Clinical Trials In Healthy Subjects Research Articles

Quantification of MDR-TB drug JBD0131 and its metabolite in plasma via UPLC-MS/MS: application in first-in-human study.

Aim: JBD0131, a novel anti-multidrug-resistant tuberculosis (MDR-TB) drug, can target and inhibit the synthesis of mycolic acids, which are crucial components of the cell wall of the Mycobacterium tuberculosis complex. To support the results of this clinical trial in healthy subjects, development of a specific and accurate quantification method for detecting JBD0131 and its metabolite DM131 in human plasma is needed.Materials & methods: Samples with prior added stabilizer were pretreated by protein precipitation method and the extracts weresubjected to ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The m/z transitions for the precursor/product ion pairs were 402.1/273 for JBD0131, 333.1/273 for DM131 and 386.1/257 for the internal standard (IS).Results: This method showed good linearity from 1 to 2000ng/ml for JBD0131 and 0.25 to 500ng/ml for DM131 and was validated in terms of selectivity, linearity, accuracy, precision, matrix effect, recovery of pretreament and stability.Conclusion: This method was sensitive and specific for measuring the plasma concentrations of JBD0131 and its metabolites. And it was applied for the investigation of the pharmacokinetics of JBD0131 and DM131 in a clinical trial.

Reversal of Pharmacologically Induced Mydriasis with Phentolamine Ophthalmic Solution

Evaluate safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an alpha-1 antagonist, in reversal of pharmacologically induced mydriasis. Two Phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy subjects. 553 healthy 12 to 80 year old subjects were randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either POS or placebo eye drops OU. Subjects received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or Paremyd (1% hydroxyamphetamine / 0.25% tropicamide). Primary endpoint was percent of subjects returning to ≤0.2 mm greater than baseline pupil diameter in study eye at 90 minutes after POS administration. Safety measures included treatment-emergent adverse events (TEAEs) and tolerability measures, including conjunctival hyperemia. In MIRA-2, 185 subjects were randomized to treatment with placebo (94) or POS (91). In MIRA-3, 368 subjects were randomized to treatment with placebo (124) or POS (244). A statistically significant greater percentage of subjects treated with POS had study eyes that showed reversal of mydriasis at 90 minutes (primary endpoint) compared with the placebo treatment (48.9% vs 6.6% for MIRA-2; p<0.0001 and 58% VS 6% for MIRA-3; p<0.0001) and as early as 60 minutes (24.5% vs 5.5% for MIRA-2; p<0.0003 and 42% VS 2% for MIRA-3; p<0.0001). Between 28 to 34% of placebo-treated subjects had not returned to baseline PD at 24 hours following pharmacological dilation compared to 8 to 11% treated with POS (p<0.0001). POS treatment had a rapid onset in reducing PD within 60- to 90-minutes, with a statistically significant time savings of 3 to 4 hours to return to baseline PD compared to placebo. One or 2 drops of POS rapidly reversed mydriasis in all subjects regardless of mydriatic agent or iris color. More subjects receiving POS reported a perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%).

A Phase 2, Open-Label Study to Evaluate the Efficacy and Safety of Mgta-145 in Combination with Plerixafor for the Mobilization of Hematopoietic Stem Cells in Patients with Sickle Cell Anemia

Background: In sickle cell anemia (SCA), a point mutation in the β-globin gene results in abnormal hemoglobin prone to polymerization under hypoxic conditions. Erythrocytes become sickle-shaped and rigid, leading to painful vaso-occlusion, ischemic tissue damage, and endothelial dysfunction. Despite significant, life-threatening risks, allogeneic hematopoietic cell transplant (allo-HCT) is the only cure for SCA. Results of autologous HCT, using the addition of a non-sickling, post-transcriptional gene silencing or gene editing to increase fetal hemoglobin, are promising and suggest an alternative option for those who lack a suitable donor. Procuring hematopoietic stem and progenitor cells (HSPCs) is challenging in patients with SCA, as granulocyte colony-stimulating factor is contraindicated due to severe adverse effects. Peripheral blood mobilization with Plerixafor (Mozobil®, Genzyme) has recently been shown to be safe and effective in SCA. While mobilization with plerixafor allows collection of an HSPC product, many SCA patients require ≥2 cycles of multiday plerixafor doses and apheresis to collect sufficient quantities of HSCs for genetic manipulation. Reports suggest 30% of patients experience vaso-occlusive events (VOEs) of grade ≥3 during and after apheresis; therefore, a considerable unmet need exists for agents that augment stem cell (SC) yields and reduce apheresis time. MGTA-145 is an agonist of cell-surface chemokine receptor 2 (CXCR2) under development for the mobilization of CD34+ cells in combination with plerixafor. MGTA-145 binds to CXCR2, resulting in HSC release, which when given with plerixafor, increases mobilization of HSCs. Preclinical studies in animal models and clinical trials in healthy subjects and patients with multiple myeloma demonstrated that MGTA-145 with plerixafor results in more rapid and robust mobilization of CD34+ cells, including primitive HSC populations, compared to plerixafor alone. Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 1 or 2 doses of MGTA-145 combined with plerixafor for the mobilization of HSCs in individuals with SCA. Study Design and Methods: This phase 2, open-label, 2-part study (NCT05445128) will enroll approximately 10-14 adults ages 18-35 years with SCA, at 3 sites in the US. Participants must have a documented diagnosis of SCA, have a hydroxyurea washout period, and have adequate white blood cell counts and cardiopulmonary, renal, and liver function. Key exclusion criteria include history of VOE requiring a visit to a healthcare facility within 30 days of screening, poorly controlled healthcare conditions, including but not limited to cardiopulmonary or hepatorenal events ≤6 months prior to screening, and cerebrovascular accident or retinal infarct ≤2 years prior to screening. In the 1st cohort of Part A, subjects will receive a single 0.24 mg/kg subcutaneous dose of plerixafor followed by a single 0.03 mg/kg IV dose of MGTA-145, with apheresis occurring within approximately 30-45 minutes of MGTA-145 dosing. After a 1-week follow-up visit and an Independent Data Monitoring Committee (DMC) review, the 2nd cohort with additional subjects may be enrolled and given plerixafor and a 0.03 or 0.015 mg/kg or lower dose of MGTA-145 (FIGURE). Following a 1-week follow-up visit and a 2nd DMC review, patients will be enrolled in Part B and will receive, on 2 consecutive days, plerixafor and the same dose of MGTA-145 as the 2nd Part A cohort, followed by apheresis on each dosing day. The primary endpoint is total yield of CD34+ cells (CD34+ cells/kg). Safety outcomes include incidence of treatment-emergent adverse events (TEAEs), drug-related TEAEs, Grade ≥3 TEAEs, treatment-emergent serious adverse events, and TEAEs leading to study drug discontinuation. Core exploratory endpoints include characterization of the phenotype and function of cells collected by apheresis and assessment of the gene-modifying potential of mobilized CD34+ cells. The results of this trial will establish if MGTA-145 with plerixafor will rapidly and safely mobilize robust numbers of high-quality SCs for HSCT in SCA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of Spaghetti Differing in Soluble Fiber and Protein Content on Glycemic Responses in Humans: A Randomized Clinical Trial in Healthy Subjects.

This randomized, single blind, cross-over study investigated the glycemic responses to three spaghetti No 7 types differing in dietary protein and soluble fiber content. Fourteen clinically and metabolically healthy, fasting individuals (25 ± 1 years; ten women; BMI 23 ± 1 kg/m2) received isoglucidic test meals (50 g available carbohydrate) and 50 g glucose reference, in random order. GI was calculated using the FAO/WHO method. Capillary blood glucose and salivary insulin samples were collected at 0, 15, 30, 45, 60, and 120 min. Subjective appetite ratings (hunger, fullness, and desire to eat) were assessed by visual analogue scales (VAS, 100 mm) at baseline and 120 min. All three spaghetti types (regular, whole wheat, and high soluble fiber–low carbohydrates) provided low GI values (33, 38, and 41, respectively, on glucose scale) and lower peak glucose values compared to glucose or white bread. No differences were observed between spaghetti No 7 types for fasting glucose, fasting and post-test-meal insulin concentrations, blood pressure (systolic and diastolic), and subjective appetite. Conclusions: all spaghetti No 7 types, regardless of soluble fiber and/or protein content, attenuated postprandial glycemic response, which may offer advantages to glycemic control.

Population Pharmacokinetic Properties of Omecamtiv Mecarbil in Healthy Subjects and Patients With Heart Failure With Reduced Ejection Fraction

Omecamtiv mecarbil is a small molecule that has been shown to improve cardiac function in patients with heart failure (HF) with reduced ejection fraction and is currently being developed as an oral modified release tablet for subjects with chronic HF. The objectives of this study were to analyze the pharmacokinetic (PK) properties of omecamtiv mecarbil and to investigate the effects of potential covariates on pertinent PK parameters using population PK modeling of data from 3 clinical trials in healthy subjects (n = 85) and 3 clinical trials in patients with HF (n = 4261). The population PK analysis was performed using a nonlinear mixed effects modeling approach. Omecamtiv mecarbil has a clearance of 11.7 L/h (0.701% relative standard error) and a central volume distribution of 275 L (2.12% relative standard error). The estimated half-life of omecamtiv mecarbil was 33 hours. Body weight and estimated glomerular filtration rate were significant covariates, but their effect on exposure was modest and lacked clinical relevance. Additional covariates, including sex, race, bilirubin, albumin, concomitant medications, New York Heart Association Functional Classification, N-terminal-pro hormone B-type natriuretic peptide, troponin I, creatine kinase MB, serum hemoglobin, tablet formulation, aspartate aminotransferase, and serum urea, were tested and found to have no impact on omecamtiv mecarbil exposures. The results of this integrated evaluation of the impact of covariates on the systemic exposure of omecamtiv mecarbil suggest that dose adjustment is not required for the studied subpopulations of patients with HF.

Population Pharmacokinetic Analysis to Assist Dose Selection of the L-Ornithine Salt of Phenylacetic Acid.

Background and Objectivel-Ornithine phenylacetate is an intravenous formulation of the l-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very limited clinical data in patients are available, with a phase II study in target patients not designed for dose finding, to support phase III dose selection in a global development program. The objective of the present population pharmacokinetic modeling and simulation was to evaluate dose selection for target patient populations with a low body weight, ethnicity, and hepatic impairment in a global clinical study.MethodsA population pharmacokinetic model was developed based on plasma concentrations of l-ornithine, phenylacetic acid, and phenylacetylglutamine data from four clinical trials in healthy subjects and patients with stable cirrhosis or hospitalized adult patients with liver cirrhosis and hepatic encephalopathy. A covariate analysis was conducted to identify source of variability to support dose selection for global clinical development of l-ornithine phenylacetate. Phenylacetylglutamine formation in the pharmacokinetic model also quantified pharmacodynamic effects measured by ammonia removal.ResultsBody weight and hepatic function were significant covariates determining phenylacetic acid exposure. After accounting for body weight, there was no difference between tested Caucasian and Asian populations in phenylacetic acid exposure. Renal dysfunction significantly reduced phenylacetylglutamine excretion. However, renal impairment had no impact on plasma phenylacetic acid and free ammonia levels. Exploratory modeling suggested that l-ornithine might enhance the removal of ammonia.ConclusionsWith a flat dosing algorithm, special consideration must be given to patients with a small body size (i.e., body weight ≤ 50 kg) and severe hepatic impairment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01075-1.

Beneficial effect of Chlorella pyrenoidosa drink on healthy subjects: A randomized, placebo-controlled, double-blind, cross-over clinical trial.

The current study aims to explore the anti-inflammatory activity of Chlorella pyrenoidosa on RAW 267.4 cells and followed by a cross-over clinical trial in healthy subjects to check the antioxidant and anti-aging properties of Chlorella water extract (CWE). For the clinical trial, 44 healthy subjects were requested to consume 27ml of either placebo or CWE for 90days (phase I) and vice-versa manner for 90days (phase II) with 4weeks of washout period. The RAW 264.7 macrophages treated with Chlorella display potent anti-inflammatory activity by significantly downregulating (p<.05) the protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Whereas, the subjects supplemented with CWE showed improved (p<.05) antioxidant status (TEAC, SOD, CAT, and DHEAs) and lower (p<.05) oxidative stress/aging markers (TBARS and 8-OHdG) as well as considerably (p<.05) protected liver (by lowering GOT and GPT). Thus, consumption of chlorella could significantly improve the overall health status by suppressing various oxidative stress markers and aging stress markers. PRACTICAL APPLICATIONS: Chlorella is considered as a popular functional food owing to its rich nutrient value and its array of biological activities. Numerous studies indicated that treatment with Chlorella spp. would considerably lower oxidative stress, inflammation, and regulate immune response which might contribute to anti-aging property in various cell and animal models. Based on the above information, we expected that Chlorella would be a better contender for the development of a novel anti-aging agent. Hence, we designed this clinical trial to assess the beneficial effects of Chlorella pyrenoidosa especially anti-aging. In agreement with our hypothesis, our results also showed that subjected supplemented with Chlorella water extract could significantly improve overall health status by suppressing various oxidative stress markers and aging stress markers. Hence, Chlorella could be developed into a novel anti-aging agent. In the future, it can be prescribed with standard anti-aging agents to improve the overall health status of the elderly population. However, large-scale clinical studies are needed to confirm our statements.

Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects

BackgroundCligosiban (formerly IX-01) is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AimTo investigate the plasma pharmacokinetics, safety, and tolerability of multiple oral doses of cligosiban in healthy male subjects; measure the amount of cligosiban in semen; and evaluate the potential of cligosiban to modulate CYP3A4. MethodsBoth studies were double-blind, placebo-controlled, parallel group designs involving sequential cohorts of 12 subjects each. Cligosiban dosage regimens were 100 mg, 400 mg, 800 mg, 1200 mg, 1,600 mg and 2,400 mg once daily for 10 days, administered as an aqueous dispersion. OutcomesBlood samplings for cligosiban assays and safety assessments were performed throughout both studies. Semen was collected on day 9 at 2–4 hours postdose in study 1 only. Safety assessments included monitoring of adverse events, 12-lead electrocardiography, vital signs, and laboratory safety assessments. Urine samples for assessment of the 6β-hydroxycortisol/cortisol ratio were collected before dosing on days 1 and 10. ResultsCligosiban was rapidly absorbed after both single and multiple dosing, with maximum plasma concentrations typically measured at 1–3 hours postdose. The terminal half-life was approximately 12 hours, and steady state was achieved by day 3. Exposure increased approximately proportionally to dose after single dosing but less than proportionally after multiple dosing. Accumulation ratios were higher at the lower doses compared with higher doses (2.3 at 100 mg vs 1.1 at 2,400 mg). The mean amount of cligosiban in semen ranged from 0.22 to 2.01 μg over the 100–1,200 mg dose range (<0.0003% of the administered dose). There were no meaningful differences in the urinary 6β-hydroxycortisol/cortisol ratio after multiple dosing with cligosiban. Cligosiban appeared to be well tolerated at all dose levels. Clinical ImplicationsCligosiban is well tolerated following once-daily dosing over a wide dose range and does not appear to modulate CYP3A4 activity, suggesting limited potential for perpetrating drug–drug interactions via this mechanism. Strengths & LimitationsThe 2 controlled trials show good toleration and pharmacokinetic data, including negligible amounts of cligosiban in semen at doses expected to be therapeutic. Toleration of cligosiban will need to be confirmed in studies in patients with PE. ConclusionCligosiban showed a good safety profile at doses predicted to be therapeutic or supratherapeutic along with a pharmacokinetic profile appropriate for as-required or once-daily dosing. There was no evidence that cligosiban inhibited or induced CYP3A4 at doses up to 2,400 mg.Muirhead GJ, Osterloh IH, Whaley S, et al. Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects. J Sex Med 2019;16:213–222.

Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist—Cligosiban—in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects

IntroductionCligosiban is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AimThree clinical studies investigated the pharmacokinetics (including effect of food and formulation), central penetration, safety, and tolerability of single oral doses of cligosiban in healthy subjects. MethodsStudy 1 was a double-blind, randomized, placebo-controlled, crossover design in 3 cohorts of 10 subjects each. Single doses of 0.3–2,400 mg cligosiban were administered as aqueous solutions or dispersions under fasting and fed (800 mg only) conditions. Studies 2 and 3 were open-label, randomized, crossover designs in 12 subjects each. Study 2 investigated 800 mg cligosiban administered as capsules and aqueous dispersion under fasting conditions, and capsules under fed conditions. Study 3 investigated 1,600 mg cligosiban administered as caplets and aqueous dispersion under fasting conditions, and caplets under fed conditions. Main Outcome MeasuresBlood sampling for cligosiban assay and safety assessments were conducted throughout all studies. Cerebrospinal fluid (CSF) samples for cligosiban assay were collected in study 2. ResultsCligosiban was rapidly absorbed under fasting conditions with peak concentrations generally occurring within 1–2 hours post-dose regardless of formulation. Maximum observed plasma concentration (Cmax) and area under the concentration time curve extrapolated to infinity (AUC0-∞) increased approximately dose-proportionally from 0.3–10 mg, but sub-proportionally from 30–2,400 mg. Cligosiban exposure was similar when administered as a dispersion or capsule (800 mg) under fasted conditions, but higher (87% increase) when administered as a caplet compared to the dispersion (1,600 mg). Food decreased the rate of absorption for all 3 formulations (median time to Cmax 3–6 hours compared to 1–2 hours fasted) but increased the extent of absorption (Cmax and AUC0-∞ increased by 75–149% and 33–49%, respectively). Cligosiban was detected in CSF at concentrations approximately 40% of unbound plasma concentrations. Cligosiban was well tolerated at all doses. Clinical ImplicationsCligosiban is well tolerated over a wide dose range, and has the pharmacokinetic properties to be taken as required prior to sexual intercourse in men with PE and to antagonize the oxytocin receptor in the brain and spinal cord. Strengths & LimitationsThree controlled trials show similar toleration and pharmacokinetic data. Cligosiban in CSF indicates its likely presence in all central nervous system tissue. These data need to be investigated and confirmed in multiple-dose studies prior to investigation in phase-II studies in men with PE. ConclusionCligosiban had a good safety/tolerability profile at doses predicted to be therapeutic or supra-therapeutic and a pharmacokinetic profile appropriate for “as-needed” dosing for men with PE.Osterloh IH, Muirhead GJ, Sultana S, et al. Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist—Cligosiban—in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects. J Sex Med 2018;15:1547–1557.

Short-term effects of six Greek honey varieties on glycemic response: a randomized clinical trial in healthy subjects.

This randomized, double blind, cross-over study investigated the glycemic response to six Greek honey grades differing in floral source and carbohydrate composition. Eleven clinically and metabolically healthy, fasting individuals (27 ± 7 years; nine women; BMI 24 ± 4 kg/m2) received isoglucidic test meals (50 g available carbohydrate) and 50 g glucose reference, in random order. GI was calculated using the FAO/WHO method. Capillary blood glucose samples were collected at 0, 15, 30, 45, 60, 90, and 120 min. Salivary insulin samples were collected at 0, 60, and 120 min. Subjective appetite ratings (hunger, fullness and desire to eat) were assessed by visual analogue scales (VAS, 100 mm) at baseline and 120 min. Fir and chestnut honeys provided medium GI values (59 and 66, respectively, on glucose scale). Citrus, heather, pine and thyme honeys provided high GI (>70 on glucose scale). Sucrose to oligosaccharides ratio, sucrose content and fructose to glucose ratio were inversely associated with GI (p < 0.05). No differences were observed between honey varieties for fasting glucose, fasting and post-test-meal insulin concentrations and subjective appetite. Honey varieties produced different glycemic responses, although having similar botanical origin and characterization, partly explained by their sucrose to oligosaccharide ratio (by 30%). Fir and chestnut honeys attenuated postprandial glycemic response, which may offer advantages to glycemic control.

Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic.

Background and ObjectivesCebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration.MethodsThe basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials.ResultsAfter oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C max] (4–6 h), a long half-value duration [HVD] (14–15 h), and a terminal phase half-life in the range of 62–96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70–80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200–1600 µg. A two-compartment disposition model with two lagged transition compartments and a first-order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration.ConclusionsCebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max after only 4–6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain.

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation.Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006).Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented.Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. DisclosuresThomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

World health organization approaches to evaluating the potential use and quality of hepatitis e vaccine.

World health organization approaches to evaluating the potential use and quality of hepatitis e vaccine.

Real-world safety data for tbo-filgrastim.

e17540 Background: Medical products registered in the European Union (EU) are subject to Periodic Safety Update Reports (PSURs), which provide comprehensive worldwide safety data assessments and benefit-risk analyses. Methods: The present PSUR for tbo-filgrastim-containing products within the TEVA group (Tevagrastim, Biograstim, Ratiograstim [marketed in the US as Granix]) analyzed safety data accumulated between April 1, 2012 and March 31, 2013 in 38 countries. Cumulative data were collected from clinical trials and post-marketing sources from September 15, 2008 (initial approval) to the end of the current PSUR period, March 31, 2013. Data were collected from spontaneous reports from healthcare professionals, consumers, scientific literature, competent authorities, and solicited case reports. Adverse reactions were categorized by system organ class (SOC), source, and seriousness. Teva pharmacovigilance requires screening of all adverse reaction reports and antibody assessment for cases of suspected immunogenicity. Results: From September 15, 2008 (initial approval) to the end of the current PSUR period, March 31, 2013, the estimated cumulative exposure to products containing tbo-filgrastim was ~4,474,929 patient-days. Estimated cumulative exposure to tbo-filgrastim in clinical trials in healthy subjects and patients with cancer was 190 and 22,099 patient-days, respectively. The global safety database processed 254 tbo-filgrastim case reports from initial product approval through March 31, 2013 (~4.5 years), including 61 (24%) from the PSUR period. Post-marketing data sources cumulatively reported 461 adverse reactions, 131 (28%) from the PSUR period. The most commonly occurring preferred terms in association with important identified and potential risks over the cumulative period were allergic type reactions (11), interstitial pneumonia (4), and splenomegaly (2). Eleven new cases were identified that required immunogenicity testing during the PSUR period. The most common reasons for requiring testing were lack of efficacy (n=7) and type II hypersensitivity (n=2). Conclusions: No new safety risks were identified for tbo-filgrastim based on PSUR data from the most recent reporting period ending March 31, 2013.

Interim Results From a Phase Ib/IIa Clinical Trial with the Soluble Fc-Gamma IIb Receptor SM101 for the Treatment of Primary Immune Thrombocytopenia

AbstractAbstract 3388 Background:Primary Immune Thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count below 100 × 109/L and an exclusion of secondary causes such as bacterial infections or hematological malignancies. Fc-gamma-receptors (FcγRs) are involved in the clearance of immune complexes, the antibody-dependent cellular cytotoxicity, the secretion of mediators and indirectly the regulation of B cell proliferation and differentiation. The investigational product SM101 represents the non-glycosylated C-terminally engineered human soluble FcγRIIB. SM101 has been investigated successfully in autoimmune models, toxicology studies and safety clinical trials in healthy subjects and is currently being investigated in phase II clinical studies in patients with ITP and Systemic Lupus Erythematosus (SLE). Recently, the dose-escalation part of the phase Ib/IIa clinical trial in ITP was completed. Objectives:The primary objective was to evaluate the safety and tolerability of SM101 at increasing dose levels in patients with chronic ITP. Secondary objectives included efficacy in terms of platelet count and pharmacokinetic (PK) evaluation of SM101. Methods:The Ib part of the clinical trial was designed as a randomized, double-blind, placebo-controlled, multi-center dose escalation study in 36 ITP patients. Each dosing cohort consisted of 4 verum and 2 placebo subjects. Major inclusion criteria included a diagnosis of chronic ITP for at least 6 months and a platelet count of less than 30 × 109/L at baseline. Concomitant corticosteroids were allowed at constant doses during the study. Eligible patients were dosed on day 1 with a 5 week safety period, followed up by the intended treatment cycle of 4 weekly infusions between day 35 and 56 and a final follow-up of 3 months. An independent Data Safety Monitoring Board was in place to review safety data after each dose cohort. Results:In total, 36 ITP patients in 6 dose groups received 5 infusions of 0.3 to 12.0 mg/kg/week SM101or placebo. 56% of the patients were females, 39% of the patients were splenectomized and 39% received concomitant corticosteroids prior to randomization. In the placebo group, 42% received rescue medication compared to 0 to 25% in the higher dose groups with SM101. No dose-limiting toxicity (DLT) occurred and no serious adverse event (SAE) was observed for patients treated with SM101. SM101 plasma levels increased proportionally with dose and the mean t1/2 across all dose groups was 42.7 h with a range of 14.0 to 99.9 h. In terms of immunogenicity, no anti-drug-antibodies against SM101 were observed. For patients without ITP rescue therapy, the highest dose group with 12 mg/kg/week SM101 showed a sustained median platelet response over 50 × 109/L in comparison to placebo after one treatment cycle with 4 infusions (Figure 1). This response persisted during the 3 months follow-up period with a median platelet count of approximately 70 × 109/L at the end of the clinical trial. The platelet response in the 12 mg/kg/week group started approximately 20 days after the beginning of the treatment cycle. [Display omitted] Conclusions:- To the author’s knowledge, this is the first time that a soluble Fcγ receptor showed efficacy in a clinical trial- In the 12 mg/kg/week group, SM101 showed a clear platelet response in patients with ITP- The duration of the platelet response persisted for at least 3 months after the last administration of SM101- Multiple doses of SM101 up to 12 mg/kg/week were well tolerated with no DLT or SAE- Further clinical trials with SM101 in ITP to support the current findings are ongoing. Disclosures:Tillmanns:SuppreMol GmbH: Employment. Sondermann:SuppreMol GmbH: Employment. Buckel:SuppreMol GmbH: Employment.

Ezogabine: An Evaluation of Its Efficacy and Safety as Adjunctive Therapy for Partial-Onset Seizures in Adults

To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamic properties, and clinical application of ezogabine (retigabine, INN), an antiepileptic drug approved in 2011. Published data from in vitro, animal, and clinical studies were obtained from PubMed and CINAHL searches, from January 1980 to March 31, 2012. Other relevant data regarding the safety and efficacy of ezogabine were obtained from the Food and Drug Administration and the European Medication Agency Web sites. Selected articles were prospective in vitro, animal, and controlled clinical studies of ezogabine. Non-English-language articles were excluded. In vitro and animal studies show that ezogabine activates voltagegated potassium channels, leading to reduction of seizure frequency by inhibiting hyperexcitability activity in the central nervous system. Additionally, ezogabine enhances γ-aminobutyric acid (GABA) activity and de novo GABA synthesis. Eight clinical studies of ezogabine have been published, 5 being Phase 1 clinical trials in healthy subjects and 3 being Phase 3 clinical trials in patients with pharmaco-resistant partial-onset seizures. Phase 3 clinical trials demonstrated the safety and efficacy of ezogabine in patients with partial-onset seizures. Clinical trials have shown that ezogabine is efficacious as an adjunctive agent in patients with pharmacoresistant partial seizures. Careful monitoring of drug interactions and adverse reactions is necessary. While ezogabine is efficacious for partial seizures, its precise role in the management of patients with epilepsy is yet to be determined.

Tolerability of a Proprietary Larch Arabinogalactan Extract: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial in Healthy Subjects

In a placebo-controlled, double-blind, randomized clinical trial, the tolerability of a proprietary larch arabinogalactan preparation (ResistAidTM) was investigated. METHODS: 199 healthy participants were randomly assigned to receive either placebo (n = 98) or an arabinogalactan preparation (n = 101) over a period of 12 weeks. As safety parameters the total number of adverse events, changes in various biochemical and laboratory parameters as well as the global evaluation of tolerability by investigator and subjects compared to placebo were evaluated. RESULTS: In total 16 adverse events were observed in 16 subjects, with no difference between the arabinogalactan and the placebo group (p = 0.935). There were no differences in the mean changes of the measured biochemical and laboratory parameters. The tolerability of the arabinogalactan extract was rated as “very good” or “good” by the investigators for 99% of the subjects and by 98% subjects in self-assessment with no statistical differences to placebo. CONCLUSION: The measured parameters as well as the evaluation of the tolerability by the investigators and the subjects demonstrate a very good tolerance profile of the proprietary arabinogalactan extract with no differences to placebo when taken for 12 weeks.

Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters - a placebo controlled clinical trial in healthy subjects

BackgroundIn Germany, Iscucin® Populi (IP), a preparation from mistletoe growing on the poplar tree, is used in cancer therapy while Viscum Mali e planta tota (VM), a preparation from mistletoe growing on the apple tree, is used in patients with osteoarthritis. Since mistletoe preparations are suspected to induce production of potentially tumor promoting cytokines like interleukin (IL)-6, further studies on the immunological effects are of interest.MethodsIn this 3-armed randomized, double blind clinical trial healthy volunteers received increasing doses of either IP (strength F, 0.0125%, G, 0.25% and H, 5%, each for 4 weeks), or VM (1:1000 [D3], 1:100 [D2] and 2% each for 4 weeks) or placebo (isotonic solution) subcutaneously twice per week over a period of 12 weeks. Physical examination was performed weekly. Routine laboratory parameters and immunological parameters (C-reactive protein (CRP), differential blood count, lymphocyte subsets, immunoglobulins, IL-6 and tumor necrosis factor (TNF)-α) were analysed every 4 weeks.Results71 subjects were included in the study (IP = 30, VM = 21, placebo = 20) of whom 69 concluded it according to protocol. Application of IP strengths G and H caused strong local reactions at the site of injection. In parallel, a distinct eosinophilia (p < 0.001 compared to placebo) occurred. Furthermore, application of all IP concentrations resulted in an increase of CD4 cell counts (p < 0.05) compared to placebo. Stimulation of IL-6 production, CRP or relevant deviations in other laboratory parameters were not observed. Because of local reactions, IP strengths G and H were considered less tolerable than placebo. VM 2% was slightly less tolerable than placebo, caused only mild local reactions and an only small increase in eosinophile counts.ConclusionTreatment with IP results in eosinophilia and an increase of CD4 cells but not in an increase of IL-6 or CRP. No safety concerns regarding the two mistletoe preparations have been raised by this study. EudraCT-Number 2007-002166-35.Trial registrationClinicalTrials.gov: NCT01378702

Dipeptidylpeptitase-4 Inhibitors (Gliptins)

Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagliptin and its primary metabolite may be significantly modified when saxagliptin is coadministered with specific strong inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms. The absence of significant drug-drug interactions could be explained by the favourable pharmacokinetic characteristics of DPP-4 inhibitors, which are not inducers or inhibitors of CYP isoforms and are not bound to plasma proteins to a great extent. Therefore, according to these pharmacokinetic findings, which were generally obtained in healthy young male subjects, no dosage adjustment is recommended when gliptins are combined with other pharmacological agents in patients with T2DM, with the exception of a reduction in the daily dosage of saxagliptin when this drug is used in association with a strong inhibitor of CYP3A4/A5. It is worth noting, however, that a reduction in the dose of sulfonylureas is usually recommended when a DPP-4 inhibitor is added, because of a pharmacodynamic interaction (rather than a pharmacokinetic interaction) between the sulfonylurea and the DPP-4 inhibitor, which may result in a higher risk of hypoglycaemia. Otherwise, any gliptin may be combined with metformin or a thiazolidinedione (pioglitazone, rosiglitazone), leading to a significant improvement in glycaemic control without an increased risk of hypoglycaemia or any other adverse event in patients with T2DM. Finally, the absence of drug-drug interactions in clinical trials in healthy subjects requires further evidence from large-scale studies, including typical subjects with T2DM - in particular, multimorbid and geriatric patients receiving polypharmacy.

Pharmacodynamics Pharmacodynamics of a Novel Designer Natriuretic Peptide, CD‐NP, in a First‐in‐Human Clinical Trial in Healthy Subjects

CD-NP is a novel chimeric natriuretic peptide (NP) consisting of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP), a venodilating peptide with limited renal actions and minimal effects on blood pressure, and the 15-AA C-terminus of Dendroaspis NP (DNP). The rationale for the design of CD-NP was to enhance the renal actions of CNP, the ligand for natriuretic peptide receptor-B, but without inducing excessive hypotension. Here we report the first-in-human studies for CD-NP, which represent the first successful clinical testing of a chimeric NP demonstrating in normal human volunteers that CD-NP possesses cyclic guanosine monophosphate-activating, natriuretic, and aldosterone-suppressing properties without inducing excessive hypotension, laying the foundation for additional studies on this first-in-class new cardiovascular therapeutic in human heart failure, which are now underway worldwide.