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26th July 2024
The interleukin (IL)-23 inhibitor risankizumab (brand name Skyrizi) has been granted marketing authorisation by the European Commission for ulcerative colitis.
The indication covers the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a biologic therapy.
This marks the fourth approved indication for risankizumab after plaque psoriasis, psoriatic arthritis and Crohn’s disease.
Risankizumab selectively blocks IL-23 by binding to its p19 subunit. The recommended induction dose is 1,200 mg administered by intravenous infusion at Week 0, Week 4 and Week 8. Starting at Week 12 and every eight weeks thereafter, a recommended maintenance dose of either 180 mg or 360 mg administered by subcutaneous injection should be based on individual patient presentation.
‘Ulcerative colitis is a chronic, unpredictable and sometimes debilitating disease, and people living with the condition need sustained symptom relief,’ said Dr Edouard Louis, professor and head of gastroenterology at Liège University Hospital and dean of faculty at Liège University in Belgium. ‘This approval introduces a new treatment option to help patients with ulcerative colitis reach their long-term treatment goals.’
The EC approval of risankizumab is based on the results of two phase 3 clinical trials, INSPIRE and COMMAND, in which the primary endpoint was clinical remission. Secondary endpoints included mucosal healing and histologic endoscopic mucosal healing (HEMH).
In the INSPIRE induction trial, a significantly higher proportion of patients treated with risankizumab 1,200 mg IV achieved the primary endpoint of clinical remission (per Adapted Mayo Score) at Week 12 than patients receiving placebo (20% vs 6%; p<.00001).
Mucosal healing (defined as ES ≤1 without friability) was observed at Week 12 in 37% of patients treated with risankizumab 1,200 mg IV compared to 12% of those receiving placebo (p<.00001). In patients without previous biologic or JAK inhibitor failure, 48% of patients treated with risankizumab 1,200 mg IV achieved mucosal healing at Week 12 versus 14% of those receiving placebo.
Some 24% of patients treated with risankizumab 1,200 mg IV achieved HEMH (defined as Geboes score ≤3.1 and ES ≤1 without friability) at week 12 versus 8% of those receiving placebo (p<.00001).
In the COMMAND maintenance trial, a significantly higher proportion of patients who received risankizumab 180 mg or 360 mg SC achieved clinical remission at Week 52 than patients in the induction-only control group: 40% and 38%, respectively, versus 25% (p≤.01).
Some 51% of patients treated with risankizumab 180 mg and 48% of patients treated with 360 mg achieved mucosal healing at Week 52 versus 32% of patients in the induction-only control group (p<.001). In patients without previous biologic or JAK inhibitor failure, 60% of patients who received risankizumab 180 mg and 76% who received 360 mg achieved mucosal healing versus 36% of patients in the induction-only control group.
Some 43% of patients treated with risankizumab 180 mg and 42% receiving 360 mg achieved HEMH at Week 52 versus 23% in those treated with the induction dose only (p≤0.01).
Professor Louis, who was also a trial investigator, added: ‘Patients treated with Skyrizi in the INSPIRE and COMMAND clinical trials experienced significant improvements in clinical remission and mucosal healing. These are important findings as mucosal healing goes beyond symptom management to restoration of the intestinal lining and is associated with improved long-term outcomes.’
The safety profile of risankizumab in both trials was consistent with the safety profile observed in previous trials across other indications, with no new safety risks observed. The most common adverse events observed were Covid-19, anaemia, nasopharyngitis and arthralgia.
27th September 2023
The use of risankizumab (brand name Skyrizi) in the treatment of adult patients with moderately to severely active Crohn‘s disease met the two primary endpoints in a head-to-head study compared to ustekinumab, its manufacturer AbbVie has announced.
While both risankizumab and ustekinumab are already approved for Crohn‘s disease and other conditions, their modes of action are different, with the former selectively blocking interleukin-23 (IL-23) signalling and the latter blocking both IL-12 and IL-23. The researchers therefore sought to determine if these differences affect treatment outcomes.
In the phase 3, multi-centre, randomised, head-to-head SEQUENCE study, the primary endpoint was non-inferiority for clinical remission at week 24 and superiority of endoscopic remission at week 48.
All participants had a confirmed diagnosis of Crohn‘s disease for at least three months and a Crohn‘s Disease Activity Index (CDAI) score of 220 to 450 at baseline. They were also considered to have moderate-to-severe disease based on an assessment of stool frequency, abdominal pain score, their Simple Endoscopy Score for Crohn‘s Disease (SES-CD), and a demonstrated intolerance or inadequate response to one or more anti-TNF therapies.
Participants assigned to risankizumab received a 600 mg intravenous induction at Weeks 0, 4 and 8 and 360 mg subcutaneous injection starting at week 12 and every eight weeks thereafter, through to week 48.
The results of the first primary endpoint, clinical remission (per CDAI, defined as CDAI <150) at week 24, met non-inferiority of risankizumab versus ustekinumab (non-inferiority margin of 10%). Remission rates were 59% in the risankizumab group and 40% in the ustekinumab group.
For the second primary endpoint of endoscopic remission (SES-CD ≤4 and at least a two-point reduction versus baseline and no sub-score greater than 1 in any individual component) at week 48, risankizumab provided a remission rate of 32% compared to 16% in the ustekinumab group (p < 0.0001).
In a commentary of these results, Dr Laurent Peyrin-Biroulet, director of the Infinity Institute, professor of gastroenterology and head of the inflammatory bowel disease group at the gastroenterology department, University Hospital of Nancy in France, said: ‘These results add to our growing body of evidence for Skyrizi in Crohn‘s disease. This study highlights the efficacy of Skyrizi compared to ustekinumab in helping eligible patients achieve clinical and endoscopic treatment goals and also reinforces the safety profile observed in previous studies.’
Full results from the SEQUENCE study will be presented at a future medical meeting and submitted for publication in a peer-reviewed journal.
2nd December 2021
Risankizumab (brand name Skyrizi) has been approved by the UK regulator, the MHRA, for the treatment of patients with active psoriatic arthritis.
Skyrizi (risankizumab) has now received approval from 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 therefore been updated to reflect this change, and now states 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 which targets the action of interleukin 23, (IL-23) which is believed to play an important role in psoriatic arthritis. The approved dose for risankizumab is 150 mg, administered by subcutaneous injection at week 0 and 4, and every 12 weeks thereafter.
The MHRA approval was made on the basis of data which came from two phase 3 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 to 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
Risankizumab (brand name Skyrizi) is now approved by the European Medicines Agency (EMA) for active active psoriatic arthritis in patients who failed to respond to one or more disease-modifying antirheumatic drugs (DMARDs).
Psoriatic arthritis can be described as an inflammatory arthritis affecting the joints and connective tissue and which is a progressive disease that ranges from mild synovitis to severe erosive arthropathy.
Psoriatic arthritis occurs in patients with the skin disease psoriasis and while psoriasis affects around 3% of the general population, up to 20% of those with psoriasis develop psoriatic arthritis. Sufferers of psoriatic arthritis will generally experience joint inflammation which causes swelling and pain and which has a negative impact on their quality of life.
The treatment of psoriatic arthritis is progressive, depending on severity and would normally begin 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 psoriatic arthritis including ixekizumab and guselkumab.
Risankizumab was previously approved by the EMA in 2019 for the treatment of plaque psoriasis but that has been extended to include psoriatic arthritis.
The EMA approval of 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 risankizumab 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 risankizumab 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 risankizumab although this was comparable to the placebo rate (3.7% and 5.5%, KSI and KS2).
According to the EMA approval, risankizumab can be used either alone or in combination with methotrexate.
4th November 2021
Using risankizumab as a treatment for patients with severe asthma was found to be of no benefit and reduced the time to asthma worsening. Risankizumab use in patients with severe asthma resulted in an earlier worsening of asthma symptoms compared to placebo. This was the conclusion of a randomised trial by a team from the Institute for Lung Health, Department of Respiratory Sciences, University of Leicester, Leicester, UK. Inflammation and a narrowing of the airways are the primary cause of asthma and this manifests clinically as a cough, wheeze, chest tightness and shortness of breath. Asthma is a very common disease and data from 2019 suggest that the condition affects around 262 million people and led to 461000 deaths. Moreover, 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. The monoclonal antibody risankizumab, binds to and inhibits IL-23 and this action has been found to be important in the treatment of psoriasis and Crohn’s disease and this could benefit patients with severe asthma although it has not been studied. 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 four 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 two or more consecutive days or an 50% increase in the number of rescue medication puffs in a 24-hour period.
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