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2nd December 2021
Skyrizi (risankizumab) has been approved by the UK regulator, the MHRA, for the use in adults with active psoriatic arthritis. This follows the EMA approval earlier this month.
The Summary of Product Characteristics (SPC) of the drug has been updated to reflect this change, stating that it is indicated either ‘alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs).’
Skyrizi is a monoclonal antibody and blocks the action of interleukin 23, (IL-23), which is believed to play an important role in psoriatic arthritis. The approved dose for risankizumab is 150mg, administered by subcutaneous injection at week 0 and 4, and every 12 weeks thereafter.
The approval was based on data from two clinical studies, KEEPsAKE-1 and KEEPsAKE-2 and although both of the trials included patients with moderate to severe PsA, the populations were slightly different. For example, KEEPsAKE-1 included patients who had with an inadequate respond to one or more DMARDs whereas KEEPsAKE-2 recruited those with an inadequate response to other biologicals. However, both studies had the same primary endpoint of an ACR20 response at week 24. In addition, secondary outcomes included improvements in several clinical manifestations of psoriatic arthritis such as physical functioning (as assessed by the Health Assessment Questionnaire Disability Index [HAQ-DI]) and minimal disease activity (MDA) and both the primary and secondary endpoints were assessed after 24 weeks of therapy.
In KEEPsAKE-1 57.3% of patients receiving risankizumab achieved the primary endpoint at week 24 compared to 33.5% in the placebo group (p < 0.001). Similarly, in KEEPsAKE 2, 51.3% achieved the primary endpoint compared with 26.5% in the placebo arm (P< 0.001).
There were also significantly greater improvements in the secondary outcomes for risankizumab-treated patients. For example, in KEEPsAKE-1, there was a -0.31 change in HAQ-DI compared to -0.11 (placebo) and in KEEPsAKE 2, a change of -0.22, compared to -0.05 in the placebo group (for both differences, p <0.001).
22nd November 2021
The European Medicines Agency (EMA) has approved the use of risankizumab (brand name Skyrizi) for the treatment of patients with active psoriatic arthritis (PsA) who have failed to adequately response to one or more disease modifying anti-rheumatic drugs (DMARDs) or who are intolerant to DMARDs.
Psoriatic arthritis is an inflammatory arthritis affecting the joints and connective tissue which is associated with psoriasis and which is present on the skin or nails. While the prevalence of psoriasis in the general population is low, at around 3%, at least 20% of psoriasis patients have PsA which is a progressive disease that ranges from mild synovitis to severe erosive arthropathy. Sufferers of PsA experience joint inflammation which causes swelling and pain and which has a negative impact on their quality of life.
The treatment of PsA starts with non-steroidal anti-inflammatories and as the disease progresses, escalates to oral corticosteroids, DMARDs and finally biologic agents. There are currently several biologics approved for the management of PsA including ixekizumab and guselkumab. Skyrizi was previously approved by the EMA in 2019 for the treatment of plaque psoriasis but that has been extended to include PsA.
The EMA approval of Skyrizi (risankizumab) was based the findings of two Phase III clinical trials, KEEPsAKE-1 and KEEPsAKE-2. Both trials were placebo-controlled trials in patients with moderate to severe PsA although KEEPsAKE-1 included patients with an inadequate respond to one or more DMARDs whereas KEEPsAKE-2 recruited those with an inadequate response to other biologicals. In both trials patients received skyrizi at subcutaneous dose of 150 mg and the primary outcome for both studies was the ‘percentage of Participants Achieving at least 20% Improvement in American College of Rheumatology (ACR20)‘.
The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).
In both trials, the ACR20 response was set as the primary endpoint and assessed after 24 weeks. Secondary endpoints included the Health assessment questionnaire disability index (HAD-DI), which represents a measure of physical function and the proportion of patients achieving minimal disease activity (MDA).
In KEEPsAKE-1 (KS1) and KEEPsAKE-2 (KS2), 57.3% and 51.3% of patients respectively, given risankizumab achieved the primary endpoint compared to 33.5% and 26.5% receiving placebo (p<0.001).
Similarly, improvements in HAQ-DI of -0.31 (KSI) and -0.22 (KS2) compared with -0.11 and -0.05, in the respective placebo groups was seen at week 24 (p<0.001). Finally, 25% (KS1) and 25.6% (KS2) of Skyrizi patients achieved MDA, compared to 10.2% (KS1) and 11.4% (KS2) of those on placebo (p<0.001).
In terms of safety, serious adverse events occurred in 2.5% (KS1) and 4% (KS2) of patients given Skyrizi although this was comparable to the placebo rate (3.7% and 5.5%, KSI and KS2).
According to the EMA approval, Skyrizi can be used either alone or in combination with methotrexate.
Source. Abbvie press release. 17th November 2021
4th November 2021
Use of risankizumab in patients with severe asthma led to a reduction in the time to worsening compared to placebo. This was the finding of a randomised trial of the drug by a team from the Institute for Lung Health, Department of Respiratory Sciences, University of Leicester, Leicester, UK. Asthma is due to inflammation and a narrowing of the airways and this leads to the major symptoms of cough, wheeze, chest tightness and a shortness of breath. In 2019, asthma was estimated to affect 262 million people and caused 461000 deaths. The prevalence of severe asthma has been estimated from a Dutch study to be 3.6% or 10.4 patients per 10,000.
The cytokine, interleukin-23 (IL-23) produced by T-helper 17 cells, has been implicated in the development of allergic asthma and in fact, serum IL-23 levels have been found to elevated in asthmatic children and therefore could be used as a marker of bronchial function impairment. Risankizumab binds to and inhibits IL-23 and this action has proved to be of value in psoriasis and Crohn’s disease and could therefore benefit patients with severe asthma although there is a lack of data in support of this view.
For the present study, the Leicester researchers conducted a phase 2a, randomised, double-blind trial to assess the efficacy and safety of risankizumab in adults with severe, persistent asthma. Patients aged 18 to 75 years and who were currently using medium to high-dose inhaled glucocorticoids with at least one additional controller medications and had a history of one or two severe asthma exacerbations in the previous 12 months, were included in the study. Individuals were randomised 1:1 to receive either 90 mg risankizumab or placebo, subcutaneously, once every 4 weeks for a total of 24 weeks. The primary endpoint was the time to the first asthma worsening, which was defined in several different ways, including a deterioration from baseline on 2 or more consecutive days or an 50% increase in the number of rescue medication puffs in a 24 hour period.
A total of 213 patients were analysed, 105 with a mean age of 54 years (65.7% female) given risankizumab. The median time to the first asthma worsening was 40 days in the risankizumab group and 86 days in the placebo arm (hazard ratio, HR = 1.46, 95% CI 1.05 – 2.04, p = 0.03). In addition, the hazard ratio for the time to the first severe exacerbation was 1.18 (95% CI 0.76 – 1.83) and hence not significantly different to placebo.
The researchers also examined sputum gene expression and found that in patients using risankizumab, there was down-regulation of genes associated with IL-23 at the end of the treatment period but this effect was absent at week 20, suggesting that attenuation of IL-23 signally was not consistent throughout the study.
The authors concluded that risankizumab was not beneficial for severe asthma and that it was actually worse than placebo. The suggested that their data challenged the view that targeting IL-23 was of value in the treatment of asthma.
Brightling CE et al. Risankizumab in Severe Asthma — A Phase 2a, Placebo-Controlled Trial. New Eng J Med 2021