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31st January 2023
A trial of a HIV vaccine has been terminated due to ineffectiveness according to Janssen Pharmaceuticals, which led on the study together with a global consortium.
Despite HIV having been first discovered in 1983, there are still no vaccines available against the virus. Moreover, data shows that currently, across the world, there are approximately 1.5 million peopled infected with the virus.
In 2021, findings from a phase 2b, proof of concept trial, Imbokodo, were made available. In the study, 2,637 sub-Saharan women, aged 18 to 35, received an investigational vaccine, based on mosaic immunogens, which are engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains.
The vaccine used a common-cold virus (adenovirus serotype 26, Ad26) and was designed to deliver four antigens to illicit an immune response. The primary endpoint of the study was based on the difference in HIV infections between the vaccine and placebo groups, from month 7 (which was one month after the third vaccination dose) through to month 24. Unfortunately, the results showed that vaccine’s efficacy was only 25.2%, although fortunately, the study did not identify any safety concerns.
In 2019, the phase 3 Mosaico study (also referred to as HPX3002/HVTN706) was initiated. The aim of the study was to evaluate the efficacy of a heterologous vaccine, Ad26.Mos4.HIV, a tetravalent vaccine, for the prevention of HIV-1 infection among HIV-1 seronegative cis-gender men and transgender individuals who had sex with cis-gender men and or transgender individuals.
The vaccine was administered four times over 12 months and with the final two vaccine doses, individuals were also given a bivalent protein formulation containing two HIV envelope proteins, clade C gp140 and mosaic gp140, adjuvanted by aluminium phosphate to boost immune responses.
However, at a meeting of the study’s independent Data and Safety Monitoring Board, it was deemed that the regime was not effective at preventing HIV infection The study’s independent Data and Safety Monitoring Board (DSMB) determined that the regimen was not effective in preventing HIV infection compared to placebo.
Commenting on the findings, Penny Heaton, Global Therapeutics Area Head Global Therapeutic Area Head, said: ‘We are disappointed with this outcome and stand in solidarity with the people and communities vulnerable to and affected by HIV.’
She added: ‘We remain steadfast in our commitment to advancing innovation in HIV, and we hope the data from Mosaico will provide insights for future efforts to develop a safe and effective vaccine. We are grateful to our Mosaico partners and the study investigators, staff and participants.’
30th January 2023
The manufacturer Regeneron described how data from a study in The Lancet, showed that Dupixent treatment plus topical corticosteroids (hydrocortisone 1%) was effective in children under 6 years of age.
The Lancet trial enrolled and randomised 162 children aged 6 months to 6 years, to the drug or placebo. In the trial, participants were included if they had an Investigator’s Global Assessment (IGA) score of 3 – 4, which represents moderate to severe disease.
The drug was given at a dose based on the bodyweight. For instance, if > 5 kg but < 15 mg, a dose of 200 mg was given once every 4 weeks and for children weighing > 15 kg but < 30 kg, a dose of 300 mg was given. The primary endpoint was set as the proportion of participants with an IGA score of 0 or 1 (i.e., clear or almost clear) skin after 16 weeks.
At week 16, there was a 24% difference in IGA scores between Dupixent and placebo and which was statistically significant (p < 0.0001). The study also observed that the drug’s safety profile was generally in line with what might be expected.
The press release describes how in practice, 85 to 90% of children will develop atopic eczema before the age of 5 years and in Europe alone, it is estimated that up to 80,000 children aged between 6 months and 5 years have uncontrolled severe atopic dermatitis and might therefore benefit from a trial of systemic therapy.
According to the EMA, Dupixent will now be indicated for the treatment of severe atopic dermatitis in children 6 months to 11 years and who are candidates for systemic therapy.
The drug was approved for the same paediatric population by the FDA in June 2022.
29th January 2023
A novel angina gene therapy led to improvements in exercise capacity and a reduction in episodes of chest pain in those with refractory angina, according to the manufacturer XyloCor Therapeutics.
Patients with refractory angina continue to experience symptoms despite maximal drug therapy. Current treatment options for such patients include ranolazine with trial data suggesting that the drug improves exercise capacity and additional relief of anginal symptoms in those prescribed atenolol, amlodipine or diltiazem. Nevertheless, real-world data have been disappointing. For example, one study found that the drug failed to reduce the composite of ischaemia-driven revascularisation or hospitalisation without revascularisation in those with a history of chronic angina and who had incomplete revascularisation after percutaneous coronary intervention. Consequently, there remains an unmet need for patients with refractory angina.
The Phase II arm of the EXACT trial is designed to assess safety of XC001 (encoberminogene rezmadenovec), which represents an angina gene therapy which is administered by a transthoracic epicardial procedure, i.e., direct intramyocardial administration. It is anticipated that XCC01 will enable expression of human vascular endothelial growth factor and thus induce angiogenesis. In short, XC001 represents a one-time gene therapy with the aim of creating new blood vessels and thereby reducing ischaemic burden in the heart. In phase 1 of the trial, 12 participants with refractory angina, underwent mini thoracotomy with 15 epicardial injections of increasing doses.
While there are no actual data has currently been reported, XyloCor Therapeutics does indicate that the angina gene therapy reduced ischaemic burden and improved total exercise duration. In fact, six months after treatment, nearly half of the patients were able to undertake physical activity without this causing angina.
The company now hopes to continue work with XC001 and is currently finalising the design of an upcoming trial.
28th January 2023
Hydroxychloroquine-induced vision-threatening retinopathy occurs in only a small proportion of patients over time with the majority of cases of mild severity according to the findings of a long-term cohort study by US and Canadian researchers.
As an anti-rheumatic treatment, hydroxychloroquine provides a survival benefit for patients with autoimmune diseases such as systemic lupus erythematosus. However, a recognised adverse effect of the drug is retinopathy although the summary of product characteristics (SPC) of the drug suggests that this complication is very uncommon, provided that the recommended daily dose is not exceeded. Despite this assertion, there is a lack of data on the incidence of retinopathy associated with longer term use.
In the present study, researchers undertook a cohort study, including patients aged 18 years and older who were prescribed hydroxychloroquine between 2004 and 2020 and who participated in retinal screening. The primary outcome for the study was hydroxychloroquine induced retinopathy. The risk of developing retinopathy was estimated over a 15-year period based on a weight-based dose of the drug, i.e., > 6 mg/kg/day (which is not advised by the SPC), 5 to 6 mg or < 5 mg/kg/day.
Hydroxychloroquine and development of retinopathy
A total of 3,325 individuals with a mean age of 58.2 years (82.7% female) were included and who had used the drug between 2004 and 2014 and then continued for a further 5 years. Overall, 65.4% were given a dose of 5 mg/kg or less and 18.6% received more than 6 mg/kg/day.
Among the entire cohort, 81 individuals developed retinopathy; 56 with mild disease, 17 moderate and 8 severe. The authors calculated a cumulative incidence of retinopathy of 2.5% over 10 years and 8.6% over 15 years.
Among patients prescribed doses in excess of 6 mg/kg/day, the cumulative risk was much higher at 21.6% compared to only 2.7% for a dose of 5 mg/kg/day. In addition, the risk for severe retinopathy at 15 years was only 1.1%.
The authors concluded that the overall risk of hydroxychloroquine retinopathy was 8.6% after 15 years and that most cases were mild, though cautioned that higher doses were associated with a greater incident risk.
Citation
Melles RB et al. Hydroxychloroquine Dose and Risk for Incident Retinopathy : A Cohort Study. Ann Intern Med 2023
27th January 2023
A T cell biomarker, represented by low levels of differentiated CD3+CD27–CD28– T cells before leukapheresis could serve as a novel marker to predict an individual’s response to CAR T cell therapy in those with relapsed/refractory diffuse large B cell lymphoma (DLBCL), according to a study by researchers from the Medical University of Vienna, Austria.
Chimeric antigen receptor (CAR) T cell therapy produces a durable response in patients with either relapsed or refractory DLBCL. However, trying to identify which groups of patients are likely to respond to therapy is difficult and currently based on lactate dehydrogenase after lymphodepletion, tumour volume and Eastern Cooperative Oncology Group performance status. Nevertheless, each of these three measures does not relate to the immune system. In the current study, the Austrian team looked at a particular T cell biomarker and made use of a matched group of healthy control patients for comparative purposes.
T cell biomarker and CAR T treatment response
A total of 33 patients (mean age = 61.8 years, 42.4% female) with either relapsed or refractory DLBCL were matched with a health control group of 24 patients (median age = 60, 41.7% female).
When compared to healthy controls, DLBCL patients had significant lymphopenia and a higher frequency of differentiated CD3+CD27–CD28– T cells (28.7% vs 6.6%, p < 0.001). There were 26 patients infused with CAR T cell therapy and the overall response (OR) 3 months after the infusion was 57.7%, with a complete response (CR) seen in 42.3% of patients.
In regression analysis, the Austrian team found that low levels of differentiated CD3+CD27–CD28– T cells (23.3% vs 35.1%) were independently associated with an overall response. In fact, the association was even more evident when patients were stratified by either complete remission or non-complete remission (13.7% vs 37.7%, p = 0.001). Using a cut-off value of below 18% of CD3+CD27–CD28– T cells was highly predictive of a complete response at 12 months (67% vs 13%, p = 0.009).
The authors concluded that a low number of CD3+CD27–CD28– T cells at leukapheresis represented a novel, pre-infusion T cell biomarker that enabled prediction of a CAR T cell response in patients with relapsed or refractory DLBCL.
Citation
Worel N et al. The frequency of differentiated CD3+CD27–CD28– T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Front Immunol 2023
Greater high-density lipoprotein cholesterol (HDL) levels in older people are associated with an increased risk of fractures according to a post hoc analysis of data collected as part of the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE fracture substudy by Australian researchers.
Fractures are a common problem with one study estimating that one in 3 women and one in 5 men would be expected to have a minimal trauma fracture after the age of 50. Interestingly, a recent meta-analysis of 12 studies with over 12,000 patients found that HDL cholesterol levels were higher among those with osteoporosis. While HDL cholesterol as a recognised protective role in cardiovascular disease, more recently, it has been found that the lipid also has a role in the pathogenesis of degenerative and metabolic bone diseases in experimental mouse models. Nevertheless, the evidence from human studies is mixed, with one study in over 2000 women finding no association between fracture risk and higher HDL cholesterol, whereas in another, higher HDL particle size was linked to a higher fracture risk.
With an element of uncertainty surrounding the role of lipids and fracture risk, in the current study, the Australian team sought to clarify this connection. They turned to data from the two ASPREE studies and examined the association between plasma HDL cholesterol levels, which were categorised into quintiles, and incident fractures. The researchers used regression analysis, adjusting for various factors including age, gender, physical activity and measures of fragility.
Higher HDL levels and incident fracture risk
A total of 16,264 individuals with a mean age of 75 years (55% female) were included in the analysis and followed for a median of 4 years. During follow-up, 10.2% of the cohort experienced at least one fracture, 4% defined as minimal trauma (i.e., falls from standing height) and the remainder trauma (i.e., falling on stairs, ladders etc).
In fully adjusted models, among those with the highest quintile HDL cholesterol, there was a 33% higher risk of fracture, compared to the lowest quintile (hazard ratio, HR = 1.33, 95% CI 1.14 – 1.54). When stratified by gender, there was still an elevated risk for both men (HR = 1.45) and women (HR = 1.29) with higher HDL levels. There were no important associations between other plasma lipids and fracture risk.
The authors concluded that a higher HDL cholesterol level was associated with an increased fracture risk in older adults, independently of common fracture risk factors.
Citation
Hussain SM et al. Association of Plasma High-Density Lipoprotein Cholesterol Level With Risk of Fractures in Healthy Older Adults. JAMA Cardiol 2023.
CTX-009 in combination with paclitaxel improved the overall response rate in patients with unresectable, advanced, metastatic or recurrent biliary tract cancer, according to findings presented at the 2023 ASCO Gastrointestinal Cancer Symposium in San Francisco.
CTX-009 is a novel, bispecific antibody which causes blockade of delta-like ligand 4 Notch-1 signalling, inhibiting tumour growth as well as an blocking vascular endothelial growth factors (VEGF), that are recognised as important factors in tumour biology with role in angiogenesis. Since the overall response rate to the use of a single VEGF inhibitor is often low, there is a need for additional angiogenesis-based therapies. In a previously reported release from the manufacturer, Compass Therapeutics, data from a phase 2 trial showed that when added to paclitaxel, CTX-009 demonstrated a 42% overall response rate based on data from 10 patients with partial responses.
The findings presented at ASCO 2023, relate to an open-label, multi-centre, single arm, phase 2 trial, in patients with unresectable, advanced biliary tract cancer. Individuals were given CTX-009 as either a second or third-line treatment at a dose of 10 mg/kg biweekly in combination with paclitaxel. The primary aim of the study was to assess the objective response rate (ORR) based on RECIST v1.1.
CTX-009 and overall response rate
A total of 24 patients (median age = 61.5 years, 58.3% male) were included and of whom, 11 were receiving CTX-009 as a second-line treatment and the remainder as a third-line agent. The median duration of follow-up was 12.1 months.
The ORR was 37.5% (95% CI 18.8 – 59.4%) and this was higher for patients receiving the drug as a second-line treatment (ORR = 63.6%) though lower when used third-line (ORR = 15.4%). In addition, the median progression-free survival was 9.4 months and the median overall survival 12.5 months.
In terms of safety, treatment-emergent adverse events > grade 3 occurred in 95.8% of patients and 6 patients discontinued treatment due to adverse events.
The authors concluded that CTX-009 showed promise in biliary tract cancer patients and called for further studies to examine the efficacy and safety of the regime.
Citation
Oh DY et al. CTX-009(ABL001), a bispecific antibody targeting DLL4 and VEGF A, in combination with paclitaxel in patients with advanced biliary tract cancer (BTC): A Phase 2 study. ACSO GI Cancer Symposium 2023
26th January 2023
Chinese researchers from the University of Shanghai have reported that the combination of ticagrelor and aspirin reduced the incidence of ischaemic major adverse cardiac events (MACE) compared to clopidogrel and aspirin, following the implantation of emergency drug-eluting stents in patients with a ST-elevation myocardial infarction.
The use of dual anti-platelet therapy combining aspirin and a P2Y12 receptor inhibitor reduces recurrent MACE in patients undergoing a percutaneous coronary intervention (PCI) with drug-eluting stents. Despite the proven value of this combination treatment, it has become clear that continued high on-treatment platelet reactivity to adenosine diphosphate, is associated with adverse clinical events. In fact, there is evidence to suggest that between 4 and 30% of patients treated with clopidogrel fail to show an adequate platelet response. Moreover, use of ticagrelor has been shown to exhibit a lower level of high on-treatment platelet reaction in comparison to clopidogrel. Despite these findings, the reason for high on-treatment high residual platelet reactivity remain unclear but elevated levels of fibrinogen despite treatment with drugs such as clopidogrel have been found to be independently associated with the risk of ischaemic myocardial injury following elective PCI in patients treated with clopidogrel.
In the current study, the Chinese team examined the impact of fibrinogen on residual platelet reactivity after an emergency drug-eluting stent implantation in patients treated with either aspirin and clopidogrel, or aspirin and ticagrelor, over a 12-month period following their stent implant. The team used a prospective design and included patients undergoing PCI and who were prescribed aspirin 100 mg with clopidogrel 75 mg daily or aspirin and ticagrelor 90 mg twice daily for at least 12 months. The researchers measured both on-treatment platelet reactivity and the fibrinogen concentration and which was divided into quartiles. The endpoint of interest was ischaemic MACE, which was a composite of several adverse cardiovascular outcomes e.g., unplanned revascularisation, ischaemic stroke.
Ticagrelor and MACE
A total of 919 patients aged between 62.9 and 65 years and of whom, between 76.8 and 83.8% were male, were included in the final analysis, with 55.8% prescribed clopidogrel.
The rates of MACE were significantly elevated among patients prescribed clopidogrel compared to ticagrelor (HR = 1.72, 95% CI 1.21 – 2.43, p = 0.004).
Overall, MACE occurred in 14.3% of the entire cohort and the highest risk was found in patients with high residual platelet reactivity and those in the highest quartile of fibrinogen levels (HR = 10.02, 95% CI 4.67 – 21.46, p < 0.001).
The authors concluded that both a high fibrinogen level and high residual platelet reactivity could be used to identify patients at risk of an ischaemic event over a 12 month period and suggested that ticagrelor provided a better prognosis than clopidogrel.
Citation
Yao Y et al. The impact of high on-treatment platelet reactivity and fibrinogen levels on ischemic events in patients with ST elevation myocardial infarction: a prospective observational study. Int J Clin Pharm 2023
Regular use of the herbicide glyphosate among farmers is associated with higher urinary levels of oxidative stress biomarkers, a key characteristic of carcinogens, according to US researchers.
Glyphosate appears to be one of the most widely used herbicides across the world. However, in 2015, the International Agency for Research on Cancer, deemed glyphosate as ‘probably carcinogenic to humans’ based on sufficient evidence derived from animal studies. Despite this assertion, the evidence derived from human studies is mixed. For example, a 2016 systemic review was unable to detect a causal relationship between use of the herbicide and lymphohematopoietic cancer. In contrast, a more recent, 2019 meta-analysis concluded that the findings from both experimental and mechanistic studies suggested a compelling link between the use of glyphosate-based herbicides and non-Hodgkin lymphoma. Moreover, while several in vitro studies indicate the the toxicological effects of glyphosate may occur through the induction of oxidative stress, the evidence from actual human studies is limited.
In the present study, the US team matched US farmers who self-reported use of glyphosate with non-farmers, with no history of cancer of exposure to pesticides within the last 10 years. Enrolled participates provided a first morning urine sample and were asked about use of specific pesticides in the last 12 months. Urinary concentrations of glyphosate and three oxidative stress biomarkers, 8-OHdG, 8-isoprostane and MDA were made and regression analysis performed after adjustments for age, lifestyle and medical factors.
Glyphosate and relationship with oxidative stress biomarkers
A total of 268 males with a mean age of 63.4 (100 of whom served as non-farming controls) were included in the analysis.
The highest quartile of glyphosate urinary concentration was significantly associated with the highest levels of 8-OHdG (geometric mean ratio, GMR = 1.15, 95% CI 1.03 – 1.28) and for MDA (GMR = 1.20, 95% CI 1.03 – 1.40) but not for 8-isoprostane.
Among farmers exposed to the herbicide within 1 day (compared to 5 to 7 days) of urine collection, there was also an association with both 8-OHdG (GMR = 1.20, 95% CI 1.01 – 1.42) and MDA (GMR = 1.28).
The authors suggested that since 8-OHdG reflects oxidative stress-induced DNA damage, their findings support the genotoxic potential of the herbicide.
They concluded that these findings may inform evaluations of the carcinogenic potential of the herbicide.
Citation
Chang VC et al. Glyphosate Exposure and Urinary Oxidative Stress Biomarkers in the Agricultural Health Study. J Natl Cancer Inst 2023.
25th January 2023
Interim advice to the UK Government has recommended that planning begin for a 2023 autumn booster programme for those at higher risk of severe Covid-19 because of age or clinical risk factors. In addition, a smaller group of people, including those of older age and those who are immunosuppressed will also be offered an extra booster dose in the spring, the JCVI has advised.
A first vaccination will no longer be available to adults under 50 years not in an at-risk group with the offer being phased out over the course of 2023, the JCVI said. But emergency surge vaccination campaigns may still be needed should a novel variant of concern emerge with clinically significant biological differences to Omicron, the committee said.
Publishing its interim advice, the JCVI said the risk of severe Covid-19 continued to be ‘disproportionately greater’ in those from older age groups, care home residents, and those with certain underlying health conditions.
But the committee added there remains ongoing uncertainty about the evolution of the virus, durability and breadth of immunity and epidemiology of infection which ‘limits the development of a routine immunisation programme against Covid-19’.
Professor Wei Shen Lim, chair of Covid-19 immunisation at the JCVI, said: ‘The Covid-19 vaccination programme continues to reduce severe disease across the population, while helping to protect the NHS.
‘That is why we have advised planning for further booster vaccines for persons at higher risk of serious illness through an autumn booster programme later this year.
We will very shortly also provide final advice on a spring booster programme for those at greatest risk.’
Latest figures from this autumn/winter booster campaign show uptake of 64.5% in the over-50s and 82.4% in those 75 and over.
The 2022 autumn booster offer will come to an end on 12 February, the Department of Health and Social Care said, encouraging anyone who has not yet to come forward to do so now.
This was first published on our sister publication Pulse.
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