MSD (Belgium)

MK-7602 is a first-in-class dual-plasmepsin inhibitor being developed to treat malaria. Safety, tolerability, and pharmacokinetics (PK) of MK-7602 following single and multiple doses were evaluated in two phase 1 studies (7602-001; 7602-002). Study 7602-001 included two parts: part 1, a randomized, single-ascending-dose (10-400 mg), placebo-controlled, double-blind study (n = 24); and part 2, a non-randomized, fixed-sequence, open-label study (n = 12) to assess the effect of itraconazole (200 mg), a cytochrome P450 3A and P-glycoprotein inhibitor, on the PK of MK-7602 (25 mg). Study 7602-002 was a randomized, placebo-controlled, multiple-ascending-dose study (n = 40); participants received MK-7602 (50-300 mg) or placebo for 7 days. Single and multiple doses of MK-7602 were generally well tolerated. Headaches were the most common adverse event (7602-001 part 1: 54.5%; 7602-002: 36.7%). MK-7602 median time to maximal concentration (Tmax) was 1.5-3.0 h, with dose-proportional increases in maximum concentration (Cmax) and the area under the curve over the dosing interval (AUC0-tau) at single and multiple doses of ≥50 mg. Terminal half-life was 31.3-41.4 h following multiple dosing, the accumulation ratio for daily dosing was 1.03-2.20, and steady-state concentrations were reached by day 3. Coadministration with itraconazole resulted in a 6- and 12-fold increase in Cmax and area under the concentration-time curve to infinity, respectively. The primary hypothesis that a well-tolerated dose of MK-7602 would achieve a trough concentration of ≥0.017 μM was met in both studies. Safety and PK characteristics support continued development of MK-7602.

People with COPD experience a severe symptom burden, yet palliative care integration remains limited in COPD treatment across Europe. The EU PAL-COPD project is a multidisciplinary, international initiative funded by Horizon Europe, running from 2024 to 2028. We will evaluate ICLEAR-EU, a non-pharmacological, team-based intervention targeting the palliative needs of people with advanced COPD. Here, we detail our project's aims, progress, and plans. ICLEAR-EU aims to facilitate collaboration between hospital respiratory teams, interdisciplinary palliative care teams, and primary care to promote shared decision-making, advance care planning, and prevent re-hospitalization after exacerbations. The intervention, originally developed and piloted in the UK, has been adapted and standardized for international use through extensive stakeholder input. ICLEAR-EU focuses on Identification, Communication, Levels of Escalation, Advance Care Planning, and ongoing Review of palliative care needs, starting when the patient is hospitalized due to a COPD exacerbation. EU PAL-COPD is the first large-scale international trial integrating palliative care into respiratory care for COPD. Using a stepped wedge cluster RCT, we will assess ICLEAR-EU’s effectiveness in approximately 1,200 people with advanced COPD across 18 hospitals in six European countries, applying cost-effectiveness analyses, mixed-methods subgroup analyses, and in-depth process and implementation evaluations. By addressing the complex palliative and end-of-life care needs of people with COPD, EU PAL-COPD aims to improve patient and family well-being while setting a new standard for coordinated care in respiratory and palliative services across Europe.

Over the past decade, calls for research assessment reform have grown, led by initiatives such as the Declaration on Research Assessment (DORA) and the Leiden Manifesto, and, more recently, the Coalition for Advancing Research Assessment (CoARA). A key element being discussed as part of research assessment reform is a shift towards more qualitative assessments, focussed on the content of research and the broad skills and competencies of researchers, and the array of contributions they make to knowledge creation and innovation. Narrative CV formats have emerged as a good practice example for enabling qualitative assessments of research projects and researchers, and are becoming more widely piloted and implemented. As part of the 2023 Dutch Recognition and Rewards Festival, the authors hosted a workshop to gather perspectives on Narrative CVs, including whether and how they may contribute to shifts in research culture that are needed to support research assessment reform. Participants, representing research organisations and the research community, discussed both beneficial and critical aspects of narrative-style CV implementations from their experiences. The effects observed since narrative CVs have been implemented were discussed, with perspectives provided on career prospects and the empowerment of the research community to direct change. Finally, the discussion turned to expectations for the future, with workshop participants calling for focus on the roles that narrative-style CVs can play in improving research careers, recognition of collaborative work, and equality, diversity, and inclusion. A short informal survey exploring levels of implementation of narrative CVs across different research organisations was run prior to the workshop, the results of which are also presented as part of this report. The authors intend to expand this discussion to other scientific and policy conferences, and this report serves as a basis for a wider and deeper dialogue in the community.

This article describes a clinical protocol utilizing soft tissue augmentation alone or in combination with guided bone regeneration (GBR), introducing simultaneous application of the one abutment one time concept for three-dimensional reconstruction of the deficient ridge. Soft and hard tissue quality and dimensions are fundamental elements for long lasting results in implant dentistry. Different techniques have been described for soft and hard tissue augmentation at time of implant placement presenting favorable results. However, multiple abutment disconnections during the prosthetic phase of treatment can compromise the results achieved during surgery. The purpose of this article is to present a surgical protocol that allows three-dimensional ridge reconstruction involving soft tissue augmentation alone, or in combination with hard tissue augmentation in one single step with the use of an one-time intermediate abutment as an anchorage device for the regenerative materials. Two clinical cases utilizing the proposed protocol are also presented, demonstrating favorable results. The application of the proposed protocol simplifies the surgical phase of treatment, protects the achieved result and enables a favorable outcome in decreased time. Utilising an intermediate abutment as an anchorage device at time of surgery can be proven an easy to apply and biologically favorable alternative way to other methods of soft tissue graft stabilization proposed in the past.

This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Background: Vaccines have been contributing to eradicate or drastically reduce the incidence of common diseases. Simultaneously, vaccine hesitancy is considered among the top ten global health threats. The COVID-19 pandemic has caused a tremendous impact on health, economics, and society worldwide, while also reinforcing faulty beliefs about the necessity of vaccine programs as a whole. This study aims to synthesise evidence on the impact of the COVID-19 pandemic on vaccine hesitancy.Methods: A scoping review of literature between 1 January 2020 and 1 August 2021 was performed.Results: COVID-19 vaccine acceptance decreased from more than 70 to <50% in 8 months starting from January 2020. Healthcare professionals demonstrate higher rates of vaccine receptivity than the public, which was more influenced by (social) media. The circulation of misinformation was associated with increased fear of side effects related to COVID-19 vaccines. Regarding other vaccines coverage, parents' intentions to vaccinate their children against influenza increased 15.8% during the COVID-19 pandemic so far. Nonetheless, the number of vaccines administered decreased, influenced by factors like fear of being exposed to the virus at healthcare facilities and restrictions.Conclusions: Several efforts should be undertaken to improve vaccine acceptance and coverage now and beyond the pandemic to optimal population protection.

Islatravir (MK‐8591) is a nucleoside analogue in development for the treatment and prevention of HIV‐1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18–60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir‐triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high‐fat meal. In Study 2, 8 participants per dose received 3 once‐weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well‐tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half‐life was 49–61 h; intracellular islatravir‐triphosphate half‐life was 118–171 h. Plasma exposure increased in an approximately dose‐proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir‐triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir‐triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

The oral explanation (OE) is a critical event during new marketing authorisation procedures in the European Union (EU). The primary objective of the present study was to investigate how many procedures, having an OE in front of the Committee for Medicinal Products for Human Use (CHMP), resulted in a regulatory approval for oncology products. Procedures for new marketing authorisation applications (MAAs) and Type II variations (new indication) for oncology products with at least one OE (with or without a Scientific Advisory Group (SAG) meeting) and for which the outcome took place between 31 January 2016 to 31 January 2020 were included in the analysis. Publicly available agendas/meeting minutes and assessment reports were used to obtain information on the products. An OE occurred in about 20% of procedures (n = 28/150) for oncology products during the review period. The majority of procedures having an OE (61%), with or without any SAG meeting, led to MAA/Type II variation approval in the Centralised Procedure. It was also observed that in 41% of the cases a successful outcome was contingent upon willingness of the applicant to restrict the indication. A majority of oncology procedures that had an OE resulted in a positive outcome suggesting that such agency interaction is an important opportunity for the applicant to have a last chance to resolve any outstanding issues at the final stage of the procedure.