Efficacy and Safety of Apremilast in the Treatment of Patients with Mild-to-Moderate Psoriasis in Japan: Results from PROMINENT, A Phase 3b, Open-Label, Single-Arm Study.

INTRODUCTION: Patients with mild-to-moderate plaque psoriasis often experience reduced quality of life and increased disease burden due to itch or involvement of psoriasis in special areas such as the scalp and nails. Systemic therapy may be used concurrently with topical therapy in patients with active disease not controlled by topical therapy alone. The objective of PROMINENT was to evaluate the efficacy and safety of apremilast in combination with topical therapy in patients with mild-to-moderate psoriasis in Japan. METHODS: PROMINENT, a phase 3b, open-label, single-arm study in Japan, enrolled adults ≥ 20 years of age with plaque psoriasis [static Physician Global Assessment (sPGA) 2 (mild) or 3 (moderate)] not adequately controlled by topical therapy. Patients received apremilast 30 mg twice daily for 16 weeks in addition to their existing topical therapy, with the option of topical therapy reduction at the discretion of their physician while continuing apremilast treatment from weeks 16 to 32. RESULTS: Of the 152 patients enrolled in the study, 136 completed week 32. The primary endpoint of sPGA response [score 0 (clear) or 1 (almost clear)] was achieved by 43.7% of patients at week 16, and 40.8% maintained response at week 32. Clinically meaningful improvements in skin, scalp, and nails were observed in > 40% of patients at weeks 16 and 32. Similarly, improvements in pruritus, quality of life, and treatment satisfaction were observed at week 16 and maintained at week 32. Common treatment-emergent adverse events through week 32 included gastrointestinal events, nasopharyngitis, and headache. CONCLUSIONS: Apremilast in combination with topical therapy resulted in clinically meaningful and sustained efficacy in physician- and patient-reported outcomes at weeks 16 and 32 in Japanese patients with mild-to-moderate psoriasis. Tolerability was consistent with available prior safety data for apremilast. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03930186.

[Pharmacological profile, clinical efficacy, and safety of Follitropin Delta produced by recombinant DNA technology in a human cell line (REKOVELLE® PEN for S.C. Injection 12†µg, 36†µg, 72†µg)].

Follitropin Delta (Rekovellle Subcutaneous Injection 12 µg/ 36 µg/72 µg Pen) is a recombinant human follicle-stimulating hormone (rFSH) developed by Ferring Pharmaceuticals Co., Ltd. Because human follicle-stimulating hormone (FSH) gene is incorporated into a human-derived cell line (human embryonic retinoblastoma: PER.C6), the Follitropin Delta is produced with having α2.3 and α2.6 linked sialic acid sugar chain which is similar to natural human FSH. Containing these two types of sialic acids linkage, similar blood dynamics with natural FSH can be expected due to the reduction of hepatic clearance. Furthermore, an individual dose algorithm defined by patient blood anti-Müllerian hormone (AMH) level and body weight can be expected to obtain optimal follicle development and reduce the safety risk. In the phase II studies, efficacy and safety of Follitropin Delta are confirmed in a dose-dependent manner, and it is confirmed the individualized dose algorism for non-Japanese is also applicable for Japanese women by the population pharmacokinetic/pharmacodynamic analysis. In the phase III studies the non-inferiority of Follitropin Delta to Follitropin Alfa or Beta is confirmed in ongoing pregnancy rate and the number of oocytes retrievable. In addition, the number of subjects who developed total ovarian hyperstimulation syndrome and/or who underwent prophylactic intervention in the Follitropin Delta was significantly lower than comparators. In conclusion, the clinical benefits of individualized doses of Follitropin Delta were confirmed in infertile women undergoing controlled ovarian stimulation (COS) in assisted reproductive technology (ART), and we propose that Follitropin Delta may provide new options to patients and real clinical settings.

Apremilast Prolongs the Time to First Biologic Therapy in Japanese Patients with Psoriasis.

INTRODUCTION: Biologic agents are used in patients with severe psoriasis who have not adequately responded to existing conventional systemic therapies. However, only a limited number of medical institutions in Japan are approved to use them, and their relatively high cost represents a substantial burden to patients. Apremilast is an oral phosphodiesterase-4 inhibitor approved in Japan for the treatment of psoriasis vulgaris in adult patients with an inadequate response to topical therapies and psoriatic arthritis in adult patients with active disease. To date, a large-scale real-world study of treatment patterns and costs associated with apremilast in Japan has not been conducted. The objective of this study was to assess whether apremilast can prolong time to first biologic therapy use and decrease total medical cost. METHODS: Using the Medical Data Vision hospital-based claims database, 506 psoriasis patients were propensity score matched and analyzed (apremilast: n = 253; non-apremilast: n = 253). RESULTS: The incidence rate of first biologic therapy use per 1000 patient-years was significantly lower in the apremilast group than in the non-apremilast group (30.3 vs. 107.6; P < 0.001), and the total medical costs per month were significantly lower in the apremilast group than in the non-apremilast group (76,594 yen/month vs. 102,411 yen/month, P < 0.001). In a sensitivity analysis of a propensity-score-matched subset of eligible patients prescribed biologics during the follow-up period (apremilast: n = 14; non-apremilast: n = 14), the incidence of first biologic therapy use was 2,797.6 per 1000 patient-years (95% CI: 1,656.9, 4,723.6) in the non-apremilast group and 856.1 per 1000 patient-years (95% CI: 507.0, 1,445.5) in the apremilast group. CONCLUSION: These results suggest that apremilast prolongs the time to first biologic therapy use in patients with psoriasis, thereby reducing the total medical cost and decreasing the economic burden on patients.

Current venous thromboembolism management and outcomes in Japan.

BACKGROUND: Epidemiology and clinical management of acute venous thromboembolism (VTE) are not readily available in Japan. METHODS AND RESULTS: The Japan VTE Treatment Registry (JAVA) is a multicenter cohort study of consecutive patients with an objectively confirmed, symptomatic acute pulmonary embolism (PE), symptomatic acute deep vein thrombosis (DVT), or asymptomatic acute proximal DVT. Of the 1,076 patients enrolled with acute VTE, 68.7% presented with an isolated DVT; 17.0% had PE alone; and 14.4% had both. VTE management was characterized by a high rate of inferior vena cava filter insertion (40.6%), frequent thrombolysis (21.1%), and sub-therapeutic unfractionated heparin-based anticoagulation, followed by warfarin prescription, mostly targeting an international normalized ratio of 2.0 (range, 1.5-2.5). During a mean observation period of 252.5 days, 29 recurrent cases of VTE were documented, yielding an incidence rate of 3.9 per 100 patient-years. A total of 123 patients died during the study period, corresponding to a rate of 16.6 deaths per 100 patient-years. The incidence of major bleeding was 3.2% per patient-year, including 2 fatal hemorrhages and 7 intracranial hemorrhages. CONCLUSIONS: VTE management in Japan is characterized by a highly aggressive strategy in the acute phase, in contrast to protocols that use low-level anticoagulation. The VTE recurrence rates in Japan and Western countries are similar, but mortality is higher in Japan, with significant variability depending on patient and management characteristics.

Temperature variations around medication cassette and carry bag in routine use of epoprostenol administration in healthy volunteers.

BACKGROUND: According to several treatment guidelines, epoprostenol is an important treatment option for pulmonary arterial hypertension. However, the pharmacokinetic characteristics and poor stability of epoprostenol at room temperature make its administration challenging. We therefore studied temperature fluctuations between the drug administration cassette and atmosphere to promote the safe use of epoprostenol. METHODS AND FINDINGS: Five healthy volunteers carried a portable intravenous infusion pump attached to a medication cassette containing saline in a bag during their ordinary activities over 16 days during which the mean atmospheric temperature was 29.6 ± 1.5°C. The temperature around the medication cassette was not less than 25°C on any occasion, and the mean period over 24 h during which the temperature around the cassette exceeded 35°C and 40°C was 96.9 ± 156.4 min and 24.4 ± 77.3 min, respectively. Significant correlations were observed between the temperatures outside the bag and around the cassette, as well as between temperatures around the cassette and of the saline solution in the cassette (r = 0.9258 and 0.8276, respectively). There were no differences in the temperatures outside the bag or around the cassette with respect to the bag material. CONCLUSIONS: Temperatures around a medication cassette and outside the bag containing the medication increase with sunlight exposure. The temperature around cassettes used for administering epoprostenol must therefore be kept low for as long as possible during hot summer conditions to maintain the drug stability.

Cilostazol's effect on the response to perivascular nerve stimulation in isolated dog cerebral and mesenteric arteries.

Clinical studies have demonstrated that cilostazol (CZ), an antiplatelet agent with type 3 phosphodiesterase inhibition, reduces the risk of secondary stroke. To analyze CZ's vascular action, especially in relation to endothelial and perivascular nerve functions, we examined CZ's effects on the responses to endothelial and nerve stimulation in dog cerebral arteries, and on the response to nerve stimulation in dog mesenteric arteries. Low concentrations of CZ (10(-8) and 10(-7) mol/L) failed to relax the cerebral arteries, but a higher concentration (10(-6) mol/L) relaxed them in an endothelium-independent manner. Substance P-induced relaxation was endothelium-dependent in the cerebral arteries, whereas transmural electrical stimulation (TES) and nicotine-induced relaxation were endothelium-independent. This relaxation was abolished by N(G)-nitro-L-arginine, an NO synthase (NOS) inhibitor. A lower concentration (10(-7) mol/L) of CZ enhanced the relaxation caused by nerve-derived NO but did not affect the relaxation caused by endothelium-derived NO in the cerebral arteries; moreover, it did not affect the contractions caused by nerve-derived noradrenaline in the mesenteric arteries under treatment with the NOS inhibitor. It is concluded that CZ may selectively enhance nitrergic nerve function, possibly via the activation of neuronal NOS, in dog cerebral arteries, since it does not affect the function of the noradrenergic nerve or that of endothelial NOS. Therefore, this novel vasodilatory effect of CZ may explain the reduction in the risk of secondary stroke in addition to the antiplatelet action and the direct vasodilatory action on smooth muscle.

Cilostazol inhibits leukocyte integrin Mac-1, leading to a potential reduction in restenosis after coronary stent implantation.

OBJECTIVES: The aim of this study was to confirm clinically a hypothesis that cilostazol inhibits leukocyte Mac-1, leading to prevention of post-stent restenosis. BACKGROUND: The platelet phosphodiesterase III inhibitor called cilostazol also inhibits alpha-granule release of P-selectin in platelets. The P-selectin-mediated platelet-leukocyte interaction promotes activation and upregulation of leukocyte Mac-1 after coronary stenting, which plays a key role on the mechanism of restenosis. Thus, cilostazol's potential inhibition of this process may lead to prevention of restenosis. METHODS: Using flow cytometric analysis of whole blood obtained from the coronary sinus, the expression of platelet membrane glycoproteins and neutrophil adhesion molecules was observed in 70 consecutive patients undergoing coronary stenting. The patients were randomly assigned to either a cilostazol or ticlopidine group before stent placement. RESULTS: The restenosis rate was lower (15% vs. 31%, p < 0.05) in the cilostazol group (n = 34) than in the ticlopidine group (n = 32). A stent-induced increase in platelet P-selectin (CD62P) expression and an increase in neutrophil Mac-1 (CD11b) expression were suppressed in the cilostazol group compared with the ticlopidine group. Angiographic late lumen loss was correlated with the relative changes in platelet P-selectin and neutrophil Mac-1 at 48 h after coronary stenting. CONCLUSIONS: Cilostazol may have effects on suppression of P-selectin-mediated platelet activation, platelet-leukocyte interaction, and subsequent Mac-1-mediated leukocyte activation, which might lead to a reduced restenosis rate after coronary stent implantation.

Enzyme immunoassay detection of platelet-derived microparticles and RANTES in acute coronary syndrome.

Platelet-derived microparticles (PDMPs) are produced by platelet activation or physical stimulation under various conditions. To evaluate changes in platelet and chemokine function in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), we measured and compared levels of PDMPs and a C-C chemokine, regulated on activation normally T-cell express and secreted (RANTES), by ELISA. Levels of PDMP and RANTES in patients with acute coronary syndrome were significantly higher than those in the control groups (PDMP: 20.1 +/- 2.9 vs 80.4 +/- 7.3 U/ml, p < 0.001; RANTES: 18.6 +/- 3.7 vs 52.1 +/- 4.6 ng/ml, p < 0.01), but did not differ between the control groups and patients with stable angina. PDMP levels were higher in patients with acute myocardial infarction (AMI) than in patients with unstable angina (PDMP: 115.0 +/- 7.1 vs 63.9 +/- 6.2 U/ml, p < 0.001). There was no difference in the RANTES levels, however, between patients with AMI and patients with unstable angina. PDMP and RANTES levels were significantly decreased after PTCA (PDMP, p < 0.001; RANTES, p < 0.05), but without differences between the two groups. In addition, the level of PDMP was significantly correlated with that of RANTES or soluble CD40 ligand. These findings suggest that PTCA may prevent the development of AMI-associated complications in which activated platelets and RANTES play roles. Our ELISA method appears to be sufficient for monitoring PDMP and RANTES levels after PTCA in patients with acute coronary syndrome.

Circulating platelet-derived microparticles with procoagulant activity may be a potential cause of thrombosis in uremic patients.

BACKGROUND: Clinical experience indicates that bleeding and thrombotic tendencies co-exist in uremic patients. Numerous studies have shown that platelet functional defects contribute to the bleeding tendency in uremic patients. In contrast, there are no solid studies clarifying the pathogenesis of the prothrombotic state in uremic patients. Platelet-derived microparticles (PMPs), which are small vesicles with procoagulant activity released from activated platelets, are thought to be involved in clinical thrombogenesis. This study addressed the question of why uremic patients are thrombophilic even though they have a bleeding tendency, focusing on the clinical significance of PMPs. METHODS: The subjects were pre-dialyzed patients, patients under hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) therapy, and age-matched healthy controls. Analyses of PMPs were performed using a flow cytometer. Annexin V was used to probe procoagulant activity of PMPs. The impacts of the HD procedure, arteriovenous (AV) fistula, and recombinant human erythropoietin (rHuEPO) treatment on the release of PMPs were additionally assessed. RESULTS: Major results are: (1) PMP counts were significantly greater in each uremic group than in controls. The PMP counts were not different among three types of uremic groups; (2) PMP counts were significantly higher in uremic patients with thrombotic events than in those without thrombotic events; and (3) the HD procedure and existence of AV fistula did not affect PMP counts, but rHuEPO treatment possibly enhanced the PMP release in these patients. CONCLUSIONS: Elevated PMP counts may trigger thrombosis in uremic patients. The primary cause of PMP elevation in uremia was not clarified in this study.