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Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects
Background
PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects.
Methods
Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD.
Results
PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (
T
max
of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased
C
max
by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUC
tau
and 0.9-fold to 1.3-fold for
C
max
. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ≥ 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed.
Conclusions
PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases.
Trial registration
Clinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015
Journal Article
Impact of physical activity programs and services for older adults: a rapid review
Background
Knowledge of which physical activity programs are most effective for older adults in different sub-populations and contexts is limited. The objectives of this rapid review were to: 1) Overview evidence evaluating physical activity programs/services for older adults; and 2) Describe impact on physical activity, falls, intrinsic capacity (physical domain), functional ability (physical, social, and cognitive/emotional domains), and quality of life.
Methods
We conducted a rapid review of primary studies from 350 systematic reviews identified in a previous scoping review (March 2021: PEDro, MEDLINE, CINAHL, Cochrane Database). For Objective 1, we included intervention studies investigating physical activity programs/services in adults ≥ 60 years. Of these, we included good quality (≥ 6/10 PEDro scale) randomised controlled trials (RCTs) with ≥ 50 participants per group in Objective 2.
Results
Objective 1: Of the 1421 intervention studies identified from 8267 records, 79% were RCTs, 87% were in high income countries and 39% were good quality. Objective 2: We identified 87 large, good quality RCTs (26,861 participants). Overall activity promotion, structured exercise and recreation/sport had positive impacts (≥ 50% between-group comparisons positive) across all outcome domains. For overall activity promotion (21 intervention groups), greatest impacts were on physical activity (100% positive) and social outcomes (83% positive). Structured exercise (61 intervention groups) had particularly strong impacts on falls (91% positive), intrinsic capacity (67% positive) and physical functioning (77% positive). Recreation/sport (24 intervention groups) had particularly strong impacts on cognitive/emotional functioning (88% positive). Multicomponent exercise (39 intervention groups) had strong impacts across all outcomes, particularly physical activity (95% positive), falls (90% positive) and physical functioning (81% positive). Results for different populations and settings are presented.
Conclusion
Evidence supporting physical activity for older adults is positive. We outline which activity types are most effective in different populations and settings.
Journal Article
Event-Based Social Networking System With Recommendation Engine
For over a decade, social networking has been ruling over the internet and plays a vital role in day-to-day life. However, for a new network to survive in this market, exclusivity is a necessity. As a result, the goal of this work is to create a network for hosting and managing volunteering and events. Furthermore, the network will feature a recommendation system to provide users with events based on their interests and preferences according to how they interact with the platform. The proposed system is exclusively meant for event post creation and management and also it focuses on event posts with interactions such as replies, likes, interest, and disinterest options. This system has been implemented and deployed with the title ‘Evento' with the recommendation engine boasting an average purity index of 0.8031 for approximately 30 users. The results for recommendations have been chosen considering purity index and fisher optimization criterion metrics. Based on the experimental results, the proposed social network system with the recommendation engine has been found to be sufficient.
Journal Article
Advance Statements for Black African and Caribbean people (AdStAC): protocol for an implementation study
Background
The UK government committed to legislating for Advance Choice Documents/Advance Statements (ACD/AS) following their recommendation by the Independent Review of the MHA (2018). ACDs/AS are yet to be implemented in routine practice despite evidence and high demand; they are associated with improved therapeutic relationships and a reduction (25%, RR 0.75, CI 0.61–0.93) in compulsory psychiatric admission. Barriers to their implementation are well documented, ranging from low knowledge levels to logistical challenges in accessing the content during episodes of acute care. In the UK this is an issue for Black people, who experience detention rates disproportionately (over three times) higher than those of White British people and have poorer care experiences and outcomes. ACDs/AS allow for Black people to have their concerns heard by mental health professionals in a care system where they often feel their views are ignored. AdStAC aims to improve Black service users’ experiences in mental health services in South London by co-producing and testing an ACD/AS implementation resource with Black service users, mental health professionals and carers/supporters of Black service users.
Methods/design
The study will take place in South London, England over three phases: 1) formative work through stakeholder workshops; 2) co-production of resources through a consensus development exercise and working groups; and 3) testing of the resources using quality improvement (QI) methods. A lived experience advisory group, staff advisory group and project steering committee will support the study throughout. The implementation resources will comprise: advance choice document/advance statement (ACD/AS) documentation, stakeholder trainings, a manual for mental health professionals to facilitate the processes of creating and revising advance statements, and informatics development.
Discussion
The implementation resources will help increase the likelihood of the new mental health legislation in England being implemented effectively; through aligning evidence-based medicine, policy and law to effectively provide positive clinical, social and financial outcomes for Black people, the National Health Service (NHS) and wider society. This study will likely benefit a wider group of people with severe mental illness, as when marginalised groups who are least engaged, can be supported with these strategies, then the strategies are likely to work for others.
Journal Article
Exploratory pharmacodynamics and efficacy of PF-06817024 in a Phase 1 study of patients with chronic rhinosinusitis and atopic dermatitis
PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP. In patients with AD, PF-06817024, in aggregate, reduced disease severity and improved symptoms, as demonstrated by greater percentage decrease from baseline in Eczema Area and Severity Index (EASI) scores and reduced pruritus numerical rating scores, compared with placebo. The efficacy in AD appeared to be bimodal with a sub-group of participants exhibiting high levels of improvement (EASI75 and EASI90) for a sustained period of time after dosing. In patients with CRSwNP, a consistent trend of decrease in eosinophil levels was observed in the PF-06817024 group, compared with placebo. Further research would be needed to confirm the clinical benefit and safety of PF-06817024 as a treatment for allergic diseases.
Trial registration
ClinicalTrials.gov, NCT02743871. Registered 15 April 2016,
https://clinicaltrials.gov/study/NCT02743871?term=NCT02743871&rank=1
.
Journal Article
Developing and testing Advance Choice Document implementation resources for Black African and Caribbean people with experience of compulsory psychiatric admission
Background
Advance Choice Documents (ACDs) have been recommended for use in England and Wales based on evidence from trials that show that they can reduce involuntary hospitalisation, which disproportionately affects Black African and Caribbean people. Our aim was therefore to develop and test ACD implementation resources and processes for Black people who have previously been involuntarily hospitalised and the people that support them.
Methods
Resource co-production workshops were held to inform the development of the ACD template and two types of training for all stakeholders, comprising a Recovery College course and simulation training. An ACD facilitator then used the ACD template developed through the workshops to create personalised ACDs with service users and mental health staff over a series of meetings. Interviews were then conducted with service user and staff participants and analysed to document their experience of the process and opinions on ACDs. Other implementation strategies were also employed alongside to support and optimise the creation of ACDs.
Results
Nine ACDs were completed and were largely reported as appropriate, acceptable, and feasible to service users and staff. Both reported it being an empowering process that encouraged hope for better future treatment and therefore better wellbeing. Uncertainty was also expressed about the confidence people had that ACDs would be adhered to/honoured, primarily due to staff workload. The information provision training and the skills training were generally considered to be informative by trainees.
Conclusions
The project has developed an ACD creation resource that was reported as agreeable to all stakeholders; however, the generalisability of the findings is limited due to the small sample size. The project also highlights the importance of staff and ACD facilitator capacity and good therapeutic relationships in ACD completion. Further research is needed to determine the adjustments needed for large scale use, including for those under age 18 and those under the care of forensic mental health services; and how to include carers/supporters more in the process.
Journal Article
Application of MLST and Pilus Gene Sequence Comparisons to Investigate the Population Structures of Actinomyces naeslundii and Actinomyces oris
Actinomyces naeslundii and Actinomyces oris are members of the oral biofilm. Their identification using 16S rRNA sequencing is problematic and better achieved by comparison of metG partial sequences. A. oris is more abundant and more frequently isolated than A. naeslundii. We used a multi-locus sequence typing approach to investigate the genotypic diversity of these species and assigned A. naeslundii (n = 37) and A. oris (n = 68) isolates to 32 and 68 sequence types (ST), respectively. Neighbor-joining and ClonalFrame dendrograms derived from the concatenated partial sequences of 7 house-keeping genes identified at least 4 significant subclusters within A. oris and 3 within A. naeslundii. The strain collection we had investigated was an under-representation of the total population since at least 3 STs composed of single strains may represent discrete clusters of strains not well represented in the collection. The integrity of these sub-clusters was supported by the sequence analysis of fimP and fimA, genes coding for the type 1 and 2 fimbriae, respectively. An A. naeslundii subcluster was identified with both fimA and fimP genes and these strains were able to bind to MUC7 and statherin while all other A. naeslundii strains possessed only fimA and did not bind to statherin. An A. oris subcluster harboured a fimA gene similar to that of Actinomyces odontolyticus but no detectable fimP failed to bind significantly to either MUC7 or statherin. These data are evidence of extensive genotypic and phenotypic diversity within the species A. oris and A. naeslundii but the status of the subclusters identified here will require genome comparisons before their phylogenic position can be unequivocally established.
Journal Article
Generation of Diversity in Streptococcus mutans Genes Demonstrated by MLST
Streptococcus mutans, consisting of serotypes c, e, f and k, is an oral aciduric organism associated with the initiation and progression of dental caries. A total of 135 independent Streptococcus mutans strains from caries-free and caries-active subjects isolated from various geographical locations were examined in two versions of an MLST scheme consisting of either 6 housekeeping genes [accC (acetyl-CoA carboxylase biotin carboxylase subunit), gki (glucokinase), lepA (GTP-binding protein), recP (transketolase), sodA (superoxide dismutase), and tyrS (tyrosyl-tRNA synthetase)] or the housekeeping genes supplemented with 2 extracellular putative virulence genes [gtfB (glucosyltransferase B) and spaP (surface protein antigen I/II)] to increase sequence type diversity. The number of alleles found varied between 20 (lepA) and 37 (spaP). Overall, 121 sequence types (STs) were defined using the housekeeping genes alone and 122 with all genes. However pi, nucleotide diversity per site, was low for all loci being in the range 0.019-0.007. The virulence genes exhibited the greatest nucleotide diversity and the recombination/mutation ratio was 0.67 [95% confidence interval 0.3-1.15] compared to 8.3 [95% confidence interval 5.0-14.5] for the 6 concatenated housekeeping genes alone. The ML trees generated for individual MLST loci were significantly incongruent and not significantly different from random trees. Analysis using ClonalFrame indicated that the majority of isolates were singletons and no evidence for a clonal structure or evidence to support serotype c strains as the ancestral S. mutans strain was apparent. There was also no evidence of a geographical distribution of individual isolates or that particular isolate clusters were associated with caries. The overall low sequence diversity suggests that S. mutans is a newly emerged species which has not accumulated large numbers of mutations but those that have occurred have been shuffled as a consequence of intra-species recombination generating genotypes which can be readily distinguished by sequence analysis.
Journal Article