Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: We assessed the efficacy, safety, and tolerability of ponesimod, an oral, selective, reversible modulator of sphingosine 1-phosphate receptor 1, in patients with moderate to severe chronic plaque psoriasis. METHODS: Between Sept 22, 2010, and Oct 24, 2012, patients with psoriasis area and severity index (PASI) scores higher than 10 were enrolled into this multicentre double-blind, phase 2 study. They received 20 mg or 40 mg ponesimod or placebo once daily for 16 weeks. Those with at least 50% reduction in PASI score at 16 weeks and who were receiving ponesimod were rerandomised to receive maintenance ponesimod therapy or placebo until week 28. The primary endpoint was reduction in PASI score from baseline of at least 75% (PASI75) at week 16. This study is registered with ClinicalTrials.gov, number NCT01208090. FINDINGS: Of 326 patients initially randomised (20 mg ponesimod n=126, 40 mg ponesimod n=133, and placebo n=67) PASI75 was achieved at week 16 in 58 (46·0%), 64 (48·1%), and nine (13·4%), respectively. The treatment effect was significant for the two ponesimod doses (both p<0·0001). Of 219 patients who entered the maintenance period, PASI75 was achieved by week 28 in 35 (71·4%) of 49 who continued on 20 mg ponesimod and 41 (77·4%) of 53 on 40 mg ponesimod, and in 19 (42·2%) of 45 who swapped from 20 mg to placebo and 19 (40·4%) of 47 from 40 mg to placebo. Ponesimod was associated with dyspnoea, raised liver enzyme concentrations, and dizziness. INTERPRETATION: Significant clinical benefit was seen at week 16 that increased with maintenance therapy. FUNDING: Actelion Pharmaceuticals.

Differential effects of ponesimod, a selective S1P1 receptor modulator, on blood-circulating human T cell subpopulations.

Ponesimod, a novel selective sphingosine-1-phosphate 1 receptor modulator in the development for the treatment of autoimmune diseases, dose-dependently reduced lymphocyte counts in peripheral blood of healthy subjects. It rapidly and transiently reduced the number of circulating T and B cells, but not natural killer cells. T lymphocyte subsets exhibited differential sensitivities with a maximum decrease from baseline ranging from 67% to 89% following high doses. Naïve T cells were more sensitive than memory T cells. CD4(+) T cells were more sensitive than CD8(+) T cells or CD4(+)CD25(+) T regulatory cells. The differential effects on specialized T cell subsets may contribute to the immunomodulatory activity of ponesimod. The therapeutic potential of ponesimod has been recently shown in phase II studies of chronic plaque psoriasis and relapsing-remitting multiple sclerosis. Our data suggest that lymphocyte sequestration underlies the therapeutic potential of ponesimod in multiple autoimmune and chronic inflammatory diseases.

Population pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator.

Ponesimod (ACT-128800), a reversible, orally active, selective S1P1 receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The availability of a variety of doses, dosing regimens, and treatment durations permitted estimation of the pharmacokinetics characterized by an absorption lag time followed by a sequential zero/first-order absorption and two compartments with first-order elimination. The PD are modeled as an indirect-effect model with rates of appearance and disappearance of lymphocytes in blood with a circadian rhythm and a drug effect on the rate of appearance. The model suggests a circadian variation of 9% and a maximum inhibition of 86% of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 0.5 × 10(9) counts/L.

A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features.

OBJECTIVE: To assess dosing, preliminary safety, and efficacy of canakinumab, a fully human anti-interleukin-1ß (anti-IL-1ß) antibody, in children with systemic juvenile idiopathic arthritis (JIA) and active systemic features. METHODS: In this phase II, multicenter, open-label, dosage-escalation study, children with systemic JIA who were ≥4 years of age, had fever, and were receiving ≤0.4 mg/kg/day of corticosteroids were administered a single subcutaneous dose of canakinumab, 0.5-9 mg/kg of body weight, and were redosed upon relapse. Response to treatment was assessed according to an adaptation of the American College of Rheumatology (ACR) pediatric criteria for improvement. RESULTS: A total of 23 children ages 4-19 years with active disease were enrolled. Of these, 1 patient was excluded from analysis, and 3 of the reenrolled patients were included twice in the efficacy analysis. By day 15 of the first treatment cycle, 15 of 25 patients (60%) had achieved an adapted ACR Pediatric 50 response, with 4 of them achieving inactive disease status. Response was sustained over time, with 11 of 13 patients able to maintain their response throughout the study. In 8 of the 11 responders who had been receiving steroids at baseline, the steroid dosage was decreased from a mean of 0.38 mg/kg/day to 0.13 mg/kg/day over the first 5 months, and 4 of them were able to discontinue steroids. At a dose of 4 mg/kg of canakinumab given subcutaneously every 4 weeks, the median percentage of patients predicted to relapse within 4 weeks was estimated to be 6% (95% confidence interval 1-21). Therapy was generally well tolerated and few patients experienced injection-site reactions. CONCLUSION: Canakinumab has a promising preliminary safety and efficacy profile in this limited cohort. Based on the findings of this trial, further studies in a larger population of children with systemic JIA are warranted.

Effects on bladder function of combining elocalcitol and tolterodine in rats with outflow obstruction.

UNLABELLED: It has previously been shown that elocalcitol might protect bladder contractile function in experimental models and that elocalcitol has beneficial effects in patients with LUTS. In humans, elocalcitol was demonstrated with a very good safety profile but only exhibited limited efficacy on LUTS in patients with BPH and overactive bladder (OAB). Recent reports show that therapies with antimuscarinics, when combined with other drugs in clinical use, might perform better than a monotherapy in managing LUTS. It is not known how a combination of elocalcitol and an antimuscarinic performs on bladder dysfunction. The present study suggests that concomitant use of secosteroids and antimuscarinics has additive beneficial effects on obstruction-related functional changes in an experimental model. If confirmed also in a clinical setting, this could allow for individual dose adjustments to improve efficacy in obstruction-related LUTS, and possibly reduce unwanted adverse activities by antimuscarinic therapy. OBJECTIVE: To evaluate the effects of tolterodine on urodynamics in elocalcitol- or vehicle-treated rats with partial urethral obstruction (PUO). MATERIALS AND METHODS: After ethical approval, 20 female Sprague-Dawley rats were subjected to PUO and treated (gavage) for 14 days (once daily) with elocalcitol (75 µg/kg) or vehicle. Cystometries were performed on day 15 in awake rats before and after i.v. administration of tolterodine (1, 10 and 100 µg/kg). RESULTS: No differences in bladder weights or body/bladder weight ratios were noted between groups. Tolterodine dose-dependently increased micturition intervals and volumes and bladder capacity in both elocalcitol- (n = 11) and vehicle-treated rats (n = 9). In elocalcitol-treated rats, flow pressure (FP) was dose-dependently reduced (12-20%) by tolterodine, whereas no effect on FP was noted in vehicle-treated animals (P < 0.05). Flow compliance (FC) was increased by tolterodine by 21-54% in vehicle-treated rats, and by 47-131% (P < 0.05 vs vehicle) in elocalcitol-treated animals. Maximal tension vs bladder weight was improved in elocalcitol-treated rats in comparison to vehicle (P < 0.05). The area under the curve (AUC) was reduced by tolterodine with 11-16% in vehicle-treated rats and 26-30% in elocalcitol -treated rats (P < 0.05). CONCLUSIONS: Elocalcitol-treatment improved the effects of tolterodine on bladder compliance at the start of flow. The effects of tolterodine on AUC suggest that elocalcitol exerts additional beneficial actions on PUO-induced functional changes during the filling phase of micturition. The reduction of FP and increase in FC by elocalcitol and tolterodine could have translational value and, if valid in humans, support combined therapy in benign prostatic obstruction (BPO)-related lower urinary tract symptoms (LUTS).

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.

Helicobacter pylori-induced interleukin-12 p40 expression.

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of T-helper lymphocyte 1 (Th1). Chronic gastritis induced by Helicobacter pylori is considered a Th1-mediated process. IL-12 levels in gastric biopsy samples of H. pylori-infected patients are higher than in those of uninfected individuals, but the cellular source of IL-12 remains elusive. IL-12 staining was detected in mucosal epithelial cells, lymphocytes, and macrophages in specimens of patients with H. pylori-positive gastritis. Therefore, we investigated IL-12 p40 mRNA induction by H. pylori in gastric epithelial cells and T cells. Although cag pathogenicity island (PAI)-positive H. pylori induced IL-12 p40 mRNA expression, an isogenic mutant of the cag PAI failed to induce it in both cell types. Supernatants from H. pylori cultures and H. pylori VacA induced IL-12 p40 mRNA expression in T cells but not in epithelial cells. The activation of the IL-12 p40 promoter by H. pylori was mediated through NF-kappaB. The transfection of IkappaB kinase and NF-kappaB-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation. Inhibitors of NF-kappaB, phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase, and Hsp90 suppressed H. pylori- and VacA-induced IL-12 p40 mRNA expression. The results indicate that H. pylori induces IL-12 p40 expression by the activation of NF-kappaB, phosphatidylinositol 3-kinase, and p38 mitogen-activated protein kinase. Hsp90 is also a crucial regulator of H. pylori-induced IL-12 p40 expression. In addition to the cag PAI, VacA might be relevant in the induction of IL-12 expression and a Th1-polarized response only in T cells.

VDR-dependent regulation of mast cell maturation mediated by 1,25-dihydroxyvitamin D3.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is a secosteroid hormone that regulates bone metabolism, controls calcium homeostasis, and possesses immunomodulatory properties. We show here that 1,25(OH)2D3 contributes to the regulation of development and function of mast cells, which play a critical role in several inflammatory disorders. 1,25(OH)2D3 promotes apoptosis and inhibits maturation of mouse bone marrow-derived mast cell precursors. Dose-dependent inhibition of mast cell differentiation by 1,25(OH)2D3 is observed at discrete, intermediate stages of mast cell development, identified by expression of c-kit, FcepsilonRI, and IL-3 receptor-alpha chain, and depends on the expression of the vitamin D receptor (VDR). It is important that mast cell progenitors obtained from VDR-ablated mice undergo an accelerated maturation in vitro and give rise to more responsive mast cells than wild-type. Furthermore, histological analysis of mast cell density in peripheral tissues reveals a moderate increase in the number of mast cells in the skin of VDR-deficient mice compared with wild-type animals. These data support the hypothesis of a physiological role of 1,25(OH)2D3 in mast cell development and suggest novel, therapeutic uses of 1,25(OH)2D3 analogs.

Inter-species differences in sensitivity to the calcemic activity of the novel 1,25-dihydroxyvitamin D3 analog BXL746.

The activities of 1,25-dihydroxyvitamin D3 and its synthetic analogs have been extensively studied in humans as well as in preclinical species, and recent data show potential therapeutic utility in cancer treatment. However, their chronic administration leads to changes in blood mineral ion concentrations, and at high doses can result in symptomatic hypercalcemia limiting therapeutic applicability. To overcome this issue, a therapeutic approach based on administration of intermittent, high doses of 1,25(OH)2D3 has been explored in prostate cancer patients. Despite these and other investigations, limited information is available on the effects of acute systemic administration of high doses of 1,25(OH)2D3 or its analogs. Here, we report a comparative analysis of the pro-calcemic effects of the novel 1,25(OH)2D3 analog BXL746 following acute or chronic administration in animals and humans. While chronic administration of BXL746 to rats, dogs and humans leads to similar modulation of calcemia in these species, single dose administration reveals >1000-fold higher sensitivity of dog compared to rat and human in induction of hypercalcemia and consequent systemic toxicity. Our data indicate that the rat is a more relevant species than the dog for the prediction of human results when acute administration of a 1,25(OH)2D3 analog is envisaged.

Transient ischemic attack before nonlacunar ischemic stroke in the elderly.

BACKGROUND: Several studies suggest transient ischemic attack (TIA) may be neuroprotective against ischemic stroke analogous to preinfarction angina's protection against acute myocardial infarction. However, this protective ischemic preconditioning-like effect may not be present in all ages, especially among the elderly. The purpose of this study was to determine the neuroprotective effect of TIAs (clinical equivalent of cerebral ischemic preconditioning) to neurologic damage after cerebral ischemic injury in patients over 65 years of age. METHODS: We reviewed the medical charts of patients with ischemic stroke for presence of TIAs within 72 hours before stroke onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale and disability by a modified Rankin scale. RESULTS: We evaluated 203 patients (>or=65 years) with diagnosis of acute ischemic stroke and categorized them according to the presence (n = 42, 21%) or absence (n = 161, 79%) of TIAs within 72 hours of stroke onset. Patients were monitored until discharged from the hospital (length of hospital stay 14.5 +/- 4.8 days). No significant differences in the National Institutes of Health Stroke Scale and modified Rankin scale scores were observed between those patients with TIAs and those without TIAs present before stroke onset at admission or discharge. CONCLUSION: These results suggest that the neuroprotective mechanism of cerebral ischemic preconditioning may not be present or functional in the elderly.

Modeling clinical efficacy of the S1P receptor modulator ponesimod in psoriasis.

BACKGROUND: Ponesimod is currently the only S1P receptor modulator studied in psoriasis. In a dose-finding study, the active doses showed similar efficacy. OBJECTIVE: Prediction of efficacy at lower doses to aid clinical phase 3 planning with respect to dose selection, duration of treatment, and patient inclusion criteria based on pharma-co-kinetic/pharmacodynamic (PK/PD) modeling and simulation. METHODS: The dose-finding study treated 326 patients (67 on placebo, 126 on 20mg, and 133 on 40mg) over 16 weeks. PK/PD modeling of steady-state trough concentrations and longitudinal PASI scores was employed to characterize data and simulate scenarios. RESULTS: PASI score continually decreased with time on ponesimod treatment, reaching a plateau at 16 weeks. Absolute and relative (percent) PASI score change was larger in patients with higher PASI score at baseline. Doses below 10mg were predicted to show lower efficacy than doses of 10mg and higher. CONCLUSION: Concentration-response modeling was able to predict the efficacy of doses that were not studied. In psoriasis patients, a dose of 10mg (not administered in the study) was predicted to show efficacy similar to 20mg. Disease status (PASI score at baseline) as study inclusion criterion has pronounced influence on study outcome.

Differential regulation of chemokine production by Fcgamma receptor engagement in human monocytes: association of CCL1 with a distinct form of M2 monocyte activation (M2b, Type 2).

CC chemokine ligand 1 (CCL1; I-309) is a CC chemokine that interacts with CC chemokine receptor 8, which is preferentially expressed in polarized T helper cell type 2 and Tc2 cells, in eosinophils, and in T regulatory cells. The present study, prompted by transcriptional profiling of human monocytes undergoing different forms of activation, was designed to characterize the production of CCL1 in monocytes compared with the production of other chemokines (CCL2, CCL22, and CCL18) differentially regulated by distinct activation signals. Lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), interleukin (IL)-1beta, tumor necrosis factor alpha, IL-4, IL-13, IL-10, IL-6, IL-18, and combinations thereof did not induce CCL1 production in monocytes, and some of these signals stimulated production of reference chemokines. Induction of CCL1 in monocytes required engagement of Fc receptor for immunoglobulin G (FcgammaR)II and exposure to IL-1beta or LPS. This combination of stimuli results in a form of M2 (M2b, Type 2) macrophage activation. FcgammaR engagement also induced CCL22 and amplified its stimulation by IL-4. In contrast, FcgammaR stimulation inhibited the IL-10- and LPS-mediated induction of CCL18. IL-10, IL-4, and IFN-gamma inhibited induction of CCL1 by FcgammaR ligation and IL-1beta. CCL1 was present in synovial fluids and macrophages in juvenile idiopathic arthritis. Thus, regulation of CCL1 in human monocytes is unique, with an obligate requirement of FcgammaR engagement and costimulation by signals (IL-1beta and LPS), which use the myeloid differentiation primary-response protein 88 adaptor protein. Thus, CCL1 is a CC chemokine with a unique pattern of regulation associated with a distinct form of M2 (Type 2, M2b) monocyte activation, which participates in macrophage-dependent regulatory circuits of innate and adaptive immunity.

Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans.

This study investigated the effects of ponesimod, a selective S1P1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was -1,292±340×106 cells/L and 275±486×106 cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naïve CD4+ T cells (CD45RA+CCR7+) from baseline was observed only after ponesimod treatment (-113±98×106 cells/L, placebo: 0±18×106 cells/L). The number of T-cytotoxic (CD3+CD8+) and T-helper (CD3+CD4+) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4+ T-central memory (CD45RA-CCR7+) cells (-437±164×106 cells/L) and CD4+ T-effector memory (CD45RA-CCR7-) cells (-131±57×106 cells/L). In addition, ponesimod treatment led to a decrease of -228±90×106 cells/L of gut-homing T cells (CLA-integrin ß7+). In contrast, when compared with placebo, CD8+ T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4+ cells was dramatically reduced, whereas CD8+ and NK cells were less affected, allowing the body to preserve critical viral-clearing functions.

Chemokine receptors in chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by recurrent episodes of leukocyte infiltration in the lung parenchyma causing progressive pulmonary tissue damage and loss of function. Recruitment of neutrophils and CD8+ T cells is linked to disease progression and is under control of chemotactic mediators produced in the inflamed COPD lung. Recent progress in elucidation of the molecular mechanisms that regulate migration of inflammatory cells into the lung has revealed interesting novel targets for therapeutic intervention in this disease. Chemokine receptors CXCR1 and CXCR2 expressed on neutrophils and CXCR3 expressed on CD8+ T cells have been identified as potential therapeutic targets to prevent recruitment of pathogenic cells into the inflamed lung. However, the observation that chemokine receptors are also expressed and functional on various types of lung resident cells including epithelial and smooth muscle cells has raised new questions on the role played by chemokine receptors in COPD. These new findings suggest that chemokine receptor signalling could contribute to the adaptive response of lung tissue resident cells to the microenvironmental changes induced by inflammation. Thus, investigation of the role played by chemokine receptors in development of COPD remains a fertile area of research. Nevertheless, validation of chemokine receptor targets in COPD has proven a difficult challenge given the lack of predictive animal models of the disease and the still poorly defined etiology and pathogenesis.

Lifestyle and prevention of cardiovascular disease in the elderly: an Italian perspective.

The life span of human beings is partially influenced by genetic factors, but outcomes of aging are profoundly influenced by lifestyle and other environmental factors. Age-related modifications of the cardiovascular system are preserved by antiaging lifestyle interventions such as physical activity and caloric restriction. Accordingly, physical activity and low body mass index reduce mortality in older men with cardiovascular diseases. Several mechanisms have been proposed to explain the protective effect of lifestyle interventions against cardiovascular diseases in the elderly, including a reduction of vulnerability (i.e., the age-related reduction of endogenous mechanisms protective against pathologic insults). The age-related reduction of ischemic preconditioning, the most powerful endogenous protective mechanism against myocardial ischemia, is restored by both physical activity and caloric restriction. Thus, older persons can implement lifestyle practices that minimize their risk of death from cardiovascular diseases.

Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases.

The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod's side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease.

Does comprehensive geriatric assessment improve the estimate of surgical risk in elderly patients? An Italian multicenter observational study.

BACKGROUND: The evaluation of surgical risk is crucial in elderly patients. At present, there is little evidence of the usefulness of comprehensive geriatric assessment (CGA) as a part of the overall assessment of surgical elderly patients. METHODS: We verified whether CGA associated with established surgical risk assessment tools is able to improve the prediction of postoperative morbidity and mortality in 377 elderly patients undergoing elective surgery. RESULTS: Overall mortality and morbidity were 2.4% and 19.9%, respectively. Multivariate analysis showed that impaired cognitive function (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.15 to 4.22; P < .02) and higher Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (OR, 1.11; 95% CI, 1.00 to 1.23; P < .04) are predictive of mortality. Higher comorbidity is predictive of morbidity (OR, 2.12; 95% CI, 1.06 to 4.22; P < .03) and higher American Society of Anesthesiologists (OR, 2.18; 95% CI, 1.31 to 3.63; P < .001) and National Confidential Enquiry into Patient Outcome of Death score (OR, 2.03; 95% CI, 1.03 to 4.00; P < .04). CONCLUSIONS: In elective surgical elderly patients, the morbidity and mortality are low. The use of CGA improves the identification of elderly patients at higher risk of adverse events, independent of the surgical prognostic indices.

Targeting chemoattractant receptors in allergic inflammation.

Asthma, atopic dermatitis, allergic rhinitis, which are amongst the most clinically relevant allergic disorders in industrialized countries affecting hundreds of millions of people world-wide, are characterized by tissue infiltration of Th2 cells, eosinophils, mast cells and basophils. Recruitment of these leukocyte subpopulations proceeds in response to specific chemotactic clues produced by tissue resident cells and is further amplified by incoming leukocytes. Over the last decade a number of receptors for chemokines and other chemoattractants have been identified on distinct leukocyte subpopulations participating to the pathogenesis of allergic inflammation. Preferential expression of discrete chemoattractant receptors on relevant cell types and their up-regulation in affected organs and animal models of allergic inflammation has helped to restrict the list of culprits. Although searching of the appropriate target for pharmacological intervention is still in progress, discrete chemoattractant receptors are already attracting a strong interest from the pharmaceutical industry. Here, we will review the most recent advances on the role that specific chemoattractant receptors play in the pathogenesis of allergic inflammation and will discuss emerging developments in this field.

Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects.

BACKGROUND: Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis). OBJECTIVES: The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2). METHODS: Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed. RESULTS: Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC0-inf), the area under the curve from time zero to the time of the last measurable concentration (AUC0-t), the terminal half-life (t ½), and the maximum plasma concentration (C max) were all within the 0.80-1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations. CONCLUSION: The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval.