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MAUI, HAWAII – Filgotinib, the oral Janus kinase (JAK) inhibitor now under Food and Drug Administration review for the treatment of RA, has a better safety profile than some of the approved oral JAK inhibitors, but that’s unlikely to save it from being saddled with a black-box safety warning label, experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“There’s probably a class label out there,” according to Mark C. Genovese, MD, professor of medicine and clinical chief of the division of immunology and rheumatology at Stanford (Calif.) University.
He cited the example of upadacitinib (Rinvoq), approved last year as the third oral JAK inhibitor for RA. Even though venous thromboembolic (VTE) events weren’t seen with any significantly increased frequency, compared with placebo, in the upadacitinib development program – unlike for the earlier-approved tofacitinib (Xeljanz) and baricitinib (Olumiant) –the FDA nevertheless required that upadacitinib’s product labeling include this black-box warning: “Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.”
“I would fully expect that there’ll be a similar label in the filgotinib package insert saying that VTEs have been seen in other members of the class,” he predicted.
His copanelist Roy Fleischmann, MD, noted that filgotinib displayed a clean long-term safety profile in a pooled analysis of the 24-week results in the 2,088 filgotinib-treated participants in all phase 3 clinical trials for RA. For example, the incidence of herpes zoster in that large treated population was a mere 0.1%.
“Herpes zoster is almost nonexistent across the program,” observed Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.
That’s consistent with what he’s heard from Japanese investigators about their experience. They tell him that in their studies the incidence of herpes zoster with filgotinib is five times less than with other JAK inhibitors.
The long-term pooled phase 3 filgotinib safety data also show less than a 0.1% incidence of adjudicated VTE/pulmonary embolism through 24 weeks. That’s a substantially lower rate than with tofacitinib or baricitinib, he noted.
The two rheumatologists, long-time observers of the FDA regulatory scene, stressed that they have no inside information regarding what the agency will do about filgotinib. It seems beyond doubt that the JAK inhibitor will be approved. But an open question of practical importance to clinicians is whether the agency will approve only the 100-mg dose or the 200-mg dose as well. The panelists agreed that having access to both would be advantageous since the clinical trials data indicate the higher dose is more effective and this greater efficacy doesn’t come at a cost of additional safety issues.
“If the 100 mg is sufficient, that’s great, but the reality is if you want to push to low disease activity or remission, the 200 mg seems to work better, particularly in patients who’ve already failed TNF [tumor necrosis factor] inhibitors or other biologics,” Dr. Genovese said. “If you’re not having additional safety concerns and you can get additional efficacy, I love the idea of having flexibility.”
Dr. Fleischmann is skeptical that the regulators will see things that way.
“There is a real risk that the FDA will do what it’s done before and say: ‘Well, the 200 works and the 100 works, so we’re going to approve the lower dose.’ But there doesn’t appear to be a big safety difference between 100 and 200. So I can see why they would approve the two doses, but I think that’d be unusual,” according to the rheumatologist.
The RA pipeline
The two speakers also highlighted several agents with novel mechanisms of action moving through the RA developmental pipeline, including olokizumab, otilimab, fenebrutinib, and a promising oral selective interleukin-1 receptor–associated kinase 4 inhibitor (IRAK4).
Olokizumab: This humanized monoclonal antibody targets IL-6. It has a different mechanism of action than the two commercially available IL-6 inhibitors approved for RA, tocilizumab (Actemra) and sarilumab (Kevzara), in that olokizumab uniquely targets the IL-6 ligand.
At the 2019 annual meeting of the American College of Rheumatology, Dr. Genovese presented the positive findings of a double-blind, placebo-controlled, randomized, phase 3 clinical trial of olokizumab in 428 RA patients with an inadequate response to methotrexate. The primary outcome, an ACR 20 response at 12 weeks, occurred in 25.9% of patients on placebo, 63.6% with 64 mg of olokizumab given subcutaneously every 2 weeks, and 70.4% with 64 mg every 4 weeks, with all participants on background methotrexate. An ACR 50 response at week 24 occurred in 7.7%, 42.7%, and 48.6%, respectively, with an acceptable side effect profile.
This was the first phase 3 trial to be presented from a large, ongoing phase 3 olokizumab developmental program for a variety of diseases.
“The results certainly support the idea that a 4-week regimen would probably be quite useful with this medication, although we’ll have to see what happens with the remaining phase 3 trials,” Dr. Genovese said.
Dr. Fleischmann posed a question: Do we really need a third IL-6 inhibitor?
That would make for a crowded field, Dr. Genovese agreed, adding that grabbing a reasonable market share for olokizumab may come down to cost, formulary access, and the convenience factor of once-monthly dosing. Whether the biologic’s unique mechanism of action in blocking the IL-6 ligand makes any practical difference in outcomes is unknown.
IRAK4 inhibitor: PF-06650833 is an oral selective reversible inhibitor of IRAK4, a key signaling kinase for IL-1 and toll-like receptors.
“This should be a really good drug for IL-1-mediated diseases,” according to Dr. Fleischmann.
In a phase 2b, double-blind, randomized, placebo-controlled, 12-week study featuring tofacitinib at 5 mg twice daily as an active comparator, the IRAK4 inhibitor exhibited dose-dependent efficacy for the primary endpoint of improvement from baseline in Simple Disease Activity Index score, compared with placebo. The same was true for the secondary endpoint, change over time in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). The trial results were also presented at the 2019 ACR annual meeting.
“This is a drug they should probably take forward and see how far it goes in RA,” he said.
Dr. Genovese concurred.
“We’re still trying to figure out how we can put together rational combinations in RA, and this might be something that could be considered as a combination play. In fact, Pfizer has already teed up a study looking at a JAK inhibitor/IRAK4 combination. The question will be whether this is a standalone or has an opportunity to be part of a combination approach,” the rheumatologist said.
Otilimab: This monoclonal antibody is a granulocyte-macrophage colony-stimulating factor inhibitor. In a secondary analysis of the BAROQUE trial, a phase 2b, 50-week study in RA inadequately responsive to methotrexate, otilimab demonstrated an impressive effect in terms of pain reduction. This new analysis, which was first presented at the 2019 ACR annual meeting, showed that, at week 12, a minimum clinically important difference in pain was achieved in 29% of placebo-treated controls, compared with 65%-75% of patients on low to higher doses of otilimab.
“The question is: Is this pain effect unique to this molecule, this pathway, or is it a simple reflection of the treated patient population?” Dr. Genovese commented. “It’s an interesting molecule. It’s being developed in RA, and it might have unique benefits on the pain side.”
A tale of two BTK inhibitors: Bruton tyrosine kinase (BTK) is an intracellular kinase viewed as a promising target in autoimmune disease. Fenebrutinib is an oral, noncovalent, reversible, and highly selective BTK inhibitor that performed well in a phase 2, randomized, double-blind, placebo-controlled clinical trial with adalimumab as an active comparator in 480 patients with an inadequate response to methotrexate in one branch, and in 98 patients with an inadequate response to TNF inhibitor therapy in the other. All subjects were on background methotrexate. (The study results were published April 9 in Arthritis & Rheumatology.)
In the group with a prior inadequate response to TNF inhibitors, the ACR 50 response rate at 12 weeks was 25% in the group on fenebrutinib at 200 mg twice daily, significantly better than the 12% rate in placebo. And there were favorable effects on biomarkers: The reduction in erythrocyte sedimentation rate from baseline was nearly twice as great with fenebrutinib, the drop in CRP was nearly three times greater than with placebo, and there was also a significantly greater decrease over time in DAS28-CRP.
In the methotrexate-inadequate responders, the ACR50 rates were 28% and 35% with the BTK inhibitor at 150 and 200 mg once daily, respectively, compared with 15% in controls.
The safety picture was encouraging, with similarly low adverse event rates across all treatment arms.
In contrast to the fenebrutinib experience, Dr. Genovese was lead investigator in a 250-patient, phase 2 study of another oral BTK inhibitor, poseltinib, which differs from fenebrutinib in that it is an irreversible covalent inhibitor. It was a failed study, with no significant difference between poseltinib and placebo in ACR 20 response at 12 weeks. It’s unclear whether the problem was insufficient dosing or that poseltinib is a failed molecule, perhaps because of its irreversible covalent binding to BTK, he said.
Other notable failures
The spleen tyrosine kinase (Syk) inhibitor known as GS-9876 showed no clinical efficacy in a phase 2, double-blind, randomized trial in 83 RA patients with an inadequate response to methotrexate or a biologic DMARD.
“This is like the fourth Syk inhibitor that’s failed. Syk inhibition is not sick, Syk is dead,” Dr. Fleischmann declared.
Cadherin-11 is an inflammatory cytokine expressed on fibroblasts in RA joints. In a phase 2, double-blind, randomized trial in 109 patients with RA inadequately responsive to TNF inhibitors, RG6125, a humanized monoclonal antibody directed against cadherin-11, failed to outperform placebo.
“It should have worked. It didn’t. So the question is whether this pathway is not an appropriate pathway, or the molecule was not quite the right molecule. I have a feeling it was possibly not the right molecule and the pathway may be viable,” according to Dr. Fleischmann.
He reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Genovese also reported financial relationships with more than a dozen pharmaceutical companies.
MAUI, HAWAII – Filgotinib, the oral Janus kinase (JAK) inhibitor now under Food and Drug Administration review for the treatment of RA, has a better safety profile than some of the approved oral JAK inhibitors, but that’s unlikely to save it from being saddled with a black-box safety warning label, experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“There’s probably a class label out there,” according to Mark C. Genovese, MD, professor of medicine and clinical chief of the division of immunology and rheumatology at Stanford (Calif.) University.
He cited the example of upadacitinib (Rinvoq), approved last year as the third oral JAK inhibitor for RA. Even though venous thromboembolic (VTE) events weren’t seen with any significantly increased frequency, compared with placebo, in the upadacitinib development program – unlike for the earlier-approved tofacitinib (Xeljanz) and baricitinib (Olumiant) –the FDA nevertheless required that upadacitinib’s product labeling include this black-box warning: “Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.”
“I would fully expect that there’ll be a similar label in the filgotinib package insert saying that VTEs have been seen in other members of the class,” he predicted.
His copanelist Roy Fleischmann, MD, noted that filgotinib displayed a clean long-term safety profile in a pooled analysis of the 24-week results in the 2,088 filgotinib-treated participants in all phase 3 clinical trials for RA. For example, the incidence of herpes zoster in that large treated population was a mere 0.1%.
“Herpes zoster is almost nonexistent across the program,” observed Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.
That’s consistent with what he’s heard from Japanese investigators about their experience. They tell him that in their studies the incidence of herpes zoster with filgotinib is five times less than with other JAK inhibitors.
The long-term pooled phase 3 filgotinib safety data also show less than a 0.1% incidence of adjudicated VTE/pulmonary embolism through 24 weeks. That’s a substantially lower rate than with tofacitinib or baricitinib, he noted.
The two rheumatologists, long-time observers of the FDA regulatory scene, stressed that they have no inside information regarding what the agency will do about filgotinib. It seems beyond doubt that the JAK inhibitor will be approved. But an open question of practical importance to clinicians is whether the agency will approve only the 100-mg dose or the 200-mg dose as well. The panelists agreed that having access to both would be advantageous since the clinical trials data indicate the higher dose is more effective and this greater efficacy doesn’t come at a cost of additional safety issues.
“If the 100 mg is sufficient, that’s great, but the reality is if you want to push to low disease activity or remission, the 200 mg seems to work better, particularly in patients who’ve already failed TNF [tumor necrosis factor] inhibitors or other biologics,” Dr. Genovese said. “If you’re not having additional safety concerns and you can get additional efficacy, I love the idea of having flexibility.”
Dr. Fleischmann is skeptical that the regulators will see things that way.
“There is a real risk that the FDA will do what it’s done before and say: ‘Well, the 200 works and the 100 works, so we’re going to approve the lower dose.’ But there doesn’t appear to be a big safety difference between 100 and 200. So I can see why they would approve the two doses, but I think that’d be unusual,” according to the rheumatologist.
The RA pipeline
The two speakers also highlighted several agents with novel mechanisms of action moving through the RA developmental pipeline, including olokizumab, otilimab, fenebrutinib, and a promising oral selective interleukin-1 receptor–associated kinase 4 inhibitor (IRAK4).
Olokizumab: This humanized monoclonal antibody targets IL-6. It has a different mechanism of action than the two commercially available IL-6 inhibitors approved for RA, tocilizumab (Actemra) and sarilumab (Kevzara), in that olokizumab uniquely targets the IL-6 ligand.
At the 2019 annual meeting of the American College of Rheumatology, Dr. Genovese presented the positive findings of a double-blind, placebo-controlled, randomized, phase 3 clinical trial of olokizumab in 428 RA patients with an inadequate response to methotrexate. The primary outcome, an ACR 20 response at 12 weeks, occurred in 25.9% of patients on placebo, 63.6% with 64 mg of olokizumab given subcutaneously every 2 weeks, and 70.4% with 64 mg every 4 weeks, with all participants on background methotrexate. An ACR 50 response at week 24 occurred in 7.7%, 42.7%, and 48.6%, respectively, with an acceptable side effect profile.
This was the first phase 3 trial to be presented from a large, ongoing phase 3 olokizumab developmental program for a variety of diseases.
“The results certainly support the idea that a 4-week regimen would probably be quite useful with this medication, although we’ll have to see what happens with the remaining phase 3 trials,” Dr. Genovese said.
Dr. Fleischmann posed a question: Do we really need a third IL-6 inhibitor?
That would make for a crowded field, Dr. Genovese agreed, adding that grabbing a reasonable market share for olokizumab may come down to cost, formulary access, and the convenience factor of once-monthly dosing. Whether the biologic’s unique mechanism of action in blocking the IL-6 ligand makes any practical difference in outcomes is unknown.
IRAK4 inhibitor: PF-06650833 is an oral selective reversible inhibitor of IRAK4, a key signaling kinase for IL-1 and toll-like receptors.
“This should be a really good drug for IL-1-mediated diseases,” according to Dr. Fleischmann.
In a phase 2b, double-blind, randomized, placebo-controlled, 12-week study featuring tofacitinib at 5 mg twice daily as an active comparator, the IRAK4 inhibitor exhibited dose-dependent efficacy for the primary endpoint of improvement from baseline in Simple Disease Activity Index score, compared with placebo. The same was true for the secondary endpoint, change over time in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). The trial results were also presented at the 2019 ACR annual meeting.
“This is a drug they should probably take forward and see how far it goes in RA,” he said.
Dr. Genovese concurred.
“We’re still trying to figure out how we can put together rational combinations in RA, and this might be something that could be considered as a combination play. In fact, Pfizer has already teed up a study looking at a JAK inhibitor/IRAK4 combination. The question will be whether this is a standalone or has an opportunity to be part of a combination approach,” the rheumatologist said.
Otilimab: This monoclonal antibody is a granulocyte-macrophage colony-stimulating factor inhibitor. In a secondary analysis of the BAROQUE trial, a phase 2b, 50-week study in RA inadequately responsive to methotrexate, otilimab demonstrated an impressive effect in terms of pain reduction. This new analysis, which was first presented at the 2019 ACR annual meeting, showed that, at week 12, a minimum clinically important difference in pain was achieved in 29% of placebo-treated controls, compared with 65%-75% of patients on low to higher doses of otilimab.
“The question is: Is this pain effect unique to this molecule, this pathway, or is it a simple reflection of the treated patient population?” Dr. Genovese commented. “It’s an interesting molecule. It’s being developed in RA, and it might have unique benefits on the pain side.”
A tale of two BTK inhibitors: Bruton tyrosine kinase (BTK) is an intracellular kinase viewed as a promising target in autoimmune disease. Fenebrutinib is an oral, noncovalent, reversible, and highly selective BTK inhibitor that performed well in a phase 2, randomized, double-blind, placebo-controlled clinical trial with adalimumab as an active comparator in 480 patients with an inadequate response to methotrexate in one branch, and in 98 patients with an inadequate response to TNF inhibitor therapy in the other. All subjects were on background methotrexate. (The study results were published April 9 in Arthritis & Rheumatology.)
In the group with a prior inadequate response to TNF inhibitors, the ACR 50 response rate at 12 weeks was 25% in the group on fenebrutinib at 200 mg twice daily, significantly better than the 12% rate in placebo. And there were favorable effects on biomarkers: The reduction in erythrocyte sedimentation rate from baseline was nearly twice as great with fenebrutinib, the drop in CRP was nearly three times greater than with placebo, and there was also a significantly greater decrease over time in DAS28-CRP.
In the methotrexate-inadequate responders, the ACR50 rates were 28% and 35% with the BTK inhibitor at 150 and 200 mg once daily, respectively, compared with 15% in controls.
The safety picture was encouraging, with similarly low adverse event rates across all treatment arms.
In contrast to the fenebrutinib experience, Dr. Genovese was lead investigator in a 250-patient, phase 2 study of another oral BTK inhibitor, poseltinib, which differs from fenebrutinib in that it is an irreversible covalent inhibitor. It was a failed study, with no significant difference between poseltinib and placebo in ACR 20 response at 12 weeks. It’s unclear whether the problem was insufficient dosing or that poseltinib is a failed molecule, perhaps because of its irreversible covalent binding to BTK, he said.
Other notable failures
The spleen tyrosine kinase (Syk) inhibitor known as GS-9876 showed no clinical efficacy in a phase 2, double-blind, randomized trial in 83 RA patients with an inadequate response to methotrexate or a biologic DMARD.
“This is like the fourth Syk inhibitor that’s failed. Syk inhibition is not sick, Syk is dead,” Dr. Fleischmann declared.
Cadherin-11 is an inflammatory cytokine expressed on fibroblasts in RA joints. In a phase 2, double-blind, randomized trial in 109 patients with RA inadequately responsive to TNF inhibitors, RG6125, a humanized monoclonal antibody directed against cadherin-11, failed to outperform placebo.
“It should have worked. It didn’t. So the question is whether this pathway is not an appropriate pathway, or the molecule was not quite the right molecule. I have a feeling it was possibly not the right molecule and the pathway may be viable,” according to Dr. Fleischmann.
He reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Genovese also reported financial relationships with more than a dozen pharmaceutical companies.
MAUI, HAWAII – Filgotinib, the oral Janus kinase (JAK) inhibitor now under Food and Drug Administration review for the treatment of RA, has a better safety profile than some of the approved oral JAK inhibitors, but that’s unlikely to save it from being saddled with a black-box safety warning label, experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“There’s probably a class label out there,” according to Mark C. Genovese, MD, professor of medicine and clinical chief of the division of immunology and rheumatology at Stanford (Calif.) University.
He cited the example of upadacitinib (Rinvoq), approved last year as the third oral JAK inhibitor for RA. Even though venous thromboembolic (VTE) events weren’t seen with any significantly increased frequency, compared with placebo, in the upadacitinib development program – unlike for the earlier-approved tofacitinib (Xeljanz) and baricitinib (Olumiant) –the FDA nevertheless required that upadacitinib’s product labeling include this black-box warning: “Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.”
“I would fully expect that there’ll be a similar label in the filgotinib package insert saying that VTEs have been seen in other members of the class,” he predicted.
His copanelist Roy Fleischmann, MD, noted that filgotinib displayed a clean long-term safety profile in a pooled analysis of the 24-week results in the 2,088 filgotinib-treated participants in all phase 3 clinical trials for RA. For example, the incidence of herpes zoster in that large treated population was a mere 0.1%.
“Herpes zoster is almost nonexistent across the program,” observed Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.
That’s consistent with what he’s heard from Japanese investigators about their experience. They tell him that in their studies the incidence of herpes zoster with filgotinib is five times less than with other JAK inhibitors.
The long-term pooled phase 3 filgotinib safety data also show less than a 0.1% incidence of adjudicated VTE/pulmonary embolism through 24 weeks. That’s a substantially lower rate than with tofacitinib or baricitinib, he noted.
The two rheumatologists, long-time observers of the FDA regulatory scene, stressed that they have no inside information regarding what the agency will do about filgotinib. It seems beyond doubt that the JAK inhibitor will be approved. But an open question of practical importance to clinicians is whether the agency will approve only the 100-mg dose or the 200-mg dose as well. The panelists agreed that having access to both would be advantageous since the clinical trials data indicate the higher dose is more effective and this greater efficacy doesn’t come at a cost of additional safety issues.
“If the 100 mg is sufficient, that’s great, but the reality is if you want to push to low disease activity or remission, the 200 mg seems to work better, particularly in patients who’ve already failed TNF [tumor necrosis factor] inhibitors or other biologics,” Dr. Genovese said. “If you’re not having additional safety concerns and you can get additional efficacy, I love the idea of having flexibility.”
Dr. Fleischmann is skeptical that the regulators will see things that way.
“There is a real risk that the FDA will do what it’s done before and say: ‘Well, the 200 works and the 100 works, so we’re going to approve the lower dose.’ But there doesn’t appear to be a big safety difference between 100 and 200. So I can see why they would approve the two doses, but I think that’d be unusual,” according to the rheumatologist.
The RA pipeline
The two speakers also highlighted several agents with novel mechanisms of action moving through the RA developmental pipeline, including olokizumab, otilimab, fenebrutinib, and a promising oral selective interleukin-1 receptor–associated kinase 4 inhibitor (IRAK4).
Olokizumab: This humanized monoclonal antibody targets IL-6. It has a different mechanism of action than the two commercially available IL-6 inhibitors approved for RA, tocilizumab (Actemra) and sarilumab (Kevzara), in that olokizumab uniquely targets the IL-6 ligand.
At the 2019 annual meeting of the American College of Rheumatology, Dr. Genovese presented the positive findings of a double-blind, placebo-controlled, randomized, phase 3 clinical trial of olokizumab in 428 RA patients with an inadequate response to methotrexate. The primary outcome, an ACR 20 response at 12 weeks, occurred in 25.9% of patients on placebo, 63.6% with 64 mg of olokizumab given subcutaneously every 2 weeks, and 70.4% with 64 mg every 4 weeks, with all participants on background methotrexate. An ACR 50 response at week 24 occurred in 7.7%, 42.7%, and 48.6%, respectively, with an acceptable side effect profile.
This was the first phase 3 trial to be presented from a large, ongoing phase 3 olokizumab developmental program for a variety of diseases.
“The results certainly support the idea that a 4-week regimen would probably be quite useful with this medication, although we’ll have to see what happens with the remaining phase 3 trials,” Dr. Genovese said.
Dr. Fleischmann posed a question: Do we really need a third IL-6 inhibitor?
That would make for a crowded field, Dr. Genovese agreed, adding that grabbing a reasonable market share for olokizumab may come down to cost, formulary access, and the convenience factor of once-monthly dosing. Whether the biologic’s unique mechanism of action in blocking the IL-6 ligand makes any practical difference in outcomes is unknown.
IRAK4 inhibitor: PF-06650833 is an oral selective reversible inhibitor of IRAK4, a key signaling kinase for IL-1 and toll-like receptors.
“This should be a really good drug for IL-1-mediated diseases,” according to Dr. Fleischmann.
In a phase 2b, double-blind, randomized, placebo-controlled, 12-week study featuring tofacitinib at 5 mg twice daily as an active comparator, the IRAK4 inhibitor exhibited dose-dependent efficacy for the primary endpoint of improvement from baseline in Simple Disease Activity Index score, compared with placebo. The same was true for the secondary endpoint, change over time in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). The trial results were also presented at the 2019 ACR annual meeting.
“This is a drug they should probably take forward and see how far it goes in RA,” he said.
Dr. Genovese concurred.
“We’re still trying to figure out how we can put together rational combinations in RA, and this might be something that could be considered as a combination play. In fact, Pfizer has already teed up a study looking at a JAK inhibitor/IRAK4 combination. The question will be whether this is a standalone or has an opportunity to be part of a combination approach,” the rheumatologist said.
Otilimab: This monoclonal antibody is a granulocyte-macrophage colony-stimulating factor inhibitor. In a secondary analysis of the BAROQUE trial, a phase 2b, 50-week study in RA inadequately responsive to methotrexate, otilimab demonstrated an impressive effect in terms of pain reduction. This new analysis, which was first presented at the 2019 ACR annual meeting, showed that, at week 12, a minimum clinically important difference in pain was achieved in 29% of placebo-treated controls, compared with 65%-75% of patients on low to higher doses of otilimab.
“The question is: Is this pain effect unique to this molecule, this pathway, or is it a simple reflection of the treated patient population?” Dr. Genovese commented. “It’s an interesting molecule. It’s being developed in RA, and it might have unique benefits on the pain side.”
A tale of two BTK inhibitors: Bruton tyrosine kinase (BTK) is an intracellular kinase viewed as a promising target in autoimmune disease. Fenebrutinib is an oral, noncovalent, reversible, and highly selective BTK inhibitor that performed well in a phase 2, randomized, double-blind, placebo-controlled clinical trial with adalimumab as an active comparator in 480 patients with an inadequate response to methotrexate in one branch, and in 98 patients with an inadequate response to TNF inhibitor therapy in the other. All subjects were on background methotrexate. (The study results were published April 9 in Arthritis & Rheumatology.)
In the group with a prior inadequate response to TNF inhibitors, the ACR 50 response rate at 12 weeks was 25% in the group on fenebrutinib at 200 mg twice daily, significantly better than the 12% rate in placebo. And there were favorable effects on biomarkers: The reduction in erythrocyte sedimentation rate from baseline was nearly twice as great with fenebrutinib, the drop in CRP was nearly three times greater than with placebo, and there was also a significantly greater decrease over time in DAS28-CRP.
In the methotrexate-inadequate responders, the ACR50 rates were 28% and 35% with the BTK inhibitor at 150 and 200 mg once daily, respectively, compared with 15% in controls.
The safety picture was encouraging, with similarly low adverse event rates across all treatment arms.
In contrast to the fenebrutinib experience, Dr. Genovese was lead investigator in a 250-patient, phase 2 study of another oral BTK inhibitor, poseltinib, which differs from fenebrutinib in that it is an irreversible covalent inhibitor. It was a failed study, with no significant difference between poseltinib and placebo in ACR 20 response at 12 weeks. It’s unclear whether the problem was insufficient dosing or that poseltinib is a failed molecule, perhaps because of its irreversible covalent binding to BTK, he said.
Other notable failures
The spleen tyrosine kinase (Syk) inhibitor known as GS-9876 showed no clinical efficacy in a phase 2, double-blind, randomized trial in 83 RA patients with an inadequate response to methotrexate or a biologic DMARD.
“This is like the fourth Syk inhibitor that’s failed. Syk inhibition is not sick, Syk is dead,” Dr. Fleischmann declared.
Cadherin-11 is an inflammatory cytokine expressed on fibroblasts in RA joints. In a phase 2, double-blind, randomized trial in 109 patients with RA inadequately responsive to TNF inhibitors, RG6125, a humanized monoclonal antibody directed against cadherin-11, failed to outperform placebo.
“It should have worked. It didn’t. So the question is whether this pathway is not an appropriate pathway, or the molecule was not quite the right molecule. I have a feeling it was possibly not the right molecule and the pathway may be viable,” according to Dr. Fleischmann.
He reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Genovese also reported financial relationships with more than a dozen pharmaceutical companies.
REPORTING FROM RWCS 2020