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Take a look at a selection of our recent media coverage:

Casirivimab and Imdevimab combination reduces incidence of symptomatic COVID-19

19th January 2022

Casirivimab and Imdevimab in combination have been found to reduce the development of symptomatic COVID-19 over 28 days compared to placebo

Casirivimab and Imdevimab used together lead to a significant reduction in the proportion of patients who develop symptomatic COVID-19 compared to those given placebo. This was the conclusion of a randomised trial by researchers from the manufacturer of the combination, Regeneron Pharmaceuticals, New York, US.

Although the arrival of effective COVID-19 vaccines have been shown to boost individuals’ immunity against the virus, therapy with monoclonal antibodies remains an alternative for those who develop an inadequate response to vaccination. However, a recent Cochrane systematic review of monoclonal antibody therapy in COVID-19, concluded that ‘our certainty in the evidence for all non‐hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS‐CoV‐2‐neutralising mAbs‘ (monoclonal antibodies).

Casirivimab and Imdevimab are two mAbs which bind to different parts of the spike protein present on the surface of COVID-19. Furthermore, trial data has revealed how this combination reduced the risk of COVID-19–related hospitalisation and all-cause mortality, as well as resolving symptoms and decreasing viral load, more quickly than placebo.

The Regeneron Pharmaceuticals team undertook a two phase study of their combination. In part A, casirivimab and Imdevimab were found to prevent both symptomatic and asymptomatic COVID-19 infection among previously uninfected household contacts of infected individuals. The present study relates to part B of their trial, in which asymptomatic, infected close contacts were treated with subcutaneous casirivimab and imdevimab.

Part B was a randomised, double-blind, phase 3 trial, designed to determine whether subcutaneous casirivimab and imdevimab could prevent progression from asymptomatic to symptomatic infection. Enrolled participants were adults with a PCR confirmed COVID-19 infection, identified within 96 hours of another household contact testing positive. Included participants were then randomised 1:1 to casirivimab and Imdevimab or placebo and the primary endpoint of the trial was the proportion of individuals who developed signs and symptoms of COVID-19 within 14 days of their positive PCR result and this was reviewed over a 28 day period following randomisation.

Findings

A total of 314 individuals with a mean age of 41 years (51.6% female) were included of whom, 204 (66%) were asymptomatic and randomised to either casirivimab and Imdevimab (100) or placebo.

Among asymptomatic individuals assigned to treatment, 29% became symptomatic compared to 42.3% of those given placebo (odds ratio, OR = 0.54, 95% CI 0.30 – 0.97, p = 0.04). Participants on treatment also experienced a 5.6 day reduction in the mean duration of symptoms compared to placebo and the total number of weeks with a high viral load was significantly reduced (489.9 weeks vs 811.9 weeks per 1000 participants, treatment vs placebo, p = 0.01).

The authors concluded that treatment with casirivimab and Imdevimab for asymptomatic COVID-19 positive individuals living with an infected household contact, significantly reduced the incidence of symptomatic infection over a period of 28 days.

Citation

O’Brien MP et al. Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection. A Randomized Clinical Trial JAMA 2022

Atorvastatin of no value for ICU COVID-19 patients

13th January 2022

Atorvastatin use among intensive care patients does not result in a significant reduction of adverse outcomes among patients with COVID-19

Atorvastatin given to patients infected with COVID-19 and admitted to an intensive care unit (ICU) is not associated with a significant reduction in adverse outcomes according to research by a team from the Rajaie Cardiovascular Medical and Research Centre, Tehran, Iran.

Hydroxymethylglutaryl coenzyme A reductase inhibitors (or statins), are known to exert a direct antithrombotic effect in models of arterial and venous thrombosis via a mechanism unrelated to the cholesterol-lowering activity, as well as having anti-inflammatory properties. Furthermore, a 2021 systematic review also identified additional pleiotropic effects including antiviral and immunomodulatory that might help treat COVID-19.

Given this potential beneficial role for statins, the Iranian team sought to examine the impact of atorvastatin on thromboembolic events or death, in patients with the COVID-19, admitted to ICU. Their study was part of the INSPIRATION trial which had two arms: one that explored the effect of prophylactic anticoagulation and the other focusing on the use of atorvastatin.

The team recruited adult patients (> 18 years of age) with a PCR confirmed COVID-19 infection, admitted to ICU and in whom there was no baseline therapeutic need for a statin. Enrolled patients were then randomised 1:1 to atorvastatin 20 mg daily or matching placebo and followed for 30 days after randomisation. For patients requiring mechanical ventilation, the drug was delivered via a nasogastric or orogastric tube. The primary outcome of interest was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation or all-cause mortality within 30 days of randomisation.

Findings

A total of 587 patients with a median age of 57 years (44% female) were randomised to atorvastatin or placebo and treatment was used for a median of 21 days and slightly less, at 19 days for placebo. The median length of stay within ICU was 5 days in both groups.

After 30 days, the primary outcome had occurred in 95 (33%) of patients assigned to atorvastatin and 108 (36%) of those given placebo (odds ratio, OR = 0.84, 95% CI 0.58 – 1.21, p = 0.35). The results for the primary outcome were largely driven by mortality, with 31% and 35% of deaths in the atorvastatin and placebo groups respectively although no patients required extracorporeal membrane oxygenation.

The use of imaging tests such as computed tomography pulmonary angiograms and doppler, revealed a similar level of venous thromboembolism diagnoses in the two groups (20% vs 20%, p = 0.64). There was also no difference in the incidence of arterial thrombosis. In subgroup analysis, there were no sex-related differences, among patients older/younger than 65 years, smokers or in those with/without obesity or diabetes.

In trying to account for their findings, the authors speculated that atorvastatin may have had a small protective effect which was undetectable or that statins were only of benefit in the early stages of COVID-19 infection prior to the inflammatory response which led to irreversible damage.

Citation

INSPIRATION-S investigators. Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial. BMJ 2022

Apatinib therapy improves progression-free survival in iodine-refractory thyroid cancer

22nd December 2021

Apatinib therapy in patients with radioactive iodine-refractory thyroid cancer is safe and able to improve progression-free survival

The use of apatinib therapy in patients with radio-active iodine-refractory thyroid cancer has been found to be safe and effective, improving progression-free survival. This was the main result from the Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY] trial, undertaken by a team from the Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking, China.

The incidence of thyroid cancer has been increasing globally over the past three decades and affects around 5 to 6% of men and women. Differentiated thyroid cancer (DTC) , which includes papillary and follicular histologies, is the most common type, accounting for over 90% of all thyroid cancers. Although radioactive iodine therapy is effective for a large proportion of patients with DTC, unfortunately around 5 to 15% of patients become refractory to therapy, prompting the need for alternatives.

Apatinib is a small-molecule angiogenesis inhibitor which suppresses vascular endothelial growth factor (VEGF) signalling. The value of apatinib therapy in radioactive iodine-refractory DTC has been examined in two small studies. In the first including 10 patients, the drug was described as a promising therapy, whereas in the second, dosing schedule study, undertaken with 20 patients, the drug produced a similar efficacy with both doses.

Based on these preliminary studies, the Chinese team, decided to undertake a randomised, double-blind, placebo trial of apatinib in patients with progressive, locally advanced or metastatic radioactive iodine-refractory DTC. The REALITY trial was conducted in adults (18 years and over) and the inclusion criteria were those whose target lesion had lost iodine uptake function, where the lesion had progressed within 12 months after radioactive iodine treatment. In addition, iodine refractory patients receiving chemotherapy or radiotherapy, at least one month prior to the first use of study treatment were also included. Participants were randomised 1:1 to apatinib, given at a dose of 500 mg once daily until disease progression or intolerable side-effects developed or matching placebo. Tumour assessment was performed with CT or MRI imaging and the primary endpoint was investigator assessed progression-free survival (PFS), which was defined as the time from randomisation to disease progression or death from any cause. Secondary endpoints included overall survival (OR) and the objective response rate (ORR).

Findings

A total of 92 patients with a mean age of 57.7 years (60.9% female) were randomised to apatinib therapy or placebo.

With a median follow-up time of 18.1 months, the median PFS was 22.2 months in the apatinib group and 4.5 months in the placebo group (hazard ratio, HR = 0.26, 95% CI 0.14 – 0.47). The 12-month PFS rate was 60.3% for apatinib compared to 12.4% in the placebo arm although this decreased to 37.2% and 4.1% (apatinib vs placebo). The ORR was 54.3% for apatinib compared to 2.2% (placebo) and the overall 12-month survival rate was 95.4% vs 79.7% (apatinib vs placebo).

In terms of safety, the most common adverse event (grade 3 or higher) was hypertension (34.8%), hand-foot syndrome (17.4%) and proteinuria (15.2%) and none of these effects were observed in the placebo group.

The authors concluded that apatinib therapy significantly improved PFS and suggested that it should be considered as a new treatment for patients with radioactive iodine-refractory DTC.

Citation

Lin Y et al. Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine–Refractory Differentiated Thyroid Cancer. The REALITY Randomized Clinical Trial JAMA Oncol 2021

Add-on dupilumab therapy reduces exacerbations in children with moderate-to-severe asthma

21st December 2021

Add-on dupilumab therapy for children with uncontrolled moderate-to-severe asthma led to a significant reduction in disease exacerbations

Add-on dupilumab treatment in children with uncontrolled moderate-to-severe asthma produced a significant reduction in the number of exacerbations over a 52-week period, according to results of a Phase III, randomised, double-blind, placebo-controlled trial by researchers from the Division of Allergy, Immunology, and Pulmonary Medicine, Monroe Carell Jr. Children’s Hospital Nashville, US.

The global prevalence of asthma in children varies across the world with an estimated 10.8% of 6–7-year-old children having the disease although rates are lower rates in Northern and Eastern Europe (4.5%) but much higher in North America (20.0%) and Oceania (29.2%). While there are differences in the definition of ‘severe’ asthma, it has been suggested that prevalence of severe childhood asthma may be up to 5% and there is more concerning evidence indicating that childhood asthma increases the risk of COPD in adults.

Asthma appears, in part, to be a Th2-driven inflammatory process, characterised by the release of the cytokines interleukin (IL)-4, IL-5 and IL-13 and higher levels of Th2 inflammation are associated with greater airway hyper-responsiveness and more severe disease though only around 50% of patients have this endotype. The monoclonal antibody, dupilumab, blocks the action of IL-4 and IL-13 and has been approved for the treatment of adults and adolescents with asthma.

In Europe, the EMA has approved add-on dupilumab (brand name Dupixent) to ‘treat severe asthma in patients aged 12 years or over whose asthma is not properly controlled by a combination of high-dose corticosteroids taken by inhalation plus another medicine used for the prevention of asthma. Dupixent is only for use in patients with a type of inflammation of the airways called ‘type 2 inflammation’. 

For the present study, the US team recruited children aged 6 to 11 years with physician diagnosed moderate-to-severe asthma. Children were defined as those with type 2 inflammatory asthma phenotype defined by an eosinophil count of > 150 cells/cubic/ml or at least 300 cells/cubic/ml at baseline.

These children were randomised 2:1 to receive subcutaneous dupilumab (or matching placebo) every two weeks for 52 weeks at a dose of 100 mg (if their weight was <30 kg) or 200 mg (if weighing >30 kg). The primary endpoint was the annualised rate of severe exacerbations during the treatment period, defined as a deterioration of asthma control requiring systemic glucocorticoids for at least 3 days, hospitalisation or an emergency department visit that resulted in systemic glucocorticoid use. A key secondary outcome was the change from baseline to week 12 in the percentage of predicted prebronchodilator FEV1 (ppFEV1).

Findings

A total of 408 children with type 2 inflammatory asthma and a mean age of 8.9 years (66.4% male) were randomised to add-on dupilumab therapy or placebo. Among these children, 43% used high-dose inhaled glucocorticoids and had an average of 2.2 severe asthma exacerbations in the past year. An additional 259 children with an eosinophil count > 300 were similarly matched to dupilumab and placebo.

In the type 2 inflammation group, the adjusted annualised rate of severe asthma exacerbations was 0.31 (95% CI 0.22 – 0.42) in the add-on dupilumab group and 0.75 (95% CI 0.54 – 1.03) in the placebo group, giving a relative risk reduction, RR of 59.3% (p < 0.001). Similarly, among those with eosinophil counts > 300, the adjusted annualised rate of severe exacerbations was 0.24 (dupilumab) and 0.67 (placebo).

Overall, the percentage of participants who had no exacerbations during the 52-week study period was 77.1% in the dupilumab group and 59.6% in the placebo group and 79% vs 58.3% in the eosinophil vs placebo groups.

The changes in ppFEV1 were also significantly better for those in the add-on dupilumab group for both asthma phenotypes.

The authors concluded that dupilumab led to a meaningful improvement through asthma exacerbations and improvements in lung function in 6 to 11 year olds with moderate-to-severe asthma.

Citation

Bacharier LB et al. Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma. N Engl J Med 2021

Molnupiravir treatment halves rate of hospitalisation in unvaccinated COVID-19 patients

20th December 2021

Molnupiravir treatment initiated within 5 days of symptom onset in unvaccinated individuals with COVID-19 halved the risk of hospitalisation

The use of oral molnupiravir treatment within 5 days of COVID-19 symptom onset, led to a 50% reduction in the risk of hospitalisation for any cause of death among unvaccinated patients. This was the main finding of a study by the MOVe-OUT group which was supported by the manufacturer of the drug, Merck Sharp and Dohme.

Molnupiravir is a small-molecule ribonucleoside pro-drug of N-hydroxycytidine (NHC) and which has been shown to inhibit the influenza virus and is phosphorylated in vivo and incorporated into viral RNA, rendering the virus non-infectious. Early trial data suggested that the drug was efficacious and safe in patients infected with COVID-19 which formed the basis for the current MOVe-OUT trial.

For the Phase II-III trial, non-hospitalised patients with mild or moderate, laboratory confirmed COVID-19, symptom onset of no more than 5 days and at least one risk factor for more severe disease, were enrolled in the study. Risk factors included age (> 60 years), active cancer, chronic kidney disease, COPD, obesity, diabetes or serious heart conditions such as heart failure and coronary artery disease. Patients were excluded where there was an anticipated need for hospitalisation (due to COVID-19) within the next 48 hours.

Those enrolled were randomised 1:1 to molnupiravir treatment (800 mg) twice daily for five days or identical placebo. The primary efficacy endpoint was the incidence of hospitalisation for any cause, which the researchers defined as > 24 hours of acute hospital care or death through to day 29. The researchers also included a primary safety outcome as the incidence of adverse events.

Findings

A total of 1433 participants with a median age of 42 (53.6% female) were assigned to molnupiravir treatment (716) or placebo. Overall, 99.4% of these individuals had at least one risk factor for severe COVID-19, most commonly obesity (73.7%), age > 60 (17.2%) and diabetes (15.9%) with disease severity classed as mild in more than half (55.2%) of all cases.

The percentage of patients meeting the primary endpoint was 7.3% (molnupiravir) and 14.1% (placebo), a treatment difference of 6.8% (95% CI -11.3 to – 2.4, p = 0.001). Patients receiving molnupiravir had a lower risk of hospitalisation or death through to day 29 (6.8% vs 9.7%). There was one death reported in the molnupiravir group and 9 in the placebo group, all of which were considered to be COVID-19-related.

In terms of safety, 30.4% vs 33% of participants in the molnupiravir treatment arm vs placebo, experienced > 1 adverse event including diarrhoea, nausea and dizziness.

Since the trial was undertaken among unvaccinated participants, the potential value of the drug in preventing breakthrough infections could not be evaluated. Nevertheless, authors concluded that molnupiravir treatment was effective for the treatment of COVID-19 and that it did not appear to have any major safety concerns.

Citation

Bernal AJ et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients N Engl J Med 2021

Tapinarof cream effective for moderately severe plaque psoriasis

17th December 2021

Tapinarof cream was found to be effective in two Phase III, randomised trials for patients with moderately severe plaque psoriasis

Topical therapy with tapinarof 1% cream has been found to be effective for plaque psoriasis over a 12 week period in patients with moderately severe disease. This was the conclusion of a study by a team from the Icahn School of Medicine at Mount Sinai, New York, US.

Psoriasis is a common, chronic, recurrent, immune-mediated disease of the skin and joints that affects around 125 million people worldwide equating to between 2 and 3% of the population. Although patients with severe psoriasis can be managed with biologics, the majority of patients have mild-to-moderate psoriasis that can be adequately controlled with topical therapy; however, adherence to topical therapy is often suboptimal.

Tapinarof is a novel, non-steroidal, topical aryl hydrocarbon receptor-modulating agent and its mode of action is attributed to specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the down-regulation of pro-inflammatory cytokines, including interleukin 17, and regulation of skin barrier protein expression to promote skin barrier normalisation. 

In the present analysis, the authors provide results obtained from two identical, randomised, double-blind, Phase III trials, PSOARING 1 and PSOARING 2, which assessed tapinarof 1% cream in adult patients (aged 18 years and over) with mild to moderate plaque psoriasis. Patients were randomised 2:1 (treatment: placebo) and assessed using the Physician’s Global Assessment (PGA) score which ranged from 0 (clear) to 4 (severe) and treatments were applied once daily. The primary efficacy endpoint was a PGA response, defined as a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points on the PGA scale. The main secondary outcome was the proportion of patients achieving a PASI 75 (which represents a 75% reduction in disease severity) and both assessments were made at week 12. The main patient reported outcome was a change of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) based on an 11-point (where 0 is no itch and 11 is the worst imaginable itch).

Findings

A total of 510 and 515 patients were enrolled in both trials with a mean age of approximately 49 years and the proportion of male patients ranging from 50.6 to 62.6%. At entry, between 79.7 and 84% of participants had a PGA score of 3 (i.e., moderate disease severity) and a PP-NRS score of approximately 5.7.

The primary end point was achieved by 35.4% and 40.2% of patients in the tapinarof groups in the two trials compared to 6% and 6.3% in those assigned to placebo (p < 0.001 for both trials). In addition, 36.1% and 47.6% of the intervention groups achieved a PASI 75 compared to 10.2% and 6.9% in the placebo groups (p < 0.001 for both trials). However, while reductions in PP-NRS scores were numerically higher in both tapinarof groups this difference was not reported as statistically significant.

The authors reported that overall, adverse events in the tapinarof group were higher 50.3% vs 22.4% in PSOARING 1 and a similar proportion was seen in the second trial. The most frequent adverse events were folliculitis, nasopharyngitis, contact dermatitis and headache, all of which were more common with tapinarof.

The authors concluded that while tapinarof was more effective than placebo, larger and longer trials were required to evaluate its efficacy compared with existing topical psoriasis treatments.

Citation

Lebwohl MG et al. Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis N Engl J Med 2021

Ivosidenib addition to azacitidine results in three-fold increase in overall survival in AML

16th December 2021

Ivosidenib added to azacitidine therapy produces a three-fold higher overall survival in older patients with acute myeloid leukaemia

Addition of ivosidenib to azacitidine therapy in older patients with acute myeloid leukaemia (AML) improved overall survival, event-free survival and clinical response according to results presented at the ASH 2021 conference by researchers from Hospital Universitari i Politècnic La Fe, Valencia, Spain.

The results were derived from the AGILE trial which is a global, Phase III, multicentre, double-blind, randomised, placebo-controlled clinical trial to evaluate the efficacy and safety of Ivosidenib (IVO) and azacitidine (AZA) compared to placebo and azacitidine in adult patients with previously untreated isocitrate dehydrogenase 1 mutations (IDH1m) AML and who are considered appropriate candidates for non-intensive therapy.

Somatic mutations in IDH1 are present in between 6 and 10% of patients with AML and Ivosidenib, is an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme and approved by the FDA for adults with relapsed/refractory mIDH1 AML and those with newly diagnosed mIDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy. Data from an earlier phase 1b study of 23 patients with newly diagnosed mIDH1 AML showed a favourable safety profile and encouraging clinical activity of the ivosidenib + azacitidine combination.

For the present study, the Spanish team randomised patients 1:1 to IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously, for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA). Included patients were those with untreated AML, confirmed mIDH1 status and not eligible for induction chemotherapy. The primary endpoint of the study was event-free survival (EFS) defined as the time from randomisation until treatment failure, i.e. failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause. The main secondary endpoints were the complete remission (CR) rate, overall survival (OS) and objective response rate (OOR). The researchers also examined the adverse event rates for both groups of patients.

Findings

A total of 146 patients were randomised to IVO+AZA or placebo+ AZA (PLA+ AZA) with 70 patients and a median age of 76 years randomised to IVO+AZA.

In terms of the primary outcome, EFS, this was statistically significant (hazard ratio, HR = 0.33, 95% CI 0.16 – 0.69, p = 0.0011) in favour of the IVO+AZA arm. In addition, the median OS was 24 months vs 7.9 months (IVO+AZA vs PLA+ AZA) (HR = 0.44, 95% CI 0.27 – 0.73, p = 0.0005) and CR rate with IVO+AZA was 47.2% vs 14.9% (PLA+AZA, p < 0.001), the median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PLA+AZA and finally, the ORR was 62.5% vs 18.9% (IVO+AZA vs PLA+ AZA, p < 0.0001).

In terms of safety, common all-grade adverse events occurring in > 20% of patients receiving IVO+AZA vs PLA+AZA were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhoea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%).

A total of 66 (93.0%) patients receiving IVO+AZA compared with 69 (94.5%) patients receiving PLA+AZA experienced a grade ≥ 3 adverse event. Based on the recommendation of the Independent Data Monitoring Committee, further enrolment into the study was prematurely discontinued due to evidence of benefit.

The authors concluded that the IVO+AZA combination demonstrated the clinical benefit in this difficult-to-treat AML population.

Citation

Montesinos, P et al. AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation. ASH conference 2021

Active disease in leukaemia patients leads to severe COVID-19 and higher mortality if neutropenic and with a poor pre-COVID prognosis

13th December 2021

Active disease in leukaemia patients produces more severe COVID-19 and higher mortality if neutropenic and with a poor pre-COVID prognosis

Active disease in leukaemia patients gives rise to more severe disease after infection with COVID-19 and a higher incidence of mortality, but only where individuals are neutropenic or of their pre-COVID-19 prognosis was under 6 months. This was the finding of a retrospective analysis by researchers based at the Division of Haematology and Oncology, Weill Cornell Medical College, New York, US, presented at ASH 2021.

The most important predictors of both a severe infection and related outcomes after infection with COVID-19 in patients acute leukemias including with acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplastic syndromes (MDS) are uncertain. However, it is possible that active disease in leukaemia might result in more severe disease due to the presence of cytopenias. Data held in the American Society of Haematology ASH RC COVID-19 Registry, which was established on 1 April, 2020 for data collection and which is regularly updated, provides researchers with a rich source of data on the impact of COVID-19 among those with leukaemia. The registry includes patient characteristics such as age, comorbidities, type of haematological malignancy (AML, MDS, ALL), neutrophil and lymphocyte count and active treatments prescribed at the time of COVID-19 diagnosis as well as the outcomes associated with infection.

Using this registry data, the US team documented patient outcomes after infection with COVID-19 stratified by disease status (active initial diagnosis and relapsed/refractory vs. remission) and type of haematologic malignancy. COVID-19 severity was defined as mild (i.e., no hospitalisation required), moderate (hospitalisation required), or severe (ICU admission required). Categorical patient characteristics for each response group and associations between response groups and characteristics (i.e., alive vs. dead, severity vs. non-severity) were summarised by frequency and multivariable analyses used to identify independent predictors of outcomes.

Findings

Data were analysed for 257 patients with AML (n=135), MDS (n=40), and ALL (n=82) with 47% of patients aged less than 60years of age. At the time of infection, active disease in leukaemia was present in 44% of individuals and the overall mortality from COVID-19 infection was 21%. Those with active disease were significantly more likely to present with moderate and severe COVID-19 compared to those in remission when the data were dichotomised as severe vs. non severe and this difference was significant (p = 0.002).

Multivariable analyses revealed that for the whole cohort, increased COVID-19 related mortality was significantly associated only with neutropenia at diagnosis (odds ratio, OR = 3.15, 95% CI 1.31-8.08, p=0.01) and where the estimated pre-COVID-19 prognosis was under 6 months (OR = 8.58, 95% CI 3.24-24.46, p<0.001). However, a further factor appeared to be avoidance of intensive care (OR = 6.66, 95% CI 2.56-18.23, p<0.001).

Restricting the analysis to only hospitalised patients revealed how an increased COVID-19 mortality was again associated with estimated pre-COVID-19 prognosis of < 6 months (OR = 6.77, 95% CI 2.34-22.24, p<0.001) and in those forgoing ICU care (OR = 3.98, 95% CI 1.45-11.66, p = 0.007). Furthermore, mortality was not affected by the type of leukaemia.

The authors concluded that their data suggest that patients with active disease experience significantly higher COVID-19 severity but not increased mortality from COVID-19, apart from those with neutropenia and a pre-COVID-19 prognosis of < 6 months, for which mortality was higher, adding that if desired by patients, aggressive support for those hospitalised patients with COVID-19 is appropriate regardless of remission status.

Desai P et al. Clinical Predictors of Outcome in Adult Patients with Acute Leukemias and Myelodysplastic Syndrome and COVID-19 Infection: Report from the American Society of Hematology Research Collaborative (ASH RC) Data Hub. ASH Conference 2021

 

Topical asivatrep, a TRPVI antagonist, effective for adults with atopic eczema

1st December 2021

Topical asivatrep is a novel TRPVI antagonist that in a Phase III trial was found more effective than placebo for adults with atopic eczema

Topical asivatrep, a transient receptor potential vanilloid subfamily V member 1 (TRPV1) antagonist, has been shown to be more effective than placebo in patients with mild to moderate atopic eczema. This was the finding from a Phase III trial by researchers from the Department of Dermatology, Hallym University, South Korea.

TRPVI is a non-selective cation channel which is expressed by keratinocytes, mast cells and sensory neurons related to itch, especially itch related to the release of histamine. Moreover, in vitro study data suggests that antagonism of TRPVI can suppress the atopic eczema-like symptoms by accelerating recovery of the skin’s barrier. More specifically, in animal models of atopic eczema-like dermatitis, topical asivatrep, has demonstrated improvements in eczema symptoms and the barrier function of the skin. In a dose ranging clinical study in adults with atopic eczema, topical asivatrep 1% was found to provide the greatest improvement in disease severity.

For the present study, the Korean team used a 1% formulation of asivatrep based on the results of the dose ranging study, for a Phase III, randomised, double-blind, placebo-controlled trial. Included patients were aged 12 years and older, with mild to moderate atopic eczema, defined by an investigators’ global assessment (IGA) score of 2 (mild) or 3 (moderate), and which affected between 5 and 30% of their body. The primary efficacy endpoint of the trial was the proportion of patients with an IGA score of 0 or 1 (i.e., clear or almost clear) after 8 weeks of treatment. Secondary endpoints included changes in EASI score, a pruritus visual analogue scale (VAS) score and a sleep disturbance score at several time points, including week 8.

Findings

A total of 240 patients with a mean age of 25.6 years (45.6% female) were included in the analysis with 157 assigned to topical asivatrep. Most (58.3%) had moderate severity atopic eczema. However, due to withdrawals and patient violations, the final analysis was based on a sample of 231 patients (153 asivatrep).

After 8 weeks of treatment, the proportion of patients achieving an IGA score of 0/1 was 36% in the asivatrep group and 12.8% in the placebo arm (p < 0.001). With respect to EASI scores, the greatest difference was observed at week 8 (44.3% vs 21.4%, asivatrep vs placebo, p < 0.001), with 9.8% of those receiving asivatrep achieving an EASI90 (i.e., 90% reduction in EASI score) compared to only 2.6% in the placebo group (p = 0.046).

There were also significant reductions in pruritus VAS scores and measures of sleep disturbance with asivatrep. In terms of safety, topical asivatrep was well tolerated and while the incidence of treatment-emergent adverse effects was slightly higher with asivatrep compared to placebo, the difference was non-significant.

The authors concluded that treatment with asivatrep cream, as a first-in-class topical agent, may be a novel treatment for patients with atopic eczema.

Citation

Park CW et al. Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD). J. Allergy Clin Immunol 2021

Sacubitril-valsartan provides no mortality benefit compared with ramipril in acute MI with reduced ejection fraction

26th November 2021

Sacubitril-valsartan offers no mortality advantage in acute MI patients and a reduced ejection fraction compared with ramipril alone

Using sacubitril-valsartan in those experiencing an acute myocardial infarction (MI) and an ejection fraction lower then 40% appears to offer no mortality benefit over the use of ramipril alone. This was the conclusion of a trial by the PARADISE-MI researchers at the Cardiovascular Division, Brigham and Women’s Hospital, Boston, US.

The mortality benefits achieved from the use of angiotensin converting enzyme (ACE) inhibitors in randomised, placebo-controlled trials among patients with left-ventricular dysfunction or heart failure, is well established and is independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Moreover, the beneficial effects of ACE inhibitors also extents to the angiotensin-receptor blocker drugs such as valsartan.

Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds which have a favourable effect on the pathogenesis of heart failure. Inhibition of neprilysin with sacubitril, therefore maintains natriuretic peptides and the combination of sacubitril-valsartan has been approved for the management of patients with chronic heart failure and a reduced ejection fraction.

Nevertheless, whether this combination would be effective among patients suffering an acute MI without prior heart failure but with a reduced ejection fraction was the subject of the present study by the US team. They conducted the Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction (PARADISE-MI), which was an international, randomised, double-blind, active comparator trial, comparing sacubitril-valsartan with ramipril alone. The trial recruited patients with a spontaneous MI within 0.5 to 7 days before presentation in association with a reduced ejection fraction (< 40%), pulmonary congestion or both. Included patients were randomised 1:1 to sacubitril-valsartan or ramipril 5mg, both given twice daily in addition to any recommended therapy. The composite primary outcome was death from cardiovascular causes or incident heart failure.

Findings

A total of 5661 patients with an average age of 63.7 years (24.1% women) and a mean ejection fraction of 36%, were randomised to either therapy and followed up for a median duration of 22 months. There were 338 (11.9%) primary outcome events in the sacubitril-valsartan group and 373 (13.2%)in the ramipril group and this difference was non-significant (hazard ratio, HR = 0.90, 95% CI 0.78 – 1.04, p = 0.17). Similarly, death due to cardiovascular causes was also not different (HR = 0.91, 95% CI 0.78 – 1.07), as was hospitalisation for heart failure or outpatient heart failure (HR = 0.84, 95% CI 0.70 – 1.02) and death due to any cause (HR = 0.88, 95% CI 0.73 – 1.05).

The authors concluded that sacubitril-valsartan offered no benefit survival benefit among those with an acute MI and a reduced ejection fraction.

Citation

Pfeffer MA. et al. Angiotensin Receptor–Neprilysin Inhibition in Acute Myocardial Infarction. N Eng J Med 2021