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25th March 2022
Tixagevimab/cilgavimab (Evusheld) is a combination of two monoclonal antibodies that has been approved by the UK’s MHRA for use before exposure to COVID-19 in order to prevent the disease. The drug would therefore be most suited to adult patients who are unable to mount a sufficient immune response after receiving a COVID-19 vaccination or alternatively, patients for whom vaccination is not recommended.
Evusheld was issued an emergency use authorisation (EUA) by the FDA in the US in December 2021 for the pre-exposure prophylaxis (prevention) of COVID-19 in certain adults and paediatric individuals (12 years of age and older weighing at least 40 kilograms. However, the combination would not be suitable for those currently infected with COVID-19 or who have had a recent and known exposure to someone infected with the virus. The two components of Evusheld are available as separate intramuscular injections and research has shown that these recognise non-overlapping sites and are simultaneously bound to the S protein and neutralise the wild-type COVID-19 virus in a synergistic manner. As a result, the manufacturer, AstraZeneca, has examined the value of Evusheld in three separate clinical studies.
Evusheld clinical efficacy
To date, none of the three major clinical studies have been fully published and the efficacy data has been made available in press releases from the manufacturer. Evusheld was examined in the PROVENT trial which was designed to assess the safety and efficacy of a single dose compared to placebo for the prevention of COVID-19. The trial included 5,197 participants and who were randomised 2:1 to a single 300 mg dose of Evusheld (AZD7442 in all press releases) or placebo and which was administered in two separate, sequential IM injections. The trial recruited individuals 18 years of age and over (including 43% who were older than 60 years of age) who would benefit from prevention and were defined as having an increased risk for an inadequate response to active immunisation or having an increased risk for COVID-19 infection. Participants at the time of screening were unvaccinated and had a negative COVID-19 test. The primary efficacy endpoint of the trial was the first case of any COVID-19 PCR confirmed, symptomatic illness occurring after the dose before day 183. According to a press release from the manufacturer, Evusheld reduced the risk of developing symptomatic COVID-19 by 77% (95% CI 46 – 90%) in comparison to those given a placebo.
A second trial, STORM CHASER, was designed to explore post-exposure prophylaxis of COVID-19 in Adult patients. The trial included 1,121 participants, randomised 2:1 as before to either Evusheld or placebo, all of whom tested negative for COVID-19 prior to receiving treatment. Again, in a press release from the manufacturer, Evusheld reduced the risk of developing symptomatic COVID-19 by 73% (95% CI 27 – 90%) compared with placebo among those who were PCR negative at the time of dosing.
The third trial, TACKLE, explored the value of Evusheld given to adults who were non-hospitalised with mild-to-moderate COVID-19 and symptomatic for seven days or less, but this time, given a 600 mg dose of the drug. The primary efficacy endpoint of the trial was the composite of either severe COVID-19 or death from any cause through day 29. According to the manufacturer press release on TACKLE, Evusheld given to participants within five days of symptom onset, saw a 67% reduced risk of developing severe COVID-19 or death compared to placebo.
On the basis of these findings, the MHRA has approved the drug and in Europe, the EMA is currently evaluating the combination.
19th January 2022
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 that 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 III 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.
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.
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
31st August 2021
Urticaria is characterised by the presence of pruritic wheals (i.e., hives), angioedema and in some cases both. In the majority of cases, urticaria resolves within two days though when it persists for longer than six weeks, the condition is referred to as chronic spontaneous urticaria (CSU). The prevalence of CSU varies across the world and one recent systematic review found a prevalence of 1.4% among Asians but only 0.1% in people from North America. All forms of urticaria are mast cell-related diseases and the symptoms due to the release of histamine and other cytokines. The condition can be manged through the use of H1 anti-histamines but evidence shows that in CSU, antihistamines at licensed doses, are effective in less than half of all patients. Other therapeutic options under investigation include monoclonal antibodies such as omalizumab which has been approved for the management of CSU although the relative effectiveness of monoclonal antibodies in antihistamine-resistant CSU is uncertain.
This led a team from the Department of Pharmaceutical care, Chiang Mai University, Thailand, to undertake a systematic review and network meta-analysis, of pharmacological therapies in antihistamine-refractory CSU. The team looked for randomised trials in both adolescents and adults with diagnosed antihistamine-refractory CSU and which had used a validated measurement tool for treatment assessment. The researchers set the primary outcome as a change in urticaria symptoms, both hives and pruritus from baseline but also considered the unacceptability of treatment in terms of the number of patients dropping out. The outcomes were reported as standardised mean differences (SMD).
There were 23 randomised trials of SCU with 2480 patients and a mean age ranging from 32.2 to 43.8 years. The trials compared a total of 28 different interventions and at licensed antihistamine doses and up-dosed (i.e., where the antihistamine dosage was increased by two to four times the licensed dose). The most effective treatment, with a large effect size, was the monoclonal antibody ligelizumab at a dose of 72 mg (SMD -1.05, 95% CI -1.37 to – 0.73) and at the higher dose of 240 mg (SMD – 1.07, 95% CI -1.39 to – 0.75). Omalizumab produced a moderate effect size at a dose of 300 mg (SMD – 0.77, 95% CI -0.91 to -0.63). There were no significant differences in treatment unacceptability.
In their discussion, the authors suggested that either ligelizumab at a dose of 72 or 240 mg and omalizumab 300mg were the most effective treatments for refractory chronic spontaneous urticaria. In addition, they called for head-to-head trials to provide improved estimates for the effectiveness of these treatments.
Nochaiwong S et al. Evaluation of Pharmacologic Treatments for H1 Antihistamine–Refractory Chronic Spontaneous Urticaria. A Systematic Review and Network Meta-analysis. JAMA Dermatol 2021
24th August 2021
Psoriasis is best described as a complex, chronic, multifactorial and inflammatory disease characterised by increased proliferation of keratinocyte cells in the skin giving rise to silvery/white plaques. The disease typically presents on extensor surfaces such as the elbows, knees and lower back and there if often involvement of the scalp. The incidence of psoriasis appears to vary across the world, with a recent study noting a wide variation. For instance, the incidence was 30.3 per 100,000 person years in Taiwan but 321 per 100,000 person years in Italy. Among those with psoriasis, one study of over 9,000 patients, found that just over half (51.8%) had mild disease, with 35.8% and 12.4% having moderate and severe disease respectively. Patients with mild to moderate disease are normally managed with topical therapies, whereas those with moderate to severe disease are increasing treated with biological agents, in particular, monoclonal antibodies. Although the precise cause of psoriasis remains to be determined, several interleukins appear to be important disease drivers, especially the interleukin-17 (IL-17) pathway which includes six similar agents, IL-17A – IL-17F. Research suggests that two members of the IL-17 family, IL-17A and IL-17F are implicated in autoimmunity and IL17F appears to regulate pro-inflammatory gene expression and which requires the IL-17A receptor, suggesting that both are involved in the pathology of psoriasis. Bimekizumab is the first monoclonal antibody which selectively inhibits both IL-17A and IL-17F and is therefore a potentially important advancement in the management of patients with moderate to severe psoriasis.
The EU approval of bimekizumab was supported by the results of three phase 3 clinical trials, all undertaken in patients with moderate to severe psoriasis. The first, BE READY, randomised 435 patients (4:1) to bimekizumab 320 mg every 4 weeks or placebo. The co-primary endpoint was a PASI90 (i.e., 90% improvement in disease severity compared to baseline) and the proportion of patients achieving a score of 0 (i.e., clear skin) or 1 (almost clear), based on a 5-point investigator global assessment (IGA) score after 16 weeks of treatment. The results showed that a staggering 91% of those assigned to bimekizumab achieved a PASI90 compared to only 1% in the placebo group. In the BE VIVID trial, 567 patients were randomised to bimekizumab (at the same dosage as the BE READY trial) or this time, ustekinumab 45 or 90 mg every 12 weeks and which is an active comparator or placebo. Once again at week 16 there was a high response in the bimekizumab group with 85% achieving a PASI90 compared to 50% in the ustekinumab. The third trial, BE SURE, enrolled 478 patients who were randomised to either bimekizumab (same dosage as in the other trials) or adalimumab (another active comparator) at a dose of 40 mg every 2 weeks. At week 16, a PASI90 was achieved 85.3% of those using bimekizumab and 57.2% of those given adalimumab.
The most common adverse effects from bimekizumab are upper respiratory tract infections (14.5%) and patients are advised to seek medical advice if they display symptoms suggestive of an infection.
The EU approval applies to all 27 member states as well as Iceland, Liechtenstein and Norway at a dose of 320 mg administered by subcutaneous injections every 4 weeks for week 16 and every 8 weeks thereafter. The drug is currently under review by the US Food and Drug administration.
Source: UCB press release 2021
6th August 2021
Systemic lupus erythematosus (SLE) is a rare, chronic autoimmune disease which affects approximately six-times more women than men. It is the most common form of lupus, accounting for approximately 70% of all cases. There is a wide geographical variation in the incidence of SLE and has been found to vary between 23.2 cases per 100,000 in North America to 0.3 cases per 100,000 in Africa and the Ukraine. Other estimates suggest a general prevalence of approximately 1 to 10 per 100,000 person-years.
SLE is a systemic illness affecting many different organ systems including the skin, with a typical butterfly rash across the cheeks, the musculoskeletal system, producing arthritis and myositis, and constitutional symptoms such as fatigue, fever and weight loss. The cause of SLE remains unclear but the condition is characterised by the presence of autoantibodies and guidance from EULAR in 2019 has suggested treatment with hydroxychloroquine, glucocorticoids, immunosuppressants and biologics, in particular, belimumab. However, it has been shown that in patients with SLE, there is excessive production of type 1 interferon (IFN) and in particular, INF-alpha. Blockage of type 1 IFN could therefore represent a potential therapeutic modality for SLE.
Cell signalling in SLE occurs via activation of the IFN pathway mediated via the type 1 IFN receptor. Moreover, blockage of this IFN pathway may reverse immune dysregulation and the tissue damage seen in SLE. Anifrolumab binds to the IFN receptor and therefore potentially reduces some of the immune dysregulation seen in SLE.
The FDA based its approval of anifrolumab on the results of three separate trials. The first in 2016, undertaken in 305 patients, showed that treatment with intravenous anifrolumab (300mg or 1000mg) every 4 weeks for 48 weeks led to a substantial reduction in disease activity in patients with moderate-to-severe SLE. Further studies included TULIP-1 and TULIP-2, both of which were Phase III trials. The primary endpoint was the rate of British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), which is a validated global measure of treatment response among those with SLE. Interestingly, anifrolumab failed to reach the BICLA endpoint in TULIP-1 (37% vs 27%, anifrolumab vs placebo) when added to standard therapy. In contrast, significantly more patients assigned to anifrolumab than placebo, achieved the primary endpoint in TULIP-2, (47.8% vs 31.5%, anifrolumab vs placebo, p = 0.001).
An ongoing clinical trial in approximately 360 participants with moderate-to-severe SLE, is currently assessing the efficacy and safety of a subcutaneous form of anifrolumab in adults receiving standard therapy, over a 52-week period.
Anifrolumab is under regulatory review in both the EU and Japan.
Source. AstraZeneca August 2021
21st June 2021
The use of monoclonal antibodies have been shown to neutralise the COVID-19 virus in cell cultures and produce a significant reduction of viral load in vivo. A combination of two mAbs, casirivimab and imdevimab, which bind to separate parts of the COVID-19 receptor binding domain of the spike protein, are able to block entry of the virus into host cells. Since the mAbs bind to separate sites, there is reduced risk of antiviral failure. The use of this mAbs cocktail, known as REGEN-COV, has been shown to reduce the risk of hospitalisation or death among infected patients, in an outpatient setting. In addition, the manufacturer, Regeneron, has provided initial data which suggests that in hospitalised, seronegative patients, REGEN-COV reduced daily viral load. Whilst encouraging, no anti-viral therapy has been shown to reduce death among those hospitalised with COVID-19. This led the RECOVERY team to undertake a randomised trial of REGEN-COV among seropositive patients, hospitalised with COVID-19. For the trial, eligible patients (those with either clinically suspected or confirmed COVID-19 infection), were randomised in a 1:1:1 ratio to either standard care or standard care plus REGEN-COV or standard care and convalescent plasma. Among patients assigned to REGEN-COV, treatment consisted of a single dose (4g of both mAbs) in 250 ml saline infused over 60 minutes. The primary outcome of the trial was 28-day all-cause mortality and secondary outcomes included the time to discharge from hospital and in those not receiving mechanical ventilation at randomisation, a composite outcome of mechanical ventilation or death.
A total of 4839 patients were randomised to REGEN-COV and 4946 to usual care. The mean age of study participants was 61.9 years (37% female) and 78% of white ethnicity. However, the complete cohort included 3153 (32%) participants who were seronegative and 5272 (54%) who were seropositive. Among those allocated to REGEN-COV, 24% of seronegative patients and 30% of patients receiving usual care died within 28 days (rate ratio, RR = 0.80, 95% CI 0.70–0.91, p = 0.001).
In an analysis all the whole cohort (irrespective or serological status), 20% of those allocated to REGEN-COV and 21% of those given standard care died within 28 days (RR = 0.94, 95% CL 0.86 – 1.03, p = 0.17). Furthermore, among seronegative patients, progression to mechanical ventilation or death was lower among those receiving REGEN-COV compared to standard care (28% vs 32%).
In discussing their results, the authors noted that there was only an apparent benefit in seronegative patients receiving REGEN-COV. The suggested that the use of REGEN-COV should be restricted to seronegative patients.
RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv 2021