An Open-Label, Randomized, Single-Dose, Crossover, Comparative Pharmacokinetics Study of YLB113 and the Etanercept Reference Product in Healthy Adult Male Subjects.

BACKGROUND AND OBJECTIVES: YLB113 is being developed as a biosimilar of the antitumor necrosis factor-alpha antagonist etanercept, which is approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) and other chronic immune-mediated inflammatory diseases. An open-label, crossover, pharmacokinetic study was conducted to compare the relative bioavailability and safety of YLB113 and the etanercept reference product (RP) Enbrel®. METHODS: Healthy male subjects aged 18-50 years were randomized to receive a single subcutaneous dose of YLB113 in one period and the etanercept RP in another period. A washout period of 28 days separated the two treatment periods. Blood samples were collected for pharmacokinetic analysis predose and until 480 h postdose during both periods. RESULTS: Overall, 52 subjects were enrolled, including 51 subjects who completed the first period and 43 subjects who completed the second period. The 90% confidence intervals for the least squares means derived from an analysis of the log-transformed pharmacokinetic parameters maximum serum concentration (Cmax), area under the serum concentration-time curve (AUC) from 0 to the last measurable concentration (AUC(0-t)) and AUC from 0 to infinity (AUC(0-∞)) for etanercept were between the limits of 80 and 125%. Thus, YLB113 met the bioequivalence criterion. YLB113 and the etanercept RP were well tolerated, with 24 subjects reporting 53 adverse events, including 42 mild and 11 moderate events. Treatment-emergent adverse events were reported by 14 and 16 subjects following the administration of YLB113 and the etanercept RP, respectively. CONCLUSIONS: A single dose of YLB113 exhibited pharmacokinetic and safety profiles comparable with those of the etanercept RP in healthy adult male subjects. Therefore, YLB113 and the etanercept RP can be considered bioequivalent. These findings support the continued development of YLB113 for use in patients with RA. JORDAN FOOD & DRUG ADMINISTRATION UNIQUE TRIAL NUMBER: 31/Clinical/2018.

A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1ß (IL-1ß) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1ß signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990.

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension.

BACKGROUND: Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing. METHODS/DESIGN: The primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study ("rollover patients") and those who did not participate in the double-blind study ("non-rollover patients"), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up. DISCUSSION: Prevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE. Trial registration NCT02741596.

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency. METHODS: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group. RESULTS: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group. CONCLUSIONS: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

Comparison of gastric emptying parameters between asymptomatic volunteers and patients with functional dyspepsia in Middle Eastern population.

OBJECTIVE: To derive the normal reference values for Middle East population using a standard method, and to validate its performance in functional dyspepsia. METHODS: A prospective study was designed to derive gastric emptying parameters in 36 healthy control subjects. We measured the lag phase, half time, and gastric retention at the first, second, and third hours. Values were compared to 49 patients with functional dyspepsia. This study was carried out between July 2005 and August 2009 at Jordan University Hospital, Amman, Jordan. RESULTS: There were no statistically significant differences between the 2 groups at lag phase. Dyspeptic patients had significantly higher gastric retention at the first, second, and third hours (p=0.045, p=0.003, p=0.002). Gastric retention at the third hour was the most sensitive parameter detecting 16 patients (32.6%). Only 3 patients (6.1%) had increased gastric retention at the first hour and normal retention at the third hour. Twelve patients (24.5%) had delayed half time; these patients had increased gastric retention either at the first or third hour. CONCLUSION: Measurement of gastric retention at the first, second, and third hour is enough to identify delayed-early and late phases of gastric emptying in functional dyspepsia patients.

Value of serum bilirubin levels in selecting patients for magnetic resonance cholangiopancreatography.

BACKGROUND/AIMS: To determine the value of serum bilirubin levels in selecting patients for MRCP. METHODOLOGY: The medical records of 142 patients who underwent MRCP between January 2002 and December 2004 were retrospectively reviewed. Clinical features, serum bilirubin levels, and MRCP results were recorded. The patients were categorized into 4 groups, according to serum bilirubin levels and MRCP findings. Bilirubin levels were considered elevated above 23.9 micromol/L for total bilirubin and above 6.8 micromol/L for direct bilirubin. Sensitivity, specificity, accuracy, and predictive values of serum bilirubin levels in identifying pancreatobiliary duct diseases were assessed. RESULTS: Complete medical records were found for 135 patients. Abnormal MRCP results were found in 75 patients (56%). Choledocholithiasis and both malignant and benign bile duct strictures represented 40%, 28%, and 23% of abnormal MRCP findings, respectively, with mean values of total and direct serum bilirubin levels of 77.9 +/- 51.6 microM and 34.7 +/- 30.3 microM (for choledocholithiasis), 170 +/- 115 microM and 56 +/- 40 microM (for malignant bile duct stricture), and 44 +/- 32 microM and 20 +/- 16 microM (for benign bile duct stricture), respectively. Sensitivity, specificity, and accuracy of serum bilirubin level tests, for the diagnoses of pancreatobiliary duct diseases, were 77%, 80%, and 79%, respectively; the positive and negative predictive values were 83% and 74%, respectively, and the corresponding likelihood ratios were 3.8 and 0.3. CONCLUSIONS: Serum bilirubin level tests alone are not sufficiently accurate for the diagnoses of pancreatobiliary duct diseases, and hence, such tests are of low importance in selecting patients for MRCP.

Clinico-radiological correlates of achalasia.

OBJECTIVE: To study the clinical and radiographic characteristics of achalasia in a cohort Jordanian patients and to investigate the presence of any clinico-radiological relationships. METHODS: Thirty-five cases of recently diagnosed untreated achalasia patients were studied at Jordan University Hospital, Amman, Jordan during the period of January 1999 to December 2002. Measurements of maximum esophageal and gastroesophageal (GE) junction diameters, as radiographic features, were obtained from films. The clinical features included age; gender; nature; frequency and duration of typical and atypical symptoms; total number of symptoms; calculated typical symptoms score; and diagnostic delay. Pearson correlation coefficients were calculated between radiographic and clinical features, and among the radiographic features themselves. Using Spearman's correlation coefficients, the later analysis was repeated for patients with diagnostic delay of 2 years or less and patients with more than 2 years. All results were evaluated based on the 0.05 level of significance. RESULTS: There were 35 consecutive achalasia patients enrolled in this study (20 females and 15 males) with a mean age of 42.3 +/- 15.6 years and diagnostic delay of 29 +/- 26 months. On average, each patient has presented 2 typical symptoms and 2 atypical symptoms. The mean typical symptoms score was almost 3 out of the full score of 6. The mean GE junction diameter was 2.4 mms and maximum esophageal diameter was 29 mms. Maximum esophageal diameter was significantly correlated with the number of typical, atypical and total symptoms as well as with the typical symptom score and diagnostic delay. Negative correlation was found between GE junction diameter and maximum esophageal diameter; but only statistically significant for patients with diagnostic delay of more than 2 years. CONCLUSION: Statistically significant relationship exists between maximum esophageal diameter and all clinical variables. Negative correlation exists between maximum esophageal diameter and GE junction diameter; however, only significant for patients with a diagnostic delay more than 2 years. The possibility of achalasia is high in patients with longer diagnostic delay who demonstrate negative relationship between maximum esophageal diameter and GE junction diameter.