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VIDEO: Venetoclax/rituximab prolongs PFS in relapsed/refractory CLL
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
REPORTING FROM ASH 2017
Don’t choose hormones to protect postmenopausal women
Hormone therapy should not be used to prevent chronic conditions in postmenopausal women, according to updated recommendations from the U.S. Preventive Services Task Force. The recommendations were published online Dec. 12 in JAMA.
In the latest recommendation statement, the USPSTF issued D recommendations against using combination estrogen and progestin to prevent chronic conditions in postmenopausal women and against using estrogen only to prevent chronic conditions in postmenopausal women who have undergone hysterectomies (JAMA. 2017 Dec 12. doi: 10.1001/jama.2017.18261). A grade D recommendation is defined as “The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.”
In response to public comments, the USPSTF team made several changes including adjusting the language to clarify that the recommendations apply only to postmenopausal women, and adding tables showing estimates of increased or decreased risk of various outcomes for postmenopausal women receiving different hormone therapies.
Approximately 40,000 women aged 53-79 years were included in an evidence report from Gerald Gartlehner, MD, of the University of North Carolina, Chapel Hill, and his colleagues that accompanied the recommendations (JAMA. 2017 Dec 12. doi: 10.1001/jama.2017.16952).
The researchers found that women taking estrogen alone had significantly lower risk of breast cancer, diabetes, and osteoporotic fractures, but significantly higher risk of gallbladder disease, stroke, urinary incontinence, and venous thromboembolism, compared with women taking placebo. In addition, women using a combination of estrogen and progestin had significantly lower risk of colorectal cancer, diabetes, and osteoporotic fractures, but significantly higher risk of breast cancer, probable dementia, gallbladder disease, stroke, urinary incontinence, and venous thromboembolism, compared with women taking placebo.
“Hormone therapy for the primary prevention of chronic conditions in menopausal women is associated with some beneficial effects but also with a substantial increase of risks for harms,” and the current evidence for the risks and benefits of hormone therapy is inconclusive, the researchers said.
The final recommendation remains consistent with the USPSTF draft statement issued earlier in 2017 and with the final recommendation statements issued in 2012.
The researchers had no relevant financial conflicts to disclose.
Twenty-five years ago, the U.S. Preventive Services Task Force advised clinicians to consider hormone therapy for the prevention of disease in all women, particularly those at risk for coronary heart disease, Deborah Grady, MD, wrote in an editorial (JAMA Intern Med. 2017 Dec 12. doi: 10.1001/jamainternmed.2017.7861). Dr. Grady was one of the coauthors of a literature review supporting the American College of Physicians’ recommendation to counsel asymptomatic postmenopausal women about hormone therapy based on data from observational studies. “No randomized trials with clinical outcomes had been conducted,” Dr. Grady said. By 2002, data from three large randomized trials told a different story, and the Task Force recommended against using estrogen alone as a strategy to prevent chronic conditions in postmenopausal women, she noted.
“I believe that the fear of hormone therapy is overblown,” Dr. Grady wrote. “When adequately informed, women with moderate to severe symptoms and without contraindications should be able to take such small risks if hormone therapy improves symptoms and quality of life,” she said.
In fact, professional societies, including the North American Menopause Society, the American College of Obstetricians and Gynecologists, and the Endocrine Society support hormone therapy for symptomatic women who are recently menopausal, said Dr. Grady. However, a key lesson learned from the ongoing research on hormone therapy is the importance of conducting clinical trials that are large enough to identify serious adverse effects, she added.
Dr. Grady is affiliated with the University of California, San Francisco. She had no financial conflicts to disclose.
Twenty-five years ago, the U.S. Preventive Services Task Force advised clinicians to consider hormone therapy for the prevention of disease in all women, particularly those at risk for coronary heart disease, Deborah Grady, MD, wrote in an editorial (JAMA Intern Med. 2017 Dec 12. doi: 10.1001/jamainternmed.2017.7861). Dr. Grady was one of the coauthors of a literature review supporting the American College of Physicians’ recommendation to counsel asymptomatic postmenopausal women about hormone therapy based on data from observational studies. “No randomized trials with clinical outcomes had been conducted,” Dr. Grady said. By 2002, data from three large randomized trials told a different story, and the Task Force recommended against using estrogen alone as a strategy to prevent chronic conditions in postmenopausal women, she noted.
“I believe that the fear of hormone therapy is overblown,” Dr. Grady wrote. “When adequately informed, women with moderate to severe symptoms and without contraindications should be able to take such small risks if hormone therapy improves symptoms and quality of life,” she said.
In fact, professional societies, including the North American Menopause Society, the American College of Obstetricians and Gynecologists, and the Endocrine Society support hormone therapy for symptomatic women who are recently menopausal, said Dr. Grady. However, a key lesson learned from the ongoing research on hormone therapy is the importance of conducting clinical trials that are large enough to identify serious adverse effects, she added.
Dr. Grady is affiliated with the University of California, San Francisco. She had no financial conflicts to disclose.
Twenty-five years ago, the U.S. Preventive Services Task Force advised clinicians to consider hormone therapy for the prevention of disease in all women, particularly those at risk for coronary heart disease, Deborah Grady, MD, wrote in an editorial (JAMA Intern Med. 2017 Dec 12. doi: 10.1001/jamainternmed.2017.7861). Dr. Grady was one of the coauthors of a literature review supporting the American College of Physicians’ recommendation to counsel asymptomatic postmenopausal women about hormone therapy based on data from observational studies. “No randomized trials with clinical outcomes had been conducted,” Dr. Grady said. By 2002, data from three large randomized trials told a different story, and the Task Force recommended against using estrogen alone as a strategy to prevent chronic conditions in postmenopausal women, she noted.
“I believe that the fear of hormone therapy is overblown,” Dr. Grady wrote. “When adequately informed, women with moderate to severe symptoms and without contraindications should be able to take such small risks if hormone therapy improves symptoms and quality of life,” she said.
In fact, professional societies, including the North American Menopause Society, the American College of Obstetricians and Gynecologists, and the Endocrine Society support hormone therapy for symptomatic women who are recently menopausal, said Dr. Grady. However, a key lesson learned from the ongoing research on hormone therapy is the importance of conducting clinical trials that are large enough to identify serious adverse effects, she added.
Dr. Grady is affiliated with the University of California, San Francisco. She had no financial conflicts to disclose.
Hormone therapy should not be used to prevent chronic conditions in postmenopausal women, according to updated recommendations from the U.S. Preventive Services Task Force. The recommendations were published online Dec. 12 in JAMA.
In the latest recommendation statement, the USPSTF issued D recommendations against using combination estrogen and progestin to prevent chronic conditions in postmenopausal women and against using estrogen only to prevent chronic conditions in postmenopausal women who have undergone hysterectomies (JAMA. 2017 Dec 12. doi: 10.1001/jama.2017.18261). A grade D recommendation is defined as “The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.”
In response to public comments, the USPSTF team made several changes including adjusting the language to clarify that the recommendations apply only to postmenopausal women, and adding tables showing estimates of increased or decreased risk of various outcomes for postmenopausal women receiving different hormone therapies.
Approximately 40,000 women aged 53-79 years were included in an evidence report from Gerald Gartlehner, MD, of the University of North Carolina, Chapel Hill, and his colleagues that accompanied the recommendations (JAMA. 2017 Dec 12. doi: 10.1001/jama.2017.16952).
The researchers found that women taking estrogen alone had significantly lower risk of breast cancer, diabetes, and osteoporotic fractures, but significantly higher risk of gallbladder disease, stroke, urinary incontinence, and venous thromboembolism, compared with women taking placebo. In addition, women using a combination of estrogen and progestin had significantly lower risk of colorectal cancer, diabetes, and osteoporotic fractures, but significantly higher risk of breast cancer, probable dementia, gallbladder disease, stroke, urinary incontinence, and venous thromboembolism, compared with women taking placebo.
“Hormone therapy for the primary prevention of chronic conditions in menopausal women is associated with some beneficial effects but also with a substantial increase of risks for harms,” and the current evidence for the risks and benefits of hormone therapy is inconclusive, the researchers said.
The final recommendation remains consistent with the USPSTF draft statement issued earlier in 2017 and with the final recommendation statements issued in 2012.
The researchers had no relevant financial conflicts to disclose.
Hormone therapy should not be used to prevent chronic conditions in postmenopausal women, according to updated recommendations from the U.S. Preventive Services Task Force. The recommendations were published online Dec. 12 in JAMA.
In the latest recommendation statement, the USPSTF issued D recommendations against using combination estrogen and progestin to prevent chronic conditions in postmenopausal women and against using estrogen only to prevent chronic conditions in postmenopausal women who have undergone hysterectomies (JAMA. 2017 Dec 12. doi: 10.1001/jama.2017.18261). A grade D recommendation is defined as “The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.”
In response to public comments, the USPSTF team made several changes including adjusting the language to clarify that the recommendations apply only to postmenopausal women, and adding tables showing estimates of increased or decreased risk of various outcomes for postmenopausal women receiving different hormone therapies.
Approximately 40,000 women aged 53-79 years were included in an evidence report from Gerald Gartlehner, MD, of the University of North Carolina, Chapel Hill, and his colleagues that accompanied the recommendations (JAMA. 2017 Dec 12. doi: 10.1001/jama.2017.16952).
The researchers found that women taking estrogen alone had significantly lower risk of breast cancer, diabetes, and osteoporotic fractures, but significantly higher risk of gallbladder disease, stroke, urinary incontinence, and venous thromboembolism, compared with women taking placebo. In addition, women using a combination of estrogen and progestin had significantly lower risk of colorectal cancer, diabetes, and osteoporotic fractures, but significantly higher risk of breast cancer, probable dementia, gallbladder disease, stroke, urinary incontinence, and venous thromboembolism, compared with women taking placebo.
“Hormone therapy for the primary prevention of chronic conditions in menopausal women is associated with some beneficial effects but also with a substantial increase of risks for harms,” and the current evidence for the risks and benefits of hormone therapy is inconclusive, the researchers said.
The final recommendation remains consistent with the USPSTF draft statement issued earlier in 2017 and with the final recommendation statements issued in 2012.
The researchers had no relevant financial conflicts to disclose.
FROM JAMA
Study supports methotrexate monotherapy with TNF inhibitor rescue for early RA treatment
For patients with early rheumatoid arthritis, starting with methotrexate and adding adalimumab after 26 weeks if needed led to clinical and functional outcomes similar to those of starting with a dual adalimumab-methotrexate regimen, according to a study published in Annals of the Rheumatic Diseases.
Although upfront adalimumab-methotrexate led to about a 14% decrease in the likelihood of radiographic progression, nearly one in four patients did well over more than a year of follow-up without ever needing to add a biologic disease-modifying antirheumatic drug (DMARD), said Arthur Kavanaugh, MD, of the University of California at San Diego, La Jolla, Calif., and his associates.
At week 26, patients who had achieved stable low disease activity (LDA; 28-joint modified Disease Activity Score of less than 3.2, based on C-reactive protein) on dual therapy were re-randomized to either stay on or withdraw from adalimumab. Patients who achieved stable LDA on methotrexate alone stayed on it. Patients who did not achieve stable LDA by week 26 either stayed on methotrexate-adalimumab or received adalimumab rescue. For the current post hoc study, Dr. Kavanaugh and his associates compared longer-term outcomes between patients who received adalimumab-methotrexate at baseline and patients who started with methotrexate only. In addition to stable LDA, the investigators assessed normal function (Health Assessment Questionnaire Disability Index less than 0.5) and radiographic nonprogression (no more than 0.5 change in modified total Sharp score).
Patients who started on adalimumab-methotrexate instead of methotrexate monotherapy were significantly more likely to achieve stable LDA (53% vs. 30%), good function (45% vs. 33%), and radiographic nonprogression (87% vs. 72%) at week 26 (Ann Rheum Dis. 2013;72:64-71). However, as-needed rescue treatment with adalimumab at week 26 achieved very similar clinical and functional outcomes compared with initial treatment with methotrexate-adalimumab. At week 52, 62% and 65% of patients in these two groups had stable LDA, and 44% and 47% had normal function, respectively. At week 78, 65% of patients in both groups had stable LDA and 45% and 48% had normal function, respectively. However, initial therapy with adalimumab-methotrexate was associated with lower chances of radiographic progression compared with methotrexate monotherapy (86% and 72% at both time points, respectively).
This is the first study to assess whether rapidly adding a TNFi improves disease outcomes compared with starting treatment with both adalimumab and methotrexate in patients with early RA, the researchers said. Importantly, 24% of patients who started on methotrexate alone never needed to add a biological DMARD, experiencing “little to no radiographic progression and mostly good physical function thereafter,” they reported. The study supports current guidelines and a stepwise treat-to-target strategy can prevent overtreatment in about one in four patients with early RA, they concluded.
AbbVie makes adalimumab, sponsored the study, and was involved in its design, analysis, writeup, and review. Dr. Kavanaugh disclosed ties to AbbVie through his institution. Nine coinvestigators disclosed ties to AbbVie; five of the nine reported current or former employment with the company.
SOURCE: Ann Rheum Dis. 2017 Nov 16. doi: 10.1136/annrheumdis-2017-211871
This study is of general interest and its design is complex, with double-blind, open re-randomization, and open-label extension arms.
There are a number of points to highlight:
1. Both methotrexate-adalimumab arms eventuate in a small advantage with respect to radiographs, with less accrued damage than with methotrexate alone. As in multiple other studies, the radiographic differences, although statistically significant, are not clinically important during this short study. However, if extended over a number of years, they could become clinically important, and that should not be ignored.
2. The authors state that methotrexate monotherapy patients who later added adalimumab achieved symptomatic and functional relief equivalent to starting on methotrexate-adalimumab – which I fully agree with – but the authors pointed out that there may well be some bias in that conclusion because the “add-on” patients did so during an open-label phase of the study. The complex design of the study makes this a bit hard to dissect.
4. Also, this study design did not allow corticosteroids. While I am a staunch advocate of minimizing steroids, some clinicians would have used steroids early on to improve early response, thus mitigating the early differential effect of methotrexate monotherapy.
So what is the bottom line? In my mind, this study supports that methotrexate-adalimumab decreases the rate of bony damage (not a new finding among biologics plus methotrexate in RA) and gently advocates that using methotrexate alone as the first DMARD is appropriate.
The data actually do not clarify the potentially important symptomatic/functional differences during the early months between the group that went from methotrexate monotherapy to methotrexate-adalimumab vs. the group that received immediate methotrexate-adalimumab, where the “immediate” methotrexate-adalimumab patients probably felt better faster. Still, one needs to consider potential toxicity and cost of the immediate methotrexate-adalimumab group, and that is not well addressed here.
When faced with a patient, I always ask how bad are the symptoms (worse leaning me toward immediate methotrexate-adalimumab) vs. how frail is the patient (more frail leaning me toward first using methotrexate) and how good is their insurance (sadly a consideration in the United States, with better insurance leaning me toward the “immediate” combo because I think other data show this yields a faster response).
Daniel E. Furst, MD, is professor of rheumatology at the University of California, Los Angeles (emeritus), at the University of Washington, Seattle, and at the University of Florence (Italy). He reported receiving grant/research support from Bristol-Myers-Squibb, Pfizer, and Roche/Genentech. He is also a consultant to AbbVie, Novartis, Pfizer, and Roche/Genentech.
This study is of general interest and its design is complex, with double-blind, open re-randomization, and open-label extension arms.
There are a number of points to highlight:
1. Both methotrexate-adalimumab arms eventuate in a small advantage with respect to radiographs, with less accrued damage than with methotrexate alone. As in multiple other studies, the radiographic differences, although statistically significant, are not clinically important during this short study. However, if extended over a number of years, they could become clinically important, and that should not be ignored.
2. The authors state that methotrexate monotherapy patients who later added adalimumab achieved symptomatic and functional relief equivalent to starting on methotrexate-adalimumab – which I fully agree with – but the authors pointed out that there may well be some bias in that conclusion because the “add-on” patients did so during an open-label phase of the study. The complex design of the study makes this a bit hard to dissect.
4. Also, this study design did not allow corticosteroids. While I am a staunch advocate of minimizing steroids, some clinicians would have used steroids early on to improve early response, thus mitigating the early differential effect of methotrexate monotherapy.
So what is the bottom line? In my mind, this study supports that methotrexate-adalimumab decreases the rate of bony damage (not a new finding among biologics plus methotrexate in RA) and gently advocates that using methotrexate alone as the first DMARD is appropriate.
The data actually do not clarify the potentially important symptomatic/functional differences during the early months between the group that went from methotrexate monotherapy to methotrexate-adalimumab vs. the group that received immediate methotrexate-adalimumab, where the “immediate” methotrexate-adalimumab patients probably felt better faster. Still, one needs to consider potential toxicity and cost of the immediate methotrexate-adalimumab group, and that is not well addressed here.
When faced with a patient, I always ask how bad are the symptoms (worse leaning me toward immediate methotrexate-adalimumab) vs. how frail is the patient (more frail leaning me toward first using methotrexate) and how good is their insurance (sadly a consideration in the United States, with better insurance leaning me toward the “immediate” combo because I think other data show this yields a faster response).
Daniel E. Furst, MD, is professor of rheumatology at the University of California, Los Angeles (emeritus), at the University of Washington, Seattle, and at the University of Florence (Italy). He reported receiving grant/research support from Bristol-Myers-Squibb, Pfizer, and Roche/Genentech. He is also a consultant to AbbVie, Novartis, Pfizer, and Roche/Genentech.
This study is of general interest and its design is complex, with double-blind, open re-randomization, and open-label extension arms.
There are a number of points to highlight:
1. Both methotrexate-adalimumab arms eventuate in a small advantage with respect to radiographs, with less accrued damage than with methotrexate alone. As in multiple other studies, the radiographic differences, although statistically significant, are not clinically important during this short study. However, if extended over a number of years, they could become clinically important, and that should not be ignored.
2. The authors state that methotrexate monotherapy patients who later added adalimumab achieved symptomatic and functional relief equivalent to starting on methotrexate-adalimumab – which I fully agree with – but the authors pointed out that there may well be some bias in that conclusion because the “add-on” patients did so during an open-label phase of the study. The complex design of the study makes this a bit hard to dissect.
4. Also, this study design did not allow corticosteroids. While I am a staunch advocate of minimizing steroids, some clinicians would have used steroids early on to improve early response, thus mitigating the early differential effect of methotrexate monotherapy.
So what is the bottom line? In my mind, this study supports that methotrexate-adalimumab decreases the rate of bony damage (not a new finding among biologics plus methotrexate in RA) and gently advocates that using methotrexate alone as the first DMARD is appropriate.
The data actually do not clarify the potentially important symptomatic/functional differences during the early months between the group that went from methotrexate monotherapy to methotrexate-adalimumab vs. the group that received immediate methotrexate-adalimumab, where the “immediate” methotrexate-adalimumab patients probably felt better faster. Still, one needs to consider potential toxicity and cost of the immediate methotrexate-adalimumab group, and that is not well addressed here.
When faced with a patient, I always ask how bad are the symptoms (worse leaning me toward immediate methotrexate-adalimumab) vs. how frail is the patient (more frail leaning me toward first using methotrexate) and how good is their insurance (sadly a consideration in the United States, with better insurance leaning me toward the “immediate” combo because I think other data show this yields a faster response).
Daniel E. Furst, MD, is professor of rheumatology at the University of California, Los Angeles (emeritus), at the University of Washington, Seattle, and at the University of Florence (Italy). He reported receiving grant/research support from Bristol-Myers-Squibb, Pfizer, and Roche/Genentech. He is also a consultant to AbbVie, Novartis, Pfizer, and Roche/Genentech.
For patients with early rheumatoid arthritis, starting with methotrexate and adding adalimumab after 26 weeks if needed led to clinical and functional outcomes similar to those of starting with a dual adalimumab-methotrexate regimen, according to a study published in Annals of the Rheumatic Diseases.
Although upfront adalimumab-methotrexate led to about a 14% decrease in the likelihood of radiographic progression, nearly one in four patients did well over more than a year of follow-up without ever needing to add a biologic disease-modifying antirheumatic drug (DMARD), said Arthur Kavanaugh, MD, of the University of California at San Diego, La Jolla, Calif., and his associates.
At week 26, patients who had achieved stable low disease activity (LDA; 28-joint modified Disease Activity Score of less than 3.2, based on C-reactive protein) on dual therapy were re-randomized to either stay on or withdraw from adalimumab. Patients who achieved stable LDA on methotrexate alone stayed on it. Patients who did not achieve stable LDA by week 26 either stayed on methotrexate-adalimumab or received adalimumab rescue. For the current post hoc study, Dr. Kavanaugh and his associates compared longer-term outcomes between patients who received adalimumab-methotrexate at baseline and patients who started with methotrexate only. In addition to stable LDA, the investigators assessed normal function (Health Assessment Questionnaire Disability Index less than 0.5) and radiographic nonprogression (no more than 0.5 change in modified total Sharp score).
Patients who started on adalimumab-methotrexate instead of methotrexate monotherapy were significantly more likely to achieve stable LDA (53% vs. 30%), good function (45% vs. 33%), and radiographic nonprogression (87% vs. 72%) at week 26 (Ann Rheum Dis. 2013;72:64-71). However, as-needed rescue treatment with adalimumab at week 26 achieved very similar clinical and functional outcomes compared with initial treatment with methotrexate-adalimumab. At week 52, 62% and 65% of patients in these two groups had stable LDA, and 44% and 47% had normal function, respectively. At week 78, 65% of patients in both groups had stable LDA and 45% and 48% had normal function, respectively. However, initial therapy with adalimumab-methotrexate was associated with lower chances of radiographic progression compared with methotrexate monotherapy (86% and 72% at both time points, respectively).
This is the first study to assess whether rapidly adding a TNFi improves disease outcomes compared with starting treatment with both adalimumab and methotrexate in patients with early RA, the researchers said. Importantly, 24% of patients who started on methotrexate alone never needed to add a biological DMARD, experiencing “little to no radiographic progression and mostly good physical function thereafter,” they reported. The study supports current guidelines and a stepwise treat-to-target strategy can prevent overtreatment in about one in four patients with early RA, they concluded.
AbbVie makes adalimumab, sponsored the study, and was involved in its design, analysis, writeup, and review. Dr. Kavanaugh disclosed ties to AbbVie through his institution. Nine coinvestigators disclosed ties to AbbVie; five of the nine reported current or former employment with the company.
SOURCE: Ann Rheum Dis. 2017 Nov 16. doi: 10.1136/annrheumdis-2017-211871
For patients with early rheumatoid arthritis, starting with methotrexate and adding adalimumab after 26 weeks if needed led to clinical and functional outcomes similar to those of starting with a dual adalimumab-methotrexate regimen, according to a study published in Annals of the Rheumatic Diseases.
Although upfront adalimumab-methotrexate led to about a 14% decrease in the likelihood of radiographic progression, nearly one in four patients did well over more than a year of follow-up without ever needing to add a biologic disease-modifying antirheumatic drug (DMARD), said Arthur Kavanaugh, MD, of the University of California at San Diego, La Jolla, Calif., and his associates.
At week 26, patients who had achieved stable low disease activity (LDA; 28-joint modified Disease Activity Score of less than 3.2, based on C-reactive protein) on dual therapy were re-randomized to either stay on or withdraw from adalimumab. Patients who achieved stable LDA on methotrexate alone stayed on it. Patients who did not achieve stable LDA by week 26 either stayed on methotrexate-adalimumab or received adalimumab rescue. For the current post hoc study, Dr. Kavanaugh and his associates compared longer-term outcomes between patients who received adalimumab-methotrexate at baseline and patients who started with methotrexate only. In addition to stable LDA, the investigators assessed normal function (Health Assessment Questionnaire Disability Index less than 0.5) and radiographic nonprogression (no more than 0.5 change in modified total Sharp score).
Patients who started on adalimumab-methotrexate instead of methotrexate monotherapy were significantly more likely to achieve stable LDA (53% vs. 30%), good function (45% vs. 33%), and radiographic nonprogression (87% vs. 72%) at week 26 (Ann Rheum Dis. 2013;72:64-71). However, as-needed rescue treatment with adalimumab at week 26 achieved very similar clinical and functional outcomes compared with initial treatment with methotrexate-adalimumab. At week 52, 62% and 65% of patients in these two groups had stable LDA, and 44% and 47% had normal function, respectively. At week 78, 65% of patients in both groups had stable LDA and 45% and 48% had normal function, respectively. However, initial therapy with adalimumab-methotrexate was associated with lower chances of radiographic progression compared with methotrexate monotherapy (86% and 72% at both time points, respectively).
This is the first study to assess whether rapidly adding a TNFi improves disease outcomes compared with starting treatment with both adalimumab and methotrexate in patients with early RA, the researchers said. Importantly, 24% of patients who started on methotrexate alone never needed to add a biological DMARD, experiencing “little to no radiographic progression and mostly good physical function thereafter,” they reported. The study supports current guidelines and a stepwise treat-to-target strategy can prevent overtreatment in about one in four patients with early RA, they concluded.
AbbVie makes adalimumab, sponsored the study, and was involved in its design, analysis, writeup, and review. Dr. Kavanaugh disclosed ties to AbbVie through his institution. Nine coinvestigators disclosed ties to AbbVie; five of the nine reported current or former employment with the company.
SOURCE: Ann Rheum Dis. 2017 Nov 16. doi: 10.1136/annrheumdis-2017-211871
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: Adding adalimumab as rescue therapy at 26 weeks achieved outcomes at 78 weeks similar to those of starting treatment with adalimumab-methotrexate.
Data source: A post hoc analysis of a 78-week, randomized, double-blind, phase 4 study of 926 methotrexate-naive patients with a less than 1-year history of active RA.
Disclosures: AbbVie makes adalimumab, sponsored the study, and was involved in its design, analysis, writeup, and review. Dr. Kavanaugh disclosed ties to AbbVie through his institution. Nine coinvestigators disclosed ties to AbbVie; five of the nine reported current or former employment with the company.
Source: Ann Rheum Dis. 2017 Nov 16. doi: 10.1136/annrheumdis-2017-211871
Gene silencer reduces mutant huntingtin protein in early-stage Huntington’s patients
An investigational gene-silencing molecule safely and dose-dependently reduced production of the mutant huntingtin protein in people with early-stage Huntington’s disease in a small, early-phase study, according to an announcement from the drug’s developer, Ionis Pharmaceuticals.
The antisense oligonucleotide IONIS-HTTRx – the first potentially disease-modifying drug for Huntington’s – will now go forward in a larger study to determine whether lowering mutant huntingtin protein (mHTT) confers any clinical benefits upon patients with the fatal neurodegenerative disease.
IONIS-HTTRx reduced mHTT by fractions that “exceeded expectations” set for the 46-person trial, C. Frank Bennett, PhD, senior vice president of research at Ionis, said in a press statement.
“The results of this trial are of groundbreaking importance for Huntington’s disease patients and families,” said Dr. Tabrizi, director of the Huntington’s Disease Centre at University College London. “For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether the drug slows disease progression.”
Upon receiving the positive data, Roche Pharma exercised its $45 million option to license the molecule. Roche now takes all regulatory and clinical development responsibility for IONIS-HTTRx.
There are few publicly available data on the IONIS-HTTRx study. It enrolled 46 patients with early-stage Huntington’s who were recruited from nine sites in the United Kingdom, Germany, and Canada. They were randomized to placebo or to four ascending doses of IONIS-HTTRx. The primary outcomes were mHTT levels in spinal fluid, safety, and tolerability. It produced significant, dose-dependent reductions of mHTT without concerning or dose-limiting safety signals, the press statement noted.
A larger study with clinical endpoints is next up, according to a statement Ionis and Roche jointly issued to the Huntington’s Disease Society of America.
“The next step for this program will be to conduct a safety and efficacy study to investigate if decreasing mutant huntingtin protein with IONIS-HTTRx can benefit people with Huntington’s disease,” the statement noted. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available. All relevant information on upcoming studies will also be posted on HDTrialFinder.org and ClinicalTrials.gov.”
Huntington’s disease is caused by an expansion of at least 36 repeats of the CAG trinucleotide sequence in the huntingtin gene. The resulting mHTT is toxic and gradually damages neurons. IONIS-HTTRx interrupts the messenger RNA that fuels this toxic protein buildup, and it is the only drug that has ever attacked the disease at this level. This development is “a historic moment in the fight against Huntington’s, as it represents the successful completion of the first trial to treat the underlying cause of Huntington’s disease, the genetic mutation itself,” according to a statement by Louise Vetter, president of the Huntington’s Disease Society of America.
“The fact that levels of mutant huntingtin were reduced in correlation to the dose of IONIS-HTTRx that was given is significant, and the fact that participants in this first Phase 1/2a study are able to continue on the drug through an open-label extension gives us optimism regarding its safety,” Ms. Vetter said.
In January 2016, the Food and Drug Administration granted orphan drug status to IONIS-HTTRX; the European Medicines Agency had previously granted it similar status.
The press release from Ionis Pharmaceuticals sounds very promising. There is reason to believe that lowering mHTT protein might prevent or delay Huntington’s disease, and this antisense molecule appears to be safe and to lower mHTT in cerebrospinal fluid. However, there are several caveats.
First, it is unclear whether lowering mHTT protein might help those who already have clinical Huntington’s disease.
Third, no information is given in the press release about the degree of reduction of mHTT observed and whether there is evidence that this lowering might be sufficient for a therapeutic effect.
Fourth, neurotoxicity may not only result from the mHTT protein but also directly from the mRNA itself. The contribution of mutant mRNA to pathogenesis is a key open question in the study of Huntington’s disease and other related “repeat disorders.”
Michael Wolfe, PhD , is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. He has no relevant disclosures.
The press release from Ionis Pharmaceuticals sounds very promising. There is reason to believe that lowering mHTT protein might prevent or delay Huntington’s disease, and this antisense molecule appears to be safe and to lower mHTT in cerebrospinal fluid. However, there are several caveats.
First, it is unclear whether lowering mHTT protein might help those who already have clinical Huntington’s disease.
Third, no information is given in the press release about the degree of reduction of mHTT observed and whether there is evidence that this lowering might be sufficient for a therapeutic effect.
Fourth, neurotoxicity may not only result from the mHTT protein but also directly from the mRNA itself. The contribution of mutant mRNA to pathogenesis is a key open question in the study of Huntington’s disease and other related “repeat disorders.”
Michael Wolfe, PhD , is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. He has no relevant disclosures.
The press release from Ionis Pharmaceuticals sounds very promising. There is reason to believe that lowering mHTT protein might prevent or delay Huntington’s disease, and this antisense molecule appears to be safe and to lower mHTT in cerebrospinal fluid. However, there are several caveats.
First, it is unclear whether lowering mHTT protein might help those who already have clinical Huntington’s disease.
Third, no information is given in the press release about the degree of reduction of mHTT observed and whether there is evidence that this lowering might be sufficient for a therapeutic effect.
Fourth, neurotoxicity may not only result from the mHTT protein but also directly from the mRNA itself. The contribution of mutant mRNA to pathogenesis is a key open question in the study of Huntington’s disease and other related “repeat disorders.”
Michael Wolfe, PhD , is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. He has no relevant disclosures.
An investigational gene-silencing molecule safely and dose-dependently reduced production of the mutant huntingtin protein in people with early-stage Huntington’s disease in a small, early-phase study, according to an announcement from the drug’s developer, Ionis Pharmaceuticals.
The antisense oligonucleotide IONIS-HTTRx – the first potentially disease-modifying drug for Huntington’s – will now go forward in a larger study to determine whether lowering mutant huntingtin protein (mHTT) confers any clinical benefits upon patients with the fatal neurodegenerative disease.
IONIS-HTTRx reduced mHTT by fractions that “exceeded expectations” set for the 46-person trial, C. Frank Bennett, PhD, senior vice president of research at Ionis, said in a press statement.
“The results of this trial are of groundbreaking importance for Huntington’s disease patients and families,” said Dr. Tabrizi, director of the Huntington’s Disease Centre at University College London. “For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether the drug slows disease progression.”
Upon receiving the positive data, Roche Pharma exercised its $45 million option to license the molecule. Roche now takes all regulatory and clinical development responsibility for IONIS-HTTRx.
There are few publicly available data on the IONIS-HTTRx study. It enrolled 46 patients with early-stage Huntington’s who were recruited from nine sites in the United Kingdom, Germany, and Canada. They were randomized to placebo or to four ascending doses of IONIS-HTTRx. The primary outcomes were mHTT levels in spinal fluid, safety, and tolerability. It produced significant, dose-dependent reductions of mHTT without concerning or dose-limiting safety signals, the press statement noted.
A larger study with clinical endpoints is next up, according to a statement Ionis and Roche jointly issued to the Huntington’s Disease Society of America.
“The next step for this program will be to conduct a safety and efficacy study to investigate if decreasing mutant huntingtin protein with IONIS-HTTRx can benefit people with Huntington’s disease,” the statement noted. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available. All relevant information on upcoming studies will also be posted on HDTrialFinder.org and ClinicalTrials.gov.”
Huntington’s disease is caused by an expansion of at least 36 repeats of the CAG trinucleotide sequence in the huntingtin gene. The resulting mHTT is toxic and gradually damages neurons. IONIS-HTTRx interrupts the messenger RNA that fuels this toxic protein buildup, and it is the only drug that has ever attacked the disease at this level. This development is “a historic moment in the fight against Huntington’s, as it represents the successful completion of the first trial to treat the underlying cause of Huntington’s disease, the genetic mutation itself,” according to a statement by Louise Vetter, president of the Huntington’s Disease Society of America.
“The fact that levels of mutant huntingtin were reduced in correlation to the dose of IONIS-HTTRx that was given is significant, and the fact that participants in this first Phase 1/2a study are able to continue on the drug through an open-label extension gives us optimism regarding its safety,” Ms. Vetter said.
In January 2016, the Food and Drug Administration granted orphan drug status to IONIS-HTTRX; the European Medicines Agency had previously granted it similar status.
An investigational gene-silencing molecule safely and dose-dependently reduced production of the mutant huntingtin protein in people with early-stage Huntington’s disease in a small, early-phase study, according to an announcement from the drug’s developer, Ionis Pharmaceuticals.
The antisense oligonucleotide IONIS-HTTRx – the first potentially disease-modifying drug for Huntington’s – will now go forward in a larger study to determine whether lowering mutant huntingtin protein (mHTT) confers any clinical benefits upon patients with the fatal neurodegenerative disease.
IONIS-HTTRx reduced mHTT by fractions that “exceeded expectations” set for the 46-person trial, C. Frank Bennett, PhD, senior vice president of research at Ionis, said in a press statement.
“The results of this trial are of groundbreaking importance for Huntington’s disease patients and families,” said Dr. Tabrizi, director of the Huntington’s Disease Centre at University College London. “For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether the drug slows disease progression.”
Upon receiving the positive data, Roche Pharma exercised its $45 million option to license the molecule. Roche now takes all regulatory and clinical development responsibility for IONIS-HTTRx.
There are few publicly available data on the IONIS-HTTRx study. It enrolled 46 patients with early-stage Huntington’s who were recruited from nine sites in the United Kingdom, Germany, and Canada. They were randomized to placebo or to four ascending doses of IONIS-HTTRx. The primary outcomes were mHTT levels in spinal fluid, safety, and tolerability. It produced significant, dose-dependent reductions of mHTT without concerning or dose-limiting safety signals, the press statement noted.
A larger study with clinical endpoints is next up, according to a statement Ionis and Roche jointly issued to the Huntington’s Disease Society of America.
“The next step for this program will be to conduct a safety and efficacy study to investigate if decreasing mutant huntingtin protein with IONIS-HTTRx can benefit people with Huntington’s disease,” the statement noted. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available. All relevant information on upcoming studies will also be posted on HDTrialFinder.org and ClinicalTrials.gov.”
Huntington’s disease is caused by an expansion of at least 36 repeats of the CAG trinucleotide sequence in the huntingtin gene. The resulting mHTT is toxic and gradually damages neurons. IONIS-HTTRx interrupts the messenger RNA that fuels this toxic protein buildup, and it is the only drug that has ever attacked the disease at this level. This development is “a historic moment in the fight against Huntington’s, as it represents the successful completion of the first trial to treat the underlying cause of Huntington’s disease, the genetic mutation itself,” according to a statement by Louise Vetter, president of the Huntington’s Disease Society of America.
“The fact that levels of mutant huntingtin were reduced in correlation to the dose of IONIS-HTTRx that was given is significant, and the fact that participants in this first Phase 1/2a study are able to continue on the drug through an open-label extension gives us optimism regarding its safety,” Ms. Vetter said.
In January 2016, the Food and Drug Administration granted orphan drug status to IONIS-HTTRX; the European Medicines Agency had previously granted it similar status.
Using “design thinking” to improve health care
Health care workers creating innovations by applying “design thinking” – “a human-centered approach to innovation” that comes from the business world – is a growing trend, according to a recent New York Times article.
“With design thinking, the innovations come from those who actually work there, providing feedback to designers to improve the final product,” wrote author Amitha Kalaichandran, MD, MHS.
“Health providers ... are uniquely positioned to come up with fresh solutions to health care problems,” Dr. Kalaichandran wrote. An example at her own hospital: The leader of the trauma team now wears an orange vest, clearly identifying who’s in charge in a potentially chaotic situation. It was an idea created by a hospital nurse.
“A 2016 report that looked at ways in which a health system can implement design thinking identified three principles behind the approach: empathy for the user, in this case a patient, doctor or other health care provider; the involvement of an interdisciplinary team; and rapid prototyping of the idea,” she wrote. “To develop a truly useful product, a comprehensive understanding of the problem the innovation aims to solve is paramount.”
In design thinking, described as creative, multidisciplinary thinking around a problem, groups naturally coalesce to find such solutions. The article cites examples such as Clinicians for Design, an international group of providers focused on improving hospital layouts, and Health Design by Us, a collaborative group that supports health care innovations such as a mobile system for diabetes management, designed by a patient.
Reference
Kalaichandran A. Design thinking for doctors and nurses. The New York Times. Aug. 3, 2017. Accessed Aug. 7, 2017.
Health care workers creating innovations by applying “design thinking” – “a human-centered approach to innovation” that comes from the business world – is a growing trend, according to a recent New York Times article.
“With design thinking, the innovations come from those who actually work there, providing feedback to designers to improve the final product,” wrote author Amitha Kalaichandran, MD, MHS.
“Health providers ... are uniquely positioned to come up with fresh solutions to health care problems,” Dr. Kalaichandran wrote. An example at her own hospital: The leader of the trauma team now wears an orange vest, clearly identifying who’s in charge in a potentially chaotic situation. It was an idea created by a hospital nurse.
“A 2016 report that looked at ways in which a health system can implement design thinking identified three principles behind the approach: empathy for the user, in this case a patient, doctor or other health care provider; the involvement of an interdisciplinary team; and rapid prototyping of the idea,” she wrote. “To develop a truly useful product, a comprehensive understanding of the problem the innovation aims to solve is paramount.”
In design thinking, described as creative, multidisciplinary thinking around a problem, groups naturally coalesce to find such solutions. The article cites examples such as Clinicians for Design, an international group of providers focused on improving hospital layouts, and Health Design by Us, a collaborative group that supports health care innovations such as a mobile system for diabetes management, designed by a patient.
Reference
Kalaichandran A. Design thinking for doctors and nurses. The New York Times. Aug. 3, 2017. Accessed Aug. 7, 2017.
Health care workers creating innovations by applying “design thinking” – “a human-centered approach to innovation” that comes from the business world – is a growing trend, according to a recent New York Times article.
“With design thinking, the innovations come from those who actually work there, providing feedback to designers to improve the final product,” wrote author Amitha Kalaichandran, MD, MHS.
“Health providers ... are uniquely positioned to come up with fresh solutions to health care problems,” Dr. Kalaichandran wrote. An example at her own hospital: The leader of the trauma team now wears an orange vest, clearly identifying who’s in charge in a potentially chaotic situation. It was an idea created by a hospital nurse.
“A 2016 report that looked at ways in which a health system can implement design thinking identified three principles behind the approach: empathy for the user, in this case a patient, doctor or other health care provider; the involvement of an interdisciplinary team; and rapid prototyping of the idea,” she wrote. “To develop a truly useful product, a comprehensive understanding of the problem the innovation aims to solve is paramount.”
In design thinking, described as creative, multidisciplinary thinking around a problem, groups naturally coalesce to find such solutions. The article cites examples such as Clinicians for Design, an international group of providers focused on improving hospital layouts, and Health Design by Us, a collaborative group that supports health care innovations such as a mobile system for diabetes management, designed by a patient.
Reference
Kalaichandran A. Design thinking for doctors and nurses. The New York Times. Aug. 3, 2017. Accessed Aug. 7, 2017.
Early weight change has no special effect on mortality in RA
Weight loss at the time of rheumatoid arthritis diagnosis had the same impact on mortality in patients with and without RA, according to research trying to solve the so-called obesity paradox in RA, which has been related to prior observations of a protective effect of obesity on mortality in RA patients.
The finding indicates that clinicians can continue to encourage patients with rheumatoid arthritis to follow healthy weight-loss strategies, according to first author of the study, Jeffrey Sparks, MD, of Brigham and Women’s Hospital in Boston.
Dr. Sparks and his colleagues examined the impact of weight change and mortality in RA patients based on data from the Nurses’ Health Study.
“Our study is the first to focus on weight change around RA diagnosis and risk of death, rather than weight change in patients who had RA for many years,” Dr. Sparks noted.
By examining changes in weight near the time of RA diagnosis, Dr. Sparks and his colleagues said that they hoped to extract information about RA-specific processes rather than the underlying pathologies that might cause weight changes near the end of life.
In the study published in Arthritis & Rheumatology, the researchers compared women diagnosed with RA during follow-up to women without RA during the same index time period of 1976-2016. The study population included 121,701 women. Of these, 902 developed incident RA and were matched with 7,884 non-RA controls.
During an average of 18 years of follow-up, 41% of the RA cohort and 29% of the controls died. The risk of death was approximately twice as high (hazard ratio, 2.78; 95% confidence interval, 1.58-4.89) among those with weight loss greater than 30 pounds at the time of RA diagnosis, compared with those whose weight remained stable. However, the risk for mortality was similarly increased (HR, 2.16; 95% CI, 1.61-2.88) among the controls with weight loss greater than 30 pounds, compared with those with stable weight. No association with mortality was noted in either group among women who gained more than 30 pounds at the time of RA diagnosis.
Dr. Sparks said he was somewhat surprised by the findings.
“We expected severe, pathologic weight loss to be associated with increased risk of death among patients with RA and comparators. It was somewhat surprising that the risks in both groups were similar,” he said. “Conversely, prior studies suggested that weight gain might have been associated with increased risk of death. However, we found no association of weight gain with risk of death,” he noted.
In addition, “Our findings argue that there is not an RA-specific mortality risk based on either weight loss or gain,” he said. “While we found that weight loss was associated with increased mortality, this was most pronounced in the severe weight loss group, so was likely due to unintentional weight loss.”
Joshua F. Baker, MD, of the University of Pennsylvania, Philadelphia, and his colleagues identified an association between weight change and risk of death in RA patients in a study first published online in Arthritis & Rheumatology in 2015 (Arthritis Rheumatol. 2015 Jul;67[7]:1711-17). That study addressed the so-called obesity paradox in RA, and Dr. Baker and his colleagues noted that weight loss associated with the development of chronic illness is a significant confounder that may explain the observed protective effect of obesity on mortality.
“It is not clear how best to monitor changes in weight, when exactly to become concerned, and what to do when changes are observed,” Dr. Baker noted. “RA patients may lose weight for a number of reasons, not all related to their arthritis, and it is unlikely that there is a ‘one size fits all’ approach,” he said.
The study was limited in part by the women-only study population, so the results might not be generalizable to men, Dr. Sparks said. “The reason for weight change was unavailable,” he added. Directions for further research include investigation of how factors such as physical activity, diet, and weight loss may affect the risk of death among individuals with and without RA, he said.
Dr. Sparks had no financial conflicts to disclose. The study was supported in part by the National Institutes of Health and the Rheumatology Research Foundation’s Disease-Targeted Innovative Award and Scientist Development Awards.
SOURCE: Sparks J et al. Arthritis Rheumatol. 2017 Nov 30. doi: 10.1002/art.40346.
Weight loss at the time of rheumatoid arthritis diagnosis had the same impact on mortality in patients with and without RA, according to research trying to solve the so-called obesity paradox in RA, which has been related to prior observations of a protective effect of obesity on mortality in RA patients.
The finding indicates that clinicians can continue to encourage patients with rheumatoid arthritis to follow healthy weight-loss strategies, according to first author of the study, Jeffrey Sparks, MD, of Brigham and Women’s Hospital in Boston.
Dr. Sparks and his colleagues examined the impact of weight change and mortality in RA patients based on data from the Nurses’ Health Study.
“Our study is the first to focus on weight change around RA diagnosis and risk of death, rather than weight change in patients who had RA for many years,” Dr. Sparks noted.
By examining changes in weight near the time of RA diagnosis, Dr. Sparks and his colleagues said that they hoped to extract information about RA-specific processes rather than the underlying pathologies that might cause weight changes near the end of life.
In the study published in Arthritis & Rheumatology, the researchers compared women diagnosed with RA during follow-up to women without RA during the same index time period of 1976-2016. The study population included 121,701 women. Of these, 902 developed incident RA and were matched with 7,884 non-RA controls.
During an average of 18 years of follow-up, 41% of the RA cohort and 29% of the controls died. The risk of death was approximately twice as high (hazard ratio, 2.78; 95% confidence interval, 1.58-4.89) among those with weight loss greater than 30 pounds at the time of RA diagnosis, compared with those whose weight remained stable. However, the risk for mortality was similarly increased (HR, 2.16; 95% CI, 1.61-2.88) among the controls with weight loss greater than 30 pounds, compared with those with stable weight. No association with mortality was noted in either group among women who gained more than 30 pounds at the time of RA diagnosis.
Dr. Sparks said he was somewhat surprised by the findings.
“We expected severe, pathologic weight loss to be associated with increased risk of death among patients with RA and comparators. It was somewhat surprising that the risks in both groups were similar,” he said. “Conversely, prior studies suggested that weight gain might have been associated with increased risk of death. However, we found no association of weight gain with risk of death,” he noted.
In addition, “Our findings argue that there is not an RA-specific mortality risk based on either weight loss or gain,” he said. “While we found that weight loss was associated with increased mortality, this was most pronounced in the severe weight loss group, so was likely due to unintentional weight loss.”
Joshua F. Baker, MD, of the University of Pennsylvania, Philadelphia, and his colleagues identified an association between weight change and risk of death in RA patients in a study first published online in Arthritis & Rheumatology in 2015 (Arthritis Rheumatol. 2015 Jul;67[7]:1711-17). That study addressed the so-called obesity paradox in RA, and Dr. Baker and his colleagues noted that weight loss associated with the development of chronic illness is a significant confounder that may explain the observed protective effect of obesity on mortality.
“It is not clear how best to monitor changes in weight, when exactly to become concerned, and what to do when changes are observed,” Dr. Baker noted. “RA patients may lose weight for a number of reasons, not all related to their arthritis, and it is unlikely that there is a ‘one size fits all’ approach,” he said.
The study was limited in part by the women-only study population, so the results might not be generalizable to men, Dr. Sparks said. “The reason for weight change was unavailable,” he added. Directions for further research include investigation of how factors such as physical activity, diet, and weight loss may affect the risk of death among individuals with and without RA, he said.
Dr. Sparks had no financial conflicts to disclose. The study was supported in part by the National Institutes of Health and the Rheumatology Research Foundation’s Disease-Targeted Innovative Award and Scientist Development Awards.
SOURCE: Sparks J et al. Arthritis Rheumatol. 2017 Nov 30. doi: 10.1002/art.40346.
Weight loss at the time of rheumatoid arthritis diagnosis had the same impact on mortality in patients with and without RA, according to research trying to solve the so-called obesity paradox in RA, which has been related to prior observations of a protective effect of obesity on mortality in RA patients.
The finding indicates that clinicians can continue to encourage patients with rheumatoid arthritis to follow healthy weight-loss strategies, according to first author of the study, Jeffrey Sparks, MD, of Brigham and Women’s Hospital in Boston.
Dr. Sparks and his colleagues examined the impact of weight change and mortality in RA patients based on data from the Nurses’ Health Study.
“Our study is the first to focus on weight change around RA diagnosis and risk of death, rather than weight change in patients who had RA for many years,” Dr. Sparks noted.
By examining changes in weight near the time of RA diagnosis, Dr. Sparks and his colleagues said that they hoped to extract information about RA-specific processes rather than the underlying pathologies that might cause weight changes near the end of life.
In the study published in Arthritis & Rheumatology, the researchers compared women diagnosed with RA during follow-up to women without RA during the same index time period of 1976-2016. The study population included 121,701 women. Of these, 902 developed incident RA and were matched with 7,884 non-RA controls.
During an average of 18 years of follow-up, 41% of the RA cohort and 29% of the controls died. The risk of death was approximately twice as high (hazard ratio, 2.78; 95% confidence interval, 1.58-4.89) among those with weight loss greater than 30 pounds at the time of RA diagnosis, compared with those whose weight remained stable. However, the risk for mortality was similarly increased (HR, 2.16; 95% CI, 1.61-2.88) among the controls with weight loss greater than 30 pounds, compared with those with stable weight. No association with mortality was noted in either group among women who gained more than 30 pounds at the time of RA diagnosis.
Dr. Sparks said he was somewhat surprised by the findings.
“We expected severe, pathologic weight loss to be associated with increased risk of death among patients with RA and comparators. It was somewhat surprising that the risks in both groups were similar,” he said. “Conversely, prior studies suggested that weight gain might have been associated with increased risk of death. However, we found no association of weight gain with risk of death,” he noted.
In addition, “Our findings argue that there is not an RA-specific mortality risk based on either weight loss or gain,” he said. “While we found that weight loss was associated with increased mortality, this was most pronounced in the severe weight loss group, so was likely due to unintentional weight loss.”
Joshua F. Baker, MD, of the University of Pennsylvania, Philadelphia, and his colleagues identified an association between weight change and risk of death in RA patients in a study first published online in Arthritis & Rheumatology in 2015 (Arthritis Rheumatol. 2015 Jul;67[7]:1711-17). That study addressed the so-called obesity paradox in RA, and Dr. Baker and his colleagues noted that weight loss associated with the development of chronic illness is a significant confounder that may explain the observed protective effect of obesity on mortality.
“It is not clear how best to monitor changes in weight, when exactly to become concerned, and what to do when changes are observed,” Dr. Baker noted. “RA patients may lose weight for a number of reasons, not all related to their arthritis, and it is unlikely that there is a ‘one size fits all’ approach,” he said.
The study was limited in part by the women-only study population, so the results might not be generalizable to men, Dr. Sparks said. “The reason for weight change was unavailable,” he added. Directions for further research include investigation of how factors such as physical activity, diet, and weight loss may affect the risk of death among individuals with and without RA, he said.
Dr. Sparks had no financial conflicts to disclose. The study was supported in part by the National Institutes of Health and the Rheumatology Research Foundation’s Disease-Targeted Innovative Award and Scientist Development Awards.
SOURCE: Sparks J et al. Arthritis Rheumatol. 2017 Nov 30. doi: 10.1002/art.40346.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Major finding: The risk of death was approximately twice as high among women with weight loss greater than 30 pounds both for those diagnosed around the same time with RA (hazard ratio, 2.78) and for controls (HR, 2.16), compared with those whose weight remained stable.
Study details: A case-control study of 8,786 participants in the Nurses’ Health Study during 1976-2016.
Disclosures: Dr. Sparks had no financial conflicts to disclose. The study was supported in part by the National Institutes of Health and the Rheumatology Research Foundation’s Disease-Targeted Innovative Award and Scientist Development Awards.
Source: Sparks J et al. Arthritis Rheumatol. 2017 Nov 30. doi: 10.1002/art.40346.
PCVs reduced CAP hospitalizations in young children but not other age groups
, but there was no clear impact apparent in other age groups, reported Annemarie van Deursen, MD, of the University Medical Centre (the Netherlands) Utrecht, and her associates.
In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the national infant immunization program in 2006; in 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). The investigators undertook a population-based retrospective study during 1999-2014 on all-cause CAP hospitalizations in all ages, identifying 155,994 CAP hospitalizations.
In children aged 0-6 months, the CAP hospitalization rate ratio (RR) was significant from 2012 onward, with an overall post-PCV RR of 0.62 and a RR of 0.19 at the end of the study period in December 2014. In children aged 6 months-1 year, the RR was statistically significant directly after the introduction of PCV, with an overall post-PCV RR of 0.67 and a RR of 0.47 in December 2014, the investigators wrote.
In none of the other age groups did the overall post-PCV hospitalization RR reach statistical significance.
The association of reductions in CAP hospitalizations in children up to 2 years with the introduction of PCV7 “supports the interpretation for a direct causal effect of PCV7, in line with IPD [invasive pneumococcal disease] results that showed a sustained overall IPD reduction in children,” the investigators said. “Furthermore, [during] each subsequent year of the post-PCV period, the reduction in CAP hospitalization rates increased in line with progressive vaccine-type–IPD reduction in the population and limited replacement by nonvaccine type in childhood IPD.”
Read more in Vaccine (2017 Nov 13. doi: 10.1016/j.vaccine.2017.10.090).
, but there was no clear impact apparent in other age groups, reported Annemarie van Deursen, MD, of the University Medical Centre (the Netherlands) Utrecht, and her associates.
In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the national infant immunization program in 2006; in 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). The investigators undertook a population-based retrospective study during 1999-2014 on all-cause CAP hospitalizations in all ages, identifying 155,994 CAP hospitalizations.
In children aged 0-6 months, the CAP hospitalization rate ratio (RR) was significant from 2012 onward, with an overall post-PCV RR of 0.62 and a RR of 0.19 at the end of the study period in December 2014. In children aged 6 months-1 year, the RR was statistically significant directly after the introduction of PCV, with an overall post-PCV RR of 0.67 and a RR of 0.47 in December 2014, the investigators wrote.
In none of the other age groups did the overall post-PCV hospitalization RR reach statistical significance.
The association of reductions in CAP hospitalizations in children up to 2 years with the introduction of PCV7 “supports the interpretation for a direct causal effect of PCV7, in line with IPD [invasive pneumococcal disease] results that showed a sustained overall IPD reduction in children,” the investigators said. “Furthermore, [during] each subsequent year of the post-PCV period, the reduction in CAP hospitalization rates increased in line with progressive vaccine-type–IPD reduction in the population and limited replacement by nonvaccine type in childhood IPD.”
Read more in Vaccine (2017 Nov 13. doi: 10.1016/j.vaccine.2017.10.090).
, but there was no clear impact apparent in other age groups, reported Annemarie van Deursen, MD, of the University Medical Centre (the Netherlands) Utrecht, and her associates.
In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the national infant immunization program in 2006; in 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). The investigators undertook a population-based retrospective study during 1999-2014 on all-cause CAP hospitalizations in all ages, identifying 155,994 CAP hospitalizations.
In children aged 0-6 months, the CAP hospitalization rate ratio (RR) was significant from 2012 onward, with an overall post-PCV RR of 0.62 and a RR of 0.19 at the end of the study period in December 2014. In children aged 6 months-1 year, the RR was statistically significant directly after the introduction of PCV, with an overall post-PCV RR of 0.67 and a RR of 0.47 in December 2014, the investigators wrote.
In none of the other age groups did the overall post-PCV hospitalization RR reach statistical significance.
The association of reductions in CAP hospitalizations in children up to 2 years with the introduction of PCV7 “supports the interpretation for a direct causal effect of PCV7, in line with IPD [invasive pneumococcal disease] results that showed a sustained overall IPD reduction in children,” the investigators said. “Furthermore, [during] each subsequent year of the post-PCV period, the reduction in CAP hospitalization rates increased in line with progressive vaccine-type–IPD reduction in the population and limited replacement by nonvaccine type in childhood IPD.”
Read more in Vaccine (2017 Nov 13. doi: 10.1016/j.vaccine.2017.10.090).
FROM VACCINE
VIDEO: Daratumumab gives kick to standard first-line myeloma therapy
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
REPORTING FROM ASH 2017
Daratumumab plus VMP boosts PFS, MRD-negativity in de novo myeloma
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The hazard ratio for progression or death with daratumumab plus VMP was 0.50 (P less than .0001).
Study details: Randomized phase 3 trial in 706 patients with multiple myeloma who were ineligible for transplant.
Disclosures: The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
Source: Mateos MV et al. ASH Abstract LBA-4.
JAK inhibitors for atopic dermatitis might hit JAK-pot
GENEVA – at the annual congress of the European Academy of Dermatology and Venereology, with three positive phase 2 randomized trials featuring one topical and two oral agents presented to enthusiastic audiences.
The way has already been paved for dermatologic researchers by veterinarians, who developed oclacitinib (Apoquel), a relatively selective Janus kinase 1 (JAK1) inhibitor, for canine AD. The medication was approved by the Food and Drug Administration in 2013 for treating AD and for controlling pruritus associated with allergic dermatitis in dogs.
PF-04965842
“Get out your pencils, everyone. This is why you’re all here at 8 o’clock on a Sunday morning,” Melinda Gooderham, MD, said, standing before a packed house at the main arena of the Geneva Convention Center, as she launched into the results of a phase II randomized, double-blind, placebo-controlled, 12-week trial of a JAK inhibitor known for now as PF-04965842. This is a JAK1-selective agent with a good effect on interleukin-4 and -13, key mediators of the Th2 cytokines implicated in the pathogenesis of AD.
The dose-ranging study included 250 adults with AD and an inadequate response to or intolerance of topical therapy. Their mean baseline Eczema Area and Severity Index (EASI) score was 25 with a 60/40 ratio of moderate to severe AD. The five-arm trial randomized patients to PF-04965842 at 10 mg, 30 mg, 100 mg, or 200 mg once daily or placebo.
The primary endpoint was the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0 or 1 – clear or almost clear – along with at least a 2-grade improvement from baseline at week 12. A clear dose-response effect was evident, with the 100- and 200-mg doses achieving response rates of 28% and 45%, respectively, compared with 6% in placebo-treated controls, reported Dr. Gooderham, medical director of the Skin Center for Dermatology in Peterborough, Ont., and a dermatologist at Queen’s University in Kingston, Ont.
Onset of action was speedy: patients in the 200-mg group reached their full improvement in IGA score by week 4 and maintained that response through week 12. Maximum improvement in EASI score – a mean 80% reduction – was achieved by week 6 and sustained thereafter. The proportion of patients in the 200-mg group achieving at least a 4-point improvement on the Pruritus Numeric Rating Scale significantly exceeded that in the placebo group as early as day 2 of the trial. At week 12, 64% of patients in the 200-mg group had achieved this level of improvement in itch, compared with 26% of controls.
A dose-dependent drop in platelet count occurred in the study, reaching a 30% decline at the 4-week nadir in the 200-mg group, followed by gradual on-treatment recovery. Both LDL and HDL cholesterol rose on active therapy – a class effect of JAK inhibitors – but the ratio between the two lipid levels remained unchanged. The two serious adverse events deemed treatment related were a case of eczema herpeticum in a patient on the 100-mg dose and pneumonia in a patient on the 200-mg dose.
Baricitinib
This once-daily oral JAK1/2 inhibitor is approved for treatment of rheumatoid arthritis in Europe and Japan. Emma Guttman-Yassky, MD, PhD, presented a phase 2 study of baricitinib in 124 adults with moderate to severe AD. Notably, prior to enrollment, all participants had to have failed to respond to a 4-week run-in period of supervised treatment with 0.1% triamcinolone cream, a midpotency topical steroid. They were then randomized to 2 mg or 4 mg of once-daily baricitinib or placebo, in all cases supplemented as needed with the topical steroid. Their median baseline EASI score was 21.
The primary endpoint was the proportion of patients achieving at least a 50% improvement in EASI score, or EASI 50 response, by week 16 from baseline in a nonresponder imputation analysis. This was achieved in 65% of patients on the 4-mg dose of baricitinib, 64% on the 2-mg dose, and 46% of controls on placebo plus the topical steroid. A statistically significant difference in EASI 50 response between the baricitinib groups and controls was seen at 1 week, with nearly the maximum effect achieved at week 4. Patients with a baseline EASI score above the median had a much more impressive treatment response because the placebo effect was smaller in participants with more severe AD.
“I think this drug can be an exciting new addition to the field,” declared Dr. Guttman-Yassky, professor and vice chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
From a baseline total SCORAD (Scoring Atopic Dermatitis) score of 55, major improvements were seen in the JAK inhibitor–treated patients by week 4. At week 16, the average reduction from baseline was 47% in the 4-mg group, 41% in the 2-mg group, and 21% in the placebo group. Both the SCORAD pruritus and sleep loss subscores showed significantly more robust improvement in the baricitinib groups than in controls. Indeed, a significant drop in pruritus scores was noted within the first week.
The 4-mg dose was associated with greater improvement and faster onset of action than the 2-mg dose on some but not all disease measures.
Dr. Guttman-Yassky described baricitinib as having “an overall acceptable safety profile,” with no serious treatment-related adverse events noted. Headache, nasopharyngitis, and asymptomatic increases in serum creatinine phosphokinase were more common in baricitinib-treated patients than with placebo.
JTE-052
Hidemi Nakagawa, MD, presented a phase 2 study of topical JTE-052 ointment in 327 Japanese adults with moderate to severe AD. The drug inhibits JAK1/2/3 as well as the tyrosine kinase pathway. It also promotes keratinocyte production of filaggrin in the skin barrier. Participants were randomized to twice-daily application of JTE-052 ointment (at 0.25%, 0.5%, 1%, or 3%), vehicle ointment, or 0.1% tacrolimus ointment twice a day for 4 weeks. The primary outcome was the change from baseline in modified EASI score in the active treatment groups compared with placebo. All doses of JTE-052 proved significantly more effective than vehicle. A dose-response effect was noted, with a 42% reduction from baseline in modified EASI score in the 0.25% JTE-052 group, a 57% reduction with 0.5%, a 55% reduction with 1% ointment, and a 73% reduction with 3%, compared with a 12% reduction decrease in patients who received vehicle. The topical tacrolimus group showed a 62% reduction from baseline, reported Dr. Nakagawa, professor and head of the division of dermatology at Jikei University, Tokyo.
All doses of JTE-052 were also significantly more effective than placebo on all secondary endpoints, which included IGA, percent body surface area affected, and Pruritus Numeric Rating Scale score.
At all but the weakest concentration, JTE-052 resulted in significant reduction in pruritus starting with the second dose on day 1 of the trial, he added.
Mild nasopharyngitis occurred in 3.4% of JTE-052–treated patients. There were no serious adverse events and no changes in laboratory parameters in the study. One patient discontinued JTE-052 because of application-site contact dermatitis, another because of application-site irritation. The results of this study were recently published in the British Journal of Dermatology (Br J Dermatol. 2017 Sep 28. doi: 10.1111/bjd.16014).
Dr. Nakagawa reported receiving research grants from and serving as a consultant to Japan Tobacco, which is developing JTE-052. Dr. Guttman-Yassky reported having financial relationships with Eli Lilly and Incyte, which sponsored the baricitinib study, as well as most other pharmaceutical companies developing therapies for AD. Dr. Gooderham reported receiving research funding from and serving as a consultant to Pfizer, which sponsored the PF-04965842 study, as well as numerous other pharmaceutical companies.
GENEVA – at the annual congress of the European Academy of Dermatology and Venereology, with three positive phase 2 randomized trials featuring one topical and two oral agents presented to enthusiastic audiences.
The way has already been paved for dermatologic researchers by veterinarians, who developed oclacitinib (Apoquel), a relatively selective Janus kinase 1 (JAK1) inhibitor, for canine AD. The medication was approved by the Food and Drug Administration in 2013 for treating AD and for controlling pruritus associated with allergic dermatitis in dogs.
PF-04965842
“Get out your pencils, everyone. This is why you’re all here at 8 o’clock on a Sunday morning,” Melinda Gooderham, MD, said, standing before a packed house at the main arena of the Geneva Convention Center, as she launched into the results of a phase II randomized, double-blind, placebo-controlled, 12-week trial of a JAK inhibitor known for now as PF-04965842. This is a JAK1-selective agent with a good effect on interleukin-4 and -13, key mediators of the Th2 cytokines implicated in the pathogenesis of AD.
The dose-ranging study included 250 adults with AD and an inadequate response to or intolerance of topical therapy. Their mean baseline Eczema Area and Severity Index (EASI) score was 25 with a 60/40 ratio of moderate to severe AD. The five-arm trial randomized patients to PF-04965842 at 10 mg, 30 mg, 100 mg, or 200 mg once daily or placebo.
The primary endpoint was the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0 or 1 – clear or almost clear – along with at least a 2-grade improvement from baseline at week 12. A clear dose-response effect was evident, with the 100- and 200-mg doses achieving response rates of 28% and 45%, respectively, compared with 6% in placebo-treated controls, reported Dr. Gooderham, medical director of the Skin Center for Dermatology in Peterborough, Ont., and a dermatologist at Queen’s University in Kingston, Ont.
Onset of action was speedy: patients in the 200-mg group reached their full improvement in IGA score by week 4 and maintained that response through week 12. Maximum improvement in EASI score – a mean 80% reduction – was achieved by week 6 and sustained thereafter. The proportion of patients in the 200-mg group achieving at least a 4-point improvement on the Pruritus Numeric Rating Scale significantly exceeded that in the placebo group as early as day 2 of the trial. At week 12, 64% of patients in the 200-mg group had achieved this level of improvement in itch, compared with 26% of controls.
A dose-dependent drop in platelet count occurred in the study, reaching a 30% decline at the 4-week nadir in the 200-mg group, followed by gradual on-treatment recovery. Both LDL and HDL cholesterol rose on active therapy – a class effect of JAK inhibitors – but the ratio between the two lipid levels remained unchanged. The two serious adverse events deemed treatment related were a case of eczema herpeticum in a patient on the 100-mg dose and pneumonia in a patient on the 200-mg dose.
Baricitinib
This once-daily oral JAK1/2 inhibitor is approved for treatment of rheumatoid arthritis in Europe and Japan. Emma Guttman-Yassky, MD, PhD, presented a phase 2 study of baricitinib in 124 adults with moderate to severe AD. Notably, prior to enrollment, all participants had to have failed to respond to a 4-week run-in period of supervised treatment with 0.1% triamcinolone cream, a midpotency topical steroid. They were then randomized to 2 mg or 4 mg of once-daily baricitinib or placebo, in all cases supplemented as needed with the topical steroid. Their median baseline EASI score was 21.
The primary endpoint was the proportion of patients achieving at least a 50% improvement in EASI score, or EASI 50 response, by week 16 from baseline in a nonresponder imputation analysis. This was achieved in 65% of patients on the 4-mg dose of baricitinib, 64% on the 2-mg dose, and 46% of controls on placebo plus the topical steroid. A statistically significant difference in EASI 50 response between the baricitinib groups and controls was seen at 1 week, with nearly the maximum effect achieved at week 4. Patients with a baseline EASI score above the median had a much more impressive treatment response because the placebo effect was smaller in participants with more severe AD.
“I think this drug can be an exciting new addition to the field,” declared Dr. Guttman-Yassky, professor and vice chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
From a baseline total SCORAD (Scoring Atopic Dermatitis) score of 55, major improvements were seen in the JAK inhibitor–treated patients by week 4. At week 16, the average reduction from baseline was 47% in the 4-mg group, 41% in the 2-mg group, and 21% in the placebo group. Both the SCORAD pruritus and sleep loss subscores showed significantly more robust improvement in the baricitinib groups than in controls. Indeed, a significant drop in pruritus scores was noted within the first week.
The 4-mg dose was associated with greater improvement and faster onset of action than the 2-mg dose on some but not all disease measures.
Dr. Guttman-Yassky described baricitinib as having “an overall acceptable safety profile,” with no serious treatment-related adverse events noted. Headache, nasopharyngitis, and asymptomatic increases in serum creatinine phosphokinase were more common in baricitinib-treated patients than with placebo.
JTE-052
Hidemi Nakagawa, MD, presented a phase 2 study of topical JTE-052 ointment in 327 Japanese adults with moderate to severe AD. The drug inhibits JAK1/2/3 as well as the tyrosine kinase pathway. It also promotes keratinocyte production of filaggrin in the skin barrier. Participants were randomized to twice-daily application of JTE-052 ointment (at 0.25%, 0.5%, 1%, or 3%), vehicle ointment, or 0.1% tacrolimus ointment twice a day for 4 weeks. The primary outcome was the change from baseline in modified EASI score in the active treatment groups compared with placebo. All doses of JTE-052 proved significantly more effective than vehicle. A dose-response effect was noted, with a 42% reduction from baseline in modified EASI score in the 0.25% JTE-052 group, a 57% reduction with 0.5%, a 55% reduction with 1% ointment, and a 73% reduction with 3%, compared with a 12% reduction decrease in patients who received vehicle. The topical tacrolimus group showed a 62% reduction from baseline, reported Dr. Nakagawa, professor and head of the division of dermatology at Jikei University, Tokyo.
All doses of JTE-052 were also significantly more effective than placebo on all secondary endpoints, which included IGA, percent body surface area affected, and Pruritus Numeric Rating Scale score.
At all but the weakest concentration, JTE-052 resulted in significant reduction in pruritus starting with the second dose on day 1 of the trial, he added.
Mild nasopharyngitis occurred in 3.4% of JTE-052–treated patients. There were no serious adverse events and no changes in laboratory parameters in the study. One patient discontinued JTE-052 because of application-site contact dermatitis, another because of application-site irritation. The results of this study were recently published in the British Journal of Dermatology (Br J Dermatol. 2017 Sep 28. doi: 10.1111/bjd.16014).
Dr. Nakagawa reported receiving research grants from and serving as a consultant to Japan Tobacco, which is developing JTE-052. Dr. Guttman-Yassky reported having financial relationships with Eli Lilly and Incyte, which sponsored the baricitinib study, as well as most other pharmaceutical companies developing therapies for AD. Dr. Gooderham reported receiving research funding from and serving as a consultant to Pfizer, which sponsored the PF-04965842 study, as well as numerous other pharmaceutical companies.
GENEVA – at the annual congress of the European Academy of Dermatology and Venereology, with three positive phase 2 randomized trials featuring one topical and two oral agents presented to enthusiastic audiences.
The way has already been paved for dermatologic researchers by veterinarians, who developed oclacitinib (Apoquel), a relatively selective Janus kinase 1 (JAK1) inhibitor, for canine AD. The medication was approved by the Food and Drug Administration in 2013 for treating AD and for controlling pruritus associated with allergic dermatitis in dogs.
PF-04965842
“Get out your pencils, everyone. This is why you’re all here at 8 o’clock on a Sunday morning,” Melinda Gooderham, MD, said, standing before a packed house at the main arena of the Geneva Convention Center, as she launched into the results of a phase II randomized, double-blind, placebo-controlled, 12-week trial of a JAK inhibitor known for now as PF-04965842. This is a JAK1-selective agent with a good effect on interleukin-4 and -13, key mediators of the Th2 cytokines implicated in the pathogenesis of AD.
The dose-ranging study included 250 adults with AD and an inadequate response to or intolerance of topical therapy. Their mean baseline Eczema Area and Severity Index (EASI) score was 25 with a 60/40 ratio of moderate to severe AD. The five-arm trial randomized patients to PF-04965842 at 10 mg, 30 mg, 100 mg, or 200 mg once daily or placebo.
The primary endpoint was the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0 or 1 – clear or almost clear – along with at least a 2-grade improvement from baseline at week 12. A clear dose-response effect was evident, with the 100- and 200-mg doses achieving response rates of 28% and 45%, respectively, compared with 6% in placebo-treated controls, reported Dr. Gooderham, medical director of the Skin Center for Dermatology in Peterborough, Ont., and a dermatologist at Queen’s University in Kingston, Ont.
Onset of action was speedy: patients in the 200-mg group reached their full improvement in IGA score by week 4 and maintained that response through week 12. Maximum improvement in EASI score – a mean 80% reduction – was achieved by week 6 and sustained thereafter. The proportion of patients in the 200-mg group achieving at least a 4-point improvement on the Pruritus Numeric Rating Scale significantly exceeded that in the placebo group as early as day 2 of the trial. At week 12, 64% of patients in the 200-mg group had achieved this level of improvement in itch, compared with 26% of controls.
A dose-dependent drop in platelet count occurred in the study, reaching a 30% decline at the 4-week nadir in the 200-mg group, followed by gradual on-treatment recovery. Both LDL and HDL cholesterol rose on active therapy – a class effect of JAK inhibitors – but the ratio between the two lipid levels remained unchanged. The two serious adverse events deemed treatment related were a case of eczema herpeticum in a patient on the 100-mg dose and pneumonia in a patient on the 200-mg dose.
Baricitinib
This once-daily oral JAK1/2 inhibitor is approved for treatment of rheumatoid arthritis in Europe and Japan. Emma Guttman-Yassky, MD, PhD, presented a phase 2 study of baricitinib in 124 adults with moderate to severe AD. Notably, prior to enrollment, all participants had to have failed to respond to a 4-week run-in period of supervised treatment with 0.1% triamcinolone cream, a midpotency topical steroid. They were then randomized to 2 mg or 4 mg of once-daily baricitinib or placebo, in all cases supplemented as needed with the topical steroid. Their median baseline EASI score was 21.
The primary endpoint was the proportion of patients achieving at least a 50% improvement in EASI score, or EASI 50 response, by week 16 from baseline in a nonresponder imputation analysis. This was achieved in 65% of patients on the 4-mg dose of baricitinib, 64% on the 2-mg dose, and 46% of controls on placebo plus the topical steroid. A statistically significant difference in EASI 50 response between the baricitinib groups and controls was seen at 1 week, with nearly the maximum effect achieved at week 4. Patients with a baseline EASI score above the median had a much more impressive treatment response because the placebo effect was smaller in participants with more severe AD.
“I think this drug can be an exciting new addition to the field,” declared Dr. Guttman-Yassky, professor and vice chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
From a baseline total SCORAD (Scoring Atopic Dermatitis) score of 55, major improvements were seen in the JAK inhibitor–treated patients by week 4. At week 16, the average reduction from baseline was 47% in the 4-mg group, 41% in the 2-mg group, and 21% in the placebo group. Both the SCORAD pruritus and sleep loss subscores showed significantly more robust improvement in the baricitinib groups than in controls. Indeed, a significant drop in pruritus scores was noted within the first week.
The 4-mg dose was associated with greater improvement and faster onset of action than the 2-mg dose on some but not all disease measures.
Dr. Guttman-Yassky described baricitinib as having “an overall acceptable safety profile,” with no serious treatment-related adverse events noted. Headache, nasopharyngitis, and asymptomatic increases in serum creatinine phosphokinase were more common in baricitinib-treated patients than with placebo.
JTE-052
Hidemi Nakagawa, MD, presented a phase 2 study of topical JTE-052 ointment in 327 Japanese adults with moderate to severe AD. The drug inhibits JAK1/2/3 as well as the tyrosine kinase pathway. It also promotes keratinocyte production of filaggrin in the skin barrier. Participants were randomized to twice-daily application of JTE-052 ointment (at 0.25%, 0.5%, 1%, or 3%), vehicle ointment, or 0.1% tacrolimus ointment twice a day for 4 weeks. The primary outcome was the change from baseline in modified EASI score in the active treatment groups compared with placebo. All doses of JTE-052 proved significantly more effective than vehicle. A dose-response effect was noted, with a 42% reduction from baseline in modified EASI score in the 0.25% JTE-052 group, a 57% reduction with 0.5%, a 55% reduction with 1% ointment, and a 73% reduction with 3%, compared with a 12% reduction decrease in patients who received vehicle. The topical tacrolimus group showed a 62% reduction from baseline, reported Dr. Nakagawa, professor and head of the division of dermatology at Jikei University, Tokyo.
All doses of JTE-052 were also significantly more effective than placebo on all secondary endpoints, which included IGA, percent body surface area affected, and Pruritus Numeric Rating Scale score.
At all but the weakest concentration, JTE-052 resulted in significant reduction in pruritus starting with the second dose on day 1 of the trial, he added.
Mild nasopharyngitis occurred in 3.4% of JTE-052–treated patients. There were no serious adverse events and no changes in laboratory parameters in the study. One patient discontinued JTE-052 because of application-site contact dermatitis, another because of application-site irritation. The results of this study were recently published in the British Journal of Dermatology (Br J Dermatol. 2017 Sep 28. doi: 10.1111/bjd.16014).
Dr. Nakagawa reported receiving research grants from and serving as a consultant to Japan Tobacco, which is developing JTE-052. Dr. Guttman-Yassky reported having financial relationships with Eli Lilly and Incyte, which sponsored the baricitinib study, as well as most other pharmaceutical companies developing therapies for AD. Dr. Gooderham reported receiving research funding from and serving as a consultant to Pfizer, which sponsored the PF-04965842 study, as well as numerous other pharmaceutical companies.
EXPERT ANALYSIS FROM THE EADV CONGRESS