P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the US for treating moderately to severely active ulcerative colitis (UC) and in multiple countries for treating relapsing forms of multiple sclerosis (MS). In a Phase 1 study of ozanimod in healthy participants, first-dose cardiac effects were mitigated with gradual dose escalation. Based on these results, an initial 7-day ozanimod dose escalation regimen was implemented in all Phase 2 and 3 UC and MS trials. The objective of this analysis was to evaluate the number of patients who were excluded from ozanimod treatment due to contraindications of pre-existing cardiac disorders and to evaluate the incidence of cardiac-related treatment-emergent adverse events (TEAEs) following first-dose ozanimod administration in all patients and patients with a history of non-exclusionary cardiac disorders in the UC and MS clinical trials. METHODS: For UC, the analysis included pooled data from the Phase 2 Touchstone (NCT01647516) and Phase 3 True North (NCT02435992) trials. For MS, the analysis included pooled data from the Phase 3 Radiance (NCT02047734) and Sunbeam (NCT02294058) trials. Patients with clinically relevant cardiac conditions or clinically significant electrocardiogram (ECG) disorders were excluded from the trials. On Day 1, all patients received ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg). Day 1 cardiac monitoring included collection of vital signs (including heart rate) prior to dosing and hourly for at least 6 hours after dosing, and ECG prior to dosing and at Hour 6 after dosing. RESULTS: Among patients screened, 26/2178 (1.2%) in the UC studies and 47/3351 (1.4%) in the MS studies were excluded due to protocol-defined pre-existing cardiac disorders. Of 496 patients who received ozanimod in the UC studies, 1 (0.2%) experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Of 1774 patients who received ozanimod in the MS studies, 11 (0.6%) experienced a cardiac-related TEAE on Day 1. In both the UC and MS studies, no cases of second- or third-degree AV block were observed. A decrease in mean heart rate from baseline (UC, 0.7 bpm; MS, 1.2 bpm) was observed at first-dose that reached a nadir at Hour 5 and returned to baseline by Hour 6. Among 496 patients with UC who received ozanimod, 34 (6.9%) had a known history of cardiac disorders, of whom 1 experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Among the 1774 patients with MS who received ozanimod, 96 (5.4%) had a known history of cardiac disorders, of whom 2 experienced symptomatic bradycardia on Day 1. CONCLUSION: In clinical trials of ozanimod, the number of patients with UC or MS who failed screening because of exclusionary cardiac disorders was low. Most patients with a history of cardiac disorders who were enrolled in ozanimod clinical trials did not have Day 1 cardiac events, and the events that occurred were manageable.

The Budget Impact of Including Rucaparib on a US Payer Formulary for the Treatment of Patients with Metastatic Ovarian Cancer.

OBJECTIVE: A budget impact model was constructed to assess the incremental budget impact that rucaparib availability would have on a US health plan. METHODS: An incremental budget impact was estimated over a 3-year horizon as the difference in total annual cost of treatment, with and without rucaparib available, for second-line maintenance, third-line treatment, and the combined maintenance and treatment settings. The hypothetical health plan includes one million covered lives, and commercial and Medicare lines of business. Alternative products included in the model were based on the National Comprehensive Cancer Network guidelines. The eligible patient population was estimated using an incidence-based approach. Modeled costs include drug acquisition, intravenous drug administration, required laboratory testing, and medical management of adverse events. RESULTS: In the maintenance setting, average total expenditures over 3 years were estimated to be US$1,465,043 with rucaparib versus US$1,461,350 without it as a treatment option; the average incremental budget impact was US$3693 (US$0.0003 per member per month [PMPM]). In the treatment setting, average total expenditures were estimated to be US$1,320,718 with rucaparib versus US$1,313,736 without it; the average incremental budget impact was US$6982 (US$0.0006 PMPM). Budget impact is smaller in commercial plans than Medicare because of the higher incidence of ovarian cancer in the over-65 population. CONCLUSION: The budget impact of adding rucaparib to the formulary for a health plan adds negligible PMPM costs of < US$0.001 in all tested settings and scenarios due to the small population eligible for therapy.

Pyoderma gangrenosum in two successive pregnancies complicating caesarean wound.

Pyoderma gangrenosum (PG) is a rare ulcerative cutaneous disorder with tendency to recur in the injured area. Though most of the time is associated with chronic systemic conditions, it can occur in isolation and can be a diagnostic dilemma. The aetiology is poorly understood. The diagnosis is based on clinical features and excluding other causes of skin ulcers, as it does not have characteristic histopathology or laboratory findings. Lesions can develop after surgery, after trauma or de novo. We are reporting a 32-year-old pregnant lady with two previous instances of pyoderma gangrenosum in the previous pregnancy, who in postoperative period following caesarean section developed the same condition for the third time. She responded well to local wound care, oral Prednisolone, and Dapsone and made a good recovery. Pregnancy being an immunologically altered status can play a role in development of pyoderma gangrenosum and one should always rule out its possibility when there is a delayed wound healing.

Direct effects of phosphate on vascular cell function.

Elevated serum phosphate has clinically been associated with vascular stiffness and cardiovascular mortality. Mechanistic studies over the past decade regarding local effects of phosphate on the vessel wall have provided insight into various pathways that culminate in vascular calcification. Smooth muscle cell phenotype change and apoptosis play prominent roles. The sodium-phosphate cotransporter PiT-1 is required for the osteochondrogenic differentiation of smooth muscle cells in vitro. Less is known about phosphate-driven valve interstitial cell calcification and elastin degradation. In this article, we review the current knowledge about phosphate-induced changes in the vascular wall.

Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease.

Arterial medial calcification (AMC), a hallmark of vascular disease in uremic patients, is highly correlated with serum phosphate levels and cardiovascular mortality. To determine the mechanisms of AMC, mice were made uremic by partial right-side renal ablation (week 0), followed by left-side nephrectomy at week 2. At 3 weeks, mice were switched to a high-phosphate diet, and various parameters of disease progression were examined over time. Serum phosphate, calcium, and fibroblast growth factor 23 (FGF-23) were up-regulated as early as week 4. Whereas serum phosphate and calcium levels declined to normal by 10 weeks, FGF-23 levels remained elevated through 16 weeks, consistent with an increased phosphate load. Elastin turnover and vascular smooth muscle cell (VSMC) phenotype change were early events, detected by week 4 and before AMC. Both AMC and VSMC loss were significantly elevated by week 8. Matrix metalloprotease 2 (MMP-2) and cathepsin S were present at baseline and were significantly elevated at weeks 8 and 12. In contrast, MMP-9 was not up-regulated until week 12. These findings over time suggest that VSMC phenotype change and VSMC loss (early phosphate-dependent events) may be necessary and sufficient to promote AMC in uremic mice fed a high-phosphate diet, whereas elastin degradation might be necessary but is not sufficient to induce AMC (because elastin degradation occurred also in uremic mice on a normal-phosphate diet, but they did not develop AMC).

Matrix remodeling in vascular calcification associated with chronic kidney disease.

Vascular calcification is a major contributor to cardiovascular disease, a leading cause of death in patients with chronic kidney disease. Mechanistic studies highlight the importance of dysregulated mineral metabolism, vascular osteochondrogenic processes, apoptosis, and deficiencies in calcification inhibitors as potential mediators of calcification in renal disease. However, the contribution of the extracellular matrix in vascular calcification associated with chronic kidney disease is less understood. Here we examine evidence that suggests important roles for elastin and elastin-degrading enzymes as potential key regulators of calcification. Additional studies aimed at further understanding their role are critical for the design of therapeutic interventions.

Comparison of sevelamer hydrochloride and sevelamer carbonate: risk of metabolic acidosis and clinical implications.

Hyperphosphatemia is highly prevalent in patients with chronic kidney disease (CKD), particularly in those with advanced or end-stage renal disease. Sevelamer hydrochloride is an ion-exchange resin that reduces serum phosphorus concentrations. The agent also produces favorable lipid profile effects and does not cause hypercalcemia. However, reported drawbacks of this agent are metabolic acidosis, high pill burden, and a relatively low affinity and selectivity for phosphate anions. Sevelamer carbonate is a new buffered formulation that does not increase the risk of metabolic acidosis. To determine the roles of these two agents in the treatment of hyperphosphatemia in patients with CKD, we performed a MEDLINE search (June 1995-June 2008) focusing on the mechanism of action of resin binding with phosphate and the development of metabolic acidosis. We also reviewed studies that evaluated the effects of sevelamer hydrochloride or sevelamer carbonate on serum bicarbonate concentrations. Several studies in patients with CKD and hyperphosphatemia who received hemodialysis or peritoneal dialysis found decreases in serum bicarbonate concentrations with the use of sevelamer hydrochloride, whereas sevelamer carbonate did not have this negative effect on bicarbonate concentrations. Both drugs appear to be equivalent in their abilities to lower serum phosphorus concentrations. However, as sevelamer carbonate does not decrease serum bicarbonate levels, it may be more appropriate for patients at risk for metabolic acidosis who require phosphate binders that do not contain calcium or aluminum.

Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.

Arterial medial calcification is a major complication in patients with chronic kidney disease and is a strong predictor of cardiovascular and all-cause mortality. We sought to determine the role of dietary phosphorus and the severity of uremia on vascular calcification in calcification-prone DBA/2 mice. Severe and moderate uremia was induced by renal ablation of varying magnitudes. Extensive arterial-medial calcification developed only when the uremic mice were placed on a high-phosphate diet. Arterial calcification in the severely uremic mice fed a high-phosphate diet was significantly associated with hyperphosphatemia. Moderately uremic mice on this diet were not hyperphosphatemic but had a significant rise in their serum levels of fibroblast growth factor 23 (FGF-23) and osteopontin that significantly correlated with arterial medial calcification. Although there was widespread arterial medial calcification, there was no histological evidence of atherosclerosis. At early stages of calcification, the osteochondrogenic markers Runx2 and osteopontin were upregulated, but the smooth muscle cell marker SM22alpha decreased in medial cells, as did the number of smooth muscle cells in extensively calcified regions. These findings suggest that phosphate loading and the severity of uremia play critical roles in controlling arterial medial calcification in mice. Further, FGF-23 and osteopontin may be markers and/or inducers of this process.

Self-associated indisulam in phospholipid-based nanomicelles: a potential nanomedicine for cancer.

This study aimed to begin development of a nanomedicine containing indisulam solubilized in sterically stabilized micelles (SSMs) composed of DSPE-PEG(2000) or sterically stabilized mixed micelles (SSMMs) composed of DSPE-PEG(2000) plus egg phosphatidylcholine. Micelles were prepared by co-precipitation and reconstitution of drug and lipids. Particle size distributions of micellar formulations were determined by quasi-elastic light scattering. Amounts of solubilized drug were determined by reverse-phase high-performance liquid chromatography (RP-HPLC). In vitro cytotoxicity of indisulam in nanocarrier was determined on the MCF-7 cell line by the National Cancer Institute-developed sulforhodamine B assay. Optimal solubilized indisulam concentrations in 5 mM total lipid were 10 microg/mL for SSMMs and 400 microg/mL for SSMs. HPLC results demonstrated that the encapsulation capacity of both micelles was over 95%. In vitro studies showed that indisulam in micellar system was more effective than free indisulam. The optimized formulation was successfully freeze-dried without any addition of lyoprotectants or cryoprotectants. We conclude that SSMs are a promising nanocarrier for indisulam, and indisulam-SSMs should be developed further as a novel targeted nanomedicine.

PEGylated phospholipid nanomicelles interact with beta-amyloid((1-42)) and mitigate its beta-sheet formation, aggregation and neurotoxicity in vitro.

beta-Amyloid (Abeta) is a hydrophobic peptide that drives the pathogenesis of Alzheimer's disease (AD) due to its aberrant aggregation. Inhibition of Abeta aggregation process is one of the most promising strategies for therapeutic intervention in AD. Here, we demonstrate that sterically stabilized (PEGylated) phospholipid nanomicelles (SSM) are effective in mitigating Abeta-42 aggregation using several deterministic techniques such as (1) Turbidimetry (2) Congo red binding (3) Thioflavine-T binding (4) Laser light scattering and (5) Electron Microscopy. alpha-Helicity of Abeta-42 is significantly augmented in the presence of SSM as demonstrated by circular dichroism (p<0.05). Cytotoxicity studies, employing human neuroblastoma SHSY-5Y cells, established that PEGylated phospholipid associated peptide demonstrated significantly lower neurotoxicity compared to lipid untreated Abeta-42 (p<0.05). Collectively, our results establish that PEGylated phospholipids abrogate transformation of Abeta-42 to amyloidogenic beta-sheeted form and impart neuroprotection in vitro. This study provides a foundation for designing nanoconstructs of PEGylated phospholipid nanomicelles in conjunction with a therapeutic agent for multitargeting the different pathophysiologies associated with AD.