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The Food and Drug Administration Arthritis Advisory Committee has voted to recommend the 2-mg dose of baricitinib, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis who have responded inadequately or poorly to methotrexate but rejected a 4-mg dose of the same drug.
In separate votes on efficacy of the 2-mg and 4-mg doses of baricitinib (14-1 and 15-0, respectively), on their safety (9-6 and 4-11), and on their benefit-risk ratio (10-5 and 5-10), the advisory committee consistently backed the 2-mg dose, but the committee rejected the 4-mg dose despite its effectiveness in improving the symptoms of rheumatoid arthritis. Although the FDA does not always follow the advice of its advisory committees, it generally does.
The New Drug Application was resubmitted by Eli Lilly and Incyte. The proposed doses included a 2-mg once-daily dose and a 4-mg dose for some patients. The original submission was filed in January of 2016 with an indication to treat moderate to severe rheumatoid arthritis, but that application was rejected primarily because of concerns about thrombotic events. Other issues with the original application included inadequate safety exposure for the 2-mg dose of baricitinib, as well as inconsistent findings concerning the efficacy of the higher 4-mg dose.
The resubmission addressed several of the issues noted by the FDA, and changed the indication to treat patients with moderate to severe RA who have had an inadequate response to methotrexate. Along with the different indication, the dosing regimen shifted to 2 mg once daily. For patients who did not adequately respond to disease-modifying antirheumatic drugs (DMARDS) or had an intolerance for one or more of these drugs, a 4-mg dose was recommended; after disease activity had been controlled, a taper to 2 mg once daily could be considered.
Apart from changes in the drug dosage and indication, the resubmission also included accumulated safety data, comparative epidemiologic data concerning venous thromboembolism and pulmonary embolism, and efficacy analyses to support the new dosing recommendations.
“The risk-benefit ratio may be less good here,” stated Donald Miller, PharmD, a professor of pharmacy practice at North Dakota State University, Fargo. “If there is a safety issue, it’s more likely to be a problem with the 4-mg dose.”
Jon Russell, MD, PhD, medical director of Fibromyalgia Research and Consulting, San Antonio, felt that the manufacturer understood that the safety signal indicated that the benefits outweighed the risks with the 4-mg dose of baricitinib.
“The drug is efficacious in resistant rheumatoid arthritis, and rheumatoid arthritis is a devastating disease. Organs are being destroyed, joints as well as organs, and it’s war. We need to make the patient aware that it’s war and then fight it like it is,” he said.
Many of the committee members mentioned that the efficacies of the 2-mg and 4-mg doses were not in question, primarily based on the data from four phase 3 clinical trials.
The studies RA-BEACON (JADW), RA-BUILD (JADX), RA-BEGIN (JADZ), and RA-BEAM (JADV) were all randomized phase 3 trials that evaluated the efficacy of baricitinib in patients with moderate to severe RA.
RA-BEACON and RA-BUILD both had similar designs and compared 2-mg and 4-mg doses of baricitinib with placebo; the trials primarily differed in their patient populations.
RA-BEACON. Investigators looked at 527 randomized patients who had failed treatment with a biologic DMARD with nearly half failing multiple classes of this drug. The primary endpoint for this study was met, with the 4-mg dose showing superior results, compared with placebo, based on American College of Rheumatology (ACR) 20 scores (P less than .0001). As early as week 1 of the trial, both patients receiving 2 mg and those receiving 4 mg of baricitinib showed significant improvement, compared with placebo. By week 4, the 4-mg dose produced as much improvement as the 2-mg dose achieved over nearly 6 months. While the 4-mg dose was considered more effective, the 2-mg dose showed improvement in ACR 20 scores, change in Disease Activity Score 28 C-reactive protein (DAS28-CRP), and change in health assessment questionnaire disability index (HAQ-DI) (P less than .001). Neither the 4-mg nor the 2-mg dose was able to reduce Simple Disease Activity Index (SDAI) scores, a difficult endpoint to achieve, particularly in such a short time frame.
RA-BUILD. The researchers looked at patients who had failed treatment with conventional DMARDs and had not been treated with biologic DMARDS. The investigators looked at 684 randomized patients and saw similar results to RA-BEACON, with both the 2-mg and 4-mg doses displaying significant improvement in ACR 20, change in DAS28-CRP, and change in HAQ-DI, as well as SDAI remission which had been absent in RA-BEACON. Patients taking the 4-mg dose showed improvement in morning joint stiffness duration and severity (P less than .0001), as well as improvements in worst joint pain (P less than .0001) and tiredness (P less than .027).
RA-BEGIN. The investigators took a different approach and compared various drug combinations, including baricitinib 4 mg alone or in combination with oral methotrexate or in patients taking methotrexate who were DMARD-naive. Ultimately, this trial displayed that baricitinib 4 mg alone was superior to methotrexate, according to ACR 20 scores. This held true across all clinical measures at week 24 whether baricitinib was administered alone or in combination with methotrexate. As it had in the previously discussed trials, the 4-mg dose improved all of the previously mentioned test scores, compared with methotrexate (P less than .0001) except for modified Total Sharp Score (mTSS) (P = 0.158). When baricitinib 4 mg was used in conjunction with methotrexate, improvements in test scores, including mTSS, were statistically significant.
RA-BEAM. The researchers compared baricitinib 4 mg with placebo and adalimumab in 1,305 patients. All patients maintained a background level of methotrexate to improve the efficacy of adalimumab. Consistent with previous studies, baricitinib 4 mg outperformed other therapies and placebo in improvement in ACR 20, change in DAS28-CRP, change in HAQ-DI, and SDAI remission, as well as improvements in morning joint stiffness duration and severity, worst joint pain, and worst tiredness (P less than .0001).
Despite the clear efficacy of baricitinib 4 mg, the primary issue of contention was safety and benefit-to-risk ratio. The primary safety concerns were serious infection from opportunistic pathogens, herpes zoster, various malignancies, arterial and venous thrombosis, and laboratory abnormalities including elevated platelet counts and liver test elevations.
The Food and Drug Administration Arthritis Advisory Committee has voted to recommend the 2-mg dose of baricitinib, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis who have responded inadequately or poorly to methotrexate but rejected a 4-mg dose of the same drug.
In separate votes on efficacy of the 2-mg and 4-mg doses of baricitinib (14-1 and 15-0, respectively), on their safety (9-6 and 4-11), and on their benefit-risk ratio (10-5 and 5-10), the advisory committee consistently backed the 2-mg dose, but the committee rejected the 4-mg dose despite its effectiveness in improving the symptoms of rheumatoid arthritis. Although the FDA does not always follow the advice of its advisory committees, it generally does.
The New Drug Application was resubmitted by Eli Lilly and Incyte. The proposed doses included a 2-mg once-daily dose and a 4-mg dose for some patients. The original submission was filed in January of 2016 with an indication to treat moderate to severe rheumatoid arthritis, but that application was rejected primarily because of concerns about thrombotic events. Other issues with the original application included inadequate safety exposure for the 2-mg dose of baricitinib, as well as inconsistent findings concerning the efficacy of the higher 4-mg dose.
The resubmission addressed several of the issues noted by the FDA, and changed the indication to treat patients with moderate to severe RA who have had an inadequate response to methotrexate. Along with the different indication, the dosing regimen shifted to 2 mg once daily. For patients who did not adequately respond to disease-modifying antirheumatic drugs (DMARDS) or had an intolerance for one or more of these drugs, a 4-mg dose was recommended; after disease activity had been controlled, a taper to 2 mg once daily could be considered.
Apart from changes in the drug dosage and indication, the resubmission also included accumulated safety data, comparative epidemiologic data concerning venous thromboembolism and pulmonary embolism, and efficacy analyses to support the new dosing recommendations.
“The risk-benefit ratio may be less good here,” stated Donald Miller, PharmD, a professor of pharmacy practice at North Dakota State University, Fargo. “If there is a safety issue, it’s more likely to be a problem with the 4-mg dose.”
Jon Russell, MD, PhD, medical director of Fibromyalgia Research and Consulting, San Antonio, felt that the manufacturer understood that the safety signal indicated that the benefits outweighed the risks with the 4-mg dose of baricitinib.
“The drug is efficacious in resistant rheumatoid arthritis, and rheumatoid arthritis is a devastating disease. Organs are being destroyed, joints as well as organs, and it’s war. We need to make the patient aware that it’s war and then fight it like it is,” he said.
Many of the committee members mentioned that the efficacies of the 2-mg and 4-mg doses were not in question, primarily based on the data from four phase 3 clinical trials.
The studies RA-BEACON (JADW), RA-BUILD (JADX), RA-BEGIN (JADZ), and RA-BEAM (JADV) were all randomized phase 3 trials that evaluated the efficacy of baricitinib in patients with moderate to severe RA.
RA-BEACON and RA-BUILD both had similar designs and compared 2-mg and 4-mg doses of baricitinib with placebo; the trials primarily differed in their patient populations.
RA-BEACON. Investigators looked at 527 randomized patients who had failed treatment with a biologic DMARD with nearly half failing multiple classes of this drug. The primary endpoint for this study was met, with the 4-mg dose showing superior results, compared with placebo, based on American College of Rheumatology (ACR) 20 scores (P less than .0001). As early as week 1 of the trial, both patients receiving 2 mg and those receiving 4 mg of baricitinib showed significant improvement, compared with placebo. By week 4, the 4-mg dose produced as much improvement as the 2-mg dose achieved over nearly 6 months. While the 4-mg dose was considered more effective, the 2-mg dose showed improvement in ACR 20 scores, change in Disease Activity Score 28 C-reactive protein (DAS28-CRP), and change in health assessment questionnaire disability index (HAQ-DI) (P less than .001). Neither the 4-mg nor the 2-mg dose was able to reduce Simple Disease Activity Index (SDAI) scores, a difficult endpoint to achieve, particularly in such a short time frame.
RA-BUILD. The researchers looked at patients who had failed treatment with conventional DMARDs and had not been treated with biologic DMARDS. The investigators looked at 684 randomized patients and saw similar results to RA-BEACON, with both the 2-mg and 4-mg doses displaying significant improvement in ACR 20, change in DAS28-CRP, and change in HAQ-DI, as well as SDAI remission which had been absent in RA-BEACON. Patients taking the 4-mg dose showed improvement in morning joint stiffness duration and severity (P less than .0001), as well as improvements in worst joint pain (P less than .0001) and tiredness (P less than .027).
RA-BEGIN. The investigators took a different approach and compared various drug combinations, including baricitinib 4 mg alone or in combination with oral methotrexate or in patients taking methotrexate who were DMARD-naive. Ultimately, this trial displayed that baricitinib 4 mg alone was superior to methotrexate, according to ACR 20 scores. This held true across all clinical measures at week 24 whether baricitinib was administered alone or in combination with methotrexate. As it had in the previously discussed trials, the 4-mg dose improved all of the previously mentioned test scores, compared with methotrexate (P less than .0001) except for modified Total Sharp Score (mTSS) (P = 0.158). When baricitinib 4 mg was used in conjunction with methotrexate, improvements in test scores, including mTSS, were statistically significant.
RA-BEAM. The researchers compared baricitinib 4 mg with placebo and adalimumab in 1,305 patients. All patients maintained a background level of methotrexate to improve the efficacy of adalimumab. Consistent with previous studies, baricitinib 4 mg outperformed other therapies and placebo in improvement in ACR 20, change in DAS28-CRP, change in HAQ-DI, and SDAI remission, as well as improvements in morning joint stiffness duration and severity, worst joint pain, and worst tiredness (P less than .0001).
Despite the clear efficacy of baricitinib 4 mg, the primary issue of contention was safety and benefit-to-risk ratio. The primary safety concerns were serious infection from opportunistic pathogens, herpes zoster, various malignancies, arterial and venous thrombosis, and laboratory abnormalities including elevated platelet counts and liver test elevations.
The Food and Drug Administration Arthritis Advisory Committee has voted to recommend the 2-mg dose of baricitinib, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis who have responded inadequately or poorly to methotrexate but rejected a 4-mg dose of the same drug.
In separate votes on efficacy of the 2-mg and 4-mg doses of baricitinib (14-1 and 15-0, respectively), on their safety (9-6 and 4-11), and on their benefit-risk ratio (10-5 and 5-10), the advisory committee consistently backed the 2-mg dose, but the committee rejected the 4-mg dose despite its effectiveness in improving the symptoms of rheumatoid arthritis. Although the FDA does not always follow the advice of its advisory committees, it generally does.
The New Drug Application was resubmitted by Eli Lilly and Incyte. The proposed doses included a 2-mg once-daily dose and a 4-mg dose for some patients. The original submission was filed in January of 2016 with an indication to treat moderate to severe rheumatoid arthritis, but that application was rejected primarily because of concerns about thrombotic events. Other issues with the original application included inadequate safety exposure for the 2-mg dose of baricitinib, as well as inconsistent findings concerning the efficacy of the higher 4-mg dose.
The resubmission addressed several of the issues noted by the FDA, and changed the indication to treat patients with moderate to severe RA who have had an inadequate response to methotrexate. Along with the different indication, the dosing regimen shifted to 2 mg once daily. For patients who did not adequately respond to disease-modifying antirheumatic drugs (DMARDS) or had an intolerance for one or more of these drugs, a 4-mg dose was recommended; after disease activity had been controlled, a taper to 2 mg once daily could be considered.
Apart from changes in the drug dosage and indication, the resubmission also included accumulated safety data, comparative epidemiologic data concerning venous thromboembolism and pulmonary embolism, and efficacy analyses to support the new dosing recommendations.
“The risk-benefit ratio may be less good here,” stated Donald Miller, PharmD, a professor of pharmacy practice at North Dakota State University, Fargo. “If there is a safety issue, it’s more likely to be a problem with the 4-mg dose.”
Jon Russell, MD, PhD, medical director of Fibromyalgia Research and Consulting, San Antonio, felt that the manufacturer understood that the safety signal indicated that the benefits outweighed the risks with the 4-mg dose of baricitinib.
“The drug is efficacious in resistant rheumatoid arthritis, and rheumatoid arthritis is a devastating disease. Organs are being destroyed, joints as well as organs, and it’s war. We need to make the patient aware that it’s war and then fight it like it is,” he said.
Many of the committee members mentioned that the efficacies of the 2-mg and 4-mg doses were not in question, primarily based on the data from four phase 3 clinical trials.
The studies RA-BEACON (JADW), RA-BUILD (JADX), RA-BEGIN (JADZ), and RA-BEAM (JADV) were all randomized phase 3 trials that evaluated the efficacy of baricitinib in patients with moderate to severe RA.
RA-BEACON and RA-BUILD both had similar designs and compared 2-mg and 4-mg doses of baricitinib with placebo; the trials primarily differed in their patient populations.
RA-BEACON. Investigators looked at 527 randomized patients who had failed treatment with a biologic DMARD with nearly half failing multiple classes of this drug. The primary endpoint for this study was met, with the 4-mg dose showing superior results, compared with placebo, based on American College of Rheumatology (ACR) 20 scores (P less than .0001). As early as week 1 of the trial, both patients receiving 2 mg and those receiving 4 mg of baricitinib showed significant improvement, compared with placebo. By week 4, the 4-mg dose produced as much improvement as the 2-mg dose achieved over nearly 6 months. While the 4-mg dose was considered more effective, the 2-mg dose showed improvement in ACR 20 scores, change in Disease Activity Score 28 C-reactive protein (DAS28-CRP), and change in health assessment questionnaire disability index (HAQ-DI) (P less than .001). Neither the 4-mg nor the 2-mg dose was able to reduce Simple Disease Activity Index (SDAI) scores, a difficult endpoint to achieve, particularly in such a short time frame.
RA-BUILD. The researchers looked at patients who had failed treatment with conventional DMARDs and had not been treated with biologic DMARDS. The investigators looked at 684 randomized patients and saw similar results to RA-BEACON, with both the 2-mg and 4-mg doses displaying significant improvement in ACR 20, change in DAS28-CRP, and change in HAQ-DI, as well as SDAI remission which had been absent in RA-BEACON. Patients taking the 4-mg dose showed improvement in morning joint stiffness duration and severity (P less than .0001), as well as improvements in worst joint pain (P less than .0001) and tiredness (P less than .027).
RA-BEGIN. The investigators took a different approach and compared various drug combinations, including baricitinib 4 mg alone or in combination with oral methotrexate or in patients taking methotrexate who were DMARD-naive. Ultimately, this trial displayed that baricitinib 4 mg alone was superior to methotrexate, according to ACR 20 scores. This held true across all clinical measures at week 24 whether baricitinib was administered alone or in combination with methotrexate. As it had in the previously discussed trials, the 4-mg dose improved all of the previously mentioned test scores, compared with methotrexate (P less than .0001) except for modified Total Sharp Score (mTSS) (P = 0.158). When baricitinib 4 mg was used in conjunction with methotrexate, improvements in test scores, including mTSS, were statistically significant.
RA-BEAM. The researchers compared baricitinib 4 mg with placebo and adalimumab in 1,305 patients. All patients maintained a background level of methotrexate to improve the efficacy of adalimumab. Consistent with previous studies, baricitinib 4 mg outperformed other therapies and placebo in improvement in ACR 20, change in DAS28-CRP, change in HAQ-DI, and SDAI remission, as well as improvements in morning joint stiffness duration and severity, worst joint pain, and worst tiredness (P less than .0001).
Despite the clear efficacy of baricitinib 4 mg, the primary issue of contention was safety and benefit-to-risk ratio. The primary safety concerns were serious infection from opportunistic pathogens, herpes zoster, various malignancies, arterial and venous thrombosis, and laboratory abnormalities including elevated platelet counts and liver test elevations.