Oral Therapy In Patients Research Articles

Secondary failure of oral therapy in patients with type 2 diabetes mellitus - possibilities of overcoming

Secondary failure of oral therapy in patients with type 2 diabetes mellitus - possibilities of overcoming

232. Safety and Effectiveness of Intravenous to Oral De-escalation Compared to Continued Vancomycin Therapy in Orthopedic Infections

BackgroundThe Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial determined oral antibiotics administered during the first six weeks of therapy were non-inferior to parenteral antibiotics. There was no difference in the incidence of serious adverse effects. The objective of this study was to evaluate the safety and effectiveness of de-escalating to oral therapy compared to continuing parenteral vancomycin therapy in patients with orthopedic infections in a real-world setting.MethodsWe conducted a single-center, retrospective cohort study of patients discharged between April 1, 2018 and April 1, 2020 with an orthopedic infection, a prescription for at least four weeks of parenteral vancomycin, and documented follow-up. The primary outcome was incidence of adverse events defined as provider documentation of the event and changes to therapy. The secondary outcome was incidence of 6-month treatment failure defined as repeat surgical intervention or therapy escalation. ResultsOne hundred fifty-seven patients were included. Twenty-nine (18.5%) patients were de-escalated to oral therapy. Three (10%) patients in the oral therapy group had an adverse event compared to 35 (27%) in the vancomycin group (p=0.058). Of the 35 patients with an adverse event in the vancomycin group, eight were due to parenteral access-related complications. Treatment failure occurred in three (10%) patients in the oral therapy group compared to 27 (21%) patients in the vancomycin group (p=0.29). Three (10%) patients in the oral therapy group had an unplanned readmission compared to 25 (20%) patients in the vancomycin group (p=0.24).Baseline Characteristics, Unplanned Readmission Rates, and Incidence of Adverse Events and 6-Month Treatment Failure ConclusionPatients de-escalated to oral therapy had fewer adverse events and similar incidences of treatment failure compared to patients maintained on parenteral vancomycin. Switching to oral therapy avoids some adverse events related to parenteral access. Our results in an uncontrolled, real-world setting are consistent with the OVIVA trial. Though limited by sample size, our data indicate switching to oral therapy in patients with an orthopedic infection improves safety outcomes without compromising effectiveness compared to continued parenteral vancomycin therapy.Disclosures Russell J. Benefield, PharmD, Paratek Pharmaceuticals (Grant/Research Support)

Clinical Efficacy of Quadruple Oral Therapy for Type2 Diabetes in Real-World Practice: A Retrospective Observational Study.

IntroductionWe aimed to evaluate the effectiveness of quadruple oral therapy in patients with inadequately controlled type 2 diabetes (T2D) with the use of three types of oral hypoglycemic agents.MethodsMedical records of 318 patients with T2D who were prescribed quadruple therapy in the Asan Medical Center were reviewed. Changes in glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels from baseline were assessed. The regimens of quadruple oral therapy included the following: (1) thiazolidinedione (TZD) add-on to metformin (MET) + sulfonylurea (SU) + dipeptidyl peptidase 4 inhibitor (DPP4i), (2) sodium-glucose cotransporter 2 inhibitor (SGLT2i) add-on to MET + SU + DPP4i, and (3) DPP4i add-on to MET + SU + TZD.ResultsThe TZD add-on significantly reduced HbA1c levels by 1.1% (from 9.0 ± 1.1 to 7.9 ± 1.1%, P < 0.001) and FPG levels by 41.4 mg/dL (from 188.9 ± 45.9 to 147.4 ± 51.3 mg/dL, P < 0.001). The SGLT2i add-on changed the mean HbA1c level from 8.9 ± 1.0 to 7.8 ± 1.0%, a reduction of 1.1% (P < 0.001) and changed the mean FPG level from 193.4 ± 46.2 to 152.6 ± 37.0 mg/dL, a reduction of 40.8 mg/dL (P < 0.001). Finally, the DPP4i add-on reduced HbA1c levels by 1.3% (from 9.1 ± 1.3 to 7.8 ± 1.4%, P < 0.001) and FPG levels by 39.3 mg/dL (from 190.7 ± 45.3 to 151.4 ± 41.6 mg/dL, P < 0.001). Patients with higher baseline HbA1c levels (≥ 9.0%) showed a better response to quadruple therapy than those with baseline HbA1c levels lower than 9.0% for all three regimens.ConclusionQuadruple oral hypoglycemic therapy can be a feasible option in patients with T2D.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00881-3) contains supplementary material, which is available to authorized users.

P4160Safety and efficacy of triple combination therapy with parenteral prostanoids in patients with Eisenmenger physiology

Abstract Aim While combination therapy is currently strongly advocated for idiopathic pulmonary arterial hypertension (PAH) patients, evidence to support its use in patients with PAH related to congenital heart disease (CHD), especially patients with Eisenmenger syndrome, is lacking. We evaluated the efficacy and safety of sequential triple combination therapy with parenteral prostanoids after failure of double oral therapy in patients with PAH-CHD and Eisenmenger physiology. Methods This is an international, multicentre, retrospective cohort study conducted in adult patients with Eisenmenger physiology on double oral PAH therapy in whom intravenous or subcutaneous prostanoid treatment was added due to clinical deterioration or failure to reach the treatment goals. Clinical status, 6-minute walk test distance (6MWD), biomarkers and haemodynamics were assessed at baseline and during the follow-up. Results A total 28 patients with Eisenmenger syndrome (6 [21%] male, age 37.6±14.3 years) were included. A post-tricuspid shunt was present in 16 (57%), 86% of whom had a ventricular septal defect. The majority (89%) were treated with subcutaneous treprostinil. At 27±14 months follow-up, WHO functional class improved in 18 (64%), remained unchanged in 8 (29%), and deteriorated in 2 (7%) patients. There was also an increase in 6MWD (mean 339±145 versus 233±140m, p=0.0001, fig 1A) and a reduction in NT-proBNP levels (median 1125 [123–5882] versus 3087 [234–7428] pg/mL, p&lt;0.0001, fig 1B). On follow-up cardiac catheterization, an improvement in right atrial pressure (8±2 versus 11±5 mmHg, p=0.01), mean pulmonary artery pressure (68±12 versus 72±17 mmHg, p=0.005), cardiac index (2.3±0.3 versus 2.0±0.5 l/min/m2, p=0.005, fig 1C), and pulmonary vascular resistance (17±7 versus 21±10, p=0.008, fig 1D), was observed compared to baseline. No patients discontinued treatment. Five (18%) patients died during follow up. Figure 1 Conclusions Triple combination therapy with subcutaneous treprostinil or endovenous epoprostenol in patients with Eisenmenger syndrome is safe and well tolerated at 2 years follow-up, resulting in a significant improvement in clinical status, exercise tolerance and haemodynamics.

Practice Patterns of Infectious Diseases Physicians in Transitioning From Intravenous to Oral Therapy in Patients With Bacteremia

BackgroundBacteremia in adult patients has traditionally been treated with extended courses of intravenous antibiotics. Data on the use of (or rapid transition to) oral therapy are limited.MethodsAdult infectious disease physicians participating in the Infectious Diseases Society of America Emerging Infections Network (EIN) were surveyed regarding their use of oral antibiotics in patients with bacteremia. Respondents were asked to assume that patients were hemodynamically stable, recovered bacteria were susceptible to potential antibiotics, adequate source control had been achieved, and patients had adequate gastrointestinal absorption. Variables of specific bacteria, oral agent, and associated infection were included.ResultsA total of 655 (50%) of 1321 EIN participants responded. Under certain conditions, 88% would transition patients with Gram-negative bacteremia to complete a course of therapy with oral antibiotics; 71% would transition patients with Gram-positive bacteremia to oral agents. Only 78 (12%) respondents would not treat any bacteremic patient with oral agents. Most respondents (≥75%) were comfortable treating infections secondary to Enterobacteriaceae, Salmonella, Pseudomonas, Stenotrophomonas, Streptococcus pneumoniae, and β-hemolytic streptococci with oral agents. Fewer than 20% endorsed use of oral antibiotics for Staphylococcus aureus or in cases of endocarditis. Fluoroquinolones and trimethoprim-sulfamethoxazole were the preferred agents in Gram-negative bacteremia; linezolid and β-lactams were the preferred agents in Gram-positive bacteremia.ConclusionsIn select circumstances, the majority of respondents would transition patients to oral antibiotics, in both Gram-negative and Gram-positive bacteremia. Most agreed with the use of oral agents in Gram-negative bacteremia caused by Enterobacteriaceae, but they would not use oral agents for Gram-positive bacteremia caused by S aureus or in endocarditis.

Fingolimod reduces CXCR4-mediated B cell migration and induces regulatory B cells-mediated anti-inflammatory immune repertoire

BackgroundFingolimod, an oral therapy for patients with relapsing Multiple Sclerosis (MS), traps CC chemokine receptor type 7 (CCR7)-expresssing lymphocytes within lymphoid tissues in the periphery, thereby supposedly reducing the infiltration of pathogenic cells into the central nervous system. Additional immunomodulatory effects of Fingolimod, involving cell function, B and T cells interactions and cross-regulation, have scarcely been studied. The objective of this study was to assess how Fingolimod therapy affects B cells functions, namely cell migration, immunoglobullin production and T cell stimulation. MethodsB cells from 36 patients with relapsing MS were obtained before and after 3 months Fingolimod therapy, while CD4 T cells were collected pre-treatment. Clinical follow-up was performed for 1 year. For in-vitro validation, Lymphoblastoid cell-lines from 16 patients were cultured with Fingolimod. B cell migration towards C-X-C Motif Chemokine Ligand 12 (CXCL12) was assessed using a transwell system. C-X-C chemokine receptor 4 (CXCR4) expression was assessed by flow cytometry and western blot. Plasma immunoglobullins and Brain-derived Neurotrophic Factor (BDNF) were assessed by ELISA or RT-PCR. Drug effect on interacting co-cultured B and T cells on cytokine profiles and T cell proliferation was explored by flow cytometry. ResultsLymphocyte count reduction did not predict clinical response of patients. Fingolimod therapy reduced CXCR4 expression and B cell migration towards CXCL12. No effect was found on immunoglobulins and BDNF. B cells from Fingolimod-treated patients induced a reduction in pro-inflammatory cytokines in T cells, while increased transforming growth factor beta (TGFβ)+ B and T cells, and downregulated IL2-secretion from proliferative T cells. ConclusionsFingolimod promotes anti-inflammatory cytokine profiles of B and T cells, through induction of regulatory B cells. Reduced B cell migration capacity in Fingolimod-treated patients leading to decreased cerebral inflammatory infiltration, may be part of the mechanism by which Fingolimod reduces disease activity in MS.

1153-P: Changes Observed during the Screening Period in Patients Enrolled in the Sitagliptin Clinical Study MK-0431-P083

MK-0431-P083, a 54-week phase III study of the DPP-4 inhibitor sitagliptin as initial oral therapy in patients 10-17 years of age with T2D was initiated in 2012 and completed enrollment in 2018. After informed consent was obtained, patient screening was initiated with a screening visit (V1), followed by a single-blind, placebo run-in (V2) for 1 week, after which they were randomized (V3, N = 201). The changes observed in select laboratory and anthropometric parameters in these 201 patients between V1 and V3 (~25 days), and adverse events (AEs) reported during the 1-week placebo run-in (V2 to V3), were summarized in a preliminary analysis. Results: (mean ± SD [95% confidence interval]) are presented below. Between V1 and V3 (25 ± 7 days, median 23 days), A1C decreased from 7.72 ± 1.02% to 7.49 ± 1.03%, a change (Δ) of -0.23 ± 0.67% [-0.32, -0.13], while FPG was unchanged. Changes were also observed in ALT (Δ: -2.55 ± 11.21 IU [-4.15, -0.95]) and AST (Δ: -1.93 ± 9.08 IU [-3.22, -0.63]). Weight and lipid parameters were unchanged. Between V2 and V3, 75 AEs were reported for 40 patients (~20% of the randomized patients). Of these AEs, 3 were assessed to be drug-related by the investigators: 2 AEs of nervousness and dyspepsia in 1 patient, and an AE of worsening gastroesophageal reflux in another. None of the 75 AEs were assessed to be severe, and none led to discontinuation from the study. These data suggest that changes may be observed in glycemic parameters during a screening period of &amp;lt;4 weeks. Furthermore, during the 1-week placebo run-in period, AEs were reported for nearly 20% of patients; remarkably, despite being told that patients received only placebo during this period, investigators considered some of the AEs to be drug-related. Disclosure C.A. Rosario: None. M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc. R. Garcia: None. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. Y. Samoilova: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp. A. Pong: None. M. Zilli: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Merck Sharp &amp; Dohme Corp. C.K. Saha: Research Support; Self; Indiana University School of Medicine. S.S. Engel: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck &amp; Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. Funding Merck &amp; Co., Inc.

2335-PUB: Clinical Trial of the Use of Sitagliptin in Pediatric Patients with T2D: Baseline Characteristics

MK-0431-P083, a multinational, 54-week, phase III study of the DPP-4 inhibitor sitagliptin (SITA) as initial oral therapy in patients 10-17 years of age with T2D, was initiated in 2012 and completed enrollment in 2018. A total of 201 patients with T2D who were either drug-naïve or on insulin alone at study entry were randomized and treated. Baseline characteristics of this population were summarized in a preliminary analysis and are presented below. Mean age was 14.0 ± 2.0 years, ∼58% were &amp;lt;15 years of age, and ∼61% were female. The majority (∼53%) were White, 14.9% were Asian, 5.5% were Black, and ∼19% were multiracial, with ∼37% describing themselves as Hispanic. The mean duration of diabetes was 0.7 ± 1.2 years, with ∼17% of participants having a duration ≥1 year. Approximately 11% of participants were on insulin at study entry. Mean BMI was 32.2 ± 7.7 kg.m-2, mean waist circumference was 100.9 ± 17.5 cm, and mean systolic and diastolic BP were 115.5 ± 10.6 mm Hg and 70.5 ± 8.5 mm Hg, respectively. Mean A1C was 7.5 ± 1.0%, and mean FPG 138.3 ± 45.2 mg/dL. Mean triglycerides were 137.4 ± 73.8 mg/dL and mean eGFR (calculated using the MDRD formula) was 200.4 ± 61.1 mL.min-1/1.73 m2. Mean ALT and AST levels were 27.3 ± 18.4 IU/L and 21.6 ± 9.8 IU/L, respectively. Among females, ∼71% had Tanner IV-V breast development, and among males, ∼63% had Tanner IV-V testicular development. These baseline data show that most participants in this study were drug-naïve, with a relatively short duration of T2D, and were predominantly female, White, and sexually mature. They were significantly obese, with central adiposity. Except for race, the demographic and anthropometric characteristics and the A1C and FPG of the participants in this global study are consistent with previous reports of patients predominantly from the United States. In addition, these baseline data confirm reports of glomerular hyperfiltration in pediatric patients with T2D. Disclosure M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc. R. Garcia: None. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. C.A. Rosario: None. Y. Samoilova: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp. Y. Zhang: Employee; Self; Merck Sharp &amp; Dohme Corp. L.W. Scherer: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. C.K. Saha: Research Support; Self; Indiana University School of Medicine. S.S. Engel: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck &amp; Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. Funding Merck &amp; Co., Inc.

Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia.

Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R-S1P5R. The drug Gilenya® (Novartis, Basel, Switzerland) (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalization and functional antagonism. Internalization of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In this study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX (lipopolysaccharide-induced CXC chemokine) expression were quantified. Results showed that pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, (i) CXCL5/LIX, (ii) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10) and (iii) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.

Difference between observed and predicted glycated hemoglobin at baseline and treatment response to vildagliptin-based dual oral therapy in patients with type 2 diabetes

AimWe aimed to investigate the association of difference between observed and predicted glycated hemoglobin (dopHbA1c) and HbA1c reduction after vildagliptin-based oral therapy in patients with type 2 diabetes (T2D). MethodsThis was a prospective observational study. Adults ≥ 20 years old with T2D and HbA1c ≧7% treated with oral anti-diabetic drugs (OADs) were eligible if their OADs were shifted to vildagliptin-based dual oral therapy. Fasting plasma glucose (FPG) and HbA1c were recorded at baseline, week 12, and week 24. To determine baseline dopHbA1c, a predicted HbA1c was calculated by inserting baseline FPG into a regression equation (HbA1c = FPG ∗ 0.0225 + 4.3806) developed from linear relationship between HbA1c and FPG in an independent cohort of 3239 outpatients with T2D (dopHbA1c = observed HbA1c – predicted HbA1c). Patients were assigned to low (≦0) or high (>0) dopHbA1c group according to their baseline dopHbA1c levels. The study endpoint was changes from baseline to week 24 in HbA1c levels. ResultsA total of 1224 patients were enrolled. Patients with a dopHbA1c >0 had a greater HbA1c reduction after vildagliptin-based dual oral therapy than those with a dopHbA1c ≦0 (−1.5 ± 2.0 vs. −0.4 ± 1.0%, p < 0.001). Baseline dopHbA1c was positively associated with HbA1c reduction from baseline to week 24 (β coefficient 0.883, 95% CI 0.811 to 0.955, p < 0.001), and the association remained significant after adjustment for confounders. ConclusionsIn T2D patients with an HbA1c ≧7%, a higher baseline dopHbA1c was associated with a greater HbA1c reduction after shifting to vildagliptin-based dual oral therapy.

Abstract C188: A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers

Abstract Background: RXDX-105 is a potent RET, BRAF and EGFR tyrosine kinase inhibitor (TKI) that exhibits high target affinity at low nanomolar concentrations. The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signaling molecules. RET gain of function alterations are associated with the development of various types of human cancer, including non-small cell lung cancer (NSCLC). BRAF plays a key role in regulating the MEK/ERK signaling pathway, which affects cell division and differentiation. Acquired BRAF mutations can result in constitutive activation of this pathway, thereby fueling cancer growth. RXDX-105 is being developed as an oral therapy for patients with solid tumors that harbor RET or BRAF mutations or gene rearrangements. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design to determine the recommended Ph 2 dose. Oral RXDX-105 was given as a fixed dose on a continuous daily schedule. Tumor response was assessed at baseline and every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) assessment was also a study objective. Results: To date, 35 pts (17 M and 18 F) received RXDX-105 across 7 dose levels (20 to 275 mg QD). Median age was 60.5 years (range 27-81). The most frequent tumors (pts) were metastatic CRC (13), ovarian cancer (3), NSCLC (3), cholangiocarcinoma (3), and pancreatic cancer (3). Median number of cycles was 2 (range 1 to 23). 34 pts experienced AEs; 6 pts experienced treatment-related G3 AEs, including anemia, hypophosphatemia, fatigue, diarrhea, abdominal pain, rash and muscle weakness. 22 SAEs were reported from 9 pts, with none considered treatment-related. No treatment-related deaths occurred. The most common AEs were: fatigue (17 pts), vomiting (13 pts), abdominal pain (12 pts), nausea (11 pts), decreased appetite (10 pts), and rash (10 pts). At the time of this report, 3 pts have had DLTs; 1 pt at 200 mg with G2 hand and foot syndrome, 1 pt at 275 mg with G3 fatigue, and 1 pt at 275 mg with G3 asymptomatic hypophosphatemia. The protocol was amended to exclude hypophosphatemia as a DLT since it has been observed with approved TKIs and can be managed by supplementation. The PK data to date have demonstrated that RXDX-105 is absorbed with a median Tmax between 2 and 6 hrs at steady state. RXDX-105 plasma concentrations declined slowly after reaching Cmax with an average terminal half-life of 28 to 42 hrs across dose levels. There was a loss of dose proportionality at doses above 150 mg, possibly due to pH-dependent drug dissolution in the stomach. The impact of the fed state on exposure is being explored. 11 pts have been on treatment for ≥ 12 weeks. No objective responses have been observed; however, 1 pt with BRAF V600E-positive papillary thyroid cancer, previously treated with RAI, EBRT and multiple surgical resections, has been on study with stable disease for almost 2 years (23 cycles). Additionally, 2 heavily pre-treated pts with squamous NSCLC achieved clinical benefit with SD for &amp;gt; 6 months; 1 patient continues. Conclusions: To date, treatment with RXDX-105 demonstrates an acceptable safety profile. Improvements in bioavailability are being investigated. Dose escalation continues. Citation Format: Ding Wang, Manish Patel, Marwan Fakih, A. Craig Lockhart, Anthony J. Olszanski, Rupal Patel, Peter D. Brown, Jennifer W. Oliver, Pratik S. Multani. A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C188.

Status of basal-supported oral therapy in Chinese type 2 diabetic patients with inadequate glycemic control on oral anti-diabetic drugs.

Timely initiation and titration of basal insulin added on to oral anti-diabetic drugs contribute to better glycemic control. However, implementation of basal-supported oral therapy in China is not yet clear. This nationwide, prospective, 12-week observational study was designed to explore the current status of basal-supported oral therapy in patients with type 2 diabetes in China. Type 2 diabetic patients with inadequate glycemic control on anti-diabetic drugs who were to start basal-supported oral therapy with insulin glargine at outpatient clinics were enrolled from 134 hospitals in China. Both the decision to initiate basal insulin and insulin dose adjustment were at the physician's discretion. Fasting plasma glucose (FPG) and haemoglobin A1c were measured, and the starting dose of insulin were recorded at baseline. Self-monitored fasting capillary blood glucose and the adjusting dose of insulin were collected during the study. A total of 11,192 out of 13,259 enrolled patients finished the 12-week study. FPG and haemoglobin A1c at basal-supported oral therapy initiation were 11.2 mmol/L and 9.4%, respectively, with insulin glargine started at 0.190 IU/kg/day. Insulin dose was increased 1.8 IU in average within 12 weeks. Fifty-nine percent of the patients achieved fasting capillary blood glucose ≤ 7.0 mmol/L. More patients achieved the glucose target in the group with lower baseline FPG level. Notable geographical differences of physicians' treatment habits in the current management of basal-supported oral therapy were also observed. A great gap between everyday clinical practice and guidelines exists in China, reflected by the delayed initiation, slow dose titration and geographical differences of basal-supported oral therapy management. A concrete guideline of basal-supported oral therapy management is needed in the clinical application.

March 2015 at a glance.

March 2015 at a glance.

Managing HCV infection: present and future

The development of direct acting antiviral agents against the hepatitis C virus has revolutionized treatment paradigms for hepatitis C. In 2011 the first HCV protease inhibitors boceprevir and telaprevir were approved, which still needed to be combined with pegylated interferon and ribavirin and were only usable in patients with genotype 1. However, the new triple therapy achieved successful cure rates of hepatitis C in almost 70% of treatment naive patients and immediately became the new gold standard of HCV therapy. With the development of further agents, in particular the recent licensing of sofosbuvir and simeprevir, two further DAA’s have become available. Thereby, for the first time Interferon free regimens are already available for genotype 2 and 3 patients allowing cure rates approaching 90% after 12 weeks of sofosbuvir and ribavirin for genotype 2 treatment naive as well as treatment-experienced patients and 24 weeks of all oral therapy for patients with genotype 3 (again treatment-naive or experienced). For genotype 1 the combination of sofosbuvir with pegylated interferon and ribavirin allows curing over 90% of patients after 12 weeks of triple therapy and therefore has become the preferred HCV therapy for this particular patient group. Also combination of sofosbuvir with other agents have been presented in particular simeprevir or daclatasvir leading to high success rates above 90% even in patients who failed previous triple therapy with one of the first HCV protease inhibitors. Therefore, where available, 2 DAA combinations ± ribavirin are rapidly becoming the new HCV treatment standard for more difficult to treat patient groups. In the near future combinations of antiviral agents with no cross resistance and improved safety profile will further reduce treatment durations and will become the new recommended HCV regimens making HCV the first viral infection to be possibly eradicated worldwide.

Transition from prostacyclin analogue infusion to oral therapy in patients with pulmonary arterial hypertension: a 5-year follow-up.

Transition from prostacyclin analogue infusion to oral therapy in patients with pulmonary arterial hypertension (PAH) is possible with acceptable short- and midterm results. However, there is a paucity of data on long-term outcomes after successful transition. Using a predefined protocol, transition to oral therapy was attempted in 22 patients with clinically stable PAH. Clinical and hemodynamic data were retrospectively collected at baseline as well as during and after transition. Parameters for successful versus nonsuccessful transition were also evaluated. All patients had severe PAH at baseline and showed clinical and hemodynamic improvement with prostacyclin analogue infusion. Initial oral agents used for transition were bosentan (63.6%), sildenafil (31.8%), and tadalafil (4.5%). Combination therapy was used in 68% of the patients. Successful transition was achieved in 11 patients (50%) with a mean transition duration of 16 months. After successful transition, clinical and hemodynamic parameters remained stable at midterm (mean, 18 months) and long-term (mean, 60 months) follow-up. Compared with the successful transition group, patients who experienced failure were older, had a higher frequency of idiopathic PAH, and had worse hemodynamic parameters during treatment with prostacyclin analogue alone, as well as during the transition period. In conclusion, successful transition from prostacyclin analogue infusion to oral therapy can be achieved in a significant proportion of patients with clinically stable PAH. After an initial successful transition, patients were able to maintain clinical and hemodynamic stability at the mid- and long-term follow-up.

THU0139 Pharmacokinetics of fostamatinib in patients with impaired hepatic function: A phase I study

BackgroundFostamatinib (R788), a spleen tyrosine kinase inhibitor, is currently being developed as an oral therapy for patients with rheumatoid arthritis1. Once administered, fostamatinib is converted to its active moiety, R406....

THU0138 Pharmacokinetics of fostamatinib in patients with impaired renal function: A phase I study

BackgroundFostamatinib (R788), a spleen tyrosine kinase inhibitor, is currently being developed as an oral therapy for patients with rheumatoid arthritis1. In humans, orally administered fostamatinib is converted to the active...

Topical therapy is underused in patients with ulcerative colitis

AbstractThe availability of new topical preparations for the treatment of left sided ulcerative colitis offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in left-sided colitis as compared to a systemic therapy. Therefore, we were interested in the use of topical therapy in patients with ulcerative colitis. The key question was whether topical treatment is more frequently used than oral therapy in patients with proctitis and left sided colitis. Data of 800 patients of the Swiss IBD cohort study were analyzed.Sixteen percent of patients of the cohort had proctitis, 21% proctosigmoiditis and 41% pancolitis. Topical therapy with 5-ASA or corticosteroids was given in 26% of patients with proctitis, a combined systemic and topical treatment was given in 13%, whereas systemic treatment with 5-ASA without topical treatment was given in 29%. Proportion of topical drug use decreased with respect to disease extension from 39% for proctitis to 13.1% for pancolitis (P=0.001). Patients with severe colitis received a significantly higher dose of topical 5-ASA than patients in remission.Side effects of topical or systemic 5-ASA or budesonide treatment were less frequently seen compared to other medications. Topical treatment was frequently stopped over time. The quality of life was the same in patients with limited disease compared to patients with pancolitis.Topical treatment in proctitis patients was underused in Switzerland. Since topical treatment is safe and effective it should be used to a larger extend.

Safety, Tolerability, and Activity of ALV003: Results from Two Phase 1 Single, Escalating-Dose Clinical Trials

Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease. The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials. In study 1 (N = 28) the study drug was administered in the fasted state; in study 2 (N = 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics). All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (N = 8) and 88 ± 5% (N = 8), respectively, of one gram of wheat bread gluten. ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.

Challenges of ensuring adherence to oral therapy in patients with solid malignancies

Challenges of ensuring adherence to oral therapy in patients with solid malignancies