User login
Adding an oral, spleen tyrosine kinase inhibitor to an existing methotrexate regimen significantly lessened rheumatoid arthritis symptoms in patients with active disease, compared with placebo.
The results, though, were not without side effects, including hypertension, neutropenia, and diarrhea.
The phase II, double-blind, placebo-controlled study was sponsored by the drug’s maker, Rigel Pharmaceuticals, and published online Sept. 22 in the New England Journal of Medicine.
Spleen tyrosine kinase (Syk) is an intracellular cytoplasmic tyrosine kinase that is present in the synovium. It is an important mediator for “immunoreceptor signaling in macrophages, neutrophils, mast cells, and B cells,” the investigators noted. Syk inhibitors have previously been studied as therapeutic agents in cancers, including breast cancer and lymphoma.
The authors of the current study, led by Dr. Michael E. Weinblatt, codirector of the division of clinical rheumatology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, looked at 457 patients at 64 sites around the world, specifically Bulgaria, Colombia, Mexico, Poland, Romania, and the United States. All patients met the American College of Rheumatology’s 1987 criteria for rheumatoid arthritis and had had active RA for at least 6 months prior to enrolling in the trial. The 1987 ACR criteria define “active” RA as involving six swollen joints, plus six tender joints, plus either an elevated erythrocyte sedimentation rate or an elevated C-reactive protein level.
Patients also had been receiving a “stable dose” of methotrexate for at least 3 months (between 7.5 mg and 25 mg/week), plus folic acid or folinic acid supplements.
Patients were randomized to four groups. The first group (n = 152) received the Syk inhibitor known as R788, in twice-daily doses of 100 mg. The second group (n = 152) received once-daily, 150-mg doses of the drug. The third group received placebo twice daily, and the fourth received once-daily placebo (total number of placebo patients = 153).
The majority of patients in all groups were female, and the mean age was 52 years in all groups.
Overall, 67% of patients in the R788 twice-daily, 100-mg dose group registered an ACR 20 response at 6 months; in the once-daily, 150-mg group, the response rate was 57%. Both numbers were significantly higher than among placebo patients, who had a response rate of 35% (P less than .001 for both comparisons).
The authors also found that patients taking the twice-daily Syk inhibitor responded sooner than those on the once-daily regimen or placebo. By the end of the first week, 36% of twice-daily patients had an ACR 20 response, compared with 23% in the once-daily R788 group and 14% in the placebo group (P less than .001 for the twice-daily group and P = .04 for the once-daily group, compared with placebo).
Moreover, by 6 months, 31% of the twice-daily R788 group had achieved RA remission (as defined by a Disease Activity Score–28 less than 2.6), compared with 21% in the once-daily group and 7% in the placebo group (P less than .001 for the twice-daily group, and P = .003 for the once-daily group, compared with placebo).
The therapy did have adverse events. Ten patients in the once-daily group and five in the twice-daily group withdrew, mostly because of nausea and diarrhea. There were also two serious infections in the once-daily group and five in the twice-daily group, as well as neutropenia and hypertension.
“Overall, the mean difference in the change in systolic pressure from baseline to month 1 between the combined R788 group and the placebo group was an increase of approximately 5 mm Hg in the R788 group,” wrote the authors (N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa1000500]).
However, after either a reduction in R788 dose or addition of hypertensive medications, all patients experienced a drop in pressure, such that by 6 months each R788 group had less than a 1-mm Hg increase in systolic pressure over baseline.
In addition to disclosing that the study was supported by Rigel, the maker of R788, Dr. Weinblatt also reported having numerous financial relationships to pharmaceutical makers, including Rigel, as did his coauthors, three of whom are employees of Rigel and hold stock or stock options in the company.
The findings from this study show “these inhibitors have considerable promise as new drugs in the treatment of rheumatoid arthritis,” Juan Rivera, Ph.D., and Dr. Robert A. Colbert wrote in an editorial accompanying the article.
Although the exact means by which spleen tyrosine kinase affects RA are “not well understood,” Dr. Rivera and Dr. Colbert added that the beneficial effects of spleen tyrosine kinase “may be linked to its role as a signaling component of Fc receptors, which bind to immunoglobulins, including autoantibodies,” (N. Engl. J. Med. 2010 Sept. 22 [doi:10.1056NEJMe1006527]).
Nevertheless, “multiple receptors and many cell types (B cells, NK cells, and osteoclasts) use Syk,” they wrote. Therefore, “the contribution of Syk to the development or severity of arthritis is unlikely to be limited to Fc receptors.”
They added that “unlike many other tyrosine kinases, Syk has tumor-suppressing properties.” Moreover, reduced expression of Syk has been found in patients with breast cancer, meaning that the drug may be contraindicated in patients with a personal or family history of this disease.
In the years since the Food and Drug Administration’s approval of imatinib (Gleevec) as the first tyrosine kinase inhibitor for chronic myelogenous leukemia, “an ever-expanding inventory” of these drugs has been used to combat varying types of cancers. This study and others “usher in a new era that extends the therapeutic use of tyrosine kinase inhibitors beyond the treatment of cancers,” they wrote.
Dr. Rivera is the chief of the laboratory of molecular immunogenetics at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Colbert is a pediatric rheumatologist at NIAMS. They stated that they had no relevant financial disclosures.
The findings from this study show “these inhibitors have considerable promise as new drugs in the treatment of rheumatoid arthritis,” Juan Rivera, Ph.D., and Dr. Robert A. Colbert wrote in an editorial accompanying the article.
Although the exact means by which spleen tyrosine kinase affects RA are “not well understood,” Dr. Rivera and Dr. Colbert added that the beneficial effects of spleen tyrosine kinase “may be linked to its role as a signaling component of Fc receptors, which bind to immunoglobulins, including autoantibodies,” (N. Engl. J. Med. 2010 Sept. 22 [doi:10.1056NEJMe1006527]).
Nevertheless, “multiple receptors and many cell types (B cells, NK cells, and osteoclasts) use Syk,” they wrote. Therefore, “the contribution of Syk to the development or severity of arthritis is unlikely to be limited to Fc receptors.”
They added that “unlike many other tyrosine kinases, Syk has tumor-suppressing properties.” Moreover, reduced expression of Syk has been found in patients with breast cancer, meaning that the drug may be contraindicated in patients with a personal or family history of this disease.
In the years since the Food and Drug Administration’s approval of imatinib (Gleevec) as the first tyrosine kinase inhibitor for chronic myelogenous leukemia, “an ever-expanding inventory” of these drugs has been used to combat varying types of cancers. This study and others “usher in a new era that extends the therapeutic use of tyrosine kinase inhibitors beyond the treatment of cancers,” they wrote.
Dr. Rivera is the chief of the laboratory of molecular immunogenetics at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Colbert is a pediatric rheumatologist at NIAMS. They stated that they had no relevant financial disclosures.
The findings from this study show “these inhibitors have considerable promise as new drugs in the treatment of rheumatoid arthritis,” Juan Rivera, Ph.D., and Dr. Robert A. Colbert wrote in an editorial accompanying the article.
Although the exact means by which spleen tyrosine kinase affects RA are “not well understood,” Dr. Rivera and Dr. Colbert added that the beneficial effects of spleen tyrosine kinase “may be linked to its role as a signaling component of Fc receptors, which bind to immunoglobulins, including autoantibodies,” (N. Engl. J. Med. 2010 Sept. 22 [doi:10.1056NEJMe1006527]).
Nevertheless, “multiple receptors and many cell types (B cells, NK cells, and osteoclasts) use Syk,” they wrote. Therefore, “the contribution of Syk to the development or severity of arthritis is unlikely to be limited to Fc receptors.”
They added that “unlike many other tyrosine kinases, Syk has tumor-suppressing properties.” Moreover, reduced expression of Syk has been found in patients with breast cancer, meaning that the drug may be contraindicated in patients with a personal or family history of this disease.
In the years since the Food and Drug Administration’s approval of imatinib (Gleevec) as the first tyrosine kinase inhibitor for chronic myelogenous leukemia, “an ever-expanding inventory” of these drugs has been used to combat varying types of cancers. This study and others “usher in a new era that extends the therapeutic use of tyrosine kinase inhibitors beyond the treatment of cancers,” they wrote.
Dr. Rivera is the chief of the laboratory of molecular immunogenetics at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Colbert is a pediatric rheumatologist at NIAMS. They stated that they had no relevant financial disclosures.
Adding an oral, spleen tyrosine kinase inhibitor to an existing methotrexate regimen significantly lessened rheumatoid arthritis symptoms in patients with active disease, compared with placebo.
The results, though, were not without side effects, including hypertension, neutropenia, and diarrhea.
The phase II, double-blind, placebo-controlled study was sponsored by the drug’s maker, Rigel Pharmaceuticals, and published online Sept. 22 in the New England Journal of Medicine.
Spleen tyrosine kinase (Syk) is an intracellular cytoplasmic tyrosine kinase that is present in the synovium. It is an important mediator for “immunoreceptor signaling in macrophages, neutrophils, mast cells, and B cells,” the investigators noted. Syk inhibitors have previously been studied as therapeutic agents in cancers, including breast cancer and lymphoma.
The authors of the current study, led by Dr. Michael E. Weinblatt, codirector of the division of clinical rheumatology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, looked at 457 patients at 64 sites around the world, specifically Bulgaria, Colombia, Mexico, Poland, Romania, and the United States. All patients met the American College of Rheumatology’s 1987 criteria for rheumatoid arthritis and had had active RA for at least 6 months prior to enrolling in the trial. The 1987 ACR criteria define “active” RA as involving six swollen joints, plus six tender joints, plus either an elevated erythrocyte sedimentation rate or an elevated C-reactive protein level.
Patients also had been receiving a “stable dose” of methotrexate for at least 3 months (between 7.5 mg and 25 mg/week), plus folic acid or folinic acid supplements.
Patients were randomized to four groups. The first group (n = 152) received the Syk inhibitor known as R788, in twice-daily doses of 100 mg. The second group (n = 152) received once-daily, 150-mg doses of the drug. The third group received placebo twice daily, and the fourth received once-daily placebo (total number of placebo patients = 153).
The majority of patients in all groups were female, and the mean age was 52 years in all groups.
Overall, 67% of patients in the R788 twice-daily, 100-mg dose group registered an ACR 20 response at 6 months; in the once-daily, 150-mg group, the response rate was 57%. Both numbers were significantly higher than among placebo patients, who had a response rate of 35% (P less than .001 for both comparisons).
The authors also found that patients taking the twice-daily Syk inhibitor responded sooner than those on the once-daily regimen or placebo. By the end of the first week, 36% of twice-daily patients had an ACR 20 response, compared with 23% in the once-daily R788 group and 14% in the placebo group (P less than .001 for the twice-daily group and P = .04 for the once-daily group, compared with placebo).
Moreover, by 6 months, 31% of the twice-daily R788 group had achieved RA remission (as defined by a Disease Activity Score–28 less than 2.6), compared with 21% in the once-daily group and 7% in the placebo group (P less than .001 for the twice-daily group, and P = .003 for the once-daily group, compared with placebo).
The therapy did have adverse events. Ten patients in the once-daily group and five in the twice-daily group withdrew, mostly because of nausea and diarrhea. There were also two serious infections in the once-daily group and five in the twice-daily group, as well as neutropenia and hypertension.
“Overall, the mean difference in the change in systolic pressure from baseline to month 1 between the combined R788 group and the placebo group was an increase of approximately 5 mm Hg in the R788 group,” wrote the authors (N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa1000500]).
However, after either a reduction in R788 dose or addition of hypertensive medications, all patients experienced a drop in pressure, such that by 6 months each R788 group had less than a 1-mm Hg increase in systolic pressure over baseline.
In addition to disclosing that the study was supported by Rigel, the maker of R788, Dr. Weinblatt also reported having numerous financial relationships to pharmaceutical makers, including Rigel, as did his coauthors, three of whom are employees of Rigel and hold stock or stock options in the company.
Adding an oral, spleen tyrosine kinase inhibitor to an existing methotrexate regimen significantly lessened rheumatoid arthritis symptoms in patients with active disease, compared with placebo.
The results, though, were not without side effects, including hypertension, neutropenia, and diarrhea.
The phase II, double-blind, placebo-controlled study was sponsored by the drug’s maker, Rigel Pharmaceuticals, and published online Sept. 22 in the New England Journal of Medicine.
Spleen tyrosine kinase (Syk) is an intracellular cytoplasmic tyrosine kinase that is present in the synovium. It is an important mediator for “immunoreceptor signaling in macrophages, neutrophils, mast cells, and B cells,” the investigators noted. Syk inhibitors have previously been studied as therapeutic agents in cancers, including breast cancer and lymphoma.
The authors of the current study, led by Dr. Michael E. Weinblatt, codirector of the division of clinical rheumatology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, looked at 457 patients at 64 sites around the world, specifically Bulgaria, Colombia, Mexico, Poland, Romania, and the United States. All patients met the American College of Rheumatology’s 1987 criteria for rheumatoid arthritis and had had active RA for at least 6 months prior to enrolling in the trial. The 1987 ACR criteria define “active” RA as involving six swollen joints, plus six tender joints, plus either an elevated erythrocyte sedimentation rate or an elevated C-reactive protein level.
Patients also had been receiving a “stable dose” of methotrexate for at least 3 months (between 7.5 mg and 25 mg/week), plus folic acid or folinic acid supplements.
Patients were randomized to four groups. The first group (n = 152) received the Syk inhibitor known as R788, in twice-daily doses of 100 mg. The second group (n = 152) received once-daily, 150-mg doses of the drug. The third group received placebo twice daily, and the fourth received once-daily placebo (total number of placebo patients = 153).
The majority of patients in all groups were female, and the mean age was 52 years in all groups.
Overall, 67% of patients in the R788 twice-daily, 100-mg dose group registered an ACR 20 response at 6 months; in the once-daily, 150-mg group, the response rate was 57%. Both numbers were significantly higher than among placebo patients, who had a response rate of 35% (P less than .001 for both comparisons).
The authors also found that patients taking the twice-daily Syk inhibitor responded sooner than those on the once-daily regimen or placebo. By the end of the first week, 36% of twice-daily patients had an ACR 20 response, compared with 23% in the once-daily R788 group and 14% in the placebo group (P less than .001 for the twice-daily group and P = .04 for the once-daily group, compared with placebo).
Moreover, by 6 months, 31% of the twice-daily R788 group had achieved RA remission (as defined by a Disease Activity Score–28 less than 2.6), compared with 21% in the once-daily group and 7% in the placebo group (P less than .001 for the twice-daily group, and P = .003 for the once-daily group, compared with placebo).
The therapy did have adverse events. Ten patients in the once-daily group and five in the twice-daily group withdrew, mostly because of nausea and diarrhea. There were also two serious infections in the once-daily group and five in the twice-daily group, as well as neutropenia and hypertension.
“Overall, the mean difference in the change in systolic pressure from baseline to month 1 between the combined R788 group and the placebo group was an increase of approximately 5 mm Hg in the R788 group,” wrote the authors (N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa1000500]).
However, after either a reduction in R788 dose or addition of hypertensive medications, all patients experienced a drop in pressure, such that by 6 months each R788 group had less than a 1-mm Hg increase in systolic pressure over baseline.
In addition to disclosing that the study was supported by Rigel, the maker of R788, Dr. Weinblatt also reported having numerous financial relationships to pharmaceutical makers, including Rigel, as did his coauthors, three of whom are employees of Rigel and hold stock or stock options in the company.
Major Finding: Adding a twice-daily, 100-mg dose of a spleen tyrosine kinase inhibitor to an existing methotrexate regimen led to a 20% reduction in active rheumatoid arthritis among 67% of patients, compared with 35% of placebo patients (P less than .001).
Data Source: A phase II, double-blind, placebo-controlled, multicenter study.
Disclosures: The study was supported by a grant from Rigel Pharmaceuticals, the maker of R788. Three authors, including lead author Dr. Weinblatt, disclosed financial relationships to multiple pharmaceutical makers, including Rigel; the remaining three disclosed being employees of Rigel and having stock or stock options in the company.