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New drug in the pipeline il-23

my little penguin

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the 108 patients who completed the 12-week double-blind induction trial, six patients were in deep remission and entered the 12-week washout phase. 102 patients were not in deep remission, 101 of whom received 12 weeks of 600 mg risankizumab (33 from the original placebo group, 34 from the 200 mg risankizumab group, and 34 from the 600 mg risankizumab group); the other patient declined to continue the study. At week 26, 54 (53%) of 101 patients treated with 600 mg rizankizumab were in clinical remission. Among patients included in the open-label extension trial, clinical remission rates at week 26 versus week 12 were: 18 (55%) versus six (18%) of 33 patients in the original placebo group; 20 (59%) versus seven (21%) of 34 patients in the original 200 mg risankizumab group; and 16 (47%) versus nine (26%) of 34 patients in the original 600 mg risankizumab group. 62 patients received risankizumab maintenance treatment, including the 54 patients who achieved clinical remission at week 26, the six patients who had achieved deep remission at week 12, and one patient because of a protocol violation. At week 52, clinical remission was maintained in 44 (71%) patients; 50 (81%) patients had a clinical response, 22 (35%) patients were in endoscopic remission, and 34 (55%) patients had an endoscopic response. 15 (24%) patients had mucosal healing and 18 (29%) patients achieved deep remission at week 52. Risankizumab was well tolerated with no new safety signals noted. The most frequent treatment-emergent adverse events were arthralgia (25 [22%] of 115 patients), headache (23 [20%]), abdominal pain (21 [18%]), nasopharyngitis (18 [16%]), nausea (18 [16%]), and pyrexia (15 [13%]). Most adverse events were mild or moderate and considered to be unrelated to study treatment. There were no treatment-related deaths.
Interpretation
Extended induction treatment with open-label intravenous risankizumab was effective in increasing clinical response and remission rates at week 26. Open-label subcutaneous risankizumab maintained remission until week 52 in most patients who were in clinical remission at week 26. Selective blockade of interleukin 23 warrants further investigation as a treatment for Crohn's disease.
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And clinical trial for those interested

 
Just approved in April for psoriasis. Some Crohn's patients will already be able to try this out now outside clinical trials, if their doctor and insurance will allow it. Quite promising.
 

my little penguin

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Objectives
To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS).
Methods
A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug.
Results
At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was –2.5% (95% CI –21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups.
Conclusions
Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS.
Trial registration number

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my little penguin

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Risankizumab May Not Be Effective in Treatment of Ankylosing Spondylitis
Sheila Jacobs



Treatment with risankizumab, an interleukin-23 (IL-23) inhibitor, is not effective in reducing the signs and symptoms of ankylosing spondylitis (AS), according to the results of a phase 2, randomized, placebo-controlled, double-blind, proof-of-concept study (ClinicalTrials.gov identifier: NCT02047110) published in the Annals of the Rheumatic Diseases.
The study was conducted at 47 centers in North America, Europe, and East Asia between March 2014 and December 2014. A total of 159 patients with biologic-naïve AS who had active disease (Bath Ankylosing Spondylitis Disease Activity score ≥4) were randomly assigned to receive risankizumab 18 mg single dose (n=40), risankizumab 90 mg (n=39), risankizumab 180 mg (n=40), or placebo (n=40). All medication was administered at baseline and then at 8, 16, and 24 weeks. Treatment occurred over a 24-week blinded period.

The primary study outcome was the percentage of participants attaining a 40% improvement in the Assessment in Spondyloarthritis International Society (ASAS40) response at 12 weeks. The key secondary end point was the change from baseline in the AS Disease Activity Score-C reactive protein (ASDAS-CRP) at 12 weeks.
The primary study outcome was not met. The ASAS40 response at 12 weeks was achieved by 25.5%, 20.5%, and 15.0% of patients in the risankizumab 18 mg-, 90 mg-, and 180 mg-groups, respectively, compared with 17.5% in the placebo group. The estimated difference in the percentage of ASAS40 responders between the risankizumab 180 mg-group and the placebo group was −2.5% (95% CI, −21.8 to 17.0; P =.42). In addition, the difference between the risankizumab 90 mg-group and the placebo group was 3.0% (95% CI, –15.9 to 20.8; P =.41) and the difference between the risankizumab 18 mg-group and the placebo group was 7.5% (95% CI, –12.1 to 26.6; P =.27).
Related Articles
Prolongation of risankizumab therapy for up to 40 weeks in participants receiving escape treatment (risankizumab 180 mg) did not significantly improve ASAS40 achievement rates. Rates of adverse events were similar across all treatment groups.

The investigators concluded that the lack of efficacy of risankizumab implies that, despite a genetic association with the IL-23 pathway, the agent may not be a relevant driver of disease pathogenesis and symptoms in patients with AS.
Disclosures: DB reports grants from AbbVie, Pfizer, UCB, MSD, Novartis, and Eli Lilly and part-time employment at UCB. MØ reports grants, personal fees, and nonfinancial support from AbbVie, BMS, Merck, UCB, and Novartis; grants and personal fees from Celgene; personal fees and nonfinancial support from Janssen, Pfizer, and Roche; and personal fees from Boehringer Ingelheim, Eli Lilly, Sanofi, Regeneron, Orion, and Hospira. JS reports personal fees from Boehringer Ingelheim, AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB. PJ reports grants from AbbVie, Daiichi Sankyo, Boehringer Ingelheim, Lilly, Novartis, Roche, and UCB and grants and personal fees from BMS and Pfizer. YD, CP, SV, DBH, SA, PS and SJP report being employees of Boehringer Ingelheim.
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Reference

Baeten D, Østergaard M, Wei JC, et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study [published online June 26, 2018]. Ann Rheum Dis. doi:10.1136/annrheumdis-2018-213328

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my little penguin

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Risankizumab (RIZ) is a new, humanised anti-IL-23 monoclonal antibody that targets the p19 subunit of interleukin-23 (IL-23). It was studied in a 24-week trial involving 159 biologic-naïve, active AS patients. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12.
In this placebo-controlled trial, the ASAS40 response rates were nearly the same for all groups 25.5%, 20.5%, 15.0%, and 17.5% (RIZ 18 mg, 90 mg, 180 mg and placebo groups). Adverse event rates were similar in all treatment groups.

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So here is my BIG ISSUE
STUDY says not effective for AS
Similar to studies on Stelara
But the dosing was a max of 180 mg

The study for CROHNS Same drug needed 600 mg
To be effective
 
This is interesting - so it could potentially work for AS if the studies were done with higher dosing? Thanks for all the information. It's always good to know there are alternative treatments if needed.
 

my little penguin

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Staff member
We don’t know if they could work or not
The issues is the studies were already done at a lower dose proving they didn’t work for AS
So no one will pay for a higher dose study

And it’s probably not the optimum pathway
 
Interesting. I will ask O's GI about it.

You never know...someone might pay for the higher dosing study. There is one out now for Entyvio at 600mg (thanks to mop for finding it for me).

My motto for the day: Never Say Never!
 

Maya142

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Staff member
IL-23 inhibitors DO NOT work for axial spondyloarthritis OR Ankylosing Spondylitis. We know several researchers who were involved in the trials - my girls and husband are in multiple AS/SpA trials and so we have discussed this more than once, since M has such severe AS.

They did work for peripheral spondyloarthritis - so if the spine or SI joints are not involved, current research shows they should work. But not if there is axial arthritis.

There is second IL-23 inhibitor still in Phase III trials for AS (not Risankizumab) and it is not doing well either apparently.

In Stelara crohns dose is 90 mg every 4-8 weeks
Similar studies done on AS lower PsA dosing
45 mg every 12 weeks
Why ....????
And MLP, we were told that the 90 mg dose was tried for AS - 90 mg every 8 weeks. Not every 4 weeks. But we have talked to multiple researchers who are prominent in the PsA and AS/Spondyloarthritis field and ALL have said Stelara failed miserably for their patients and the most promising research shows JAK inhibitors and IL-17 inhibitors are the next step for AS. We are seeing a researcher at NIH next week for a study M is in but we already asked him about IL-23 inhibitors last year and he was also very clear that they are not effective for AS or axial SpA and he'll try Stelara only for patients who have peripheral arthritis and absolutely NO spinal involvement.

I will ask about the newer IL-23 inhibitors though (not Stelara) -- it would be very convenient if they did work for AS, since they work for IBD too.
 
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