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CAR T-cell products shine in real-world setting, reveal new insights
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
FROM CART21
FDA expands sacubitril/valsartan indication to embrace some HFpEF
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
Romosozumab may not increase cardiovascular risk after all
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
FROM RWCS 2021
Consider home subcutaneous immune globulin for refractory dermatomyositis
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
FROM RWCS 2021
Checkpoint inhibitors’ ‘big picture’ safety shown with preexisting autoimmune diseases
Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).
“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.
To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.
Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).
The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.
Incidence of immune-related adverse events
The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.
The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.
Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”
Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).
Study largely bypasses the effects of checkpoint inhibitors on RA patients
“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”
Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.
“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”
She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.
That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”
Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”
The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.
Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).
“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.
To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.
Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).
The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.
Incidence of immune-related adverse events
The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.
The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.
Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”
Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).
Study largely bypasses the effects of checkpoint inhibitors on RA patients
“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”
Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.
“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”
She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.
That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”
Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”
The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.
Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).
“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.
To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.
Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).
The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.
Incidence of immune-related adverse events
The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.
The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.
Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”
Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).
Study largely bypasses the effects of checkpoint inhibitors on RA patients
“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”
Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.
“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”
She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.
That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”
Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”
The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.
FROM ANNALS OF INTERNAL MEDICINE
Cumulative exposure to high-potency topical steroid doses drives osteoporosis fractures
In support of previously published case reports, in a dose-response relationship.
In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.
“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.
The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.
Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.
For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.
The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.
“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.
Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.
“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”
If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.
The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.
The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.
“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said
For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.
“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.
In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”
The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.
“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.
To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.
Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.
In support of previously published case reports, in a dose-response relationship.
In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.
“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.
The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.
Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.
For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.
The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.
“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.
Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.
“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”
If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.
The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.
The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.
“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said
For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.
“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.
In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”
The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.
“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.
To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.
Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.
In support of previously published case reports, in a dose-response relationship.
In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.
“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.
The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.
Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.
For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.
The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.
“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.
Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.
“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”
If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.
The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.
The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.
“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said
For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.
“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.
In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”
The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.
“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.
To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.
Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.
FROM JAMA DERMATOLOGY
FDA approves first drug that protects against chemo-induced myelosuppression
A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.
The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.
Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.
“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
First drug of its type
Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.
Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.
“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.
“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
Approval based on randomized, placebo-controlled trials
The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.
These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.
Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.
Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.
The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.
The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.
The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.
A version of this article first appeared on Medscape.com.
A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.
The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.
Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.
“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
First drug of its type
Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.
Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.
“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.
“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
Approval based on randomized, placebo-controlled trials
The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.
These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.
Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.
Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.
The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.
The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.
The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.
A version of this article first appeared on Medscape.com.
A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.
The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.
Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.
“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
First drug of its type
Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.
Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.
“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.
“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
Approval based on randomized, placebo-controlled trials
The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.
These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.
Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.
Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.
The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.
The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.
The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.
A version of this article first appeared on Medscape.com.
Semaglutide for weight loss? A good first STEP, with caveats
The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.
“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.
The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.
“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.
However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”
Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.
“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.
However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”
Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.
Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.
And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.
In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
‘Pressing need’ to address obesity; semaglutide filed for obesity
There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.
Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.
In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”
Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.
Topline results from STEP 1 were presented June 4, 2020.
And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.
The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
Most patients had 5% weight loss with semaglutide
The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m2 or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.
Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).
On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.
Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.
Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).
Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).
At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).
Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).
About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.
Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.
In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.
The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
GI disorders and ‘important limitations’
More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).
More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.
Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.
Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.
The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.
A version of this article first appeared on Medscape.com.
The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.
“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.
The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.
“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.
However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”
Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.
“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.
However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”
Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.
Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.
And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.
In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
‘Pressing need’ to address obesity; semaglutide filed for obesity
There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.
Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.
In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”
Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.
Topline results from STEP 1 were presented June 4, 2020.
And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.
The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
Most patients had 5% weight loss with semaglutide
The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m2 or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.
Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).
On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.
Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.
Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).
Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).
At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).
Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).
About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.
Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.
In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.
The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
GI disorders and ‘important limitations’
More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).
More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.
Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.
Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.
The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.
A version of this article first appeared on Medscape.com.
The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.
“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.
The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.
“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.
However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”
Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.
“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.
However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”
Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.
Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.
And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.
In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
‘Pressing need’ to address obesity; semaglutide filed for obesity
There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.
Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.
In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”
Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.
Topline results from STEP 1 were presented June 4, 2020.
And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.
The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
Most patients had 5% weight loss with semaglutide
The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m2 or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.
Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).
On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.
Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.
Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).
Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).
At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).
Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).
About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.
Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.
In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.
The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
GI disorders and ‘important limitations’
More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).
More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.
Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.
Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.
The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.
A version of this article first appeared on Medscape.com.
Antidepressants may scupper efficacy of MDMA for PTSD
Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after methylenedioxymethamphetamine (MDMA)-assisted psychotherapy than their peers who had not recently taken SSRIs.
Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, said in an interview.
“As psychedelic medicines become available, it’s going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA,” Dr. Feduccia said.
The study was published online Nov. 20, 2020, in Psychopharmacology (doi: 10.1007/s00213-020-05710-w).
Reduced response
The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), NRIs, and norepinephrine-dopamine reuptake inhibitors (NDRIs).
Prior research shows that, when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.
The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.
For 16 of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).
The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration.
Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were at least 50.
After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores, compared with the taper group (mean, 45.7 vs. 70.3; P = .009).
About two-thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.
The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II, compared with the taper group (mean, 12.7 vs. 22.6; P = .010).
“Another really interesting” observation, said Dr. Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group, compared with the nontaper group.
“This suggests that MDMA didn’t have the same physiological response in individuals who tapered SSRIs. This should be followed up,” she said.
The investigators offerred several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.
These include the down-regulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use, reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use, and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.
Important clinical implications
In a comment, Steven R. Thorp, PhD, professor at Alliant International University, San Diego, said the findings are “very interesting” and likely “not well known.”
“There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research,” Dr. Thorp said.
“Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only,” Dr. Thorp noted.
“This study suggests that, in addition to the other potential disadvantages of medications (e.g., cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy,” Dr. Thorp added.
The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies, a nonprofit organization. Dr. Feduccia received salary support for full-time employment with MAPS Public Benefit Corporation. Dr. Thorp disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after methylenedioxymethamphetamine (MDMA)-assisted psychotherapy than their peers who had not recently taken SSRIs.
Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, said in an interview.
“As psychedelic medicines become available, it’s going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA,” Dr. Feduccia said.
The study was published online Nov. 20, 2020, in Psychopharmacology (doi: 10.1007/s00213-020-05710-w).
Reduced response
The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), NRIs, and norepinephrine-dopamine reuptake inhibitors (NDRIs).
Prior research shows that, when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.
The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.
For 16 of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).
The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration.
Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were at least 50.
After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores, compared with the taper group (mean, 45.7 vs. 70.3; P = .009).
About two-thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.
The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II, compared with the taper group (mean, 12.7 vs. 22.6; P = .010).
“Another really interesting” observation, said Dr. Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group, compared with the nontaper group.
“This suggests that MDMA didn’t have the same physiological response in individuals who tapered SSRIs. This should be followed up,” she said.
The investigators offerred several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.
These include the down-regulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use, reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use, and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.
Important clinical implications
In a comment, Steven R. Thorp, PhD, professor at Alliant International University, San Diego, said the findings are “very interesting” and likely “not well known.”
“There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research,” Dr. Thorp said.
“Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only,” Dr. Thorp noted.
“This study suggests that, in addition to the other potential disadvantages of medications (e.g., cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy,” Dr. Thorp added.
The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies, a nonprofit organization. Dr. Feduccia received salary support for full-time employment with MAPS Public Benefit Corporation. Dr. Thorp disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after methylenedioxymethamphetamine (MDMA)-assisted psychotherapy than their peers who had not recently taken SSRIs.
Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, said in an interview.
“As psychedelic medicines become available, it’s going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA,” Dr. Feduccia said.
The study was published online Nov. 20, 2020, in Psychopharmacology (doi: 10.1007/s00213-020-05710-w).
Reduced response
The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), NRIs, and norepinephrine-dopamine reuptake inhibitors (NDRIs).
Prior research shows that, when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.
The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.
For 16 of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).
The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration.
Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were at least 50.
After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores, compared with the taper group (mean, 45.7 vs. 70.3; P = .009).
About two-thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.
The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II, compared with the taper group (mean, 12.7 vs. 22.6; P = .010).
“Another really interesting” observation, said Dr. Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group, compared with the nontaper group.
“This suggests that MDMA didn’t have the same physiological response in individuals who tapered SSRIs. This should be followed up,” she said.
The investigators offerred several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.
These include the down-regulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use, reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use, and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.
Important clinical implications
In a comment, Steven R. Thorp, PhD, professor at Alliant International University, San Diego, said the findings are “very interesting” and likely “not well known.”
“There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research,” Dr. Thorp said.
“Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only,” Dr. Thorp noted.
“This study suggests that, in addition to the other potential disadvantages of medications (e.g., cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy,” Dr. Thorp added.
The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies, a nonprofit organization. Dr. Feduccia received salary support for full-time employment with MAPS Public Benefit Corporation. Dr. Thorp disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Unprecedented’ long-term survival after immunotherapy in pretreated NSCLC
Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.
This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.
“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
Pembrolizumab survival data
The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.
This is the latest update on data from this trial, which has been described as “really extraordinary.”
The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.
Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.
The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.
In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.
Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”
He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.
At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].
“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.
Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”
Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.
“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.
“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”
Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”
However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”
H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”
He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”
Nivolumab survival data
The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.
Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.
The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.
Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.
Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.
“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.
Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”
Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.
For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”
KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.
A version of this article first appeared on Medscape.com.
Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.
This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.
“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
Pembrolizumab survival data
The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.
This is the latest update on data from this trial, which has been described as “really extraordinary.”
The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.
Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.
The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.
In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.
Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”
He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.
At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].
“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.
Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”
Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.
“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.
“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”
Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”
However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”
H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”
He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”
Nivolumab survival data
The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.
Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.
The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.
Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.
Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.
“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.
Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”
Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.
For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”
KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.
A version of this article first appeared on Medscape.com.
Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.
This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.
“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
Pembrolizumab survival data
The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.
This is the latest update on data from this trial, which has been described as “really extraordinary.”
The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.
Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.
The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.
In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.
Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”
He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.
At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].
“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.
Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”
Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.
“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.
“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”
Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”
However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”
H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”
He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”
Nivolumab survival data
The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.
Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.
The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.
Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.
Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.
“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.
Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”
Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.
For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”
KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.
A version of this article first appeared on Medscape.com.