User login
Response rates for rheumatoid arthritis patients taking either 5 mg or 10 mg twice-daily of the oral Janus kinase inhibitor tofacitinib were at least 20% greater after 6 months than for those who started on placebo and switched to the therapy, according to a new study.
Lead investigator Dr. Joel Kremer and his colleagues concluded that tofacitinib (Xeljanz) – when taken in combination with a nonbiologic disease-modifying antirheumatic drug (DMARD) – rapidly reduced the signs and symptoms of RA and improved physical functioning. But, they added, since the majority of patients in their study were taking methotrexate, extrapolating the results to other nonbiologic DMARDs should be done with caution.
They also noted that this trial supported findings in previous studies that tofacitinib works well with methotrexate. One such study was published in the Lancet and was also funded by Pfizer (Lancet 2013 [doi:10.1016/S0140-6736(12)61424-X]).
In the trial, paid for by Pfizer and conducted at 114 centers in 19 countries, 792 patients were randomly assigned 4:4:1:1 to twice-daily treatment with 5 mg of tofacitinib; 10 mg of tofacitinib; or placebo. The study was published Aug. 19 in the Annals of Internal Medicine.
At 3 months, placebo patients who did not respond were blindly switched to the 5-mg or 10-mg dose. Patients taking tofacitinib who did not respond at 3 months continued on the same dose. After 6 months, all patients still on placebo were switched blindly to either the 5-mg or 10-mg dose.
At 6 months, the response rates – defined as 20% improvement in the tender or painful and swollen joint count at three months (ACR20) – were 21% greater for patients taking 5 mg, and 26% greater for patients taking 10 mg, when compared with patients who had been on placebo for 3 months and then switched to one of the two doses.
There was a significantly greater improvement (P less than .001) at 3 months in the Health Assessment Questionnaire Disability Index (HAQ-DI) for patients in the treatment arms, and more of those patients had a Disease Activity Score for 28 joints (DAS28-4) of less than 2.6 at 6 months than did the placebo groups.
Patients were enrolled if they were aged 18 years or older and had a rheumatoid arthritis diagnosis consistent with the 1987 American College of Rheumatology criteria, and an inadequate response to treatment with one or more nonbiologic or biologic DMARDs. They were also required to continue treatment with one or more nonbiologic DMARDs throughout the study. Those taking methotrexate had to have been receiving it for at least 4 months and at stable dosing over at least 6 weeks before the study start. Low-dose, oral corticosteroid therapy was also allowed.
Exclusion criteria included previous treatment with lymphocyte-depleting therapies within a year of the study start; a depressed hemoglobin, hematocrit, leukocyte, or platelet count; or a history of autoimmune rheumatic disease or most cancers. Patients were also excluded if they had experienced an infection requiring hospitalization or intravenous antibiotics within 6 months of baseline, oral antibiotics within 2 weeks of baseline, or infection with herpes zoster, hepatitis B or C, or HIV.
Only 651 (82%) of the 792 patients enrolled completed the study. The mean age across the four treatment groups was 51-53 years old, and at least three-quarters of the participants were female. Two-thirds to 73% of patients continued to take background DMARDs during the study, and at least a quarter received two or more DMARDs. Methotrexate was the most frequently prescribed DMARD.
At 3 months, half of the placebo patients did not have a response and were then switched to either 5 mg (38 patients) or 10 mg (40 patients) of tofacitinib. In the treatment group at 3 months, 80 (26%) patients taking 5 mg and 58 (18%) patients taking 10 mg had no response. A total of 27% of those taking placebo had a response according to the ACR20 criteria.
The authors reported statistically significant response rates for ACR20 and ACR50 by the second week for both treatment arms. DAS28-4, DAS28-4 less than 2.6, and Functional Assessment of Chronic Illness Therapy-Fatigue response rates also were statistically significant over time for the tofacitinib treatment groups when compared with placebo.
The authors reported a higher adverse event and serious adverse event rate for patients on placebo, but a higher discontinuation rate for those taking tofacitinib.
Over a year, the adverse event rate was 172/100 patient-years for tofacitinib 5 mg, 176 for the 10 mg group, and 342 for the placebo-to-tofacitinib groups. The most common adverse events in the tofacitinib groups were upper respiratory tract infections and nasopharyngitis. The discontinuation rate from adverse events was 5.4/100 patient-years for placebo, 6.2 for the 5-mg group, and 9.7 for the 10-mg group.
The authors reported four treatment-related opportunistic infections: disseminated herpes zoster, cryptococcal pneumonia, and two cases of pulmonary tuberculosis. There were four deaths during the study, but only one, respiratory failure, was deemed to be treatment related.
The trial’s Cardiovascular Safety Endpoint Adjudication Committee determined that three patients had events that were notable: a transient ischemic attack in a patient taking 5 mg, a cerebrovascular accident in a patient taking 5 mg, and heart failure in a patient taking 10 mg who eventually died.
In patients taking tofacitinib, the authors also reported decreases in mean neutrophil counts at 3 months and increases in high- and low-density lipoprotein levels that were sustained at 12 months after baseline.
These results have not impressed the European Medicines Agency. In July, the EMA’s Committee for Medicinal Products for Human Use (CHMP) reaffirmed an opinion issued in April that tofacitinib’s benefits did not outweigh its risks. The CHMP recommended against approval of the drug. Pfizer said in a release that it is evaluating the opinion and "will determine next steps to resubmit" its approval application.
Dr. Kremer is the founder and president of the Consortium of Rheumatology Researchers of America (CORRONA) registry, which receives funding from Pfizer. He received a research grant from Pfizer to conduct the study and has been a consultant to Pfizer for the development of tofacitinib. Several other authors reported receiving grants from Pfizer and performing consultant work to Pfizer in relation to the trial. Other authors are Pfizer employees.
On Twitter @aliciaault
Dr. Kremer and his associates' report is a good study that will reassure rheumatologists that it is possible to use tofacitinib with nonbiologic DMARDs. It also reinforces that the dose of tofacitinib that is approved in North America is too low for many patients. There is a nice dose response for DAS28 remission (placebo, 2.6%; tofacitinib, 5 mg twice daily, 8.5%; tofacitinib 10 mg twice daily, 12.5%) and HAQ-DI (-0.16, -0.44, and -0.53, respectively). This was less the case for the ACR20 responses (30.8%, 52.1%, and 56.6%, respectively), but even here there is some trend toward a dose response.
On the other hand, there are some aspects of this study that could be clearer. The patients themselves had long disease duration and relatively high disease activity, so it is not clear that the results apply to all patients. Furthermore, about 10% of patients were on biologics prior to entering the study, and it is not clear how long those biologics had actually been stopped. (The inclusion criteria were not very clear on this aspect.) The patients were allowed on more than one DMARD, and it would have been good to know the breakdown of responses by the number of concomitant DMARDs. Also, nearly 60% of the patients were on corticosteroids, and there is no discussion of the effect of this drug on response or toxicity. Finally, the breakdown of patients was about 20% on placebo initially, compared with 80% on initial tofacitinib, thus introducing the possibility of an unbalanced early response.
The bottom line is that this article is generally reassuring and allows rheumatologists to use tofacitinib more broadly. It reinforces the need for sufficient data to allow higher doses of drugs to be approved in the United States, but, like many studies, leaves many questions (especially on how to consider combinations and corticosteroids) and does not allow the degree of generalization that would have been ideal.
Daniel E. Furst, M.D., is the Carl M. Pearson Professor of Rheumatology at the at the University of California, Los Angeles. He has been a consultant to Pfizer and has received travel support and meals from the company. He has also been a consultant to or received grant support from other pharmaceutical companies marketing drugs for rheumatoid arthritis, including Abbott, Amgen, and Bristol-Myers Squibb.
Dr. Kremer and his associates' report is a good study that will reassure rheumatologists that it is possible to use tofacitinib with nonbiologic DMARDs. It also reinforces that the dose of tofacitinib that is approved in North America is too low for many patients. There is a nice dose response for DAS28 remission (placebo, 2.6%; tofacitinib, 5 mg twice daily, 8.5%; tofacitinib 10 mg twice daily, 12.5%) and HAQ-DI (-0.16, -0.44, and -0.53, respectively). This was less the case for the ACR20 responses (30.8%, 52.1%, and 56.6%, respectively), but even here there is some trend toward a dose response.
On the other hand, there are some aspects of this study that could be clearer. The patients themselves had long disease duration and relatively high disease activity, so it is not clear that the results apply to all patients. Furthermore, about 10% of patients were on biologics prior to entering the study, and it is not clear how long those biologics had actually been stopped. (The inclusion criteria were not very clear on this aspect.) The patients were allowed on more than one DMARD, and it would have been good to know the breakdown of responses by the number of concomitant DMARDs. Also, nearly 60% of the patients were on corticosteroids, and there is no discussion of the effect of this drug on response or toxicity. Finally, the breakdown of patients was about 20% on placebo initially, compared with 80% on initial tofacitinib, thus introducing the possibility of an unbalanced early response.
The bottom line is that this article is generally reassuring and allows rheumatologists to use tofacitinib more broadly. It reinforces the need for sufficient data to allow higher doses of drugs to be approved in the United States, but, like many studies, leaves many questions (especially on how to consider combinations and corticosteroids) and does not allow the degree of generalization that would have been ideal.
Daniel E. Furst, M.D., is the Carl M. Pearson Professor of Rheumatology at the at the University of California, Los Angeles. He has been a consultant to Pfizer and has received travel support and meals from the company. He has also been a consultant to or received grant support from other pharmaceutical companies marketing drugs for rheumatoid arthritis, including Abbott, Amgen, and Bristol-Myers Squibb.
Dr. Kremer and his associates' report is a good study that will reassure rheumatologists that it is possible to use tofacitinib with nonbiologic DMARDs. It also reinforces that the dose of tofacitinib that is approved in North America is too low for many patients. There is a nice dose response for DAS28 remission (placebo, 2.6%; tofacitinib, 5 mg twice daily, 8.5%; tofacitinib 10 mg twice daily, 12.5%) and HAQ-DI (-0.16, -0.44, and -0.53, respectively). This was less the case for the ACR20 responses (30.8%, 52.1%, and 56.6%, respectively), but even here there is some trend toward a dose response.
On the other hand, there are some aspects of this study that could be clearer. The patients themselves had long disease duration and relatively high disease activity, so it is not clear that the results apply to all patients. Furthermore, about 10% of patients were on biologics prior to entering the study, and it is not clear how long those biologics had actually been stopped. (The inclusion criteria were not very clear on this aspect.) The patients were allowed on more than one DMARD, and it would have been good to know the breakdown of responses by the number of concomitant DMARDs. Also, nearly 60% of the patients were on corticosteroids, and there is no discussion of the effect of this drug on response or toxicity. Finally, the breakdown of patients was about 20% on placebo initially, compared with 80% on initial tofacitinib, thus introducing the possibility of an unbalanced early response.
The bottom line is that this article is generally reassuring and allows rheumatologists to use tofacitinib more broadly. It reinforces the need for sufficient data to allow higher doses of drugs to be approved in the United States, but, like many studies, leaves many questions (especially on how to consider combinations and corticosteroids) and does not allow the degree of generalization that would have been ideal.
Daniel E. Furst, M.D., is the Carl M. Pearson Professor of Rheumatology at the at the University of California, Los Angeles. He has been a consultant to Pfizer and has received travel support and meals from the company. He has also been a consultant to or received grant support from other pharmaceutical companies marketing drugs for rheumatoid arthritis, including Abbott, Amgen, and Bristol-Myers Squibb.
Response rates for rheumatoid arthritis patients taking either 5 mg or 10 mg twice-daily of the oral Janus kinase inhibitor tofacitinib were at least 20% greater after 6 months than for those who started on placebo and switched to the therapy, according to a new study.
Lead investigator Dr. Joel Kremer and his colleagues concluded that tofacitinib (Xeljanz) – when taken in combination with a nonbiologic disease-modifying antirheumatic drug (DMARD) – rapidly reduced the signs and symptoms of RA and improved physical functioning. But, they added, since the majority of patients in their study were taking methotrexate, extrapolating the results to other nonbiologic DMARDs should be done with caution.
They also noted that this trial supported findings in previous studies that tofacitinib works well with methotrexate. One such study was published in the Lancet and was also funded by Pfizer (Lancet 2013 [doi:10.1016/S0140-6736(12)61424-X]).
In the trial, paid for by Pfizer and conducted at 114 centers in 19 countries, 792 patients were randomly assigned 4:4:1:1 to twice-daily treatment with 5 mg of tofacitinib; 10 mg of tofacitinib; or placebo. The study was published Aug. 19 in the Annals of Internal Medicine.
At 3 months, placebo patients who did not respond were blindly switched to the 5-mg or 10-mg dose. Patients taking tofacitinib who did not respond at 3 months continued on the same dose. After 6 months, all patients still on placebo were switched blindly to either the 5-mg or 10-mg dose.
At 6 months, the response rates – defined as 20% improvement in the tender or painful and swollen joint count at three months (ACR20) – were 21% greater for patients taking 5 mg, and 26% greater for patients taking 10 mg, when compared with patients who had been on placebo for 3 months and then switched to one of the two doses.
There was a significantly greater improvement (P less than .001) at 3 months in the Health Assessment Questionnaire Disability Index (HAQ-DI) for patients in the treatment arms, and more of those patients had a Disease Activity Score for 28 joints (DAS28-4) of less than 2.6 at 6 months than did the placebo groups.
Patients were enrolled if they were aged 18 years or older and had a rheumatoid arthritis diagnosis consistent with the 1987 American College of Rheumatology criteria, and an inadequate response to treatment with one or more nonbiologic or biologic DMARDs. They were also required to continue treatment with one or more nonbiologic DMARDs throughout the study. Those taking methotrexate had to have been receiving it for at least 4 months and at stable dosing over at least 6 weeks before the study start. Low-dose, oral corticosteroid therapy was also allowed.
Exclusion criteria included previous treatment with lymphocyte-depleting therapies within a year of the study start; a depressed hemoglobin, hematocrit, leukocyte, or platelet count; or a history of autoimmune rheumatic disease or most cancers. Patients were also excluded if they had experienced an infection requiring hospitalization or intravenous antibiotics within 6 months of baseline, oral antibiotics within 2 weeks of baseline, or infection with herpes zoster, hepatitis B or C, or HIV.
Only 651 (82%) of the 792 patients enrolled completed the study. The mean age across the four treatment groups was 51-53 years old, and at least three-quarters of the participants were female. Two-thirds to 73% of patients continued to take background DMARDs during the study, and at least a quarter received two or more DMARDs. Methotrexate was the most frequently prescribed DMARD.
At 3 months, half of the placebo patients did not have a response and were then switched to either 5 mg (38 patients) or 10 mg (40 patients) of tofacitinib. In the treatment group at 3 months, 80 (26%) patients taking 5 mg and 58 (18%) patients taking 10 mg had no response. A total of 27% of those taking placebo had a response according to the ACR20 criteria.
The authors reported statistically significant response rates for ACR20 and ACR50 by the second week for both treatment arms. DAS28-4, DAS28-4 less than 2.6, and Functional Assessment of Chronic Illness Therapy-Fatigue response rates also were statistically significant over time for the tofacitinib treatment groups when compared with placebo.
The authors reported a higher adverse event and serious adverse event rate for patients on placebo, but a higher discontinuation rate for those taking tofacitinib.
Over a year, the adverse event rate was 172/100 patient-years for tofacitinib 5 mg, 176 for the 10 mg group, and 342 for the placebo-to-tofacitinib groups. The most common adverse events in the tofacitinib groups were upper respiratory tract infections and nasopharyngitis. The discontinuation rate from adverse events was 5.4/100 patient-years for placebo, 6.2 for the 5-mg group, and 9.7 for the 10-mg group.
The authors reported four treatment-related opportunistic infections: disseminated herpes zoster, cryptococcal pneumonia, and two cases of pulmonary tuberculosis. There were four deaths during the study, but only one, respiratory failure, was deemed to be treatment related.
The trial’s Cardiovascular Safety Endpoint Adjudication Committee determined that three patients had events that were notable: a transient ischemic attack in a patient taking 5 mg, a cerebrovascular accident in a patient taking 5 mg, and heart failure in a patient taking 10 mg who eventually died.
In patients taking tofacitinib, the authors also reported decreases in mean neutrophil counts at 3 months and increases in high- and low-density lipoprotein levels that were sustained at 12 months after baseline.
These results have not impressed the European Medicines Agency. In July, the EMA’s Committee for Medicinal Products for Human Use (CHMP) reaffirmed an opinion issued in April that tofacitinib’s benefits did not outweigh its risks. The CHMP recommended against approval of the drug. Pfizer said in a release that it is evaluating the opinion and "will determine next steps to resubmit" its approval application.
Dr. Kremer is the founder and president of the Consortium of Rheumatology Researchers of America (CORRONA) registry, which receives funding from Pfizer. He received a research grant from Pfizer to conduct the study and has been a consultant to Pfizer for the development of tofacitinib. Several other authors reported receiving grants from Pfizer and performing consultant work to Pfizer in relation to the trial. Other authors are Pfizer employees.
On Twitter @aliciaault
Response rates for rheumatoid arthritis patients taking either 5 mg or 10 mg twice-daily of the oral Janus kinase inhibitor tofacitinib were at least 20% greater after 6 months than for those who started on placebo and switched to the therapy, according to a new study.
Lead investigator Dr. Joel Kremer and his colleagues concluded that tofacitinib (Xeljanz) – when taken in combination with a nonbiologic disease-modifying antirheumatic drug (DMARD) – rapidly reduced the signs and symptoms of RA and improved physical functioning. But, they added, since the majority of patients in their study were taking methotrexate, extrapolating the results to other nonbiologic DMARDs should be done with caution.
They also noted that this trial supported findings in previous studies that tofacitinib works well with methotrexate. One such study was published in the Lancet and was also funded by Pfizer (Lancet 2013 [doi:10.1016/S0140-6736(12)61424-X]).
In the trial, paid for by Pfizer and conducted at 114 centers in 19 countries, 792 patients were randomly assigned 4:4:1:1 to twice-daily treatment with 5 mg of tofacitinib; 10 mg of tofacitinib; or placebo. The study was published Aug. 19 in the Annals of Internal Medicine.
At 3 months, placebo patients who did not respond were blindly switched to the 5-mg or 10-mg dose. Patients taking tofacitinib who did not respond at 3 months continued on the same dose. After 6 months, all patients still on placebo were switched blindly to either the 5-mg or 10-mg dose.
At 6 months, the response rates – defined as 20% improvement in the tender or painful and swollen joint count at three months (ACR20) – were 21% greater for patients taking 5 mg, and 26% greater for patients taking 10 mg, when compared with patients who had been on placebo for 3 months and then switched to one of the two doses.
There was a significantly greater improvement (P less than .001) at 3 months in the Health Assessment Questionnaire Disability Index (HAQ-DI) for patients in the treatment arms, and more of those patients had a Disease Activity Score for 28 joints (DAS28-4) of less than 2.6 at 6 months than did the placebo groups.
Patients were enrolled if they were aged 18 years or older and had a rheumatoid arthritis diagnosis consistent with the 1987 American College of Rheumatology criteria, and an inadequate response to treatment with one or more nonbiologic or biologic DMARDs. They were also required to continue treatment with one or more nonbiologic DMARDs throughout the study. Those taking methotrexate had to have been receiving it for at least 4 months and at stable dosing over at least 6 weeks before the study start. Low-dose, oral corticosteroid therapy was also allowed.
Exclusion criteria included previous treatment with lymphocyte-depleting therapies within a year of the study start; a depressed hemoglobin, hematocrit, leukocyte, or platelet count; or a history of autoimmune rheumatic disease or most cancers. Patients were also excluded if they had experienced an infection requiring hospitalization or intravenous antibiotics within 6 months of baseline, oral antibiotics within 2 weeks of baseline, or infection with herpes zoster, hepatitis B or C, or HIV.
Only 651 (82%) of the 792 patients enrolled completed the study. The mean age across the four treatment groups was 51-53 years old, and at least three-quarters of the participants were female. Two-thirds to 73% of patients continued to take background DMARDs during the study, and at least a quarter received two or more DMARDs. Methotrexate was the most frequently prescribed DMARD.
At 3 months, half of the placebo patients did not have a response and were then switched to either 5 mg (38 patients) or 10 mg (40 patients) of tofacitinib. In the treatment group at 3 months, 80 (26%) patients taking 5 mg and 58 (18%) patients taking 10 mg had no response. A total of 27% of those taking placebo had a response according to the ACR20 criteria.
The authors reported statistically significant response rates for ACR20 and ACR50 by the second week for both treatment arms. DAS28-4, DAS28-4 less than 2.6, and Functional Assessment of Chronic Illness Therapy-Fatigue response rates also were statistically significant over time for the tofacitinib treatment groups when compared with placebo.
The authors reported a higher adverse event and serious adverse event rate for patients on placebo, but a higher discontinuation rate for those taking tofacitinib.
Over a year, the adverse event rate was 172/100 patient-years for tofacitinib 5 mg, 176 for the 10 mg group, and 342 for the placebo-to-tofacitinib groups. The most common adverse events in the tofacitinib groups were upper respiratory tract infections and nasopharyngitis. The discontinuation rate from adverse events was 5.4/100 patient-years for placebo, 6.2 for the 5-mg group, and 9.7 for the 10-mg group.
The authors reported four treatment-related opportunistic infections: disseminated herpes zoster, cryptococcal pneumonia, and two cases of pulmonary tuberculosis. There were four deaths during the study, but only one, respiratory failure, was deemed to be treatment related.
The trial’s Cardiovascular Safety Endpoint Adjudication Committee determined that three patients had events that were notable: a transient ischemic attack in a patient taking 5 mg, a cerebrovascular accident in a patient taking 5 mg, and heart failure in a patient taking 10 mg who eventually died.
In patients taking tofacitinib, the authors also reported decreases in mean neutrophil counts at 3 months and increases in high- and low-density lipoprotein levels that were sustained at 12 months after baseline.
These results have not impressed the European Medicines Agency. In July, the EMA’s Committee for Medicinal Products for Human Use (CHMP) reaffirmed an opinion issued in April that tofacitinib’s benefits did not outweigh its risks. The CHMP recommended against approval of the drug. Pfizer said in a release that it is evaluating the opinion and "will determine next steps to resubmit" its approval application.
Dr. Kremer is the founder and president of the Consortium of Rheumatology Researchers of America (CORRONA) registry, which receives funding from Pfizer. He received a research grant from Pfizer to conduct the study and has been a consultant to Pfizer for the development of tofacitinib. Several other authors reported receiving grants from Pfizer and performing consultant work to Pfizer in relation to the trial. Other authors are Pfizer employees.
On Twitter @aliciaault
FROM ANNALS OF INTERNAL MEDICINE
Major finding: ACR20 response rates were 21% greater in the 5 mg twice-daily tofacitinib arm and 26% greater in the 10 mg twice-daily arm, when compared with a combined placebo arm.
Data source: A 1-year, double-blind, 792-patient study, conducted in 114 centers in 19 countries.
Disclosures: The study was funded by Pfizer. Dr. Kremer is the founder and president of the Consortium of Rheumatology Researchers of North America. (CORRONA) registry, which receives funding from Pfizer. He received a research grant from Pfizer to conduct the study and has been a consultant to Pfizer for the development of tofacitinib. Several other authors reported receiving grants from Pfizer and performing consultant work to Pfizer in relation to the trial. Other authors are Pfizer employees.
