Ligelizumab is a highly potent, humanized IgG1, anti-IgE monoclonal antibody. To explore its optimal subcutaneous delivery, the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of ...ligelizumab from two Phase 1 studies in healthy volunteers (HVs) and four Phase 2 and 3 studies in patients with chronic spontaneous urticaria (CSU) were assessed. Using different injection volumes or durations of a liquid-in-vial (LIVI) formulation or different formulations (LIVI vs. prefilled syringe (PFS)), single-dose ligelizumab showed comparable PK exposure in HVs. Steady-state exposure of ligelizumab was also comparable between LIVI and PFS following multiple dosing in CSU patients. The total IgE level (a PD marker) and tolerability were similar between the two formulations in both HVs and patients. Furthermore, the PK, total IgE, and tolerability were comparable for PFS administered either by patients or healthcare providers (HCPs). Collective evidence demonstrated that the injection duration or volume, formulation, or administrator had no apparent impact on the PK, PD, and tolerability of ligelizumab, supporting no clinically relevant difference between LIVI and PFS, and that PFS can be administered by patients or HCPs. This report provides a comprehensive assessment based on data of multiple clinical endpoints from both HVs and patients to inform formulation development and commercial use of a monoclonal antibody.
Background
Chronic spontaneous urticaria (CSU) negatively impacts patients' sleep, thereby reducing health‐related quality of life (HRQoL). Half of patients with inadequately controlled CSU report ...sleep interference often or every night, which can lead to depression, anxiety, social, and work‐related problems.
Methods
This randomized, double‐blind, placebo‐controlled Phase 2b core study (NCT02477332) included adult patients ≥18 years with moderate to severe CSU inadequately controlled with H1‐antihistamines. The current analysis includes patients randomized to receive ligelizumab 72 or 240 mg, omalizumab 300 mg or placebo every 4 weeks (q4w) for five injections over 20 weeks with treatment‐free follow‐up for 24 weeks. Patients could enter the open‐label extension study (NCT02649218) from Week 32 onwards if their weekly urticaria activity score was ≥12, which included an open‐label treatment (52 weeks of ligelizumab 240 mg q4w) and a 48‐week post‐treatment follow‐up. Weekly Sleep Interference Scores (SIS7, range 0 no interference–21 substantial interference), Weekly Activity Interference Score (AIS7), Dermatology Life Quality Index (DLQI) scores, and Overall Work Impairment were assessed.
Results
Mean baseline SIS7 scores were balanced between the treatment arms for ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab 300 mg (n = 85), and placebo (n = 43). By Week 12, patients experienced large improvements in sleep interference, with least square mean (standard error) changes from baseline (CFB) in SIS7 of −7.84 (0.58), −7.55 (0.61), −6.98 (0.60), and −5.85 (0.81), respectively. By Week 12, CFB in AIS7 were −8.25 (0.57), −8.25 (0.59), −7.30 (0.60), and −5.62 (0.79), DLQI scores were −9.79 (0.77), −9.93 (0.81), −8.35 (0.79), and −6.99 (1.11), and Overall Work Impairment scores were −28.96 (3.73), −30.76 (3.71), −25.74 (3.91), and −20.13 (5.10) for ligelizumab 72 and 240 mg, omalizumab 300 mg and placebo, respectively. Improvements in each patient‐reported outcome were sustained with ligelizumab 240 mg treatment during the extension study.
Conclusions
Ligelizumab showed effective and sustained responses in managing sleep interference in patients with CSU, and numerically higher responses than with omalizumab and placebo. Treating the symptoms of CSU with ligelizumab improved disease burden, HRQoL, and markedly improved sleep quality.
Protein structure plays a pivotal role in elucidating mechanisms of parasite functioning and drug resistance. Moreover, protein structure aids the determination of protein function, which can ...together with the structure be used to identify novel drug targets in the parasite. However, various structural features in Plasmodium falciparum proteins complicate the experimental determination of protein structures. Limited similarity to proteins in the Protein Data Bank and the shortage of solved protein structures in the malaria parasite necessitate genome-scale structural annotation of P. falciparum proteins. Additionally, the annotation of a range of structural features facilitates the identification of suitable targets for experimental and computational studies.
An integrated structural annotation system was developed and applied to P. falciparum, Plasmodium vivax and Plasmodium yoelii. The annotation included searches for sequence similarity, patterns and domains in addition to the following predictions: secondary structure, transmembrane helices, protein disorder, low complexity, coiled-coils and small molecule interactions. Subsequently, candidate proteins for further structural studies were identified based on the annotated structural features.
The annotation results are accessible through a web interface, enabling users to select groups of proteins which fulfil multiple criteria pertaining to structural and functional features 1. Analysis of features in the P. falciparum proteome showed that protein-interacting proteins contained a higher percentage of predicted disordered residues than non-interacting proteins. Proteins interacting with 10 or more proteins have a disordered content concentrated in the range of 60-100%, while the disorder distribution for proteins having only one interacting partner, was more evenly spread.
A series of P. falciparum protein targets for experimental structure determination, comparative modelling and in silico docking studies were putatively identified. The system is available for public use, where researchers may identify proteins by querying with multiple physico-chemical, sequence similarity and interaction features.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization.
To develop an IGA scale, training ...module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability.
Expert dermatologists participated in the development of the validated IGA for AD (vIGA-ADTM). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination.
Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W Kendall's W, 0.809; intraclass correlation ICC, 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification.
Ratings were assessed on photographs.
A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed.
Objective
To evaluate the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).
Methods
This was a 3‐part open‐label study with an ...initial 6‐month treatment period in which patients with HIDS (n = 9) received canakinumab subcutaneously at a dose of 300 mg (or 4 mg/kg for those weighing ≤40 kg) every 6 weeks (period 1 P1), followed by a 6‐month withdrawal period (period 2 P2), and then a 24‐month extension treatment period with canakinumab at the same dose (period 3 P3). The primary end point was reduction in the frequency of attacks during treatment periods as compared to the historical period (HP; defined as the period in which patients did not receive drugs other than nonsteroidal antiinflammatory drugs and/or steroids).
Results
All 9 patients completed P1 and P2, whereas only 8 patients completed P3. All patients achieved a complete response during P1, and only 2 required dose adjustments. The number of attacks per patient decreased from a median of 5 (range 3–12) during the HP to a median of 0 (range 0–2) during P1. During P2, 7 of 9 patients experienced a disease flare within a median of 110 days (range 62–196) after the last canakinumab dose. Laboratory findings were normalized by day 15 of treatment and remained at normal levels throughout the study. Analysis of blood transcriptome profiles, assessed during P1, showed up‐regulated levels of interferon and myeloid‐related inflammatory responses in untreated patients compared to healthy controls, and these rapidly decreased following canakinumab injection, reaching levels comparable to those of healthy controls. At least 1 adverse event (AE) was detected in all 9 patients. Most of the AEs were mild in intensity, with infections being the most frequent AE. Serious AEs were reported in 4 patients.
Conclusion
The results of this study demonstrate the efficacy and safety of canakinumab treatment to control active HIDS and to suppress inflammation‐related transcriptional responses.
Malaria is the cause of over one million deaths per year, primarily in African children. The parasite responsible for the most virulent form of malaria, is Plasmodium falciparum. Protein structure ...plays a pivotal role in elucidating mechanisms of parasite functioning and resistance to anti-malarial drugs. Protein structure furthermore aids the determination of protein function, which can together with the structure be used to identify novel drug targets in the parasite. However, various structural features in P. falciparum proteins complicate the experimental determination of protein three dimensional structures. Furthermore, the presence of parasite-specified inserts results in reduced similarity of these proteins to orthologous proteins with experimentally determined structures. The lack of solved structures in the malaria parasite, together with limited similarities to proteins in the Protein Data Bank, necessitate genome-scale structural annotation of P. falciparumproteins. Additionally, the annotation of a range of structural features facilitates the identification of suitable targets for structural studies.An integrated structural annotation system was constructed and applied to all the predicted proteins in P. falciparum, Plasmodium vivax and Plasmodium yoelii. Similarity searches against the PDB, Pfam, Superfamily, PROSITE and PRINTS were included. In addition, the following predictions were made for the P. falciparum proteins: secondary structure, transmembrane helices, protein disorder, low complexity, coiled-coils and small molecule interactions. P. falciparumprotein-protein interactions and proteins exported to the RBC were annotated from literature. Finally, a selection of proteins were threaded through a library of SCOP folds. All the results are stored in a relational PostgreSQL database and can be viewed through a web interface (http://deepthought.bi.up.ac.za:8080/Annotation). In order to select groups of proteins which fulfill certain criteria with regard to structural and functional features, a query tool was constructed. Using this tool, criteria regarding the presence or absence of all the predicted features can be specified.Analysis of the results obtained revealed that P. falciparum protein-interacting proteins contain a higher percentage of predicted disordered residues than non-interacting proteins. Proteins interacting with 10 or more proteins have a disordered content concentrated in the range of 60-100%, while the disorder distribution for proteins having only one interacting partner, was more evenly spread. Comparisons of structural and sequence features between the three species, revealed that P. falciparum proteins tend to be longer and vary more in length than the other two species. P. falciparumproteins also contained more predicted low complexity and disorder content than proteins from P. yoelii and P. vivax.P. falciparumprotein targets for experimental structure determination, comparative modeling and in silico docking studies were putatively identified based on structural features. For experimental structure determination, 178 targets were identified. These targets contain limited contents of predicted transmembrane helix, disorder, coiled-coils, low complexity and signal peptide, as these features may complicate steps in the experimental structure determination procedure. In addition, the targets display low similarity to proteins in the PDB. Comparisons of the targets to proteins with crystal structures, revealed that the structures and predicted targets had similar sequence properties and predicted structural features. A group of 373 proteins which displayed high levels of similarity to proteins in the PDB, were identified as targets for comparitive modeling studies. Finally, 197 targets for in silico docking were identified based on predicted small molecule interactions and the availability of a 3D structure.
Malaria is the cause of over one million deaths per year, primarily in African children. The parasite responsible for the most virulent form of malaria, is Plasmodium falciparum. Protein structure ...plays a pivotal role in elucidating mechanisms of parasite functioning and resistance to anti-malarial drugs. Protein structure furthermore aids the determination of protein function, which can together with the structure be used to identify novel drug targets in the parasite. However, various structural features in P. falciparum proteins complicate the experimental determination of protein three dimensional structures. Furthermore, the presence of parasite-specific inserts results in reduced similarity of these proteins to orthologous proteins with experimentally determined structures. The lack of solved structures in the malaria parasite, together with limited similarities to proteins in the Protein Data Bank, necessitate genome-scale structural annotation of P. falciparum proteins. Additionally, the annotation of a range of structural features facilitates the identification of suitable targets for structural studies. An integrated structural annotation system was constructed and applied to all the predicted proteins in P. falciparum, Plasmodium vivax and Plasmodium yoelii. Similarity searches against the PDB, Pfam, Superfamily, PROSITE and PRINTS were included. In addition, the following predictions were made for the P. falciparum proteins: secondary structure, transmembrane helices, protein disorder, low complexity, coiled-coils and small molecule interactions. P. falciparum protein-protein interactions and proteins exported to the RBC were annotated from literature. Finally, a selection of proteins were threaded through a library of SCOP folds. All the results are stored in a relational PostgreSQL database and can be viewed through a web interface (http://deepthought.bi.up.ac.za:8080/Annotation). In order to select groups of proteins which fulfill certain criteria with regard to structural and functional features, a query tool was constructed. Using this tool, criteria regarding the presence or absence of all the predicted features can be specified. Analysis of the results obtained revealed that P. falciparum protein-interacting proteins contain a higher percentage of predicted disordered residues than non-interacting proteins. Proteins interacting with 10 or more proteins have a disordered content concentrated in the range of 60-100%, while the disorder distribution for proteins having only one interacting partner, was more evenly spread. Comparisons of structural and sequence features between the three species, revealed that P. falciparum proteins tend to be longer and vary more in length than the other two species. P. falciparum proteins also contained more predicted low complexity and disorder content than proteins from P. yoelii and P. vivax. P. falciparumprotein targets for experimental structure determination, comparative modeling and in silico docking studies were putatively identified based on structural features. For experimental structure determination, 178 targets were identi_ed. These targets contain limited contents of predicted transmembrane helix, disorder, coiled-coils, low complexity and signal peptide, as these features may complicate steps in the experimental structure determination procedure. In addition, the targets display low similarity to proteins in the PDB. Comparisons of the targets to proteins with crystal structures, revealed that the structures and predicted targets had similar sequence properties and predicted structural features. A group of 373 proteins which displayed high levels of similarity to proteins in the PDB, were identified as targets for comparitive modeling studies. Finally, 197 targets for in silico docking were identified based on predicted small molecule interactions and the availability of a 3D structure.
Dissertation (MSc)--University of Pretoria, 2008.
Biochemistry
unrestricted
Thesis (M.Sc.)(Biochemistry))-University of Pretoria, 2007.
Summary in English. Includes bibliographical references. Available on the Internet via the World Wide Web.
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