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

Biologics most effective in treatment-resistant chronic spontaneous urticaria

31st August 2021

In patients with treatment-resistant chronic spontaneous urticaria, two biologics produced the largest improvement in symptoms.

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).

Findings
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.

Citation
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

EU approves bimekizumab for moderate to severe psoriasis

24th August 2021

Bimekizumab is the first agent that inhibits the two cytokines IL-17A and 1L-17F which are both involved in the development of psoriasis.

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.

Clinical efficacy
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

Anifrolumab approved by FDA for systemic lupus erythematosus

6th August 2021

The interferon antagonist anifrolumab has been cleared for the treatment of adults with moderate-to-severe systemic lupus erythematosus by the FDA.

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.

Anifrolumab
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

REGEN-COV mortality benefits limited to seronegative COVID-19 patients

21st June 2021

While REGEN-COV contains two monoclonal antibodies binding to different viral sites, it is only effective in seronegative patients.

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.

Findings
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.

Citation
RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv 2021