JAK-1 inhibitors heading for validation in phase III trials

LONDON – ABT-494 and filgotinib – two investigational and highly selective oral Janus kinase-1 inhibitors – are both showing promise in the treatment of patients with rheumatoid arthritis, according to the results of two separate phase II studies presented at the European Congress of Rheumatology.

In the BALANCE-2 study, 62%-80% patients who had an inadequate response to methotrexate alone achieved the primary endpoint of an ACR20 response after 12 weeks of combination treatment with methotrexate and ABT-494, depending on the dose used, versus 46% for placebo plus methotrexate. The secondary endpoint of ACR50 was reached by a respective 38%-50% vs. 18%, and ACR70 response was achieved by 16%-28% vs. 6%.

And in the DARWIN-1 study, 56%-79% of patients treated with different doses of filgotinib plus methotrexate achieved the trial’s primary endpoint, which was again ACR20 at 12 weeks, versus 44% for placebo plus methotrexate. ACR50 and ACR70 responses were also similarly high and maintained up to 24 weeks of follow-up.

Both drugs had safety and tolerability data that supported their further development, the respective study investigators said.

“I think the results are rather straightforward. There was significant improvement in signs and symptoms of RA with fast onset,” said René Westhovens, MD, PhD, of the University of Leuven (Belgium), who presented the data from the DARWIN-1 study. “These robust data support the future development of filgotinib in RA,” he said.

Mark Genovese, MD, of Stanford (Calif.) University, who presented the findings of the BALANCE-2 study, said: “ABT-494 has been shown to have significant improvements in symptoms and signs [of RA] based on our endpoints of ACR [response], DAS[28], and CDAI [clinical disease activity index].” Like ACR50 and ACR70, DAS28 and CDAI were secondary efficacy endpoints and showed significantly greater changes from baseline versus placebo, started from around 2 weeks.

In an interview, Peter Taylor, PhD, who chaired the session at the meeting where the findings were presented, said: “We’ve seen a lot of data about JAK inhibitors at various stages of development at EULAR 2016, with varying selectivity, and the clinical data unequivocally validates Janus kinases as a therapeutic target.”

Dr. Taylor, the Norman Collisson Professor of Musculoskeletal Sciences at the University of Oxford (England), added: “[JAK inhibitors] show very significant promise with favorable safety data overall, but there are subtle differences between the drugs which need further detailed analysis to understand what it means in a clinical context.”

BALANCE-2 was a double-blind, placebo-controlled, dose-ranging phase IIB study designed to look at the safety and efficacy of ABT-494 in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Five doses of ABT-494 were tested: four given twice-daily (3, 6, 12, and 18 mg) and one given once-daily (24 mg). A total of 300 patients were enrolled and 299 were randomized, 50 to placebo, 50 each to the once-daily doses, and 49 to the twice-daily dose group. The mean weekly methotrexate dose at baseline was 14-16 mg across the groups.

“In general, the safety and tolerability of ABT-494 was satisfactory at the doses tested, consistent with what would have been expected,” Dr. Genovese said.

There was a numerically higher rate of any adverse event in the groups treated with ABT-494, at 40%, 46%, 58%, and 50% for the twice-daily regimens of 3, 6, 12, and 18 mg, as well as 35% for the once-daily 24-mg dose. The rate was 26% for placebo plus methotrexate.

Infections occurred in a respective 20%, 14%, 24%, 22% across the twice-daily dosing groups, respectively, compared with 18% for the once-daily 24-mg dose and 14% for placebo plus methotrexate, he noted. While there were some grade 2-3 abnormalities in liver enzymes and dose-related decreases in hemoglobin seen at higher doses, these did not appear to have significant clinical impact. The ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) was also affected slightly.

DARWIN-1 involved a total of 599 enrolled and 594 randomized and exposed patients with RA treated with placebo plus methotrexate or methotrexate plus one of six dosing regimens of filgotinib: 50, 100, or 200 mg once daily, or 25, 50, or 100 mg twice daily, for 24 weeks, with around 85 patients in each group. Each patient previously had an inadequate response to methotrexate alone. At the 12-week halfway point, patients taking placebo and the 50-mg dose could be reassigned to filgotinib 100 mg once daily or 50 mg twice daily if their tender or swollen joint counts had not improved. The mean weekly dose of methotrexate at baseline was 16.4-17.5 mg across the groups.

In addition to the improved ACR responses, significant improvements with filgotinib versus placebo were seen in the secondary endpoints of DAS28 (including DAS28 based on C-reactive protein), CDAI, and the Health Assessment Questionnaire-Disability Index.

There were infrequent serious adverse events, which included serious infections, and adverse events leading to discontinuations, Dr. Westhovens observed, and nothing that would not have been expected or different from placebo. There was a small decrease in neutrophil counts and increase in creatinine, but neither had any clinical consequences. Interestingly, there was a dose-dependent increase in hemoglobin but no reduction in lymphocyte counts, he said. HDL-C increased more than LDL-C.

Five phase III trials with ABT-494 are currently underway in patients with RA:

• SELECT-COMPARE will enroll an estimated 1,500 RA patients who have had an inadequate response to a stable dose of methotrexate and will compare additional treatment with ABT-494 against additional treatment with adalimumab (Humira) or placebo.

• SELECT-NEXT will enroll an estimated 600 RA patients who have had an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and are then given ABT-494 or placebo on top.

• SELECT-BEYOND will enroll around 450 RA patients on stable csDMARDs who have an inadequate response or intolerance to biologic DMARDs and compare adding ABT-494 or placebo.

• SELECT-MONOTHERAPY will enroll 600 RA patients who have had an inadequate methotrexate response and compare ABT-494 monotherapy to methotrexate monotherapy.

• SELECT-EARLY will enroll 975 methotrexate-naive, moderately-to-severely active RA patients and compare giving ABT-494 monotherapy to methotrexate monotherapy.

Most of these trials should have primary endpoint data available for analysis by mid to late 2017 or 2018 and be finished by 2020 or 2021.

Filgotinib, formerly known as GLPG0634, is also about to enter phase III trials, but the details of these trials have not yet been revealed other than that they will begin mid-2016.

The BALANCE-2 study was funded by AbbVie. Dr. Genovese is a consultant for, and has received grants from AbbVie, Eli Lilly, Astellas, Vertex, Pfizer, Galapagos, and Gilead.

The DARWIN-1 study was funded by Galapagos. Dr. Westhovens is the principal investigator for the study. He also disclosed receiving research funding from Roche and speaker’s honoraria from Bristol-Myers Squibb.

Dr. Taylor was not involved in either study but has consulted for Eli Lilly, Pfizer, and Galapagos.

LONDON – ABT-494 and filgotinib – two investigational and highly selective oral Janus kinase-1 inhibitors – are both showing promise in the treatment of patients with rheumatoid arthritis, according to the results of two separate phase II studies presented at the European Congress of Rheumatology.

In the BALANCE-2 study, 62%-80% patients who had an inadequate response to methotrexate alone achieved the primary endpoint of an ACR20 response after 12 weeks of combination treatment with methotrexate and ABT-494, depending on the dose used, versus 46% for placebo plus methotrexate. The secondary endpoint of ACR50 was reached by a respective 38%-50% vs. 18%, and ACR70 response was achieved by 16%-28% vs. 6%.

And in the DARWIN-1 study, 56%-79% of patients treated with different doses of filgotinib plus methotrexate achieved the trial’s primary endpoint, which was again ACR20 at 12 weeks, versus 44% for placebo plus methotrexate. ACR50 and ACR70 responses were also similarly high and maintained up to 24 weeks of follow-up.

Both drugs had safety and tolerability data that supported their further development, the respective study investigators said.

“I think the results are rather straightforward. There was significant improvement in signs and symptoms of RA with fast onset,” said René Westhovens, MD, PhD, of the University of Leuven (Belgium), who presented the data from the DARWIN-1 study. “These robust data support the future development of filgotinib in RA,” he said.

Mark Genovese, MD, of Stanford (Calif.) University, who presented the findings of the BALANCE-2 study, said: “ABT-494 has been shown to have significant improvements in symptoms and signs [of RA] based on our endpoints of ACR [response], DAS[28], and CDAI [clinical disease activity index].” Like ACR50 and ACR70, DAS28 and CDAI were secondary efficacy endpoints and showed significantly greater changes from baseline versus placebo, started from around 2 weeks.

In an interview, Peter Taylor, PhD, who chaired the session at the meeting where the findings were presented, said: “We’ve seen a lot of data about JAK inhibitors at various stages of development at EULAR 2016, with varying selectivity, and the clinical data unequivocally validates Janus kinases as a therapeutic target.”

Dr. Taylor, the Norman Collisson Professor of Musculoskeletal Sciences at the University of Oxford (England), added: “[JAK inhibitors] show very significant promise with favorable safety data overall, but there are subtle differences between the drugs which need further detailed analysis to understand what it means in a clinical context.”

BALANCE-2 was a double-blind, placebo-controlled, dose-ranging phase IIB study designed to look at the safety and efficacy of ABT-494 in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Five doses of ABT-494 were tested: four given twice-daily (3, 6, 12, and 18 mg) and one given once-daily (24 mg). A total of 300 patients were enrolled and 299 were randomized, 50 to placebo, 50 each to the once-daily doses, and 49 to the twice-daily dose group. The mean weekly methotrexate dose at baseline was 14-16 mg across the groups.

“In general, the safety and tolerability of ABT-494 was satisfactory at the doses tested, consistent with what would have been expected,” Dr. Genovese said.

There was a numerically higher rate of any adverse event in the groups treated with ABT-494, at 40%, 46%, 58%, and 50% for the twice-daily regimens of 3, 6, 12, and 18 mg, as well as 35% for the once-daily 24-mg dose. The rate was 26% for placebo plus methotrexate.

Infections occurred in a respective 20%, 14%, 24%, 22% across the twice-daily dosing groups, respectively, compared with 18% for the once-daily 24-mg dose and 14% for placebo plus methotrexate, he noted. While there were some grade 2-3 abnormalities in liver enzymes and dose-related decreases in hemoglobin seen at higher doses, these did not appear to have significant clinical impact. The ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) was also affected slightly.

DARWIN-1 involved a total of 599 enrolled and 594 randomized and exposed patients with RA treated with placebo plus methotrexate or methotrexate plus one of six dosing regimens of filgotinib: 50, 100, or 200 mg once daily, or 25, 50, or 100 mg twice daily, for 24 weeks, with around 85 patients in each group. Each patient previously had an inadequate response to methotrexate alone. At the 12-week halfway point, patients taking placebo and the 50-mg dose could be reassigned to filgotinib 100 mg once daily or 50 mg twice daily if their tender or swollen joint counts had not improved. The mean weekly dose of methotrexate at baseline was 16.4-17.5 mg across the groups.

In addition to the improved ACR responses, significant improvements with filgotinib versus placebo were seen in the secondary endpoints of DAS28 (including DAS28 based on C-reactive protein), CDAI, and the Health Assessment Questionnaire-Disability Index.

There were infrequent serious adverse events, which included serious infections, and adverse events leading to discontinuations, Dr. Westhovens observed, and nothing that would not have been expected or different from placebo. There was a small decrease in neutrophil counts and increase in creatinine, but neither had any clinical consequences. Interestingly, there was a dose-dependent increase in hemoglobin but no reduction in lymphocyte counts, he said. HDL-C increased more than LDL-C.

Five phase III trials with ABT-494 are currently underway in patients with RA:

• SELECT-COMPARE will enroll an estimated 1,500 RA patients who have had an inadequate response to a stable dose of methotrexate and will compare additional treatment with ABT-494 against additional treatment with adalimumab (Humira) or placebo.

• SELECT-NEXT will enroll an estimated 600 RA patients who have had an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and are then given ABT-494 or placebo on top.

• SELECT-BEYOND will enroll around 450 RA patients on stable csDMARDs who have an inadequate response or intolerance to biologic DMARDs and compare adding ABT-494 or placebo.

• SELECT-MONOTHERAPY will enroll 600 RA patients who have had an inadequate methotrexate response and compare ABT-494 monotherapy to methotrexate monotherapy.

• SELECT-EARLY will enroll 975 methotrexate-naive, moderately-to-severely active RA patients and compare giving ABT-494 monotherapy to methotrexate monotherapy.

Most of these trials should have primary endpoint data available for analysis by mid to late 2017 or 2018 and be finished by 2020 or 2021.

Filgotinib, formerly known as GLPG0634, is also about to enter phase III trials, but the details of these trials have not yet been revealed other than that they will begin mid-2016.

The BALANCE-2 study was funded by AbbVie. Dr. Genovese is a consultant for, and has received grants from AbbVie, Eli Lilly, Astellas, Vertex, Pfizer, Galapagos, and Gilead.

The DARWIN-1 study was funded by Galapagos. Dr. Westhovens is the principal investigator for the study. He also disclosed receiving research funding from Roche and speaker’s honoraria from Bristol-Myers Squibb.

Dr. Taylor was not involved in either study but has consulted for Eli Lilly, Pfizer, and Galapagos.

LONDON – ABT-494 and filgotinib – two investigational and highly selective oral Janus kinase-1 inhibitors – are both showing promise in the treatment of patients with rheumatoid arthritis, according to the results of two separate phase II studies presented at the European Congress of Rheumatology.

In the BALANCE-2 study, 62%-80% patients who had an inadequate response to methotrexate alone achieved the primary endpoint of an ACR20 response after 12 weeks of combination treatment with methotrexate and ABT-494, depending on the dose used, versus 46% for placebo plus methotrexate. The secondary endpoint of ACR50 was reached by a respective 38%-50% vs. 18%, and ACR70 response was achieved by 16%-28% vs. 6%.

And in the DARWIN-1 study, 56%-79% of patients treated with different doses of filgotinib plus methotrexate achieved the trial’s primary endpoint, which was again ACR20 at 12 weeks, versus 44% for placebo plus methotrexate. ACR50 and ACR70 responses were also similarly high and maintained up to 24 weeks of follow-up.

Both drugs had safety and tolerability data that supported their further development, the respective study investigators said.

“I think the results are rather straightforward. There was significant improvement in signs and symptoms of RA with fast onset,” said René Westhovens, MD, PhD, of the University of Leuven (Belgium), who presented the data from the DARWIN-1 study. “These robust data support the future development of filgotinib in RA,” he said.

Mark Genovese, MD, of Stanford (Calif.) University, who presented the findings of the BALANCE-2 study, said: “ABT-494 has been shown to have significant improvements in symptoms and signs [of RA] based on our endpoints of ACR [response], DAS[28], and CDAI [clinical disease activity index].” Like ACR50 and ACR70, DAS28 and CDAI were secondary efficacy endpoints and showed significantly greater changes from baseline versus placebo, started from around 2 weeks.

In an interview, Peter Taylor, PhD, who chaired the session at the meeting where the findings were presented, said: “We’ve seen a lot of data about JAK inhibitors at various stages of development at EULAR 2016, with varying selectivity, and the clinical data unequivocally validates Janus kinases as a therapeutic target.”

Dr. Taylor, the Norman Collisson Professor of Musculoskeletal Sciences at the University of Oxford (England), added: “[JAK inhibitors] show very significant promise with favorable safety data overall, but there are subtle differences between the drugs which need further detailed analysis to understand what it means in a clinical context.”

BALANCE-2 was a double-blind, placebo-controlled, dose-ranging phase IIB study designed to look at the safety and efficacy of ABT-494 in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Five doses of ABT-494 were tested: four given twice-daily (3, 6, 12, and 18 mg) and one given once-daily (24 mg). A total of 300 patients were enrolled and 299 were randomized, 50 to placebo, 50 each to the once-daily doses, and 49 to the twice-daily dose group. The mean weekly methotrexate dose at baseline was 14-16 mg across the groups.

“In general, the safety and tolerability of ABT-494 was satisfactory at the doses tested, consistent with what would have been expected,” Dr. Genovese said.

There was a numerically higher rate of any adverse event in the groups treated with ABT-494, at 40%, 46%, 58%, and 50% for the twice-daily regimens of 3, 6, 12, and 18 mg, as well as 35% for the once-daily 24-mg dose. The rate was 26% for placebo plus methotrexate.

Infections occurred in a respective 20%, 14%, 24%, 22% across the twice-daily dosing groups, respectively, compared with 18% for the once-daily 24-mg dose and 14% for placebo plus methotrexate, he noted. While there were some grade 2-3 abnormalities in liver enzymes and dose-related decreases in hemoglobin seen at higher doses, these did not appear to have significant clinical impact. The ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) was also affected slightly.

DARWIN-1 involved a total of 599 enrolled and 594 randomized and exposed patients with RA treated with placebo plus methotrexate or methotrexate plus one of six dosing regimens of filgotinib: 50, 100, or 200 mg once daily, or 25, 50, or 100 mg twice daily, for 24 weeks, with around 85 patients in each group. Each patient previously had an inadequate response to methotrexate alone. At the 12-week halfway point, patients taking placebo and the 50-mg dose could be reassigned to filgotinib 100 mg once daily or 50 mg twice daily if their tender or swollen joint counts had not improved. The mean weekly dose of methotrexate at baseline was 16.4-17.5 mg across the groups.

In addition to the improved ACR responses, significant improvements with filgotinib versus placebo were seen in the secondary endpoints of DAS28 (including DAS28 based on C-reactive protein), CDAI, and the Health Assessment Questionnaire-Disability Index.

There were infrequent serious adverse events, which included serious infections, and adverse events leading to discontinuations, Dr. Westhovens observed, and nothing that would not have been expected or different from placebo. There was a small decrease in neutrophil counts and increase in creatinine, but neither had any clinical consequences. Interestingly, there was a dose-dependent increase in hemoglobin but no reduction in lymphocyte counts, he said. HDL-C increased more than LDL-C.

Five phase III trials with ABT-494 are currently underway in patients with RA:

• SELECT-COMPARE will enroll an estimated 1,500 RA patients who have had an inadequate response to a stable dose of methotrexate and will compare additional treatment with ABT-494 against additional treatment with adalimumab (Humira) or placebo.

• SELECT-NEXT will enroll an estimated 600 RA patients who have had an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and are then given ABT-494 or placebo on top.

• SELECT-BEYOND will enroll around 450 RA patients on stable csDMARDs who have an inadequate response or intolerance to biologic DMARDs and compare adding ABT-494 or placebo.

• SELECT-MONOTHERAPY will enroll 600 RA patients who have had an inadequate methotrexate response and compare ABT-494 monotherapy to methotrexate monotherapy.

• SELECT-EARLY will enroll 975 methotrexate-naive, moderately-to-severely active RA patients and compare giving ABT-494 monotherapy to methotrexate monotherapy.

Most of these trials should have primary endpoint data available for analysis by mid to late 2017 or 2018 and be finished by 2020 or 2021.

Filgotinib, formerly known as GLPG0634, is also about to enter phase III trials, but the details of these trials have not yet been revealed other than that they will begin mid-2016.

The BALANCE-2 study was funded by AbbVie. Dr. Genovese is a consultant for, and has received grants from AbbVie, Eli Lilly, Astellas, Vertex, Pfizer, Galapagos, and Gilead.

The DARWIN-1 study was funded by Galapagos. Dr. Westhovens is the principal investigator for the study. He also disclosed receiving research funding from Roche and speaker’s honoraria from Bristol-Myers Squibb.

Dr. Taylor was not involved in either study but has consulted for Eli Lilly, Pfizer, and Galapagos.