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MAUI, HAWAII – Arguably the most exciting therapeutic development in axial spondyloarthritis in the past year was the demonstrated efficacy and safety of the investigational oral selective Janus kinase 1 inhibitor filgotinib in the setting of active ankylosing spondylitis, speakers agreed at the 2019 Rheumatology Winter Clinical Symposium.
“This is big, big news,” commented symposium director Arthur Kavanaugh, MD. “This is going to be a big deal.”
Other recent clinical trials of note in axial spondyloarthritis (SpA) highlighted by Dr. Kavanaugh and Eric Ruderman, MD, professor of medicine at Northwestern University, Chicago, included a positive phase 3 study of certolizumab pegol (Cimzia) in nonradiographic SpA, two positive phase 3 trials of the interleukin-17A antagonist ixekizumab (Taltz) in radiographic SpA, a positive phase 2b trial of the dual IL-17A/F antagonist bimekizumab, and publication of three surprisingly negative phase 3 trials of the IL-12/23 inhibitor ustekinumab (Stelara).
Filgotinib
TORTUGA was a phase 2b, double-blind, multicenter trial of 116 European patients with active ankylosing spondylitis nonresponsive to NSAIDs who were randomized to oral filgotinib at 200 mg once daily or placebo for 12 weeks. Filgotinib reduced the Ankylosing Spondylitis Disease Activity Score (ASDAS) by a mean of 1.47 points from baseline, a significantly better result for the primary outcome than the 0.57-point decrease in controls (Lancet. 2018 Dec 1;392[10162]:2378-87).
Dr. Ruderman was also favorably impressed with the oral Janus kinase 1 (JAK1) inhibitor’s performance on the secondary outcome measures, including a mean 2.41-point reduction from baseline on the Bath Ankylosing Spondylitis Disease Activity Index, compared with a 1.44-point decrease in controls, with the difference being significant from week 8 onward. The filgotinib group also did significantly better on validated measures of physical function, spinal mobility, physical function, quality of life, peripheral arthritis, fatigue, and spinal and sacroiliac joint inflammation as assessed by MRI.
One patient in the filgotinib group, a smoker, developed pneumonia and another experienced deep venous thrombosis.
The study results are an exciting development because SpA treatments with new mechanisms of action are sorely needed. NSAIDs are considered first-line pharmacotherapy at present, with various tumor necrosis factor (TNF) inhibitors as well as the IL-17 inhibitor secukinumab (Cosentyx) the only approved biologic alternatives.
“This is the most impressive data I’ve seen that JAK inhibitors are effective in ankylosing spondyloarthritis,” commented Paul Emery, MD, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
TORTUGA was the first positive phase 2 trial of a selective JAK1 inhibitor in SpA. However, Dr. Kavanaugh noted that while a phase 2 trial of tofacitinib (Xeljanz) failed to meet its “very convoluted” primary endpoint, the JAK1/3 inhibitor was positive for key secondary endpoints, including favorable MRI changes. And a phase 3 trial of tofacitinib in SpA is underway.
A key remaining question pending the outcome of definitive phase 3 trials is whether specificity of JAK enzyme inhibition matters or if a class effect is at work, according to Dr. Kavanaugh, professor of medicine at the University of California, San Diego.
Certolizumab pegol
The TNF inhibitor is already approved for ankylosing spondylitis, among other indications, but it has now demonstrated efficacy and safety in nonradiographic SpA in a phase 3 trial structured with guidance from the Food and Drug Administration.
“It seems likely that UCB will get the indication for this,” according to Dr. Ruderman.
This 317-patient trial was remarkable in that it entailed a full 52 weeks of double-blind therapy with certolizumab at the standard dose of 200 mg every 2 weeks or placebo. The ASDAS Major Improvement rate, defined as at least a 2-point improvement from baseline, was 47% in the active treatment arm, compared with 7% on placebo. The Assessment in Ankylosing Spondylitis International Society 40% (ASAS 40) response rate, a more patient-reported outcome measure, was 57% in the certolizumab group and 16% in controls in this trial, which was recently published (Arthritis Rheumatol. 2019 March 8. doi: 10.1002/art.40866). All participants had to have baseline MRI evidence of sacroiliac joint inflammation and/or an elevated C-reactive protein.
By way of background, Dr. Ruderman explained that the FDA required 52 weeks of double-blind, placebo-controlled therapy because the agency’s advisory committee had formerly expressed reservations about considering an expanded indication for TNF inhibitors in nonradiographic as opposed to radiographic SpA.
“They were very concerned that approval could result in patients with mechanical back pain or fibromyalgia being treated with biologics. And they weren’t sure nonradiographic SpA was a discrete entity. They wondered if it remits on its own,” according to the rheumatologist.
Dr. Ruderman is curious to see how the FDA is going to handle this situation in light of the positive phase 3 certolizumab results. Will the agency require other companies that market TNF inhibitors to mount a similarly rigorous 52-week, double-blind, placebo-controlled trial in order to obtain an expanded indication? That would seem to pose ethical issues now. Or will the companies be able to gain an expanded indication by retrospective analysis of outcomes in patients with nonradiographic SpA in their existing trials databases? Stay tuned.
Ixekizumab
The COAST-V trial was a phase 3, randomized, double-blind, active- and placebo-controlled trial of 341 patients with radiographic SpA who hadn’t previously been treated with a biologic disease-modifying antirheumatic drug. They were assigned to 80 mg of ixekizumab every 2 weeks, 80 mg every 4 weeks, adalimumab (Humira) at 40 mg every 2 weeks, or placebo. The primary endpoint – an ASAS 40 response at week 16 – was achieved in 52% of patients on ixekizumab every 2 weeks, 48% of those who received ixekizumab every 4 weeks, 36% on adalimumab, and 18% on placebo (Lancet. 2018 Dec 8;392[10163]:2441-51).
In contrast, the phase 3 COAST-W trial included 316 patients with radiographic SpA who were inadequate responders or intolerant to one or more prior anti-TNF agents. The 16-week ASAS 40 response rate was 30.6% with ixekizumab every 2 weeks, similar at 25.4% with ixekizumab every 4 weeks, and 12.5% with placebo (Arthritis Rheumatol. 2018 Oct 20. doi: 10.1002/art.40753).
While the COAST-V trial convincingly showed both ixekizumab and adalimumab were more effective than placebo, the patient numbers were way too small to draw any conclusions about the relative efficacy of the two biologics, according to Dr. Ruderman.
“I don’t think these results are surprising,” Dr. Kavanaugh commented. “It would have been surprising if ixekizumab was ineffective, given that secukinumab works. But it’s nice to have the proof.”
Bimekizumab
This investigational dual IL-17A/F inhibitor demonstrated efficacy and safety for SpA in a 297-patient, phase 2b trial presented at the 2018 European Congress of Rheumatology.
“It’s effective, but it doesn’t look like it’s particularly more effective than either of the existing IL-17A inhibitors. We’ll see going forward if there truly is an advantage here to the additional inhibition of IL-17F in this population. I will say that the preclinical and laboratory data on the potential advantages of IL-17F inhibition are mostly in the psoriasis/psoriatic arthritis space. It’s not clear in ankylosing spondyloarthritis specifically whether we should expect to see a difference,” Dr. Ruderman said.
Ustekinumab
The IL-12/23 inhibitor proved no better than placebo in patients with SpA in three separate phase 3, randomized trials recently published as a single summary article (Arthritis Rheumatol. 2019 Feb;71[2]:258-70).
“Ustekinumab was effective in an earlier open study, so I think everybody was surprised by this,” Dr. Kavanaugh said.
He reported serving as a consultant to and/or receiving research funding from a dozen pharmaceutical companies. Dr. Ruderman reported financial relationships with eight companies.
MAUI, HAWAII – Arguably the most exciting therapeutic development in axial spondyloarthritis in the past year was the demonstrated efficacy and safety of the investigational oral selective Janus kinase 1 inhibitor filgotinib in the setting of active ankylosing spondylitis, speakers agreed at the 2019 Rheumatology Winter Clinical Symposium.
“This is big, big news,” commented symposium director Arthur Kavanaugh, MD. “This is going to be a big deal.”
Other recent clinical trials of note in axial spondyloarthritis (SpA) highlighted by Dr. Kavanaugh and Eric Ruderman, MD, professor of medicine at Northwestern University, Chicago, included a positive phase 3 study of certolizumab pegol (Cimzia) in nonradiographic SpA, two positive phase 3 trials of the interleukin-17A antagonist ixekizumab (Taltz) in radiographic SpA, a positive phase 2b trial of the dual IL-17A/F antagonist bimekizumab, and publication of three surprisingly negative phase 3 trials of the IL-12/23 inhibitor ustekinumab (Stelara).
Filgotinib
TORTUGA was a phase 2b, double-blind, multicenter trial of 116 European patients with active ankylosing spondylitis nonresponsive to NSAIDs who were randomized to oral filgotinib at 200 mg once daily or placebo for 12 weeks. Filgotinib reduced the Ankylosing Spondylitis Disease Activity Score (ASDAS) by a mean of 1.47 points from baseline, a significantly better result for the primary outcome than the 0.57-point decrease in controls (Lancet. 2018 Dec 1;392[10162]:2378-87).
Dr. Ruderman was also favorably impressed with the oral Janus kinase 1 (JAK1) inhibitor’s performance on the secondary outcome measures, including a mean 2.41-point reduction from baseline on the Bath Ankylosing Spondylitis Disease Activity Index, compared with a 1.44-point decrease in controls, with the difference being significant from week 8 onward. The filgotinib group also did significantly better on validated measures of physical function, spinal mobility, physical function, quality of life, peripheral arthritis, fatigue, and spinal and sacroiliac joint inflammation as assessed by MRI.
One patient in the filgotinib group, a smoker, developed pneumonia and another experienced deep venous thrombosis.
The study results are an exciting development because SpA treatments with new mechanisms of action are sorely needed. NSAIDs are considered first-line pharmacotherapy at present, with various tumor necrosis factor (TNF) inhibitors as well as the IL-17 inhibitor secukinumab (Cosentyx) the only approved biologic alternatives.
“This is the most impressive data I’ve seen that JAK inhibitors are effective in ankylosing spondyloarthritis,” commented Paul Emery, MD, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
TORTUGA was the first positive phase 2 trial of a selective JAK1 inhibitor in SpA. However, Dr. Kavanaugh noted that while a phase 2 trial of tofacitinib (Xeljanz) failed to meet its “very convoluted” primary endpoint, the JAK1/3 inhibitor was positive for key secondary endpoints, including favorable MRI changes. And a phase 3 trial of tofacitinib in SpA is underway.
A key remaining question pending the outcome of definitive phase 3 trials is whether specificity of JAK enzyme inhibition matters or if a class effect is at work, according to Dr. Kavanaugh, professor of medicine at the University of California, San Diego.
Certolizumab pegol
The TNF inhibitor is already approved for ankylosing spondylitis, among other indications, but it has now demonstrated efficacy and safety in nonradiographic SpA in a phase 3 trial structured with guidance from the Food and Drug Administration.
“It seems likely that UCB will get the indication for this,” according to Dr. Ruderman.
This 317-patient trial was remarkable in that it entailed a full 52 weeks of double-blind therapy with certolizumab at the standard dose of 200 mg every 2 weeks or placebo. The ASDAS Major Improvement rate, defined as at least a 2-point improvement from baseline, was 47% in the active treatment arm, compared with 7% on placebo. The Assessment in Ankylosing Spondylitis International Society 40% (ASAS 40) response rate, a more patient-reported outcome measure, was 57% in the certolizumab group and 16% in controls in this trial, which was recently published (Arthritis Rheumatol. 2019 March 8. doi: 10.1002/art.40866). All participants had to have baseline MRI evidence of sacroiliac joint inflammation and/or an elevated C-reactive protein.
By way of background, Dr. Ruderman explained that the FDA required 52 weeks of double-blind, placebo-controlled therapy because the agency’s advisory committee had formerly expressed reservations about considering an expanded indication for TNF inhibitors in nonradiographic as opposed to radiographic SpA.
“They were very concerned that approval could result in patients with mechanical back pain or fibromyalgia being treated with biologics. And they weren’t sure nonradiographic SpA was a discrete entity. They wondered if it remits on its own,” according to the rheumatologist.
Dr. Ruderman is curious to see how the FDA is going to handle this situation in light of the positive phase 3 certolizumab results. Will the agency require other companies that market TNF inhibitors to mount a similarly rigorous 52-week, double-blind, placebo-controlled trial in order to obtain an expanded indication? That would seem to pose ethical issues now. Or will the companies be able to gain an expanded indication by retrospective analysis of outcomes in patients with nonradiographic SpA in their existing trials databases? Stay tuned.
Ixekizumab
The COAST-V trial was a phase 3, randomized, double-blind, active- and placebo-controlled trial of 341 patients with radiographic SpA who hadn’t previously been treated with a biologic disease-modifying antirheumatic drug. They were assigned to 80 mg of ixekizumab every 2 weeks, 80 mg every 4 weeks, adalimumab (Humira) at 40 mg every 2 weeks, or placebo. The primary endpoint – an ASAS 40 response at week 16 – was achieved in 52% of patients on ixekizumab every 2 weeks, 48% of those who received ixekizumab every 4 weeks, 36% on adalimumab, and 18% on placebo (Lancet. 2018 Dec 8;392[10163]:2441-51).
In contrast, the phase 3 COAST-W trial included 316 patients with radiographic SpA who were inadequate responders or intolerant to one or more prior anti-TNF agents. The 16-week ASAS 40 response rate was 30.6% with ixekizumab every 2 weeks, similar at 25.4% with ixekizumab every 4 weeks, and 12.5% with placebo (Arthritis Rheumatol. 2018 Oct 20. doi: 10.1002/art.40753).
While the COAST-V trial convincingly showed both ixekizumab and adalimumab were more effective than placebo, the patient numbers were way too small to draw any conclusions about the relative efficacy of the two biologics, according to Dr. Ruderman.
“I don’t think these results are surprising,” Dr. Kavanaugh commented. “It would have been surprising if ixekizumab was ineffective, given that secukinumab works. But it’s nice to have the proof.”
Bimekizumab
This investigational dual IL-17A/F inhibitor demonstrated efficacy and safety for SpA in a 297-patient, phase 2b trial presented at the 2018 European Congress of Rheumatology.
“It’s effective, but it doesn’t look like it’s particularly more effective than either of the existing IL-17A inhibitors. We’ll see going forward if there truly is an advantage here to the additional inhibition of IL-17F in this population. I will say that the preclinical and laboratory data on the potential advantages of IL-17F inhibition are mostly in the psoriasis/psoriatic arthritis space. It’s not clear in ankylosing spondyloarthritis specifically whether we should expect to see a difference,” Dr. Ruderman said.
Ustekinumab
The IL-12/23 inhibitor proved no better than placebo in patients with SpA in three separate phase 3, randomized trials recently published as a single summary article (Arthritis Rheumatol. 2019 Feb;71[2]:258-70).
“Ustekinumab was effective in an earlier open study, so I think everybody was surprised by this,” Dr. Kavanaugh said.
He reported serving as a consultant to and/or receiving research funding from a dozen pharmaceutical companies. Dr. Ruderman reported financial relationships with eight companies.
MAUI, HAWAII – Arguably the most exciting therapeutic development in axial spondyloarthritis in the past year was the demonstrated efficacy and safety of the investigational oral selective Janus kinase 1 inhibitor filgotinib in the setting of active ankylosing spondylitis, speakers agreed at the 2019 Rheumatology Winter Clinical Symposium.
“This is big, big news,” commented symposium director Arthur Kavanaugh, MD. “This is going to be a big deal.”
Other recent clinical trials of note in axial spondyloarthritis (SpA) highlighted by Dr. Kavanaugh and Eric Ruderman, MD, professor of medicine at Northwestern University, Chicago, included a positive phase 3 study of certolizumab pegol (Cimzia) in nonradiographic SpA, two positive phase 3 trials of the interleukin-17A antagonist ixekizumab (Taltz) in radiographic SpA, a positive phase 2b trial of the dual IL-17A/F antagonist bimekizumab, and publication of three surprisingly negative phase 3 trials of the IL-12/23 inhibitor ustekinumab (Stelara).
Filgotinib
TORTUGA was a phase 2b, double-blind, multicenter trial of 116 European patients with active ankylosing spondylitis nonresponsive to NSAIDs who were randomized to oral filgotinib at 200 mg once daily or placebo for 12 weeks. Filgotinib reduced the Ankylosing Spondylitis Disease Activity Score (ASDAS) by a mean of 1.47 points from baseline, a significantly better result for the primary outcome than the 0.57-point decrease in controls (Lancet. 2018 Dec 1;392[10162]:2378-87).
Dr. Ruderman was also favorably impressed with the oral Janus kinase 1 (JAK1) inhibitor’s performance on the secondary outcome measures, including a mean 2.41-point reduction from baseline on the Bath Ankylosing Spondylitis Disease Activity Index, compared with a 1.44-point decrease in controls, with the difference being significant from week 8 onward. The filgotinib group also did significantly better on validated measures of physical function, spinal mobility, physical function, quality of life, peripheral arthritis, fatigue, and spinal and sacroiliac joint inflammation as assessed by MRI.
One patient in the filgotinib group, a smoker, developed pneumonia and another experienced deep venous thrombosis.
The study results are an exciting development because SpA treatments with new mechanisms of action are sorely needed. NSAIDs are considered first-line pharmacotherapy at present, with various tumor necrosis factor (TNF) inhibitors as well as the IL-17 inhibitor secukinumab (Cosentyx) the only approved biologic alternatives.
“This is the most impressive data I’ve seen that JAK inhibitors are effective in ankylosing spondyloarthritis,” commented Paul Emery, MD, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
TORTUGA was the first positive phase 2 trial of a selective JAK1 inhibitor in SpA. However, Dr. Kavanaugh noted that while a phase 2 trial of tofacitinib (Xeljanz) failed to meet its “very convoluted” primary endpoint, the JAK1/3 inhibitor was positive for key secondary endpoints, including favorable MRI changes. And a phase 3 trial of tofacitinib in SpA is underway.
A key remaining question pending the outcome of definitive phase 3 trials is whether specificity of JAK enzyme inhibition matters or if a class effect is at work, according to Dr. Kavanaugh, professor of medicine at the University of California, San Diego.
Certolizumab pegol
The TNF inhibitor is already approved for ankylosing spondylitis, among other indications, but it has now demonstrated efficacy and safety in nonradiographic SpA in a phase 3 trial structured with guidance from the Food and Drug Administration.
“It seems likely that UCB will get the indication for this,” according to Dr. Ruderman.
This 317-patient trial was remarkable in that it entailed a full 52 weeks of double-blind therapy with certolizumab at the standard dose of 200 mg every 2 weeks or placebo. The ASDAS Major Improvement rate, defined as at least a 2-point improvement from baseline, was 47% in the active treatment arm, compared with 7% on placebo. The Assessment in Ankylosing Spondylitis International Society 40% (ASAS 40) response rate, a more patient-reported outcome measure, was 57% in the certolizumab group and 16% in controls in this trial, which was recently published (Arthritis Rheumatol. 2019 March 8. doi: 10.1002/art.40866). All participants had to have baseline MRI evidence of sacroiliac joint inflammation and/or an elevated C-reactive protein.
By way of background, Dr. Ruderman explained that the FDA required 52 weeks of double-blind, placebo-controlled therapy because the agency’s advisory committee had formerly expressed reservations about considering an expanded indication for TNF inhibitors in nonradiographic as opposed to radiographic SpA.
“They were very concerned that approval could result in patients with mechanical back pain or fibromyalgia being treated with biologics. And they weren’t sure nonradiographic SpA was a discrete entity. They wondered if it remits on its own,” according to the rheumatologist.
Dr. Ruderman is curious to see how the FDA is going to handle this situation in light of the positive phase 3 certolizumab results. Will the agency require other companies that market TNF inhibitors to mount a similarly rigorous 52-week, double-blind, placebo-controlled trial in order to obtain an expanded indication? That would seem to pose ethical issues now. Or will the companies be able to gain an expanded indication by retrospective analysis of outcomes in patients with nonradiographic SpA in their existing trials databases? Stay tuned.
Ixekizumab
The COAST-V trial was a phase 3, randomized, double-blind, active- and placebo-controlled trial of 341 patients with radiographic SpA who hadn’t previously been treated with a biologic disease-modifying antirheumatic drug. They were assigned to 80 mg of ixekizumab every 2 weeks, 80 mg every 4 weeks, adalimumab (Humira) at 40 mg every 2 weeks, or placebo. The primary endpoint – an ASAS 40 response at week 16 – was achieved in 52% of patients on ixekizumab every 2 weeks, 48% of those who received ixekizumab every 4 weeks, 36% on adalimumab, and 18% on placebo (Lancet. 2018 Dec 8;392[10163]:2441-51).
In contrast, the phase 3 COAST-W trial included 316 patients with radiographic SpA who were inadequate responders or intolerant to one or more prior anti-TNF agents. The 16-week ASAS 40 response rate was 30.6% with ixekizumab every 2 weeks, similar at 25.4% with ixekizumab every 4 weeks, and 12.5% with placebo (Arthritis Rheumatol. 2018 Oct 20. doi: 10.1002/art.40753).
While the COAST-V trial convincingly showed both ixekizumab and adalimumab were more effective than placebo, the patient numbers were way too small to draw any conclusions about the relative efficacy of the two biologics, according to Dr. Ruderman.
“I don’t think these results are surprising,” Dr. Kavanaugh commented. “It would have been surprising if ixekizumab was ineffective, given that secukinumab works. But it’s nice to have the proof.”
Bimekizumab
This investigational dual IL-17A/F inhibitor demonstrated efficacy and safety for SpA in a 297-patient, phase 2b trial presented at the 2018 European Congress of Rheumatology.
“It’s effective, but it doesn’t look like it’s particularly more effective than either of the existing IL-17A inhibitors. We’ll see going forward if there truly is an advantage here to the additional inhibition of IL-17F in this population. I will say that the preclinical and laboratory data on the potential advantages of IL-17F inhibition are mostly in the psoriasis/psoriatic arthritis space. It’s not clear in ankylosing spondyloarthritis specifically whether we should expect to see a difference,” Dr. Ruderman said.
Ustekinumab
The IL-12/23 inhibitor proved no better than placebo in patients with SpA in three separate phase 3, randomized trials recently published as a single summary article (Arthritis Rheumatol. 2019 Feb;71[2]:258-70).
“Ustekinumab was effective in an earlier open study, so I think everybody was surprised by this,” Dr. Kavanaugh said.
He reported serving as a consultant to and/or receiving research funding from a dozen pharmaceutical companies. Dr. Ruderman reported financial relationships with eight companies.
REPORTING FROM RWCS 2019