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17th February 2023
Manufacturer Ena Respiratory has revealed that in a phase 2a clinical study, when delivered intra-nasally, INNA-051 significantly reduced the duration of flu infection and led to a dose-related trend towards a reduction in symptom duration.
The body’s innate immune system is designed to provide the first line of defence against microbial pathogens via the use of Toll-like receptors (TLR), i.e., microbe recognition receptors present on the surface of cells. There are several types of TLR produced by cells and evidence suggests that three, TLR2, TLR1 and TLR6 (together with an unknown co-receptor), interact with a large variety of microbial ligands. Moreover, any alteration or absence of TLR2 function, correlates with a reduced immune protection against pathogens that possess TLR2 ligands. Given the important role of TLRs in the earliest phase of a host’s immune response, the development of TLR agonists is a promising therapeutic strategy. In fact, work from 2012 showed that the use of a TLR-2 agonist in mice offered protection against influenza.
INNA-051 is a first-in-class, TLR2/6 agonist and was originally tested as a treatment for COVID-19. In earlier work with ferrets infected with the virus, intra-nasal administration of the INNA-51 significantly reduced viral RNA in both the nose and throat by up to 96%. However, with the introduction of COVID-19 vaccines, there was less need for such treatments but the company continued to explore the potential of the drug in the treatment of other viruses and have found that it induced innate immune priming in response to rhinovirus infection.
INNA-051 and influenza
Top-line data has been published from a randomised trial in which 123 adults were randomised to either two doses of INNA-051 (low and high) or placebo and then challenged with a large dose of H3N2 influenza A virus. Unfortunately, the company reported that interpreting the results were complicated by the lower than expected infection rates in the placebo arm and a larger than predicted prior immunity across all groups. Nevertheless, in post hoc analysis, it was found that participants treated with the higher dose of INNA-051 had a statistically significant shorter duration of infection, as well as a non-significant reduction in the duration of symptoms.
Although INNA-051 is not currently licensed for use outside of clinical trials, the evidence appears to suggest that a prophylactic approach, based on boosting the innate immune system in the nose could be of clinical benefit for those exposed to respiratory viruses.
16th February 2023
Supplementing with vitamin D has no effect on asthma control or the risk of disease exacerbations according to the findings of an updated Cochrane systemic review.
Asthma is a chronic inflammatory respiratory disease and which globally, in 2019, was estimated to affect 262 million people in 2019, leading to 455,000 deaths. The potential role of vitamin D in asthma control is unclear though one study observed that among those deficient in the vitamin, the odds of having an exacerbation were 25% greater compared to those with levels in the normal range. Moreover, other work in children with severe, therapy-resistant asthma, found that lower vitamin D levels were linked to increased airway smooth muscle mass together with worse asthma control and lung function.
In 2016, a Cochrane review examined the possible value of vitamin D for the management of asthma and concluded that the vitamin is likely to reduce the risk of severe asthma exacerbations and healthcare. However, the authors could not determine if these benefits were confined to those who had suboptimal vitamin D levels. The current review provided an updated meta-analysis based on subsequently published trials and included patients with mild to moderate asthma.
Asthma control and vitamin D use
A total of 20 studies, 15 of which included 1,155 children and 5 with 1,070 adults were included in the updated analysis. The researchers performed several subgroup analyses based on initial vitamin D status as well as the dosage and regime of the vitamin used.
Overall, use of vitamin D did not reduce or increase the proportion of patients who experienced one or more disease exacerbations requiring treatment with systemic corticosteroids (Odds ratio, OR = 1.04, 95% CI 0.81 – 1.34). In addition, vitamin D had no effect on the rate of asthma exacerbations and subgroup analysis failed to reveal any effect based on vitamin D status, dose, dosage frequency or patient age.
Secondary outcomes examined included exacerbations leading to hospitalisation and measures of asthma control but again, vitamin D had no impact on any of the assessed outcomes.
The authors concluded that in contrast to their 2016 review, the current analysis failed to identify any benefits from vitamin D supplementation on asthma exacerbations or asthma control.
Citation
Williamson A et al. Vitamin D for the management of asthma. Cochrane Database of Systematic reviews, 2023
While prior work has revealed a heightened capsaicin cough reflex sensitivity in those with COPD, Japanese researchers have observed the opposite and found that this reduced sensitivity is associated with an increased risk of both an acute exacerbation or community-acquired pneumonia requiring hospitalisation.
According to the World Health Organisation, COPD was the third highest global cause of death in 2020. Moreover, community-acquired pneumonia (CAP) can often co-exists in patients hospitalised with an acute exacerbation of COPD. Typically patients with COPD experience cough, sputum and dyspnoea and it is know that the presence of both cough and sputum production are associated with frequent disease exacerbations leading to hospitalisation. Previous studies in animals, suggest that patients with COPD have a heightened response to stimulation with capsaicin, leading to a greater number of coughs. Such heightened responses have an important role in helping to protect the airways from particles although other work has identified a reduced capsaicin cough response in those with recurrent pneumonia.
In the present study, the Japanese team speculated that among those with COPD, rather than being more sensitive, as seen in previous work, the capsaicin cough reflex sensitivity would actually be lower due to the fact that many exacerbations occur alongside a co-existent CAP infection. The team prospectively recruited COPD patients and performed a number of baseline tests that included various lung and cardiac function tests, blood eosinophil counts as well as the capsaicin cough reflex sensitivity. These patients were then monitored over the next 12 months for cases of an acute exacerbation or CAP infections leading to hospitalisation.
Capsaicin cough reflex sensitivity and COPD exacerbations
A total of 68 patients with a mean age of 74 years (85.3% male) were included in the study and during the 12 month follow-up, 8 patients (3 with an exacerbation of COPD and 5 with CAP) were hospitalised.
Capsaicin cough reflex sensitivity scores were lower among those hospitalised and using multivariate regression analysis, the researchers identified that a decreased cough sensitivity was significantly associated with an acute exacerbation or CAP infection requiring hospitalisation (odds ratio, OR = 2.19, 95% CI 1.08 – 4.44, P = 0.029). In addition, an eosinophil count ≥300 µL was also significantly associated with hospitalisation (OR = 45.9, 95% CI 1.09 – 1934, P = 0.045).
The authors concluded that use of the capsaicin cough reflex sensitivity in those with COPD, may have a role in the prevention of severe acute exacerbations or pneumonia that require hospitalisation.
Citation
Kanemitsu Y et al. Decreased capsaicin cough reflex sensitivity predicts hospitalisation due to COPD. BMJ Open Respir Res 2023
15th February 2023
US researchers have developed a CT biomarker based model that is able to predict exacerbations in patients with chronic obstructive pulmonary disease (COPD) and which could ultimately be used to identify those at risk of such exacerbations.
Chronic obstructive pulmonary disease is associated with a high level of morbidity, disability and mortality, affecting around 10.3% of the world’s population aged between 30 and 79. The condition is associated with disease exacerbations which contribute to a decline in lung function over time and often result in hospitalisation. In recent years, computed tomography (CT) has been used to identify the phenotypic abnormalities in COPD that can be seen and quantitatively evaluated such as airway wall thickening which contributes to airflow limitations. Nevertheless, the value of using these CT derived markers to help predict exacerbations in COPD has not been explored and was the subject of the current study. The US team hypothesised that a CT biomarker model that included measures such as parenchymal texture and airway wall thickness could be used to predict disease exacerbations. They retrospectively examined patient data obtained from the SIROMICS cohort study, which sought to better understand COPD exacerbations. The team used 3-year follow-up data to develop their models for predicting exacerbations and which together CT-based measure of density gradient texture and airway structure also included several variables such as age, gender, exacerbation history. The performance of the model was assessed using the receiver operating characteristics curve (AUC) and compared to models based on exacerbation history and the exercise capacity (BODE) index.
CT biomarker model prediction of exacerbations
A total of 1956 participants with a mean age of 63.1 years (52%) completed the 3-year follow-up and were included in the analysis.
The CT biomarker model had an AUC of 0.854 for prediction of at least one severe exacerbation within 3 years and 0.93 for consistent exacerbations (defined as at least one acute episode in each of the three years. This was higher than models based on either exacerbation history (AUC = 0.823) or using the BODE index (AUC = 0.812).
In a further analysis using an external cohort of nearly 7,000 participants, the CT biomarker model had an AUC of 0.768 for at least one severe exacerbation.
The authors suggested that CT biomarker models could in the future, potentially be used to investigate the underlying disease mechanisms that lead to an exacerbation.
Citation
Chaudhary MFA et al. Predicting severe chronic obstructive pulmonary disease exacerbations using quantitative CT: a retrospective model development and external validation study. Lancet Digit Health 2023
Participants who continued to exercise for up to 10 years following completion of a 12 month randomised trial, had a significantly lower risk of developing incident type 2 diabetes according to the findings of a study by Chinese researchers.
Globally, type 2 diabetes affects around 462 million people or just over 6% of the entire population. Lifestyle modifications such as diet or increased exercise are known to reduce the risk of developing the disease. However, most of the available evidence for effects of lifestyle modification has been derived from high-risk individuals, for instance, those with elevated fasting glucose levels, or those who are both overweight and having impaired glucose tolerance. A further problem is that many of these intervention studies were of a relatively short duration. It is therefore less unclear whether maintenance of lifestyle modifications such as increased physical activity, over the longer term, still reduces the risk of developing T2D.
In the current study, Chinese researchers reported the longer term outcomes of a 12 month randomised trial they had undertaken. In the original trial, participants with non-alcoholic fatty liver disease, were randomised to vigorous to moderate physical activity, moderate exercise (brisk walking) or no exercise for 12 months. The results of the trial showed that both forms of exercise were effective at reducing intrahepatic triglyceride levels compared to those who did not exercise.
Following the trial, the majority of the study participants were followed-up after 2 and 10 years to assess the incidence of T2D, defined as a fasting plasma glucose of 6.9 mmol/L and a HBA1c of > 6.5% and or the use of anti-diabetic treatment.
Continued exercise and incident type 2 diabetes
From an original cohort of 208 participants who completed the year long trial, 195 and 179 remained for subsequent assessment after 2 and 10 years respectively.
The cumulative incidence of T2D was 2.1 per 100 person-years, 1.9 and 4.1 in those who continued with vigorous, moderate or no exercise respectively. In fact, the risk of T2D was reduced by 49% among those performing vigorous exercise (relative risk, RR = 0.51, 95% CI 0.27 – 0.94, p = 0.01) and by 53% among moderate level intensity exercise (RR = 0.47, 95% CI 0.25 – 0.89, p = 0.01) compared to the non-exercising group.
While both exercise groups had significant reductions in HBA1c levels compared to non-exercisers during the follow-up period, fasting plasma glucose levels while numerically lower in the two exercising groups than the non-exercise control group, these differences were non-significant.
The authors suggested that vigorous to moderate aerobic physical activity could be used to prevent T2D, particularly in those with obesity.
Citation
Chen Y et al. Effect of Moderate and Vigorous Aerobic Exercise on Incident Diabetes in Adults With Obesity: A 10-Year Follow-up of a Randomized Clinical Trial. JAMA Intern Med 2023
According to the findings of a systematic review in the Lancet, COVID-19 vaccine effectiveness wanes over time, even following booster doses, indicating that in the longer-term, it may be necessary to continue with preventative measures such as face-mask wearing and physical distancing to help manage the pandemic.
While the introduction of COVID-19 vaccines had an enormous impact on hospitalisations and mortality due to infection with the virus, it has been recognised that induced antibody levels reduce over time. A previous systematic review in 2022 observed that while vaccine efficacy against severe disease only dropped by 10% from one to six months, it reduced by approximately 21% against infection after 6 months and by nearly 25% against symptomatic illness. However, the analysis did not consider the impact of COVID-19 booster doses. As a result, in the current study, researchers examined the effectiveness of vaccination against infection, hospitalisation and death among those who had received a booster dose.
The team examined studies that provided data on vaccine effectiveness for at least 112 days after the primary series of vaccinations or at least 84 days after receipt of a booster dose. They set the primary outcomes of interest as effectiveness against COVID-19 infection, hospitalisation and mortality.
Vaccine effectiveness against COVID-19 outcomes
A total of 68 studies were included in the final analysis.
Overall effectiveness against any strain of COVID-19 reduced from 83% after a primary series of vaccinations to 62% by 112 to 139 days. Similarly, baseline effectiveness against hospitalisation was initially high at 92% but dropped to 79% after 168 – 195 days, as did effectiveness against mortality (91% to 86%) over the same period of time.
Among those who had received booster doses and for which most studies included the omicron variant, vaccine effectiveness against infection was initially 70% but reduced to 43% after 112 days. Similarly, boosted doses against hospitalisation reduced from a baseline of 89% to 71% over the same period of time. The authors reported that there was insufficient data to assess the impact on mortality.
Commenting on their findings, the authors suggested that maintaining COVID-19 prevention behaviours including the wearing of face-masks and physical distancing as well as vaccination may be necessary to reduce transmission of the virus, given how immunity wanes over time. They called for future studies to investigate the effectiveness of simultaneously using multiple approaches such as vaccination and face-masks as transmission preventative strategies.
Citation
Wu N et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir Med 2023
14th February 2023
The provision of neoadjuvant chemotherapy (NAC) for patients with operable colon cancer lead to histopathologic down-staging and better 2-year disease control according to the findings of study by Swedish and UK researchers.
Colorectal cancer is the 3rd most common cancer globally with 1.9 million new cases in 2020 and 935,173 deaths. The use of neoadjuvant chemotherapy has been shown to be of value at reducing tumour size and stage in patients with other operable cancers such as gastric and lower oesophageal adenocarcinomas but this approach has not been explored in the treatment of patients with colon cancer, possibly due to risk that treatment toxicities may compromise patient’s fitness for subsequent surgery.
However, despite the potential concerns, in the current study, researchers randomised patients 2:1 with radiologically staged T3-4, NO-2, MO colon cancer to either 6 weeks of preoperative oxaliplatin-fluoropyrimidine therapy followed by 18 weeks of postoperative adjuvant therapy (the intervention group) or postoperative chemotherapy only and which served as the control arm. They set the primary outcome as residual or recurrent disease within 2 years of randomisation, defined as no resection or macroscopic incomplete resection, that is, residual tumour or metastases following surgery. For the secondary outcomes, the team looked at several measures including surgical morbidity, histopathologic stage and cause-specific mortality.
Neoadjuvant chemotherapy and cancer surgery outcomes\
A total of 686 patients assigned to NAC and 351 control patients were included in the analysis.
The primary outcome occurred significantly less frequently in those assigned to NAC (rate ratio, RR = 0.72, 95% CI 0.54 – 0.98, p = 0.037). Moreover, there was also a reduction, albeit non-significant, in colon-cancer specific mortality (RR = 0.74, 95% CI 0.52 – 1.05, p = 0.095).
In addition, the researchers observed substantial reductions in T stage (21% vs 31%, NAC vs control, p < 0.001) and a higher proportion of NAC patients had histopathologically complete resections (94% vs 89%, p < 0.001).
Based on these findings, the authors concluded that NAC should be considered as a treatment option for patients with locally advanced colon cancer.
Citation
Morton D et al. Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial. J Clin Oncol 2023
Vitamin D supplementation may be of value to patients with type 2 diabetes, especially if they have suboptimal levels of the vitamin according to a meta-analysis undertaken by US and Iranian researchers.
It has been estimated that in 2017, a staggering 462 million individuals had type 2 diabetes, corresponding to just over 6% of the global population. While there are several therapies available for the management of type 2 diabetes, new treatments will always be needed, given the high prevalence of the disorder. One such potential treatment is vitamin D supplementation and while this is usually given to regulate calcium and phosphorus levels, in recent years, a purported role has been suggested for several diseases. For example, data from the prospective Nurses’ Health study found that higher vitamin D and calcium intake was associated with a 33% lower risk of type 2 diabetes. Nevertheless, studies that involved actual vitamin D supplementation produced mixed findings. For example, one study 6-month trial found that supplementing with the vitamin in patients with type 2 diabetes, failed to affect either insulin sensitivity or secretion. In contrast, an 8-week intervention study demonstrated significant reductions in fasting plasma glucose, insulin and HOMA-IR.
As a result, in the current study, researchers performed a meta-analysis to examine the effect of using the vitamin on indices of glycaemic control including fasting plasma glucose (FPG), HbA1c and HOMA-IR.
Vitamin D supplementation and glycaemic measures
A total of 46 eligible trials were identified including 4,313 patients with type 2 diabetes and a mean age of 56.5 years and of whom 2,164 received the vitamin intervention. The majority of the studies (42) used an oral supplement, whereas in four trials, it was given via intramuscular injection.
The pooled analysis for HbA1c showed a significant reduction compared to placebo for vitamin D (weighted mean difference, WMD = -0.20, p < 0.001). Similarly, there was a significant reduction in FPG (WMD = -0.28 mmol/L, p < 0.001) and HOMA-IR (WMD = -0.42, p = 0.019) in those given vitamin D.
The authors concluded that although vitamin D supplementation had a positive impact of glycaemic indices, they cautioned that the substantial heterogeneity between the included studies, raised the possibility of publication bias.
Citation
Farahmand MA et al. What is the impact of vitamin D supplementation on glycemic control in people with type-2 diabetes: a systematic review and meta-analysis of randomized controlled trails. BMC Endocr Disord 2023
13th February 2023
A team of UK researchers have developed a novel prostate cancer (PaC) screening test based on measurement of five chromosome conformations that were originally detected in association with advanced PaC and which, together with the prostate specific antigen (PSA) test, has a high degree of accuracy for detecting the cancer.
Prostate cancer is the second most common cancer in men and in 2020, there were just over 1.4 million new cases worldwide. Further investigations for suspected PaC are based on the results of a PSA test and the threshold has conventionally been set at 3 to 4 to differentiate between ‘normal’ and ‘abnormal’ although cancer can be present at lower PSA levels. However, while other tests have been developed, these all generally have a low positive predictive value. While imaging modalities have shown promise as screening tests, the recent PROSTAGRAM study which compared PSA test, MRI and ultrasound, found that all provided a similar level of accuracy for detecting PaC.
In the current study, researchers developed an assay based on specific chromosome conformation changes in certain genes in the blood of men with PaC. Using samples from the PROSTAGRAM study, which included men diagnosed with PaC and control patients, the team set out to establish whether their novel assay (EpiSwitch) in combination with a PSA test could improve the accuracy of PaC diagnosis.
Novel prostate cancer test performance
Samples from 109 men (88 control and 21 with PaC) were analysed. Based on a PSA cut-off level of 3 ng/mL, the test had an accuracy of 79%. The EpiSwitch test alone had an accuracy of only 64% but when the EpiSwitch test was combined with the PSA test, the accuracy was 94%.
The researchers reported that using the EpiSwitch test and the PSA level taken as a continuous variable, there was a high positive predictive (92%) and negative predictive value (94%) for the diagnosis of PaC. Although the study was based on a relatively small number of patient samples, the authors called for further studies to examine the value of the test in larger patient samples.
Citation
Pchejetski D et al. Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection. Cancers 2023
Upadacitinib (brand name Rinvoq) was previously been approved for ulcerative colitis and is now licensed in moderate to severe Crohn’s disease.
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has now approved upadacitinib for use in patients with moderate to severely active Crohn’s disease and who have had either an inadequate response or were intolerant to, conventional therapy or a biological agent.
Crohn’s disease is a form of inflammatory bowel disease that affects any part of the gastrointestinal tract and which is thought to affect around 10 million people worldwide and has a major impact on health-related quality of life.
Patients with Crohn’s will often receive oral corticosteroids to manage a disease flare, although those with more severe disease receive biologics either with or without immunomodulators to induce and maintain remission.
Upadacitinib is a Janus kinase inhibitor and a Phase II trial, evaluating the efficacy of 3 mg, 6 mg, 12 mg 24 mg twice daily or 24 mg daily, concluded that the drug induced endoscopic remission in a significant proportion of patients in comparison to placebo.
The MHRA decision was based on the findings of three other clinical studies.
In the first, U-EXCEED, a significantly higher proportion of patients treated with upadacitinib 45 mg daily achieved clinical remission per SF/AP at week 12 compared to placebo (40% vs 14%, p<0.001) and an endoscopic response compared to placebo (35% vs 4%, p<0.001).
In the second trial, U-EXCEL, again more patients given a 12-week induction regimen of upadacitinib 45 mg daily achieved clinical remission (51% vs 22%, p < 0.001) and endoscopic response (46% vs 13%, p < 0.001) compared to placebo.
In the third study, U-ENDURE which was a maintenance trial, patients who had responded to 12 weeks of upadacitinib 45 mg, were re-randomised to 15 mg, 30 mg or placebo and assessed at week 52.
The results showed that clinical remission occurred in 36 and 46% respectively (i.e., for 15 and 30 mg) compared to 14% for placebo (p < 0.001).
Similarly, endoscopic response occurred in 28 and 40% compared to 7% in the placebo group (p < 0.001).
Interestingly, a recently published real-world study of upadacitinib in patients with Crohn’s disease has shown that the drug induced subjective and objective responses in 25% and 42% of patients, respectively.
Updated information on the indications for rinvoq can be found in the summary of product characteristics.
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