediated reactions that follow exposure of sensitized mast cells to an allergen are designated early- and late-phase asthmatic responses (EAR and LAR). EAR is characterized by release of histamine and other preformed mediators within 1 hour of allergen exposure. It is often followed by LAR, an infiltration of the airways by inflammatory cells associated with an episode of more prolonged, and usually more severe airflow obstruction, 4 to 8 hours after antigen exposure. Chronic airway symptoms result from persistent LAR caused by continuous allergen exposure. IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity. IgE-mediated mast cell activation contributes to chronic tissue eosinophilia and airway remodeling, with permanent loss in pulmonary function. Omalizumab (rhuMAb-E25) is a recombinant, humanized, monoclonal anti-IgE antibody of mouse origin developed for the treatment of IgE-mediated diseases. Omalizumab binds to free IgE at the same site as the high-affinity receptor. Although it attaches to free IgE, it does not bind to IgA, IgG, or cell-bound IgE. It therefore does not induce cross-linking of cell-bound IgE, which would lead to the release of allergic mediators. It has been reported to decrease serum IgE levels in a dose-dependent manner, inhibit EAR and LAR, and cause a down-regulation of FcepsilonRI receptors on basophils. Omalizumab has been reported to be safe and effective in improving asthma control and reducing the requirement for oral and inhaled corticosteroids. This double-blind, randomized, placebo-controlled study evaluated the safety, steroid-sparing effects, and impact on disease exacerbations of omalizumab in the treatment of childhood asthma. Methods. Participants were 334 males and premenarchal females aged 6 to 12 years, with moderate to severe allergic asthma requiring treatment with inhaled corticosteroids. During a run-in phase, all children were switched to equivalent doses of beclomethasone dipropionate (BDP), and the dose was adjusted to assure maintenance of asthma control achieved with previous corticosteroid treatment. Children were randomized to subcutaneously administered placebo (N = 109) or omalizumab (N = 225) at a dose based on body weight and initial serum IgE (0.016 mg/kg/IgE [IU/mL] per 4 weeks). BDP dose (initial range 168-420 microg/d) was kept stable for 16 weeks (stable-steroid phase), reduced over 8 weeks to the minimum effective dose (steroid-reduction phase), and maintained constant for the final 4 weeks. RESULTS: More participants in the omalizumab group decreased their BDP dose, and their reduction was greater than that of the placebo group (median reduction 100% vs 66.7%). BDP was withdrawn completely in 55% of the omalizumab group versus 39% of the placebo group. The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the omalizumab group. The treatment differences were statistically significant during the steroid-reduction phase, during which fewer participants in the omalizumab group had asthma exacerbation episodes (18.2% vs 38.5%), and the mean number of episodes per patient was smaller than with placebo (0.42 vs 2.72). Five asthma exacerbations requiring hospitalization all occurred in the placebo group. Participants' and investigators' global evaluations of treatment effectiveness were more favorable for omalizumab than placebo. Investigators rated effectiveness excellent for 31.5% of the omalizumab group versus 16.3% of the placebo group and good for 44.7% of the omalizumab group versus 32.7% of the placebo group. There was little change in asthma symptom scores or spirometry measurements during either the stable-steroid or steroid dose-reduction phase, with minimal differences between the treatment groups. The requirement for rescue medication in the omalizumab group during both the stable-steroid and steroid dose-reduction phases was consistently lower than at baseline. At week 28, the median number of puffs of rescue medication taken daily was 0 in the omalizumab group and 0.46 in the placebo group. The change from baseline was significant in favor of omalizumab. (ABSTRACT TRUNCATED)

Efficacy, pharmacodynamics, and pharmacokinetics of CGP 51901, an anti-immunoglobulin E chimeric monoclonal antibody, in patients with seasonal allergic rhinitis.

The efficacy, pharmacodynamics, and pharmacokinetics of CGP 51901, a recombinant monoclonal mouse-human chimeric anti-human immunoglobulin E (IgE) antibody were evaluated for 153 patients with seasonal allergic rhinitis treated with placebo or with 15, 30, or 60 mg CGP 51901 in six biweekly doses. Seasonal allergic rhinitis was chosen to validate the concept of anti-IgE therapy because the causal and temporal relation between allergen confrontation and IgE-mediated evocation of symptoms is firmly established. A sustained 85% or greater reduction of serum free IgE levels was shown to be effective in improving clinical symptoms. The concentration of CGP 51901 needed to maintain 85% or greater reduction of IgE was estimated to be about 5000 ng/ml. Baseline IgE levels and body weights of the patients greatly influenced the pharmacokinetic and pharmacodynamic profiles of CGP 51901. A population model was developed and refined to take into account patient baseline IgE level and body weight. The model was able to help predict multiple-dose pharmacokinetic and pharmacodynamic profiles on the basis of single-dose pharmacokinetic and pharmacodynamic measurements in the therapeutically effective dose range.

Immune regulation in type 1 diabetes.

The non-obese diabetic (NOD) mouse is an animal model of insulin-dependent diabetes mellitus (IDDM) that shows many of the characteristics of human IDDM. In the NOD model, there exists a discrepancy between the onset of insulitis and diabetes suggesting the potential existence of some form of immune regulation that delays beta cell destruction. Our transfer system using NOD-scid/scid (NOD-scid) mice as recipients of donor NOD cells suggested that immune regulatory cells exist in the periphery of NOD mice, not in the islets. These regulatory cells are considered to be memory CD4+ cells which show a Th2 (or Th zero) type cytokine profile following activation in vitro. The function of the memory CD4+ cells seems to change from protective to pathogenic as the disease progresses. Moreover, cytokine profiles of this CD4+ CD45RBlow (memory) population shifted from a Th2 (or Th zero) to a Th1 type response coincident with the onset of hyperglycaemia. These data suggest that the progression of NOD disease from insulitis to frank hyperglycaemia is under the control of CD4+ CD45RBlow immune 'regulatory' cells.

Pathogenic and protective roles of CD45RB(low) CD4+ cells correlate with cytokine profiles in the spontaneously autoimmune diabetic mouse.

The adoptive transfer of splenocytes from diabetic NOD mice to NOD-scid/scid (NOD-scid) recipients results in diabetes. This model was used to test the effect of cotransfer of splenocyte subsets from young nondiabetic NOD mice. As shown previously in other NOD models, the CD4+ subset from young nondiabetic mice significantly delayed the onset of diabetes in splenocyte cotransfers (P < 0.001). The data presented here showed that the development of diabetes in NOD-scid recipients correlated with a rapid increase in peripheral CD45RB(low) CD4+ cells. However, the CD45RB(low) subset of CD4+ cells from young nondiabetic mice protected from diabetes transfer in this model. We therefore examined whether CD45RB(low) CD4+ cells from diabetic mice were pathogenic rather than protective. CD45RB(low) CD4+ splenocytes from diabetic NOD mice were transferred along with CD8+ splenocytes from diabetic mice into NOD-scid recipients, and all of the recipients became diabetic within 5 weeks posttransfer. In contrast, no recipients (0 of 10) of CD45RB(high) CD4+ cells along with CD8+ splenocytes from diabetic mice became diabetic within 5 weeks posttransfer (P < 0.001). A correlate for the difference between CD45RB(low) CD4+ cells from diabetic NOD mice and CD45RB(low) CD4+ cells from nondiabetic mice, which showed protective effect in splenocyte cotransfers, was found in cytokine production after stimulation with anti-CD3 antibodies in vitro. CD45RB(low) CD4+ cells from diabetic mice showed a significantly higher ratio (approximately fivefold) of gamma-interferon (IFN-gamma) to interleukin (IL)-4 when compared with CD45RB(low) CD4+ cells from nondiabetic mice (P < 0.001). In conclusion, the function of the CD45RB(low) population of CD4+ cells changes from a protective to a pathogenic one during the development of disease in the NOD mouse. This change in function correlates with cytokine production in vitro; increased IFN-gamma-to-IL-4 ratio is associated with pathogenic potential and occurs coincident with (or after) the onset of diabetes.

Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice.

In an effort to study the development of diabetes in NOD mice, our laboratory developed a novel adoptive transfer model using NOD-scid/scid (NOD-scid) mice as recipients of islet-infiltrating lymphocytes from donor prediabetic female NOD mice. We first confirmed previous results that demonstrated that splenocytes of diabetic and prediabetic female NOD mice could transfer diabetes to NOD-scid mice. We demonstrated that the kinetics of disease transfer were dependent on the age of transferred lymphocytes and reiterated the kinetics of diabetes in conventional female NOD mice. We then demonstrated that islet-infiltrating lymphocytes from prediabetic female NOD mice could transfer diabetes. In contrast with the age-dependent transfer of diabetes seen using splenocytes, islet-infiltrating lymphocytes obtained from prediabetic female NOD mice aged > or = 40 days rapidly transferred diabetes to NOD-scid recipients. The time required to transfer insulin-dependent diabetes mellitus (IDDM) using islet-infiltrating lymphocytes from young prediabetic mice (25 +/- 9 days) was not statistically different from the time required to transfer IDDM using splenocytes from overtly diabetic mice (32 +/- 5 days). Cotransfer of splenocyte cells or CD4+, but not CD8+ spleen cells, from 60- to 80-day-old prediabetic female NOD mice together with either splenocytes from diabetic mice or islet-infiltrating lymphocytes from prediabetic NOD mice delayed the rapid transfer of IDDM, suggesting that CD4+ cells mediated immunoregulation. Use of the NOD-scid islet-infiltrating lymphocyte-adoptive transfer model should help elucidate the pathophysiology of the early inflammatory events leading to insulitis and subsequent beta-cell destruction.(ABSTRACT TRUNCATED AT 250 WORDS)