Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor MTPS9579A in asthma.

BACKGROUND: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. METHODS: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. RESULTS: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. CONCLUSIONS: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

The postauricular fascia: classification, anatomy, and potential surgical applications.

In recent times, there has been evolving interest in the fascial structure of the ear, especially in relation to otoplasty techniques. Although the fascial tissues used in these procedures are referred to as "postauricular/retroauricular fascia," the sparse anatomical studies that exist use this terminology to describe what is the adjacent thicker and more fibrous structure of the superficial temporal area continuous with the mastoid region, rather than the tissue actually used in these procedures which is adherent to the posterior surface of the ear. There are clear clinical differences in the properties of these two structures, and this study set out to identify the anatomical nature of these differences, looking in detail at the anatomy and vascularity of the fascia directly posterior and adherent to the ear itself, highlighting its unique properties, and how it interfaces with the rest of the fascia. We provide a nomenclature to differentiate the fascia adherent to the posterior of the ear (the intrinsic postauricular fascia) from the more fibrous tissues continuous with the scalp fascia (the extrinsic postauricular fascia). Clinical applications for the fascia are suggested based on the vascularity and anatomy described, and our clinical experience.

Serious Infection Rates Among Patients with Select Autoimmune Conditions: A Claims-Based Retrospective Cohort Study from Taiwan and the USA.

INTRODUCTION: Serious infections are an important concern for patients with autoimmune conditions. We sought to estimate serious infection rates among patients with select autoimmune conditions relative to the general population in Taiwan and the USA. METHODS: This retrospective cohort study estimated setting-specific standardized serious infection incidence rates and ratios among patients with systemic lupus erythematosus, including extra-renal lupus and lupus nephritis, rheumatoid arthritis and primary membranous nephropathy, compared with the general population using insurance claims for hospitalizations between 2000 and 2013. Multivariable Cox proportional hazard models were used to estimate adjusted hazard ratios for serious infections, adjusting for age, sex, index year, prior serious infection, comorbidities and medications. RESULTS: In Taiwan, serious infection rates were 22.7, 28.7, 70.6, 43.4 and 215.3 per 1000 person-years among the general population and among cohorts of patients with primary membranous nephropathy, rheumatoid arthritis, extra-renal lupus and lupus nephritis, respectively. In the USA, serious infection rates were 2.6, 9.0, 15.6, 21.0 and 63.3 per 1000 person-years among the general population and among cohorts of patients with primary membranous nephropathy, rheumatoid arthritis, extra-renal lupus and lupus nephritis, respectively. Patients had significantly higher serious infection rates than the general population in both settings, largely driven by bacterial, respiratory, urinary tract and opportunistic infections. Patients with lupus nephritis had the highest burden of serious infections relative to the general population, with 7- to 25-fold higher adjusted hazard ratios in Taiwan and the USA, respectively. CONCLUSION: This study identified a significant excess serious infection burden among patients with targeted autoimmune conditions compared with the general populations in Taiwan and the USA.

A phase I, randomized, ascending-dose study to assess safety, pharmacokinetics, and activity of GDC-8264, a RIP1 inhibitor, in healthy volunteers.

Receptor-interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)-α, Toll-like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1-mediated inflammation and cell death. GDC-8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo-controlled, double-blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single- (5-225 mg) and multiple- (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC-8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC-8264. All adverse events in GDC-8264-treated subjects in both stages were mild. GDC-8264 exhibited dose-proportional increases in systemic exposure; the mean terminal half-life ranged from 10-13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC-8264 had minimal renal excretion at all doses. A high-fat meal had no significant effect on the PKs of GDC-8264. In an ex vivo stimulation assay of whole blood, GDC-8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK-PD modeling, the GDC-8264 half-maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC-8264 support its further development for treatment of RIP1-driven diseases.

Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis.

BACKGROUND: Allergic rhinitis is characterized by mast cell degranulation induced by antigen cross-linking of IgE. It has been proposed that some patients with rhinitis show nasal allergy in the absence of systemic markers of atopy, termed entopy. Recent murine studies suggest the existence of an IgE-independent hypersensitivity response involving antigen-induced mast cell activation, mediated by immunoglobulin free light chains (FLCs). OBJECTIVES: To determine whether FLC is associated with mast cell-mediated nasal hypersensitivity and its relationship with eosinophilic activity in allergic and nonatopic rhinitis. METHODS: Patients with allergy and nonallergic rhinitis with eosinophilia syndrome (NARES) had levels of soluble FLC measured in nasal secretions and serum. In addition, levels of the nasal inflammatory mediators mast cell tryptase and eosinophil cationic protein were quantified. Cellular expression of kappa and lambda FLC was characterized in the nasal mucosa of allergic and nonatopic idiopathic rhinitis and control subjects by using immunohistochemistry. Immunopositive cells were phenotyped by using laser microdissection and PCR. RESULTS: Free light chain was significantly increased in nasal secretions of subjects with allergy and NARES, and in serum of patients with NARES. Nonatopic patients with allergy showed significantly increased nasal mast cell tryptase and eosinophil cationic protein. FLC-positive cells were significantly increased in allergic and nonatopic mucosa, and were shown to be mast cells and plasma cells. CONCLUSION: Nasal FLC is significantly increased in allergic and nonatopic rhinitis nasal mucosa, suggesting a role in nasal hypersensitivity. Further studies are needed to identify which allergens trigger FLC-mediated responses in nonatopic rhinitis.

Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study. METHODS: Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48. RESULTS: Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. CONCLUSION: While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition.

Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI.

Mechanistic understanding of complex clinical drug-drug interactions (DDIs) with potential involvement of multiple elimination pathways has been challenging, especially given the general lack of specific probe substrates for transporters. Here, we conducted a clinical DDI study to evaluate the interaction potential of fenebrutinib using midazolam (MDZ; CYP3A), simvastatin (CYP3A and OATP1B), and rosuvastatin (BCRP and OATP1B) as probe substrates. Fenebrutinib (200 mg) increased the area under the curve (AUC) of these probe substrates twofold to threefold. To evaluate the mechanism of the observed DDIs, we measured the concentration of coproporphyrin I (CP-I) and coproporphyrin III (CP-III), endogenous biomarkers of OATP1B. There was no change in CP-I or CP-III levels with fenebrutinib, suggesting that the observed DDIs were caused by inhibition of CYP3A and BCRP rather than OATP1B, likely due to increased bioavailability. This is the first published account using an endogenous transporter biomarker to understand the mechanism of complex DDIs involving multiple elimination pathways.

Physiologically-Based Pharmacokinetic Model-Informed Drug Development for Fenebrutinib: Understanding Complex Drug-Drug Interactions.

Fenebrutinib is a CYP3A substrate and time-dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically-based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug-drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic-absorption model accounting for the effects of excipient complexation with fenebrutinib was used to rationalize the unexpected observation of itraconazole-fenebrutinib DDI (maximum plasma concentration (Cmax ) decreased, and area under the curve (AUC) increased). The totality of the evidence from sensitivity analysis and clinical and nonclinical data suggested that fenebrutinib is likely a sensitive CYP3A substrate. This advanced PBPK application allowed the use of model-informed approach to facilitate the development of concomitant medication recommendations for fenebrutinib without requiring additional clinical DDI studies.

Understanding the Effect of Hydroxypropyl-ß-Cyclodextrin on Fenebrutinib Absorption in an Itraconazole-Fenebrutinib Drug-Drug Interaction Study.

Cyclodextrins are widely used pharmaceutical excipients, particularly for insoluble compounds dosed orally, such as the oral solution of itraconazole, which is frequently used in clinical drug-drug interaction studies to inhibit cytochrome P450 3A. Since cyclodextrins act by forming inclusion complexes with their coformulated drug, they could have an unintended consequence of affecting absorption if they form a strong complex with the potential victim drug in an itraconazole drug-drug interaction study. This observation was made in a drug-drug interaction study with the Bruton's tyrosine kinase (BTK) inhibitor fenebrutinib and itraconazole, in which, relative to the control group, the expected increase in fenebrutinib maximum plasma concentration (Cmax ) was not observed in the itraconazole group, and a delay in time to reach maximum plasma concentration (Tmax ) was observed in the itraconazole group. The in vitro binding constant between fenebrutinib and hydroxypropyl-ß-cyclodextrin was determined to be 2 × 105  M-1 , and the apparent permeability of fenebrutinib across a Madin-Darby canine kidney cell monolayer decreased in a cyclodextrin concentration-dependent manner. This observation was confirmed in vivo, in a pentagastrin-pretreated dog model, in which fenebrutinib was administered with or without cyclodextrin; a reduction in Cmax , a prolonged Tmax , and increased fenebrutinib recovery in feces replicated the previous observation in healthy volunteers and supported the hypothesis that complexation with cyclodextrin decreased rate and extent of fenebrutinib absorption. Physiologically-based pharmacokinetic modeling was used to translate the in vitro effect of cyclodextrin on fenebrutinib apparent permeability to the in vivo effect on absorption, which was then confirmed using the in vivo dog pharmacokinetic data.

Ophthalmic manifestations of paranasal sinus mucocoeles.

PURPOSE: To investigate the ophthalmic manifestations of paranasal sinus mucocoeles. METHODS: A retrospective study of all patients (1992-1998) diagnosed with paranasal sinus mucocoeles. All patients had a CT scan. RESULTS: Of the 45 patients, only 3 (6.7%) did not have ophthalmic symptoms or signs. The most common (64.4%) presenting feature was peri-orbital swelling, often associated with pain and tenderness. Other presenting features included diplopia, proptosis, hypoglobus, diplopia, decreased colour vision, epiphora, facial swelling and nasal polyps. The frontal sinus was the most commonly (70%) involved site. CONCLUSIONS: Paranasal sinus mucocoeles present most commonly with ophthalmic symptoms and signs. Patients with this condition are therefore highly likely to present initially to the ophthalmology department. Awareness of the aetiology of this condition is important so that appropriate and timely referral is made to the otolaryngologists to ensure appropriate management of this condition.

Pediatric Dose Selection and Utility of PBPK in Determining Dose.

Interest in determining safe and efficacious doses for drug administration in pediatric patients has increased dramatically in recent years. However, published pediatric clinical studies have failed to increase proportionally with adult clinical study publications. In order to assess the current state of pediatric dose determination and the supporting role of physiologically based pharmacokinetic modeling and simulation in determining pediatric dose, the pediatric clinical literature (2006-2016) and case examples of pediatric PBPK modeling efforts were reviewed. The objective of this assessment was to investigate the contribution of PBPK to our understanding of the differences between children and adults, which lead to differences in drug dose. Pediatric and adult dose data were available for 31 small molecule drugs. In general, pediatric dose was well-correlated with adult data, with an apparent tendency for higher body weight- or body surface area-normalized pediatric dose. Overall performance of pediatric PBPK modeling approaches was considered to adequately predict observed data. However, model performance was dependent upon age group simulated, with approximately half of neonatal predictions falling outside of 1.5-fold of observed. In conclusion, there is a clear need for further refinement of starting dose in pediatric phase 1 studies, and utilization of PBPK could lead to reduced numbers of patients required to establish safe and efficacious doses in the pediatric population.

Mucosal thickening in allergic and idiopathic rhinitis mucosa and its probable mechanism.

BACKGROUND: Rhinitis is a prevalent condition characterized by nasal mucosal irritation. Conflicting studies suggest that the mucosa of patients with allergic and nonallergic rhinitis undergoes thickening. OBJECTIVES: To investigate mucosal epithelial thickening in allergic and idiopathic rhinitis and to determine if the mechanism is a consequence of altered proliferation or apoptosis. METHODS: Interactive image analysis was performed on histologic sections of inferior nasal turbinate tissue to measure epithelial thickness in 3 patient groups. Patients with allergic rhinitis (n = 15), patients with idiopathic rhinitis (n = 15), and a healthy control group (n = 10) were compared. Immunohistochemical and morphometric analyses were used to quantify cell proliferation (Mib-1), apoptosis (terminal uridine nick end labeling technique), and the antiapoptotic factor Bcl-2. RESULTS: Idiopathic epithelium was found to be significantly thickened compared with healthy epithelium (P = .04). Epithelial thickening occurred in some allergic patients, but the findings did not reach statistical significance (P = .22). No statistically significant difference in proliferation as evidenced by Mib-1 staining was seen among the 3 patient groups. Allergic mucosa differed statistically significantly to that of patients with idiopathic rhinitis (P = .01) and healthy controls (P = .005) in showing increased Bcl-2 staining, suggesting reduced apoptosis. CONCLUSIONS: Allergic epithelium shows significantly decreased apoptosis, which might explain the increased epithelial thickening seen in some study participants. This mechanism does not, however, appear to explain the significantly increased thickening seen in the idiopathic epithelium. Furthermore, both allergic and nonallergic epithelium showed regional thinning and thickening possibly involving an inflammatory infiltrate.

Reduction of TLR2 gene expression in allergic and nonallergic rhinitis.

BACKGROUND: Immunomodulators, including toll-like receptors (TLRs) and defensins, produced in response to pathogenic stimuli, can direct the developing immune system toward a T(H)1 nonallergic phenotype. Increased human beta-defensin (HBD) 4 expression is associated with infection. OBJECTIVE: To determine whether reduced mucosal levels of TLRs and defensins contribute to the inflammation seen in chronic allergic and nonallergic rhinitis. METHODS: Real-time polymerase chain reaction was used to determine gene expression levels of HBDs 1 through 4 and TLRs 2 and 4. Immunohistochemical analysis was used to study the localization and distribution of protein for alpha-defensins 1 through 3, HBD2, neutrophil elastase, and TLR2 in sections of nasal turbinate tissue from adults with persistent allergic and idiopathic rhinitis, healthy nasal mucosa, and tonsil tissue. RESULTS: Allergic mucosa showed a significant (P = .02) reduction in TLR2 messenger RNA expression compared with control mucosa and generally reduced expression for TLR4 and HBDs. Although not significant, the nonallergic group also showed reduced expression for TLRs and HBDs. With the exception of HBD4, increased target gene levels were seen in tonsil tissue. Protein expression of HBD2 and TLR2 was localized in lining and submucosal glandular epithelium but insignificant differences were seen for HBDs, TLRs, neutrophils, and a-defensin between the rhinitic and control patient groups. CONCLUSIONS: Subjects with allergic and nonallergic rhinitis show reduced TLR and HBD gene expression. The significant reduction in TLR2 gene expression in allergic adults supports the concept that increased TLR2 protects against the development of allergy. The low levels of HBD4 detected in both rhinitis groups suggest lack of an underlying infection pathophysiological feature.

A prospective randomized blinded cross-over trial using nasal drops in patients with nasal polyposis: an evaluation of effectiveness and comfort level of two head positions.

BACKGROUND: The aim of this study was to compare the efficacy and the degree of discomfort caused by the Mygind's (supine and head extended) position and the lying on the side head down (LSHD) position used for instilling nasal drops. We performed a prospective randomized blinded cross-over trial. METHODS: Twenty-three patients with nasal polyps were recruited and were given Betnesol nasal drops for 6 weeks after assessing their peak nasal inspiratory flow rate and grading the polyps. The assessor was blinded to the position used by the patient that was selected randomly. The patients were reviewed after 6 weeks when both their flow rates and their polyp grades were reassessed. They were given a visual analog chart to record the ease by which drops could be instilled and any discomfort caused by the position. After a 2-week washout period the patients were treated for another 6 weeks with the same drops using the other head position. RESULTS: Twenty-one patients completed the study. The LSHD and Mygind's positions were equally effective in controlling the nasal polypi. Mygind's position was easier to instill drops in the nose although LSHD position caused less discomfort for the patient. The nasal peak inspiratory flow increased linearly as the polyp size decreased. In 86 and 90% of the patients the nasal obstruction and nasal discharge, respectively, were well controlled. CONCLUSION: The drops were efficacious in both head positions. The LSHD position caused the least discomfort, although patients found Mygind's position easier to instill drops. Steroid nasal drops are an effective way to manage patients with nasal polyposis.