Insights from modelling malaria vaccines for policy decisions: the focus on RTS,S

Mathematical models are increasingly used to inform decisions throughout product development pathways from pre-clinical studies to country implementation of novel health interventions. This review illustrates the utility of simulation approaches by reviewing the literature on malaria vaccine modelling, with a focus on its link to the development of policy guidance for the first licensed product, RTS,S/AS01. The main contributions of modelling studies have been in inferring the mechanism of action and efficacy profile of RTS,S; to predicting the public health impact; and economic modelling mainly comprising cost-effectiveness analysis. The value of both product-specific and generic modelling of vaccines is highlighted.

The Risk of Nonsteroidal Anti-Inflammatory Drugs in Pediatric Medicine: Listen Carefully to Children with Pain

Over the last decades, the use of over-the-counter analgesics in the general population has increased in Germany. Ibuprofen is one of the most commonly used nonsteroidal anti-inflammatory drug (NSAID) and is frequently prescribed to children as an analgesic and/or antipyretic. Besides having a well-established safety and efficacy profile when used in appropriate doses, cases of NSAID-induced acute kidney injury (AKI) have been described in the pediatric population, particularly in the context of dehydration and in combination with other drugs. The ingestion of more than 400 mg/kg is associated with severe or life-threatening toxicity. This report is about two previously healthy adolescents, who developed AKI after taking high daily dose of ibuprofen as a pain reliever without any appropriate medical supervision. With these case reports, in addition to the side effect profiles of this analgesic, we would also like to present a certain therapeutic recommendation that we applied in these patients, and furthermore appeal to pediatricians to strictly set the indications for ibuprofen intake.

Efficacy Profiles of Antimicrobials Evaluated against Staphylococcus Species Isolated from Canine Clinical Specimens

Cross-resistance occurs between antimicrobials with either similar mechanisms of action and/or similar chemical structures, or even between unrelated antimicrobials. This study employed a multivariate approach to investigate the associations between the efficacy profile of antimicrobials and the clustering of eleven different antimicrobial agents based on their efficacy profile. Records of the susceptibility of 382 confirmed Staphylococcus species isolates against 15 antimicrobials based on the disc diffusion method were included in this study. Tetrachoric correlation coefficients were computed to assess the correlations of antimicrobial efficacy profiles against Staphylococcus aureus. Principal components analysis and factor analysis were used to assess the clustering of antimicrobial susceptibility profiles. Strong correlations were observed among aminoglycosides, penicillins, fluroquinolones, and lincosamides. Three main factors were extracted, with Factor 1 dominated by the susceptibility profile of enrofloxacin (factor loading (FL) = 0.859), gentamicin (FL = 0.898), tylosin (FL = 0.801), and ampicillin (FL = −0.813). Factor 2, on the other hand, was dominated by the susceptibility profile of clindamycin (FL = 0.927) and lincomycin-spectinomycin (FL = 0.848) and co-trimazole (FL = −0.693). Lastly, Factor 3 was dominated by the susceptibility profile of amoxicillin-clavulanic acid (FL = 0.848) and cephalothin (FL = 0.824). Antimicrobials belonging to the same category or class of antimicrobial, tended to exhibit similar efficacy profiles, therefore, laboratories must choose only one of the antimicrobials in each group to help reduce the cost of antimicrobial susceptibility tests.

Erenumab versus topiramate for the prevention of migraine – a randomised, double-blind, active-controlled phase 4 trial

Background We compared the tolerability and efficacy of erenumab, a monoclonal antibody binding to the calcitonin gene-related peptide receptor, to topiramate for migraine prophylaxis in adults. Methods HER-MES was a 24-week, randomised, double-blind, double-dummy, controlled trial conducted in 82 sites in Germany. Patients with ≥4 migraine days per month and naïve to study drugs were randomly assigned (1:1) to either subcutaneous erenumab (70 or 140 mg/month) plus topiramate placebo (erenumab group) or oral topiramate at the individual dose with optimal efficacy (50–100 mg/day) plus erenumab placebo (topiramate group). The primary endpoint was medication discontinuation due to an adverse event during the double-blind phase. The proportion of patients that achieved ≥50% reduction from baseline in monthly migraine days during the last 3 months of the double-blind phase was a secondary endpoint. Results Seven hundred and seventy-seven patients were randomised (from 22 February 2019 to 29 July, 2020) and 95.1% completed the study. In the erenumab group, 10.6% discontinued medication due to adverse events compared to 38.9% in the topiramate group (odds ratio, 0.19; 95% confidence interval 0.13–0.27; p < 0.001). Significantly more patients achieved a ≥50% reduction in monthly migraine days from baseline with erenumab (55.4% vs. 31.2%; odds ratio 2.76; 95% confidence interval 2.06–3.71; p < 0.001). No new safety signals occurred. Conclusions Erenumab demonstrated a favourable tolerability and efficacy profile compared to topiramate. Trial registration: ClinicalTrials.gov NCT03828539, URL: https://clinicaltrials.gov/ct2/show/NCT03828539

Asciminib in Real-Life Clinical Practice, Safety and Efficacy Profile in Chronic Myeloid Leukemia Pretreated Patients

Introduction: asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that potently inhibits aberrant kinase activity of the BCR-ABL1 oncoprotein via allosteric binding. asciminib has shown high efficacy profile in heavily pretreated Chronic Myeloid Leukemia (CML) patients with an adequate safety profile in phase I and III clinical trials. However, data from the use of asciminib in real life setting are still scarce. Methods: We gathered real-life retrospective data from 49 patients with BCR-ABL1 positive CML treated with asciminib (mean dose: 40 mg twice daily) between October 2018 and July 2021 at 33 institutions. The indication of asciminib was made according to the criterion of the attending physician and the drug was granted by Novartis under a controlled access program. Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % IS in all centers. Treatment responses were calculated with the patients at risk at each specific time points. For the event free survival (EFS), the events were treatment discontinuation due to any reason, progression or death. Data collection followed the local regulations for observational studies. Results: Median time on asciminib was 11,69 months for the entire cohort. Patients' characteristics are displayed on Table 1. Most patients were heavily pretreated with at least 3 prior TKI lines in 45 patients (91,83%), 18 of them receiving prior Ponatinib. Switch to asciminib occurred due to intolerance in 32 patients and due to resistance in the remaining 17. Fifteen patients (30,61%) harbored mutations in BCR-ABL1 (3 with a T315 mutation). Regarding efficacy (Table 2), probability of reaching or maintaining previous responses were 94%, 45% and 21% for complete hematological response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR), respectively. Considering probabilities of improving previous response, rates were 40%, 42% and 33% for the same parameters. Probabilities to obtain CCyR and MMR in resistant and intolerant patients were 29% (4/14) vs 55% (6/11) and 27% (4/15) vs 52% (11/21), respectively. Amid the patients previously treated with Ponatinib, probabilities of reaching or maintaining previous response were 53% (9/17) and 35% (6/17) for CCyR and MMR respectively, and 30% (3/10), 23% (3/13) displayed improvement of response. Regarding responses in patients with mutations, 39% (5/13) achieved or maintained CCyR and 31% (4/13) MMR; whereas 20% (2/10) and 18% (2/11) improved such responses. Of the three patients with T315I mutation, one discontinued due to progression to advanced stages, and the rest maintained the previous response. With a median follow-up of 11,69 months, the estimated EFS was 80% (figure 1). In terms of safety (Table 3), the most frequent extra-hematological adverse events (AE) were: fatigue (16,2%), joint pain (13,5%) and nausea (8,1%), most of them grade 1-2. Grade 3-4 AE were observed in 10% of patient (fatigue (2), cholestasis enzyme elevation (1), hypertension (1), pancreatitis (1) and pericardial effusion (1)). Thrombocytopenia was shown as the most frequent AE (16,3%), with 6% of patients suffering from grade 3-4. Dose reduction was required in 15 patients (30,6%). After a median follow up of 51 weeks, 73,5% of the patients remained on treatment. Only fourteen patients discontinued treatment due to progression or loss of efficacy, whereas 6% of patients discontinuing treatment due to intolerance. Conclusions: The results presented are in line with the data obtained in clinical trials, positioning asciminib as a potential safe and efficacious treatment for CML patients with failure to several TKI lines. Figure 1 Figure 1. Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; Celgene/Bristol-Myers-Squibb,: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding.

Safety and Efficacy of Damoctocog Alfa Pegol Prophylaxis in Patients with Severe Hemophilia A: Interim Results of a Post-Marketing, Interventional Study

Background Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an approved factor (F)VIII treatment indicated for use in previously treated patients with hemophilia A aged ≥12 years, based on its safety and efficacy profile as demonstrated in the PROTECT VIII trial (NCT01580293).Here, we report preliminary results of a post-marketing interventional study of damoctocog alfa pegol prophylaxis in previously FVIII-treated patients with severe hemophilia A aged ≥18 years. Methods This is an ongoing, multicenter, single group, uncontrolled, open-label, post-marketing, interventional, phase IV trial (NCT04085458) of damoctocog alfa pegol in previously FVIII-treated patients with severe hemophilia A, aged ≥18 years (Figure 1). Eligible patients receive prophylaxis with damoctocog alfa pegol for 100 exposure days (EDs), starting with 45 IU/kg every 5 days (E5D) (recommended dose) or 40 IU/kg twice-weekly (2×W) until their next planned visit (Visit 3 after 10-15 EDs). At Visit 3, patients can either continue with the same regimen, increase their dose, or switch regimen to 2×W, E5D, or every 7 days (E7D), based on their needs as judged by the investigator. Patients who switched prophylaxis regimen after their third visit were assigned to a variable frequency (VAR) group. Patients with ≥1 infusion of damoctocog alfa pegol and bleeding data for ≥3 months were eligible for inclusion in the modified intent-to-treat cohort and are included in this interim analysis. Primary endpoint is FVIII inhibitor development (titer ≥0.6 Bethesda units). Secondary endpoints include treatment emergent adverse events (TEAE), anti-PEG (polyethylene glycol) antibody development and annualized bleeding rate (ABR). Bleeds and study drug consumption were recorded using an electronic patient diary. All analyses are exploratory. Results By June 1, 2021, 32 patients have been enrolled. Of these, 30 patients have had ≥1 infusion of damoctocog alfa pegol and bleeding data for ≥3 months, and are thus included in this analysis (2×W, n = 7; E5D, n = 8; E7D, n = 9; VAR, n = 6). Median (range) age at start of FVIII treatment was 5.0 (0-15.0) years, with the majority (n = 24; 80.0%) starting with an on-demand regimen. Median (range) age for starting prophylaxis was 32.0 (0-64) years. At data cutoff, median (range) total time in study was 422 (112-554) days and 87 (30-114) EDs. Safety data are presented in Table 1. No patients developed FVIII inhibitors, PEG antibodies or anti-drug antibodies. Sixteen (53.3%) patients developed TEAE, with the majority being mild in severity (n = 12, 40.0%). Three (10.0%) patients experienced mild or moderate TEAEs, which were considered study drug-related by the investigator. At data cutoff, median (quartile, [Q]1; Q3) total and joint ABRs were 1.82 (0.7; 5.5) and 0.37 (0.0; 2.6), respectively. Of 20 patients who were treated for ≥12 months, 30% (n = 6) had zero total bleeds and 60% (n = 12) had zero joint bleeds in their last year of treatment. Conclusions Preliminary results from 30 patients observed for up to 80 weeks show that individualized prophylaxis regimens of damoctocog alfa pegol were well tolerated in this post-marketing study. No immunogenicity concerns were observed, with no patients developing FVIII inhibitors, anti-PEG or anti-drug antibodies. Despite many patients starting prophylaxis late, ABRs were low and a large proportion achieved zero bleeds. These data support the favorable safety and efficacy profile of damoctocog alfa pegol prophylaxis in routine clinical use. Figure 1 Figure 1. Disclosures Holme: Bayer, Octapharma, Pfizer and Shire: Research Funding; Bayer, Novo Nordisk, Octapharma, Pfizer, Shire and Sobi: Consultancy. Hvitfeldt Poulsen: Pfizer: Research Funding; Bayer, Novo Nordisk, Sobi, Pfizer, Octapharma: Other: Congress Support. Tueckmantel: Bayer: Current Employment. Alvarez Roman: Amgen, Bayer, CSL Behring, Novartis, Novo Nordisk, Shire/Takeda, Sobi, Roche: Speakers Bureau; Shire/Takeda: Research Funding. De Cristofaro: Shire/Takeda: Research Funding; Bayer, Takeda: Consultancy; Bayer: Other: Congress Support; Sobi: Consultancy.

PARP Inhibitors in Combination with Radiotherapy: To Do or Not to Do?

Background: Despite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) is unclear. Aim: We conducted a literature analysis with the aim to evaluate the efficacy and safety profile of a combination with RT and PARP-I. Method: The key issues for the current review were expressed in two questions according to the Population, Intervention, Control, Outcome (PICO) criteria: 1. What is the outcome and 2. What is the toxicity in patients treated with a combination of PARP-I and RT for a newly diagnosed or recurrent tumors? Results: A total of 12 clinical studies met the inclusion criteria including seven single-arm dose-escalation phase I studies, two phase II (two- and three-arms controlled trials) trials, one parallel-arm phase I study, and two phase I/II studies published between 2015 and 2021. RT was performed with photon beams and several schedules according to the clinical situation. The acute toxicity ≥ grade 3 ranged between 25% and >96%, which was divided into hematological or non-hematological adverse events. Conclusions: despite the heterogeneity of the evaluated patient populations and tumor types, and the limited number of the studies, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear.

Potential action on the central nervous system of neroli oil extracted from Citrus aurantium

The essential oil from C. aurantium has been widely studied due to its potential anxiolytic action on several receptors in the Central Nervous System (CNS). Although it presents variations in its phytochemical composition depending on its origin, we can highlight that many compounds remain present, such as linalool that demonstrated antagonistic activity on glutamatergic receptors, possible inhibitory action of noradrenaline and serotonin receptors, besides the ability to activate GABA receptors in association with some flavonoids present in the oil. It is globally known that the underlying pathology called anxiety influences worldwide as an antecedent of conflicting psychological and physical disorders, which are associated with various neuronal disorders. In this regard, the oil extracted from C. aurantium flowers shows a potential therapeutic application for the treatment of anxiety disorders. However, more studies are needed to elucidate its complete role on the CNS and to verify and prove its safety and efficacy profile.

Safety and efficacy of tenecteplase versus alteplase in patients with acute ischaemic stroke (TRACE): a multicentre, randomised, open label, blinded-endpoint (PROBE) controlled phase II study

BackgroundTenecteplase (TNK) possesses several pharmacological characteristics superior to conventional alteplase (rt-PA), with well-established safety and efficacy profile in Caucasians. There exists controversy over the optimal dose of intravenous rt-PA for East Asians with acute ischaemic stroke (AIS). Current study aimed to determine the safety dose range of recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) for patients with AIS in China.MethodsThis multicentre, prospective, randomised, open-label, blinded end-point, phase II study compared three tiers of 0.1, 0.25, 0.32 mg/kg rhTNK-tPA (to a maximum of 40 mg) with standard 0.9 mg/kg rt-PA (to a maximum of 90 mg) in patients who were eligible for intravenous thrombolysis. The safety outcome were symptomatic intracranial haemorrhage (sICH) within 36 hours.ResultsBetween May 2018 and February 2020, 240 patients were randomly assigned to four group, 4 of whom did not receive study treatment. The intention-to-treat analysis included 236 patients. There was no difference in the improvement on National Institutes of Health Stroke Scale at day 14 in the 3 tiers and control group (63.3%, 77.2%, 66.7% vs 62.7%). The number of sICH was 3 of 60 (5.0%) in the 0.1 mg/kg group, none in the 0.25 mg/kg group, 2 of 60 (3.3%) in the 0.32 mg/kg group and 1 (1.7%) of 59 in the rt-PA group. There were no significant between-group differences in severe adverse events.ConclusionsSimilar to the Caucasians, rhTNK-tPA was well tolerated in Chinese patients with AIS at all doses administered within 3 hours of symptom onset. The dose-efficacy profile of rhTNK-tPA needs to be established with future investigations.Trial registration numberNCT04676659.