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9th January 2023
A large prospective study by Chinese researchers has found that both separately and combined, coffee and tea consumption is inversely associated with a reduced cardiovascular disease (CVD) and all-cause mortality, highlighting the potential importance of incorporating both into an individual’s diet, provided that these observed associations are causal.
Long-term and moderate consumption of coffee is known to be significantly and inversely associated with cardiovascular disease risk, with the greatest reduction seen with 3 to 5 cups per day. In addition, evidence from China also suggests that daily green tea consumption is associated with a lower risk of incident type 2 diabetes and a lower risk of all-cause mortality in diabetics though the associations for other types of tea is less clear. Nevertheless, emerging data suggests that higher green tea and coffee consumption is inversely associated with a lower risk of cardiovascular disease and stroke in the general population. To date, however, only one study has examined the mortality benefit from coffee and tea consumption, finding that higher consumption of both was associated with reduced all-cause mortality, although the study was restricted to patients with type 2 diabetes. Consequently, it remains unclear whether the benefits of consuming both drinks are more generalisable. In the present study, the Chinese researchers aimed to examine the separate and combined associations of consuming the two beverages, with total and cause-specific mortality (including cardiovascular disease, CVD, respiratory and digestive disease using data from a population-based longitudinal cohort of individuals registered with the UK Biobank.
Intake of coffee and tea were assessed at baseline using a self-reported questionnaire but the researchers also collected information on a range of factors including age, gender, sociodemographic, behavioural (e.g., smoking, exercise, alcohol intake and dietary intake). Intake of both drinks categorised as coffee: none, < 1–2, 3–4 and ≥ 5 cups/day and tea: none, < 1–1, 2–4 and ≥ 5 cups/day.
Coffee and tea intake and mortality outcomes
A total of 498,158 participants with a median age of 58 years (54% female) were included in the analysis. These individuals were followed up for a median of 12.1 years, during which time 34,699 deaths were identified.
In a separate analysis and after adjusting for potential confounders, drinking less than 1 – 2 cups/day of coffee, was inversely associated with a lower risk of all the health outcomes assessed. For example, a 9% lower risk for all-cause mortality (hazard ratio, HR = 0.91, 95% CI 0.88–0.93)and a 6% reduced risk for cardiovascular mortality (HR = 0.94, 95% CI 0.88–1.00). Among those drinking tea, 2 – 4 cups/day was associated with a lower risk for all-cause (HR = 0.86, 95% CI 0.83–0.88) as well as CVD mortality (HR = 0.88 95% CI 0.81–0.94).
However, in joint analyses and compared to those who did not drink either beverage, the combination of < 1 – 2 cups/day of coffee and 2 – 4 cups/day of tea, significantly lowered all-cause mortality (HR = 0.78 95% CI 0.73-0.85) and CVD mortality (HR = 0.76 95% CI 0.64-0.91). Interestingly, the lowest mortality occurred for gastrointestinal disease from drinking both < 1 – 2 cup/day of coffee and ≥ 5 cups/day of tea (HR = 0.42, 95% CI 0.34-0.53).
The authors concluded that consumption of both drinks were both separately and jointly, inversely associated with all-cause and cause-specific mortality.
Citation
Chen Y et al. Consumption of coffee and tea with all-cause and cause-specific mortality: a prospective cohort study. BMC Med 2022
Higher lipoprotein A levels among patients with hypertension, increase their risk of an adverse cardiovascular event according to the findings of a study by US researchers.
Lipoprotein A is a form of low-density lipoprotein (LDL) and an established, genetically determined risk factor for atherosclerosis, coronary artery disease, stroke, thrombosis, and aortic stenosis. It is synthesised in the liver and its plasma concentration ranges from < 1 mg to > 1,000 mg/dL although concentrations above 50 mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Levels are largely determined by genetics with up to 90% of the concentration explained by a single gene, the LPA gene. Moreover, concentrations above 50 mg/dL are observed in roughly 20% of the Caucasian population and in an even higher proportion of African-American and Asian-Indian people. It can therefore be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.
Given this relationship with cardiovascular disease risk, in the current study, US researchers used data from the Multi-Ethnic Study of Atherosclerosis (MESA) trial, to examine the longitudinal relationship of Lipoprotein A and hypertension to cardiovascular outcomes in a large multi-ethnic cohort, who were initially free of cardiovascular disease. MESA was designed to include patients from different ethnicities and aimed to include approximately 38% White, 28% African-American, 23% Hispanic and 11% Asian (of Chinese descent) individuals.
Among risk factors for cardiovascular disease, hypertension is associated with the strongest evidence for causation. As a result, in the current study, researchers categorised participants into four groups based on both lipoprotein A (Lp(a)) and the presence/absence of hypertension, which was defined by a systolic pressure of 140 mmHg or higher and a diastolic of 90 mmHg or the use of antihypertensive medicines. Group 1 had Lp(a) levels below <50 mg/dL and no hypertension; group 2 had Lp(a) levels ≥50 mg/dL but no hypertension; group 3 had Lp(a) <50 mg/dL and hypertension, whereas participants in group 4 had both an elevated Lp(a) (≥50 mg/dL) and hypertension. Individuals were then followed up until an adverse cardiovascular event.
Lipoprotein A levels, hypertension and adverse cardiovascular events
A total of 6,674 individuals with mean age of 62.1 years (52.8% female) and of whom, 38.6% were White, 27.5% Black, 22.1% Hispanic and 11.9% Chinese American, were followed for a mean of 13.9 years. During this time 809 participants experienced a cardiovascular disease event.
Using group 1 as the reference, those with Lp (a) ≥50 mg/dL and no hypertension (group 2) had no significant increased risk for cardiovascular disease events (Hazard ratio, HR = 1.09, 95% CI 0.79 – 1.50). In contrast, participants in group 3 (i.e., Lp(a) <50 mg/dL and hypertension) had a statistically significant increase in risk (HR = 1.66, 95% CI 1.39 – 1.98). The risk was also significantly elevated for those in group 4 (HR = 2.07, 95% CI 1.63 – 2.62).
In further analysis, the researchers identified that those with an elevated Lp(a) and with hypertension had an increased risk of cardiovascular disease events (HR = 1.24, 95% CI 1.01 – 1.53) relative to those with hypertension but lower Lp(a).
The authors concluded that while hypertension was a major contributor to cardiovascular risk, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease.
Citation
Rikhi R et al. Association of Lp(a) (Lipoprotein[a]) and Hypertension in Primary Prevention of Cardiovascular Disease: The MESA. Hypertension 2022
Glofitamab therapy following obinutuzumab pre-treatment, led to a fast and durable complete response rate in patients with refractory or relapsed mantle cell lymphoma after the use of Bruton tyrosine kinase inhibitors according to a study presented at the American Society of Haematology (ASH) conference in in New Orleans, US.
Mantle cell lymphoma (MCL) is a rare, subtype of B-cell non-Hodgkin lymphomas characterised by a translocation resulting in over-expression of the cyclin D1 gene. It develops from malignant B-lymphocytes within a region of a lymph node known as the mantle zone and largely affects men aged between 60 and 70 years of age, with around 1 in 200,000 diagnoses per year. The first-line treatment consists of intensive chemotherapy with autologous stem cell transplant for the fit or less intensive chemotherapy for less fit and transplant-ineligible individuals, although many eventually relapse with a progressive clinical course. Treatment with Bruton tyrosine kinase inhibitors such as ibrutinib is common although among ibrutinib-refractory MCL patients, there is a short survival. For example, one trial in 114 patients found that the median overall survival following cessation of ibrutinib was 2.9 months.
Glofitamab is a T-cell-engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and mono-valency for CD3 on T cells. In a phase 1 trial of patients with relapsed or refractory B-cell non-Hodgkin lymphoma, the drug showed favourable activity with frequent and durable complete responses and a predictable and manageable safety profile.
In the current study reported at ASH, patients were pre-treated with obinutuzumab 7 days prior to the first dose of glofitamab to mitigate the risk of cytokine release syndrome (CRS). Intravenous glofitamab step-up dosing was given on day 8 (2.5 mg) and 15 (10 mg) of the the first cycle, followed by a target dose of 16mg after 1000mg obinutuzumab or 30mg after 2000mg obinutuzumab, from the first day of the second cycle, then every 3 weeks for up to 12 cycles.
Glofitamab response rate
A total of 37 patients with a median age of 72 years (73% male) received glofitamab step-up dosing and of whom, 16 received pre-treatment with obinutuzumab 1000 mg. The majority (91.9%) had Stage III/IV disease and the median number of prior therapies was 3 with 64.9% having received a Bruton Kinase inhibitor. In addition, patients received glofitamab a median of 1.9 months after their last, treatment.
After a median follow-up of 8 months, overall response rate (ORR) and complete response (CR) rates were 83.8% and 73.0% respectively, across both obinutuzumab cohorts although the CR rate was higher with obinutuzumab 2000 mg (81% vs 62.5%). However, most impressive, was that across both cohorts, the median time to achieving a complete response was 51 days and an estimated 71.6% of patients with a CR remained in response at 9 months, with a median CR of 10 months.
In terms of safety, the most common adverse events were CRS (75.7%) and neutropenia (40.5%) although the CRS rates were lower with the higher dose of obinutuzumab (66.7% vs 87.5%). Neurologic adverse events occurred in 15.4% of all patients although none discontinued treatment due to adverse events.
The authors concluded that using a fixed-duration glofitamab monotherapy induced high and durable CR rates, the majority of which were achieved early, in heavily pretreated patients with MCL, most of whom had prior Bruton kinase inhibitor therapy and thus a particularly poor prognosis.
Citation
Phillips TJ et al. Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma. Abstract No 74, ASH 2022
6th January 2023
Philip Mease is a rheumatologist based in Seattle, Washington, and has been in practice since 1982. He spoke to Hospital Healthcare Europe about the management of psoriatic arthritis and findings from the DISCOVER-2 trial.
Philip Mease has an interest in psoriatic arthritis (PsA), which arose after working alongside a dermatology department in Seattle where he treated many patients referred by dermatologists for the treatment of their arthritic component. His work on PsA took off after undertaking a clinical trial with etanercept in 2000.
Since then, he has continued to play an active role in clinical research on PsA, as well as mentoring clinicians and was involved in the establishment of GRAPPA, a multidisciplinary, non-profit, organisation that promotes and disseminates information on PsA.
As Dr Mease explained, ‘psoriatic arthritis is a condition that occurs in people with psoriasis’ and that in the US and Western Europe, psoriasis occurs in around three out of 100 individuals and, of those, ‘one out of the three will have manifestations of PsA.’ He described how PsA is a unique presentation in that any joint in the body can become inflamed. A key feature of PsA Dr Mease added, was how patients can get inflammation where tendons or ligaments insert into bone. For many, the Achilles tendon is affected and this is referred to as enthesitis and which, he says, ‘can be quite disabling for patients, especially low extremity enthesitis.’ A further hallmark presentation, dactylitis, occurs on fingers or toes in which the whole digit swells, becoming sausage-like, reflecting inflammation in both the synovium and bone. Another area of the bone affected in 40-50% of patients he said, was the spine and whilst quite disabling, he finds this is often missed because of the belief that back pain invariably occurs due to degenerative arthritis of the spine as opposed to an immunologic inflammation.
Given the combination of a painful arthritis and an unsightly skin and nail disease, Dr Mease is unsurprised that such patients experience a significant detriment in their quality of life, characterised by a higher incidence of depression and suicidal ideation than for most other chronic disease.
As Dr Mease explained, rheumatoid arthritis tends to be more common in women and is predominately restricted to inflammation of the synovial lining tissue of the joints and without some of the defining features (e.g. enthesis) of PsA. In contrast, PsA is equigender – occurring equally in males and females – and tends to present in fewer joints. He also noted that PsA rarely occurs in the absence of the cutaneous manifestation of psoriasis that sometimes the arthritis precedes the development of skin-related symptoms. On average, he says, ‘people will develop psoriasis about 10 years before they develop the arthritis manifestations.’
Unfortunately, and unlike rheumatoid arthritis, Dr Mease revealed how there are no specific clinical biomarkers indicative of PsA. Consequently, the diagnosis is a clinical one and rests on the presence of specific symptoms and the presence of concomitant psoriasis.
While there are some biomarkers that are elevated in PsA, none of these are particularly informative. For instance, inflammatory markers such as C-reactive protein are sometimes elevated, but as he says, ‘this only happens in around 40% of the time, even in patients with very active disease.’ Occasionally, he added, a gene marker, HLA b27 is measured when investigating the presence of spinal involvement but again, ‘maybe about 30% of patients with spinal involvement will have the presence of this particular gene marker.’
While disabling, as Dr Mease explained, the symptoms of PsA such as joint pain, stiffness and swelling can vary considerably among sufferers. For some patients, these symptoms can be particularly burdensome, occurring daily, whereas for others, symptoms may persist for several weeks at a time before quiescence. A further complication is PsA is degenerative, resulting in the destruction of bones and joints, leading to constant, debilitating pain.
He believes that PsA can be diagnosed by both dermatologists and rheumatologists although recognises how many dermatologists freely admit to being unable to differentiate between PsA and osteoarthritis or sometimes, might not even enquire about the presence of musculoskeletal symptoms in their psoriasis patients.
With a cosmetically disfiguring skin disease and associated painful joints, the burden upon PsA sufferers is huge, severely impacting on social and occupational activities and ultimately their quality-of-life. Dr Mease discussed how in practice patients become overburdened by heightened levels of pain and fatigue together with social embarrassment due to the visible nature of their skin condition.
Although untreated, PsA becomes degenerative over a period of several years, Dr Mease mentioned how in a patient who first presents with dactylitic digit, ‘we can see within a year the destruction of the joint within that finger or toe.’
Although the presence of psoriasis, particularly severe disease, is known to be linked with a higher risk of cardiovascular disease, the association with PsA is less well defined. Nevertheless, as Dr Mease noted, ‘we know that the deeper the inflammatory burden that the patient has, the greater likelihood of associated cardiovascular risk.’ Moreover, given how there is already a genetically predisposed risk for cardiovascular risk in both PsA and psoriasis patients, he sees it as vital to educate both patients and clinicians about this potential higher cardiovascular risk.
According to Dr Mease, ‘psoriatic arthritis is considered to be an auto-immune disease due to the activation of predominately T lymphocytes but also to some extent, B lymphocyte as well as other immune cells such as natural killer cells.’ Each of these different cells have the capacity to over-produce key pro-inflammatory cytokines including tumour necrosis factor (TNF) and interleukins 17, 23 and, to a lesser extent, interleukin-6. These inflammatory molecules migrate to areas of inflammation and stimulate cells to become overactive. Consequently, these molecules have become a key target for treatment.
While initial management for a psoriasis patient who complains of joint aches and pains might be over-the-counter or prescribed non-steroidal anti-inflammatory agents, by the time they reach a rheumatologist, many will no longer find these drugs to be effective.
While the next step in the UK is the use of immunosuppressants such as methotrexate, Dr Mease described that in the US, recent guidance suggested earlier use of an anti-TNF agent. This he says, is because anti-TNF agents are known to be more effective than immunosuppressants such as methotrexate and help to delay both disease progression and ultimately destruction of joints, making them more cost-effective.
However, Dr Mease depicted how there is a reluctance to use biologics before drugs like methotrexate due to the higher cost of the former agents. Nonetheless, he thinks that this stance may well change in the future after more widespread adoption of biosimilars, which while still expensive, are considerably cheaper than their original reference products and therefore serve to increase patient access to treatment.
Dr Mease described how the overarching aim of the DISCOVER-2 trial was to investigate the ‘safety and efficacy of guselkumab, an IL-23 inhibitor, in treating the various clinical domains of PsA including the ability to inhibit structural damage progression or not.’ The trial itself included over 700 patients with psoriatic arthritis and enabled researchers to document safety and efficacy for the drug and which would form part of the submission required for regulatory approval.
The main efficacy and safety outcomes were assessed after 24 weeks but further assessments were made at 52 and 100 weeks. He stated that an important part of the analysis was the use of non-responder imputation. Using this approach, participants who discontinued therapy for any number of different reasons would be counted as a non-responder.
This was a more stringent test and, as Dr Mease explained, given that ‘three-quarters of the patients had an ACR20 [a composite efficacy measure] response, it was a comment about the efficacy and longevity of the effect of the medication.’
The trial also found how patients responded quickly, with responses seen as early as one month after starting treatment. In addition, Dr Mease described how there was also a climbing response over time, ‘so that an ACR20 response was achieved by about two-thirds of patients at the 24-week mark and by about 50% of patients at the 16-week mark’ and continued to climb as the study continued and were even higher at the 100-week mark.
Dr Mease thinks that the trial showed how treatment with guselkumab not only provides a relatively fast onset of action but also that the response continues to increase over time and probably becomes maximal after 52 weeks. As well as clinical efficacy, Dr Mease described how guselkumab produced a statistically superior response to placebo for all the quality-of-life measures assessed in the trial.
While clearly the response to treatment wanes over time, he noted how biologic registry data, which include thousands of patients, suggests that for this class of drugs, the persistency of response is between 1.5 and 3 years. A further and reassuring point he added was that the emerging registry data tend to mirror the safety profile of agents observed in clinical trials.
Dr Mease also said that there are currently several other drugs being considered for the management of PsA, including interleukin (IL)-17 and -23 inhibitors and TNF inhibitors. Nevertheless, he thinks that IL-23 is a somewhat attractive target for PsA given how blockage of this cytokine is effective against both cutaneous and arthritic symptoms. He mentioned how it was also effective in a subgroup of patients with psoriatic spondylitis in their spine.
Dr Mease described the emergence of therapies with different molecular targets. One intracellular pathway target is tyrosine kinase 2, which is part of the Janus kinase (JAK) family. The use of an inhibitor of this pathway, deucravacitinib, has been shown to be well tolerated and improves disease severity. In addition, two oral JAK inhibitors, tofacitinib and upadacitinib, have already received FDA approval for PsA. Finally, although not currently available, neurokinin 2 inhibitors are under development for the treatment of not only PsA, but also rheumatoid arthritis and lupus.
Dr Mease believes that the last 25 years has witnessed a significant improvement in both the understanding and treatment of PsA and that today, is what he described as a ‘terrific time to treat people with the condition because we can actually often get them into remission or low disease activity.’
5th January 2023
Receiving a COVID-19 vaccination has been found to reduce the risk of subsequently developing post-COVID-19 condition (or long covid) although the vaccine effectiveness is low according to the findings of a meta-analysis by US researchers.
Vaccine effectiveness is a measure of how well vaccination protects individuals against a condition but differs from the efficacy measured in a trial, because efficacy cannot predict exactly just how effective a vaccine might be in a larger and more variable population. Nevertheless, real-world evidence suggests that some vaccines, such as BNT162b2, have an effectiveness comparable to that reported in phase III clinical trials. Although in practice, many patients make a full recovery after an acute COVID-19 infection, for a minority, there is the continuation or development of other symptoms. The World Health Organisation has described this as ‘Post COVID-19 condition’ and which occurs in individuals with a history of probable or confirmed COVID-19 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
While the effectiveness of vaccination against COVID-19 is widely accepted, what is uncertain, is whether vaccination reduces the risk of post–COVID-19 condition. This was the subject of the current study by the US researchers who reviewed the literature on the effectiveness of COVID-19 vaccines for post–COVID-19 condition and pooled the results of published studies to allow for a more precise estimate of effectiveness. The team looked for studies that: involved vaccinated and unvaccinated individuals and evaluated the long-term effectiveness of the COVID-19 vaccine. Post–COVID-19 conditions were defined as a wide range of health symptoms that were present 3 or more weeks after having COVID-19. Any studies without a comparison between vaccinated and unvaccinated individuals (or other vaccinated control group) were excluded. The team calculated the pooled diagnostic odds ratio (DORs) for post–COVID-19 conditions between vaccinated (i.e., those who received at least 1 dose of a COVID-19 vaccine) and unvaccinated individuals.
Vaccination and effectiveness against post-COVID-19 condition
A total of 10 studies with 1,600,830 individuals evaluated the effect of vaccination on post–COVID-19 conditions and of which 6, were included in the meta-analysis. The pooled prevalence of post–COVID-19 conditions was 39.1% among those who were unvaccinated and 37.6% among those who received at least 1 dose.
The pooled DOR for post–COVID-19 conditions among individuals who received at least 1 dose was 0.708 (95% CI 0.69 – 0.73), giving an estimated vaccine effectiveness of 29.2% (95% CI, 27.5%–30.8%).
However, vaccine effectiveness varied depending on whether an individual received the vaccine before or after being infected with COVID-19. For example, effectiveness was 35.3% (95% CI 32.3% – 38.1%) among those who received the COVID-19 vaccine before having COVID-19 but 27.4% (95% CI 25.4% – 29.3%) among those who received it after being infected.
The authors concluded that COVID-19 vaccination before and after having COVID-19 provided a low but statistically significant decrease in post–COVID-19 conditions for the variants circulating during the study period. They added that a more standardised definition of post–COVID-19 conditions was also needed both for research and clinical purposes.
Citation
Marra AR et al. The effectiveness of coronavirus disease 2019 (COVID-19) vaccine in the prevention of post–COVID-19 conditions: A systematic literature review and meta-analysis. Antimicrob Steward Health Epidemiol 2022
According to AstraZeneca, the Committee for Medicinal Products for Human Use (CHMP), has adopted a positive opinion recommending a change to the marketing authorisation for Enhertu.
The drug can now be used as monotherapy for the treatment of adult patients with unresectable or metastatic HER2‑low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.
The World Health Organization estimates that in 2020, there were 2.3 million women diagnosed with breast cancer and which led to 685 000 deaths. In Europe alone in 2020, there were 531,086 cases of breast cancer that resulted in 141,765 deaths.
The human epidermal growth factor receptor 2 (HER-2) is a receptor tyrosine-protein kinase normally involved in the proliferation and division of breast cells and HER2-positive breast cancers are an aggressive type of breast cancer that tend to grow faster and are more likely to spread.
It is known that around 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridisation. Moreover, this low HER2 expression is a promising new target for antibody-drug conjugates and Enhertu (which contains trastuzumab deruxtecan) is one such specifically engineered HER2-directed antibody drug conjugate.
Enhertu clinical efficacy
CHMP based its decision of data from the DESTINY-BREAST04 trial which compared previously treated patients with HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation (ISH)-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR-negative disease against standard of care physician’s choice of chemotherapy.
The study found that Enhertu demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive disease (PFS hazard ratio, HR = 0.51, 95% CI 0.40 – 0.64, p < 0.001). In addition, the median overall survival in the hormone receptor–positive cohort was 23.9 months in the Enhertu group and 17.5 months in the physician’s choice group (HR for death = 0.64, 95% CI, 0.48 to 0.86, p = 0.003).
The safety profile of Enhertu was consistent with previous clinical trials with the most common Grade 3 or higher treatment-emergent adverse events were neutropenia (13.7%), anaemia (8.1%), fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%) and nausea (4.6%).
A summary of the CHMP provides details on the full indications for Enhertu.
A placebo response makes a significant contribution to the reduction in pain scores seen in cannabinoid clinical trials according to the findings of a systematic review and meta-analysis by Swedish researchers.
Pain is one of the most common symptoms experienced by patients in different health care settings, often leading to loss of function for the affected individual as well as a decline in their quality of life. Although there are wide range of medicines which act as pain-killers, in recent years, there has been increasing interest in the medical properties of cannabinoids. However, the evidence supporting the value of cannabinoids in pain management is limited.
In fact, a 2021 systematic review concluded on how the available evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or cannabis-based medicines in the management of pain. These findings suggest that there may be an important placebo response in such trials and which arise from patients’ positive expectancies.
Furthermore, it is believed that different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes and create a sense of well-being.
But how large is the placebo response in clinical trials examining the role of cannabinoids in the management of pain? This was the key question addressed in the current study where researchers set out to evaluate the size of placebo responses in double-blind randomised clinical trials in which cannabinoids, cannabis, and cannabis-based medicine were compared with placebo in the treatment of clinical pain.
The researchers measured the change in pain intensity from before to after treatment, measured as bias-corrected standardised mean difference (Hedges g), which provides an assessment of the effect size. A small effect is represented by a value of 0.2, whereas a medium effect is 0.5 and a large effect 0.8.
Placebo response in cannabinoid trials
The researchers identified a total of 20 eligible trials with 1459 individuals (mean age = 51 years, 56% female). Studies included patients with neuropathic pain and multiple sclerosis.
The effect size of the active drug (cannabinoids) on pain intensity was large (mean Hedges g = 0.95, p <0 .001). However, pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean Hedges g = 0.64, p < 0.001).
In a further analysis, the researchers looked at the media attention paid to these findings and found that this attention was independent of how biased the study was, the extent of the placebo response or how low the treatment effect was.
The authors concluded that placebos contribute significantly to the pain reduction seen in cannabinoid clinical trials. In addition, the positive media attention and wide dissemination possibly leads to high expectations and hence may shape the placebo response in future trials.
Citation
Gedin F et al. Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022.
21st December 2022
Data presented at the 64th American Society of Haematology (ASH) conference in New Orleans, showed that elranatamab is efficacious and has a manageable safety profile in patients with relapsed or refractory multiple myeloma (RRMM).
Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterised by the abnormal increase of monoclonal immunoglobulins and which if left unchecked, can ultimately lead to specific end-organ damage. It is an uncommon cancer, with the global, age-standardised rate incidence estimated to be 1·78 per 100 000 people but with a mortality rate of 1·14 (95% UI 1·07-1·21) per 100 000 people in 2020. Most patients present with symptoms related to organ involvement, including hypercalcaemia, renal insufficiency, anaemia, and bone lesions (known as calcium, renal failure, anaemia, and bone lesions [CRAB] symptoms). In contrast, a minority of patients are asymptomatic but are identified through abnormal blood and/or urine tests.
At the ASH conference, data were presented for elranatamab, which is a bispecific antibody that targets expression of B-cell maturation antigen (BCMA) and CD3 on T-cells, activates and redirects the T-cell mediated immune response against MM. The findings come from the MagnetisMM-1 trial designed to assess the safety and tolerability at increasing dose levels of elranatamab in patients with relapse/ refractory multiple myeloma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose. Within the trial, elranatamab was administered subcutaneously at doses from 80 to 1000µg/kg either weekly or every 2 weeks.
Elranatamab clinical response
A total of 55 patients with a median age of 64 years and of whom, 27% were Black/African American or Asian, received elranatamab at a dose ≥215μg/kg. The median number of prior regimens was 5 (range 2-14) with 91% being triple-class refractory, 69% of whom had prior stem cell transplantation, 29% had a high cytogenetic risk and 24% received prior BCMA-targeted therapy.
After a median follow-up of 12.0 months and including only those with an International Myeloma Working Group (IMWC) confirmed responses, the objective response rate (ORR) was 64% (95% CI 50 – 75%) and with 56% of participants achieving very good partial response (VGPR) or better and 38% achieving complete response (CR) or better.
Among 35 responders, the probability of being event-free at 12 months was 59% (95% CI 39-74%) and the Kaplan-Meier estimate for the median duration of response was 17.1 months (95% CI 10.6 – not estimable). Elranatamab induced durable clinical and molecular responses and 100% (12/12) of evaluable patients with confirmed CR or better achieved minimal residual disease (MRD) negativity at a sensitivity of 1×10-5 including 2 participants with MRD negativity and ongoing stringent complete response beyond 2 years.
The most common treatment-emergent adverse effects included the cytokine release syndrome in 67% of participants but this was limited to grade 1 (33%) or grade 2 (33%) severity with no grade 3 or higher responses.
The authors concluded that elranatamab induced durable clinical and molecular responses for patients with relapsed or refractory MM, with an ORR of 64% and more than half of these patients (38%) achieving CR or better, and 100% of evaluable patients able to achieve MRD negativity. They added that these results support further development of elranatamab for patients with MM.
Citation
Raje N et al. Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma. Abstract No 158, ASH 2022
Moderna, in conjunction with Merck, has found that the investigational, personalised cancer vaccine, mRNA-4157/V940, combined with pembrolizumab, was more effective than pembrolizumab alone at reducing the risk of death or recurrence in patients with stage III/IV melanoma following complete resection.
Melanoma of the skin is the 17th most common cancer worldwide with 324,635 new cases and 57,043 deaths in 2020. Although patients diagnosed at Stage 1 have an excellent prognosis, this drops significantly as the disease spreads. For example, regional melanoma (stage 3) has a 63.6% 5-year survival and this drops to 22.5% for those with stage 4 (metastatic) disease.
Pembrolizumab (brand name Keytruda) is a human, programmed death receptor-1 (PD-1) therapy and works to enable T cells to invade melanoma anywhere in the body. The drug is already licensed as monotherapy for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma.
The KEYNOTE-942 study is an on-going phase 2b randomised study designed to assess whether postoperative adjuvant therapy with mRNA-4157/V940 and pembrolizumab improves recurrence free survival (RFS) compared to pembrolizumab alone in participants with complete resection of cutaneous melanoma and a high risk of recurrence. mRNA-4157/V940 is designed to stimulate an immune response by generating a specific T cell action based on the unique mutational signature of a patient’s tumour.
In the trial, and following complete surgical resection, patients were randomised to receive mRNA-4157/V940 (nine total doses of mRNA-4157) and pembrolizumab 200 mg every three weeks up to 18 cycles (for approximately one year) or pembrolizumab alone. The primary endpoint of the trial was recurrence-free survival whereas secondary endpoints include distant metastasis-free survival and safety.
mRNA-4157/V940 preliminary efficacy data
The results are for 157 patients with stage III/IV melanoma. The data show adjuvant mRNA-4157/V940 and pembrolizumab reduced the risk of recurrence or death by 44% (hazard ratio, HR = 0.56, 95% CI 0.31 – 1.08, one-sided p = 0.0266) compared with pembrolizumab alone.
In terms of safety, serious treatment-related adverse events occurred in 14.4% of patients who received the combination treatment compared to 10% with pembrolizumab alone.
Stéphane Bancel, Moderna’s Chief Executive Officer, said: ‘Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomised clinical trial in melanoma.’
The companies plan to discuss the results with regulatory authorities and initiate a Phase 3 study in melanoma patients in 2023.
According the findings of a systematic review and meta-analysis undertaken by Korean researchers and presented at the American Society of Haematology conference, 2022, tafasitamab showed a trend for best efficacy among failed autologous stem cell transplantation (ASCT) or ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients.
Diffuse large B cell lymphoma is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas and which presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extra-nodal site. Non-Hodgkin lymphomas account for about 80% of all lymphomas and while there are more than 30 subtypes, the common ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Although 5-year survival rates range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Moreover, outcomes for refractory or relapsed patients are poor, with one study of 861 patients, 636 of whom had refractory disease, finding that the median overall survival was 6.3 months and that only 20% of patients were alive at 2 years. For patients with relapsed/refractory disease, there are several combination chemotherapy regimens available including tafasitamab-cxix, polatuzumab vedotin-piiq, bendamustine as well as CAR T cell therapies. Nevertheless, the most effective treatment remains to be determined.
In the present study, the Korean researchers performed a systematic review and meta‐analysis to identify prospective phase II or III clinical studies evaluating the efficacy of treatments for ASCT-failed or ineligible relapse/refractory DLBCL patients. They used random effects models to estimate one-year progression-free survival rate, complete remission rate, and subgroup differences. In addition, meta-regression models were performed with adjustment for relevant covariates, particularly the median number of previous lines of systemic therapy and CAR T cell therapy was used as a reference treatment in the meta-regression analysis.
Tafasitamab and one-year progression-free survival
The researchers identified 56 cohorts in 50 studies with 3,544 relapsed/refractory DLBCL patients. For the analysis, treatment regimens were divided into nine groups: CAR T cell therapy, chemotherapy, lenalidomide-based therapy, ibrutinib-based therapy, tafasitamab-based therapy, polatuzumab plus bendamustine and rituximab (pola-BR), loncastuximab, selinexor, and others.
The pooled one-year progression-free survival rate was 0.40 (95% CI 0.35 – 0.46) for CAR T cell therapy, 0.23 (95% CI 0.16 – 0.30) for chemotherapy, 0.28 (95% CI 0.19 – 0.37) for lenalidomide and 0.46 (95% CI 0.37 – 0.56) for tafasitamab.
Although CAR T cell treatment was significantly better than many of the others, in fact, loncastuximab, pola-BR, and tafasitamab were all shown to have no significant difference in efficacy to CAR T cell therapy after adjustment for the median number of prior lines of treatment in the meta-regression analysis.
The authors concluded that tafasitamab showed a trend of best efficacy and that CAR T cell therapy was no more effective than tafasitamab, loncastuximab or pola-BR. However, because of the high level of heterogeneity, the authors called for randomised controlled trials to confirm their findings.
Citation
Kim J et al. Comparison of Several Salvage Treatments of Relapsed/Refractory Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta‐Analysis. Abstract 2986 ASH conference 2022
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