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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Novel myasthenia gravis therapies bring opportunities, challenges
PHOENIX – , according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).
The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.
The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
Assessing the risk/benefit ratio
Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.
Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.
The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.
Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.
In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.
Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.
Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.
FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
Treatment strategies
In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.
During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”
Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.
Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.
PHOENIX – , according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).
The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.
The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
Assessing the risk/benefit ratio
Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.
Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.
The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.
Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.
In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.
Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.
Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.
FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
Treatment strategies
In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.
During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”
Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.
Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.
PHOENIX – , according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).
The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.
The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
Assessing the risk/benefit ratio
Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.
Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.
The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.
Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.
In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.
Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.
Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.
FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
Treatment strategies
In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.
During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”
Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.
Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.
AT AANEM 2023
Alternative antirejection regimen is efficacious in pediatric heart transplant
Study challenges everolimus boxed warning
according to the first phase 3 trial to compare antirejection strategies in the pediatric setting.
Even though MMF and tacrolimus have never been evaluated for pediatric cardiac transplant in a controlled trial, this combination is widely considered a standard based on adult data, said Christopher Almond, MD, a professor of pediatric cardiology at Stanford (Calif.) Medicine.
Everolimus has not been widely used in an antirejection regimen in children following heart transplant in part because of a boxed warning. The warning was added to labeling when this agent was associated with increased infection and increased mortality in adults if given within 3 months of transplant.
In this non-inferiority trial, called TEAMMATE, patients were randomized to the MMF-based or everolimus-based regimen 6 months after transplant.
Everolimus- vs. MMF-based antirejection
The study enrolled 210 children and adolescents 21 years of age or younger. The control arm treatment consisted of MMF (660 mg/m2 every 12 hours) plus standard dose of tacrolimus (initially 7-10 ng/mL followed at 6 months by 5-8 ng/mL).
In the experimental arm, patients received everolimus (3-8 ng/mL) plus a low dose of tacrolimus (initially 3-5 ng/mL followed at 6 months by 2.5-4.5 ng/mL).
The primary endpoint was score on the major adverse transplant event (MATE-6) tool. Based on gradations of severity, this assigns values for cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), acute cellular rejection (ACR), antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder (PTLD).
Thirty months after randomization, the MATE-6 scores were 1.96 in the everolimus group and 2.18 in the MMF group, which conferred the everolimus-based regimen with a numerical but not a significant advantage over the MMF-based regimen. For the goal of noninferiority, the everolimus regimen “met the prespecified safety criterion for success,” Dr. Almond said.
Numerical advantage for everolimus on efficacy
The primary efficacy endpoint was the MATE-3 score, which is limited to CAV, CKD, and ACR. Again, the mean score on this metric (0.93 vs. 1.25) was lower on the everolimus-based regimen but not significantly different.
Looking at specific events in the MATE-6 score, the everolimus-based regimen was associated with lower numerical rates of CAV and CKD, but a higher rate of PTLD, Dr. Almond reported.
On the MATE-3 efficacy analysis, the everolimus-based regimen was again associated with lower numerical rates of CAV and CKD but higher rates of ACR.
In terms of adverse events, including those involving the gastrointestinal tract, blood cells, proteinuria, and interstitial lung disease, most did not differ markedly even if many were numerically more common in the MMF-based arm. The exception was aphthous stomatitis, which was more common on everolimus (32% vs. 7%; P < .001). There were more discontinuations for an adverse event in the MMF arm (21% vs. 12%; P < .001).
Other differences included a lower proportion of patients in the everolimus arm with anti-HLA antibodies (17% vs. 30%; P < .05). Total cholesterol levels at the end of the study were lower but not significantly different in the MMF group, while the higher median glomerular filtration rate was higher on everolimus, and this did reach statistical significance (P < .05).
Infection rates overall were similar, but cytomegalovirus (CMV) infection was more common on the MMF-based regimen. The 30% lower rate of CMV infection in the everolimus proved to be potentially clinically meaningful when it was considered in the context of MATE-3. When these two endpoints were combined (MATE-3 and CMV infection as a prespecified secondary endpoint, the difference was statistically significant (P = .03) in favor of the everolimus-based regimen,
Study supports safety of everolimus regimen
The take-home message is that the everolimus-based regimen, which “is safe in children and young adults when initiated at 6 months after transplant,” can be considered as an alternative to MFF, Dr. Almond concluded.
However, one of the coauthors of the study, Joseph Rossano, MD, chief of the division of cardiology, Children’s Hospital of Philadelphia, suggested a stronger message.
“These data provide compelling reasons to consider initiation of the combination of everolimus and tacrolimus at 6 months post transplant in pediatric heart transplant recipients,” Dr. Rossano said.
Even though the everolimus-based regimen met the terms of noninferiority overall, patients who received this combination rather than the MMF-based regimen “were less likely to have the combined endpoints of vasculopathy, CKD, rejection and CMV infection. Additionally, they were less likely to make donor specific antibodies,” he said.
He also said that this study challenges the current boxed warning for everolimus. He pointed out that the warning, based on early use of everolimus in adults, does not appear to be an issue for children treated at 6 months.
Early mortality based on infection “was not observed in our study,” he said.
The AHA-invited discussant, Antonio G. Cabrera, MD, division chief of pediatric cardiology, University of Utah, Salt Lake City, drew the same conclusions. Based on the study, the everolimus-based regimen can only be described as noninferior to the MMF-based regimen, but Dr. Cabrera listed the same relative advantages as Dr. Rossano, including better kidney function.
Overall, either regimen might be more appealing based on several variables, but Dr. Cabrera said these data suggest everolimus-based treatment “should be considered” as one of two evidence-based options,
Dr. Almond reported no potential financial conflicts of interest. Dr. Rossano reports financial relationships with Abiomed, Bayer, Cytokinetics, Merck, and Myokardia. Dr. Cabrera reported no potential financial conflicts of interest.
Study challenges everolimus boxed warning
Study challenges everolimus boxed warning
according to the first phase 3 trial to compare antirejection strategies in the pediatric setting.
Even though MMF and tacrolimus have never been evaluated for pediatric cardiac transplant in a controlled trial, this combination is widely considered a standard based on adult data, said Christopher Almond, MD, a professor of pediatric cardiology at Stanford (Calif.) Medicine.
Everolimus has not been widely used in an antirejection regimen in children following heart transplant in part because of a boxed warning. The warning was added to labeling when this agent was associated with increased infection and increased mortality in adults if given within 3 months of transplant.
In this non-inferiority trial, called TEAMMATE, patients were randomized to the MMF-based or everolimus-based regimen 6 months after transplant.
Everolimus- vs. MMF-based antirejection
The study enrolled 210 children and adolescents 21 years of age or younger. The control arm treatment consisted of MMF (660 mg/m2 every 12 hours) plus standard dose of tacrolimus (initially 7-10 ng/mL followed at 6 months by 5-8 ng/mL).
In the experimental arm, patients received everolimus (3-8 ng/mL) plus a low dose of tacrolimus (initially 3-5 ng/mL followed at 6 months by 2.5-4.5 ng/mL).
The primary endpoint was score on the major adverse transplant event (MATE-6) tool. Based on gradations of severity, this assigns values for cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), acute cellular rejection (ACR), antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder (PTLD).
Thirty months after randomization, the MATE-6 scores were 1.96 in the everolimus group and 2.18 in the MMF group, which conferred the everolimus-based regimen with a numerical but not a significant advantage over the MMF-based regimen. For the goal of noninferiority, the everolimus regimen “met the prespecified safety criterion for success,” Dr. Almond said.
Numerical advantage for everolimus on efficacy
The primary efficacy endpoint was the MATE-3 score, which is limited to CAV, CKD, and ACR. Again, the mean score on this metric (0.93 vs. 1.25) was lower on the everolimus-based regimen but not significantly different.
Looking at specific events in the MATE-6 score, the everolimus-based regimen was associated with lower numerical rates of CAV and CKD, but a higher rate of PTLD, Dr. Almond reported.
On the MATE-3 efficacy analysis, the everolimus-based regimen was again associated with lower numerical rates of CAV and CKD but higher rates of ACR.
In terms of adverse events, including those involving the gastrointestinal tract, blood cells, proteinuria, and interstitial lung disease, most did not differ markedly even if many were numerically more common in the MMF-based arm. The exception was aphthous stomatitis, which was more common on everolimus (32% vs. 7%; P < .001). There were more discontinuations for an adverse event in the MMF arm (21% vs. 12%; P < .001).
Other differences included a lower proportion of patients in the everolimus arm with anti-HLA antibodies (17% vs. 30%; P < .05). Total cholesterol levels at the end of the study were lower but not significantly different in the MMF group, while the higher median glomerular filtration rate was higher on everolimus, and this did reach statistical significance (P < .05).
Infection rates overall were similar, but cytomegalovirus (CMV) infection was more common on the MMF-based regimen. The 30% lower rate of CMV infection in the everolimus proved to be potentially clinically meaningful when it was considered in the context of MATE-3. When these two endpoints were combined (MATE-3 and CMV infection as a prespecified secondary endpoint, the difference was statistically significant (P = .03) in favor of the everolimus-based regimen,
Study supports safety of everolimus regimen
The take-home message is that the everolimus-based regimen, which “is safe in children and young adults when initiated at 6 months after transplant,” can be considered as an alternative to MFF, Dr. Almond concluded.
However, one of the coauthors of the study, Joseph Rossano, MD, chief of the division of cardiology, Children’s Hospital of Philadelphia, suggested a stronger message.
“These data provide compelling reasons to consider initiation of the combination of everolimus and tacrolimus at 6 months post transplant in pediatric heart transplant recipients,” Dr. Rossano said.
Even though the everolimus-based regimen met the terms of noninferiority overall, patients who received this combination rather than the MMF-based regimen “were less likely to have the combined endpoints of vasculopathy, CKD, rejection and CMV infection. Additionally, they were less likely to make donor specific antibodies,” he said.
He also said that this study challenges the current boxed warning for everolimus. He pointed out that the warning, based on early use of everolimus in adults, does not appear to be an issue for children treated at 6 months.
Early mortality based on infection “was not observed in our study,” he said.
The AHA-invited discussant, Antonio G. Cabrera, MD, division chief of pediatric cardiology, University of Utah, Salt Lake City, drew the same conclusions. Based on the study, the everolimus-based regimen can only be described as noninferior to the MMF-based regimen, but Dr. Cabrera listed the same relative advantages as Dr. Rossano, including better kidney function.
Overall, either regimen might be more appealing based on several variables, but Dr. Cabrera said these data suggest everolimus-based treatment “should be considered” as one of two evidence-based options,
Dr. Almond reported no potential financial conflicts of interest. Dr. Rossano reports financial relationships with Abiomed, Bayer, Cytokinetics, Merck, and Myokardia. Dr. Cabrera reported no potential financial conflicts of interest.
according to the first phase 3 trial to compare antirejection strategies in the pediatric setting.
Even though MMF and tacrolimus have never been evaluated for pediatric cardiac transplant in a controlled trial, this combination is widely considered a standard based on adult data, said Christopher Almond, MD, a professor of pediatric cardiology at Stanford (Calif.) Medicine.
Everolimus has not been widely used in an antirejection regimen in children following heart transplant in part because of a boxed warning. The warning was added to labeling when this agent was associated with increased infection and increased mortality in adults if given within 3 months of transplant.
In this non-inferiority trial, called TEAMMATE, patients were randomized to the MMF-based or everolimus-based regimen 6 months after transplant.
Everolimus- vs. MMF-based antirejection
The study enrolled 210 children and adolescents 21 years of age or younger. The control arm treatment consisted of MMF (660 mg/m2 every 12 hours) plus standard dose of tacrolimus (initially 7-10 ng/mL followed at 6 months by 5-8 ng/mL).
In the experimental arm, patients received everolimus (3-8 ng/mL) plus a low dose of tacrolimus (initially 3-5 ng/mL followed at 6 months by 2.5-4.5 ng/mL).
The primary endpoint was score on the major adverse transplant event (MATE-6) tool. Based on gradations of severity, this assigns values for cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), acute cellular rejection (ACR), antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder (PTLD).
Thirty months after randomization, the MATE-6 scores were 1.96 in the everolimus group and 2.18 in the MMF group, which conferred the everolimus-based regimen with a numerical but not a significant advantage over the MMF-based regimen. For the goal of noninferiority, the everolimus regimen “met the prespecified safety criterion for success,” Dr. Almond said.
Numerical advantage for everolimus on efficacy
The primary efficacy endpoint was the MATE-3 score, which is limited to CAV, CKD, and ACR. Again, the mean score on this metric (0.93 vs. 1.25) was lower on the everolimus-based regimen but not significantly different.
Looking at specific events in the MATE-6 score, the everolimus-based regimen was associated with lower numerical rates of CAV and CKD, but a higher rate of PTLD, Dr. Almond reported.
On the MATE-3 efficacy analysis, the everolimus-based regimen was again associated with lower numerical rates of CAV and CKD but higher rates of ACR.
In terms of adverse events, including those involving the gastrointestinal tract, blood cells, proteinuria, and interstitial lung disease, most did not differ markedly even if many were numerically more common in the MMF-based arm. The exception was aphthous stomatitis, which was more common on everolimus (32% vs. 7%; P < .001). There were more discontinuations for an adverse event in the MMF arm (21% vs. 12%; P < .001).
Other differences included a lower proportion of patients in the everolimus arm with anti-HLA antibodies (17% vs. 30%; P < .05). Total cholesterol levels at the end of the study were lower but not significantly different in the MMF group, while the higher median glomerular filtration rate was higher on everolimus, and this did reach statistical significance (P < .05).
Infection rates overall were similar, but cytomegalovirus (CMV) infection was more common on the MMF-based regimen. The 30% lower rate of CMV infection in the everolimus proved to be potentially clinically meaningful when it was considered in the context of MATE-3. When these two endpoints were combined (MATE-3 and CMV infection as a prespecified secondary endpoint, the difference was statistically significant (P = .03) in favor of the everolimus-based regimen,
Study supports safety of everolimus regimen
The take-home message is that the everolimus-based regimen, which “is safe in children and young adults when initiated at 6 months after transplant,” can be considered as an alternative to MFF, Dr. Almond concluded.
However, one of the coauthors of the study, Joseph Rossano, MD, chief of the division of cardiology, Children’s Hospital of Philadelphia, suggested a stronger message.
“These data provide compelling reasons to consider initiation of the combination of everolimus and tacrolimus at 6 months post transplant in pediatric heart transplant recipients,” Dr. Rossano said.
Even though the everolimus-based regimen met the terms of noninferiority overall, patients who received this combination rather than the MMF-based regimen “were less likely to have the combined endpoints of vasculopathy, CKD, rejection and CMV infection. Additionally, they were less likely to make donor specific antibodies,” he said.
He also said that this study challenges the current boxed warning for everolimus. He pointed out that the warning, based on early use of everolimus in adults, does not appear to be an issue for children treated at 6 months.
Early mortality based on infection “was not observed in our study,” he said.
The AHA-invited discussant, Antonio G. Cabrera, MD, division chief of pediatric cardiology, University of Utah, Salt Lake City, drew the same conclusions. Based on the study, the everolimus-based regimen can only be described as noninferior to the MMF-based regimen, but Dr. Cabrera listed the same relative advantages as Dr. Rossano, including better kidney function.
Overall, either regimen might be more appealing based on several variables, but Dr. Cabrera said these data suggest everolimus-based treatment “should be considered” as one of two evidence-based options,
Dr. Almond reported no potential financial conflicts of interest. Dr. Rossano reports financial relationships with Abiomed, Bayer, Cytokinetics, Merck, and Myokardia. Dr. Cabrera reported no potential financial conflicts of interest.
FROM AHA 2023
Avoid adding to minority stress when treating headache in LGBTQIA+ patients
It is “important not to assume that just because someone is a member of the LGBTQ+ community they will need psychiatric or behavioral health support,” said Maya A. Marzouk, PhD, division of behavioral medicine and clinical psychology, Cincinnati Children’s Hospital Medical Center.
Instead, it is useful not to make any assumptions. There is a potential association between minority status and headache susceptibility, but it is more reasonable initially to address the diagnosis and treatment of headache in LGBTQIA+ patients the same way it is addressed in any other patient, Dr. Marzouk said at the 2023 Scottsdale Headache Symposium.
The acronym to describe individuals with gender identities different from male and female and sexual orientations not limited to heterosexuality has been in almost constant evolution over several decades. An addition sign that accompanies LGBTQIA refers to those who do not identify with any letters in the acronym (lesbian, gay, bisexual, transsexual, queer/questioning, intersex, and asexual).
Take steps to normalize the interaction
Although many clinicians have been acclimated to these diverse identifies, not all have risen above preconceptions that become obstacles to effective care, according to Dr. Marzouk. In the context of headache management, Dr. Marzouk emphasized the need to be respectful of the range of gender identities and sexual orientations and to take steps to normalize the interaction.
For example, Dr. Marzouk advised using gender-neutral language at the start of each patient encounter and ask open-ended questions about gender, sexual identify, and pronouns to avoid patient discomfort from misidentification. In turn, the clinicians can establish their own gender identification and preferred pronouns to reinforce the idea that doing so is normal behavior.
This change in approach should be made “for all patients. Do not try to guess who needs them,” she said.
Intake forms and office atmosphere, such as signs and images, should also be welcoming to all patients, she added. Rather than trying to make adjustments for a LGBTQIA+ visit, Dr. Marzouk said a uniform approach helps normalize the experience of LGBTQIA+ patients without singling them out.
Despite the effort to provide an open and welcoming environment, Dr. Marzouk acknowledged that mistakes are difficult to avoid for those with limited experience serving the LGBTQIA+ community. When mistakes are made, she advised clinicians to immediately acknowledge the mistake and ask for guidance from the patient.
The potential offense is making the patient feel “other” or abnormal.
A higher rate of migraine
The interactions that LBGTQIA+ patients have with others outside their community is a possible explanation for the substantial rate of headache as well as headache with comorbid psychiatric disorders in this population.
In a survey published in 2020, the rate of migraine was 19.7% in heterosexual women, 26.7% in lesbians, and 36.8% in bisexual women. Among men, it rose from 9.8% in heterosexuals to 14.8% in gays and then to 22.8% in bisexuals.
Migraine relative to headache is also associated with more mood disorders among LGBTQIA+ individuals. In a study published in 2022, LGBTQIA+ patients with migraine relative to those with headache were more likely to have depression (46.4% vs. 22.3%; P < .001), anxiety (72.1% vs. 51.6%; P < .001), and posttraumatic stress disorder (37.5% vs. 21.4%; P < .001).
A vicious cycle of underdiagnosis and undertreatment
These associations are consistent with minority stress theory, according to Dr. Marzouk. This theory postulates that the associated stress of discrimination, rejection, and microaggressions, such as explicit efforts to make LGBTQIA+ individuals to feel “other,” produces epigenetic changes and dysregulation of the hypothalamic-pituitary-adrenal axis. In turn, this plays a role in the pathogenesis of migraine.
The inconsistency with which minority stress affects LGBTQIA+ patients might be due to relative differences in social support, coping skills, an innate resilience to these effects, Dr. Marzouk explained.
Dr. Marzouk characterized the LGBTQIA+ community as “underserved” for treatment of headache. She suggested that medical mistrust and self-blame among LGBTQIA+ individuals might be factors contributing to a vicious cycle of underdiagnosis and undertreatment. Efforts by the medical community to reach out to the LGBTQIA+ community are appropriate to address an unmet need.
“Individuals with psychiatric comorbidities may experience even more benefit from migraine care,” she said.
Clinical studies should be more inclusive
While agreeing in principle with these remarks, Eric A. Kaiser, MD, PhD, department of neurology, University of Pennsylvania, Philadelphia, said that this area would be better advanced if studies routinely included patients with diverse-gender identities and sexual orientations. Speaking about how to organize these studies, Dr. Kaiser suggested that enrollment criteria should explicitly seek these individuals and that these differences should be captured in the baseline characteristics.
“For example, gender options could include man, woman, non-binary, gender diverse, gender nonconforming, or gender nonspecified,” he said.
To close “the significant knowledge gap that exists in managing headache disorders in sexually- and gender- diverse people,” Dr. Kaiser said that clinical research studies, like patient treatment of diverse populations, “should be conducted with welcoming and affirming practices.”
Dr. Marzouk reported no potential conflicts of interest. Dr. Kaiser reported financial relationships with Amgen and Lundbeck.
It is “important not to assume that just because someone is a member of the LGBTQ+ community they will need psychiatric or behavioral health support,” said Maya A. Marzouk, PhD, division of behavioral medicine and clinical psychology, Cincinnati Children’s Hospital Medical Center.
Instead, it is useful not to make any assumptions. There is a potential association between minority status and headache susceptibility, but it is more reasonable initially to address the diagnosis and treatment of headache in LGBTQIA+ patients the same way it is addressed in any other patient, Dr. Marzouk said at the 2023 Scottsdale Headache Symposium.
The acronym to describe individuals with gender identities different from male and female and sexual orientations not limited to heterosexuality has been in almost constant evolution over several decades. An addition sign that accompanies LGBTQIA refers to those who do not identify with any letters in the acronym (lesbian, gay, bisexual, transsexual, queer/questioning, intersex, and asexual).
Take steps to normalize the interaction
Although many clinicians have been acclimated to these diverse identifies, not all have risen above preconceptions that become obstacles to effective care, according to Dr. Marzouk. In the context of headache management, Dr. Marzouk emphasized the need to be respectful of the range of gender identities and sexual orientations and to take steps to normalize the interaction.
For example, Dr. Marzouk advised using gender-neutral language at the start of each patient encounter and ask open-ended questions about gender, sexual identify, and pronouns to avoid patient discomfort from misidentification. In turn, the clinicians can establish their own gender identification and preferred pronouns to reinforce the idea that doing so is normal behavior.
This change in approach should be made “for all patients. Do not try to guess who needs them,” she said.
Intake forms and office atmosphere, such as signs and images, should also be welcoming to all patients, she added. Rather than trying to make adjustments for a LGBTQIA+ visit, Dr. Marzouk said a uniform approach helps normalize the experience of LGBTQIA+ patients without singling them out.
Despite the effort to provide an open and welcoming environment, Dr. Marzouk acknowledged that mistakes are difficult to avoid for those with limited experience serving the LGBTQIA+ community. When mistakes are made, she advised clinicians to immediately acknowledge the mistake and ask for guidance from the patient.
The potential offense is making the patient feel “other” or abnormal.
A higher rate of migraine
The interactions that LBGTQIA+ patients have with others outside their community is a possible explanation for the substantial rate of headache as well as headache with comorbid psychiatric disorders in this population.
In a survey published in 2020, the rate of migraine was 19.7% in heterosexual women, 26.7% in lesbians, and 36.8% in bisexual women. Among men, it rose from 9.8% in heterosexuals to 14.8% in gays and then to 22.8% in bisexuals.
Migraine relative to headache is also associated with more mood disorders among LGBTQIA+ individuals. In a study published in 2022, LGBTQIA+ patients with migraine relative to those with headache were more likely to have depression (46.4% vs. 22.3%; P < .001), anxiety (72.1% vs. 51.6%; P < .001), and posttraumatic stress disorder (37.5% vs. 21.4%; P < .001).
A vicious cycle of underdiagnosis and undertreatment
These associations are consistent with minority stress theory, according to Dr. Marzouk. This theory postulates that the associated stress of discrimination, rejection, and microaggressions, such as explicit efforts to make LGBTQIA+ individuals to feel “other,” produces epigenetic changes and dysregulation of the hypothalamic-pituitary-adrenal axis. In turn, this plays a role in the pathogenesis of migraine.
The inconsistency with which minority stress affects LGBTQIA+ patients might be due to relative differences in social support, coping skills, an innate resilience to these effects, Dr. Marzouk explained.
Dr. Marzouk characterized the LGBTQIA+ community as “underserved” for treatment of headache. She suggested that medical mistrust and self-blame among LGBTQIA+ individuals might be factors contributing to a vicious cycle of underdiagnosis and undertreatment. Efforts by the medical community to reach out to the LGBTQIA+ community are appropriate to address an unmet need.
“Individuals with psychiatric comorbidities may experience even more benefit from migraine care,” she said.
Clinical studies should be more inclusive
While agreeing in principle with these remarks, Eric A. Kaiser, MD, PhD, department of neurology, University of Pennsylvania, Philadelphia, said that this area would be better advanced if studies routinely included patients with diverse-gender identities and sexual orientations. Speaking about how to organize these studies, Dr. Kaiser suggested that enrollment criteria should explicitly seek these individuals and that these differences should be captured in the baseline characteristics.
“For example, gender options could include man, woman, non-binary, gender diverse, gender nonconforming, or gender nonspecified,” he said.
To close “the significant knowledge gap that exists in managing headache disorders in sexually- and gender- diverse people,” Dr. Kaiser said that clinical research studies, like patient treatment of diverse populations, “should be conducted with welcoming and affirming practices.”
Dr. Marzouk reported no potential conflicts of interest. Dr. Kaiser reported financial relationships with Amgen and Lundbeck.
It is “important not to assume that just because someone is a member of the LGBTQ+ community they will need psychiatric or behavioral health support,” said Maya A. Marzouk, PhD, division of behavioral medicine and clinical psychology, Cincinnati Children’s Hospital Medical Center.
Instead, it is useful not to make any assumptions. There is a potential association between minority status and headache susceptibility, but it is more reasonable initially to address the diagnosis and treatment of headache in LGBTQIA+ patients the same way it is addressed in any other patient, Dr. Marzouk said at the 2023 Scottsdale Headache Symposium.
The acronym to describe individuals with gender identities different from male and female and sexual orientations not limited to heterosexuality has been in almost constant evolution over several decades. An addition sign that accompanies LGBTQIA refers to those who do not identify with any letters in the acronym (lesbian, gay, bisexual, transsexual, queer/questioning, intersex, and asexual).
Take steps to normalize the interaction
Although many clinicians have been acclimated to these diverse identifies, not all have risen above preconceptions that become obstacles to effective care, according to Dr. Marzouk. In the context of headache management, Dr. Marzouk emphasized the need to be respectful of the range of gender identities and sexual orientations and to take steps to normalize the interaction.
For example, Dr. Marzouk advised using gender-neutral language at the start of each patient encounter and ask open-ended questions about gender, sexual identify, and pronouns to avoid patient discomfort from misidentification. In turn, the clinicians can establish their own gender identification and preferred pronouns to reinforce the idea that doing so is normal behavior.
This change in approach should be made “for all patients. Do not try to guess who needs them,” she said.
Intake forms and office atmosphere, such as signs and images, should also be welcoming to all patients, she added. Rather than trying to make adjustments for a LGBTQIA+ visit, Dr. Marzouk said a uniform approach helps normalize the experience of LGBTQIA+ patients without singling them out.
Despite the effort to provide an open and welcoming environment, Dr. Marzouk acknowledged that mistakes are difficult to avoid for those with limited experience serving the LGBTQIA+ community. When mistakes are made, she advised clinicians to immediately acknowledge the mistake and ask for guidance from the patient.
The potential offense is making the patient feel “other” or abnormal.
A higher rate of migraine
The interactions that LBGTQIA+ patients have with others outside their community is a possible explanation for the substantial rate of headache as well as headache with comorbid psychiatric disorders in this population.
In a survey published in 2020, the rate of migraine was 19.7% in heterosexual women, 26.7% in lesbians, and 36.8% in bisexual women. Among men, it rose from 9.8% in heterosexuals to 14.8% in gays and then to 22.8% in bisexuals.
Migraine relative to headache is also associated with more mood disorders among LGBTQIA+ individuals. In a study published in 2022, LGBTQIA+ patients with migraine relative to those with headache were more likely to have depression (46.4% vs. 22.3%; P < .001), anxiety (72.1% vs. 51.6%; P < .001), and posttraumatic stress disorder (37.5% vs. 21.4%; P < .001).
A vicious cycle of underdiagnosis and undertreatment
These associations are consistent with minority stress theory, according to Dr. Marzouk. This theory postulates that the associated stress of discrimination, rejection, and microaggressions, such as explicit efforts to make LGBTQIA+ individuals to feel “other,” produces epigenetic changes and dysregulation of the hypothalamic-pituitary-adrenal axis. In turn, this plays a role in the pathogenesis of migraine.
The inconsistency with which minority stress affects LGBTQIA+ patients might be due to relative differences in social support, coping skills, an innate resilience to these effects, Dr. Marzouk explained.
Dr. Marzouk characterized the LGBTQIA+ community as “underserved” for treatment of headache. She suggested that medical mistrust and self-blame among LGBTQIA+ individuals might be factors contributing to a vicious cycle of underdiagnosis and undertreatment. Efforts by the medical community to reach out to the LGBTQIA+ community are appropriate to address an unmet need.
“Individuals with psychiatric comorbidities may experience even more benefit from migraine care,” she said.
Clinical studies should be more inclusive
While agreeing in principle with these remarks, Eric A. Kaiser, MD, PhD, department of neurology, University of Pennsylvania, Philadelphia, said that this area would be better advanced if studies routinely included patients with diverse-gender identities and sexual orientations. Speaking about how to organize these studies, Dr. Kaiser suggested that enrollment criteria should explicitly seek these individuals and that these differences should be captured in the baseline characteristics.
“For example, gender options could include man, woman, non-binary, gender diverse, gender nonconforming, or gender nonspecified,” he said.
To close “the significant knowledge gap that exists in managing headache disorders in sexually- and gender- diverse people,” Dr. Kaiser said that clinical research studies, like patient treatment of diverse populations, “should be conducted with welcoming and affirming practices.”
Dr. Marzouk reported no potential conflicts of interest. Dr. Kaiser reported financial relationships with Amgen and Lundbeck.
FROM THE 2023 SCOTTSDALE HEADACHE SYMPOSIUM
Benralizumab proves noninferior to mepolizumab for rare vasculitis, EGPA
SAN DIEGO – Treatment with benralizumab (Fasenra) achieved remission at 36 and 48 weeks at rates similar to those of mepolizumab (Nucala) in a head-to-head phase 3 trial of the two drugs for patients with a relapsing or refractory case of the rare vasculitis eosinophilic granulomatosis with polyangiitis (EGPA).
Benralizumab, a monoclonal antibody from AstraZeneca that binds to the alpha chain of the interleukin (IL)-5 receptor, is indicated as an add-on maintenance treatment for patients 12 years and older with severe eosinophilic asthma but is not currently approved for EGPA. Mepolizumab is a humanized monoclonal antibody targeting IL-5 and the only approved drug for EGPA.
Peter A. Merkel, MD, presented the trial, known as MANDARA, during a late-breaking poster session at the annual meeting of the American College of Rheumatology. A total of 140 patients with EGPA received either subcutaneous benralizumab 30 mg or mepolizumab 300 mg every 4 weeks for 52 weeks. The trial, which began recruitment in late 2019, was limited to patients at least 18 years of age with relapsing/refractory EGPA that required stable use of oral glucocorticoids (OGCs) and immunosuppressive therapy for at least 4 weeks prior to randomization, and the primary endpoint was the proportion of patients who achieved remission at weeks 36 and 48. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 plus an OGC dose of no more than 4 mg/day. Secondary endpoints included rates of accrued and maintained remission, OGC use, clinical benefit and complete response, blood eosinophil counts, total BVAS, and Vascular Damage Index scores. The mean age of the 140 patients was 52 years, and 60% were women.
Dr. Merkel and colleagues reported that the adjusted remission rate at both weeks 36 and 48 was 59.2% for those in the benralizumab arm and 56.5% for those in the mepolizumab arm (P = .7278). The percentage of patients who achieved a BVAS of 0 was similar between the two arms (83% in the benralizumab arm vs. 84.2% for those in the mepolizumab arm; P = .8502), as was the percentage of patients on an OGC dose of up to 4 mg/day (62.1% vs. 57.9%; P = .5942). At 48-52 weeks, 86.1% of patients in the benralizumab arm achieved up to a 50% reduction in OGC use, compared with 73.9% of those in the mepolizumab arm (P = .0611), and 41.4% of patients in the benralizumab arm achieved a 100% reduction in OGC use, compared with 25.8% of those in the mepolizumab arm (P = .0406).
In findings related to safety, the top three adverse events were COVID-19 (21.4% in the benralizumab arm vs. 27.1% in the mepolizumab arm, respectively), headache (17.1% vs. 15.7%), and arthralgia (17.1% vs. 11.4%).
“We were pleased with the findings because they met our expectations,” Dr. Merkel, chief of rheumatology and professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, said in an interview. “The hypothesis was that these two drugs would be equivalent and safe. The implication for patients is that they’ll have another treatment option for EGPA, which is an underrecognized disease with need for more effective treatments. I anticipate that the drug will be approved for use in EGPA, providing another option for treating this complicated multisystem eosinophilic-associated disease. Having more options for our biologic therapies is good.”
He characterized the retention of patients in MANDARA as “remarkable, despite the COVID-19 pandemic. Patients with rare diseases are quite dedicated to helping conduct research. They know that their disease is not common and that they could help others.”
The study was sponsored and funded by AstraZeneca. Dr. Merkel disclosed that he has received consulting fees and research support from many pharmaceutical companies, including AstraZeneca.
SAN DIEGO – Treatment with benralizumab (Fasenra) achieved remission at 36 and 48 weeks at rates similar to those of mepolizumab (Nucala) in a head-to-head phase 3 trial of the two drugs for patients with a relapsing or refractory case of the rare vasculitis eosinophilic granulomatosis with polyangiitis (EGPA).
Benralizumab, a monoclonal antibody from AstraZeneca that binds to the alpha chain of the interleukin (IL)-5 receptor, is indicated as an add-on maintenance treatment for patients 12 years and older with severe eosinophilic asthma but is not currently approved for EGPA. Mepolizumab is a humanized monoclonal antibody targeting IL-5 and the only approved drug for EGPA.
Peter A. Merkel, MD, presented the trial, known as MANDARA, during a late-breaking poster session at the annual meeting of the American College of Rheumatology. A total of 140 patients with EGPA received either subcutaneous benralizumab 30 mg or mepolizumab 300 mg every 4 weeks for 52 weeks. The trial, which began recruitment in late 2019, was limited to patients at least 18 years of age with relapsing/refractory EGPA that required stable use of oral glucocorticoids (OGCs) and immunosuppressive therapy for at least 4 weeks prior to randomization, and the primary endpoint was the proportion of patients who achieved remission at weeks 36 and 48. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 plus an OGC dose of no more than 4 mg/day. Secondary endpoints included rates of accrued and maintained remission, OGC use, clinical benefit and complete response, blood eosinophil counts, total BVAS, and Vascular Damage Index scores. The mean age of the 140 patients was 52 years, and 60% were women.
Dr. Merkel and colleagues reported that the adjusted remission rate at both weeks 36 and 48 was 59.2% for those in the benralizumab arm and 56.5% for those in the mepolizumab arm (P = .7278). The percentage of patients who achieved a BVAS of 0 was similar between the two arms (83% in the benralizumab arm vs. 84.2% for those in the mepolizumab arm; P = .8502), as was the percentage of patients on an OGC dose of up to 4 mg/day (62.1% vs. 57.9%; P = .5942). At 48-52 weeks, 86.1% of patients in the benralizumab arm achieved up to a 50% reduction in OGC use, compared with 73.9% of those in the mepolizumab arm (P = .0611), and 41.4% of patients in the benralizumab arm achieved a 100% reduction in OGC use, compared with 25.8% of those in the mepolizumab arm (P = .0406).
In findings related to safety, the top three adverse events were COVID-19 (21.4% in the benralizumab arm vs. 27.1% in the mepolizumab arm, respectively), headache (17.1% vs. 15.7%), and arthralgia (17.1% vs. 11.4%).
“We were pleased with the findings because they met our expectations,” Dr. Merkel, chief of rheumatology and professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, said in an interview. “The hypothesis was that these two drugs would be equivalent and safe. The implication for patients is that they’ll have another treatment option for EGPA, which is an underrecognized disease with need for more effective treatments. I anticipate that the drug will be approved for use in EGPA, providing another option for treating this complicated multisystem eosinophilic-associated disease. Having more options for our biologic therapies is good.”
He characterized the retention of patients in MANDARA as “remarkable, despite the COVID-19 pandemic. Patients with rare diseases are quite dedicated to helping conduct research. They know that their disease is not common and that they could help others.”
The study was sponsored and funded by AstraZeneca. Dr. Merkel disclosed that he has received consulting fees and research support from many pharmaceutical companies, including AstraZeneca.
SAN DIEGO – Treatment with benralizumab (Fasenra) achieved remission at 36 and 48 weeks at rates similar to those of mepolizumab (Nucala) in a head-to-head phase 3 trial of the two drugs for patients with a relapsing or refractory case of the rare vasculitis eosinophilic granulomatosis with polyangiitis (EGPA).
Benralizumab, a monoclonal antibody from AstraZeneca that binds to the alpha chain of the interleukin (IL)-5 receptor, is indicated as an add-on maintenance treatment for patients 12 years and older with severe eosinophilic asthma but is not currently approved for EGPA. Mepolizumab is a humanized monoclonal antibody targeting IL-5 and the only approved drug for EGPA.
Peter A. Merkel, MD, presented the trial, known as MANDARA, during a late-breaking poster session at the annual meeting of the American College of Rheumatology. A total of 140 patients with EGPA received either subcutaneous benralizumab 30 mg or mepolizumab 300 mg every 4 weeks for 52 weeks. The trial, which began recruitment in late 2019, was limited to patients at least 18 years of age with relapsing/refractory EGPA that required stable use of oral glucocorticoids (OGCs) and immunosuppressive therapy for at least 4 weeks prior to randomization, and the primary endpoint was the proportion of patients who achieved remission at weeks 36 and 48. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 plus an OGC dose of no more than 4 mg/day. Secondary endpoints included rates of accrued and maintained remission, OGC use, clinical benefit and complete response, blood eosinophil counts, total BVAS, and Vascular Damage Index scores. The mean age of the 140 patients was 52 years, and 60% were women.
Dr. Merkel and colleagues reported that the adjusted remission rate at both weeks 36 and 48 was 59.2% for those in the benralizumab arm and 56.5% for those in the mepolizumab arm (P = .7278). The percentage of patients who achieved a BVAS of 0 was similar between the two arms (83% in the benralizumab arm vs. 84.2% for those in the mepolizumab arm; P = .8502), as was the percentage of patients on an OGC dose of up to 4 mg/day (62.1% vs. 57.9%; P = .5942). At 48-52 weeks, 86.1% of patients in the benralizumab arm achieved up to a 50% reduction in OGC use, compared with 73.9% of those in the mepolizumab arm (P = .0611), and 41.4% of patients in the benralizumab arm achieved a 100% reduction in OGC use, compared with 25.8% of those in the mepolizumab arm (P = .0406).
In findings related to safety, the top three adverse events were COVID-19 (21.4% in the benralizumab arm vs. 27.1% in the mepolizumab arm, respectively), headache (17.1% vs. 15.7%), and arthralgia (17.1% vs. 11.4%).
“We were pleased with the findings because they met our expectations,” Dr. Merkel, chief of rheumatology and professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, said in an interview. “The hypothesis was that these two drugs would be equivalent and safe. The implication for patients is that they’ll have another treatment option for EGPA, which is an underrecognized disease with need for more effective treatments. I anticipate that the drug will be approved for use in EGPA, providing another option for treating this complicated multisystem eosinophilic-associated disease. Having more options for our biologic therapies is good.”
He characterized the retention of patients in MANDARA as “remarkable, despite the COVID-19 pandemic. Patients with rare diseases are quite dedicated to helping conduct research. They know that their disease is not common and that they could help others.”
The study was sponsored and funded by AstraZeneca. Dr. Merkel disclosed that he has received consulting fees and research support from many pharmaceutical companies, including AstraZeneca.
AT ACR 2023
Smartphone app detects voice quality changes indicating worsening heart failure
Worsening heart failure is accompanied by a build-up of fluid in the lungs. An AI smartphone app that picks up changes in a heart failure patient’s voice quality caused by this fluid accumulation and then alerts the physician about them – nearly 3 weeks before that ongoing decompensation would necessitate hospitalization and/or lead the physician to urgently introduce intravenous diuretics – is getting experts to sit up and take notice.
“In this incredibly prevalent waxing and waning condition, finding ways to identify worsening heart failure to prevent hospitalization and progressive disease is incredibly important,” observed American Heart Association (AHA)-appointed discussant David Ouyang, MD, assistant professor, Smidt Heart Institute, Division of Artificial Intelligence in Medicine, Cedars Sinai, Los Angeles. “Heart failure remains among the most common causes of hospitalization for older adults in the United States.
“The other standout feature is that we all use our cell phones on a daily basis,” Dr. Ouyang said at a late-breaking trial press briefing at the AHA 2023 annual meeting where results of the HearO Community Study were presented. “The ability to capture data from routine speech (patients speak five sentences into their phones every morning) is remarkable ... The HearO® technology was able to detect a substantial proportion of worsening heart failure events, with an average per individual of only three false positives over the course of a year. And, adherence to the study protocol was 81%. That’s higher than in many other kinds of routine patient monitoring studies,” he added.
Accumulating fluid changes speech
(e.g., pharynx, velum, tongue, and vocal folds). In the Israeli study, investigators enrolled 416 adults (75% were male, average age was 68 years) whose New York Heart Association (NYHA) 2-3 heart failure with either reduced or preserved ejection fraction was stable but placed them at-risk for heart failure events. The study goal was to analyze their speech data using the HearO® system to refine and test its ability to detect impending heart failure deterioration. Patients recorded five sentences in their native language (Hebrew, Russian, Arabic, or English) into the smartphone app daily. In a training phase of the study, distinct speech measures from 263 participants were used to develop the AI algorithm. Then, the algorithm was used in the remaining 153 participants to validate the tool’s effectiveness. In its ultimate form, once a deviation from the patient’s predefined baseline is detected, the app will generate a notice and send it to the health care practitioners.
Lead study author William T. Abraham, MD, FAHA, professor of medicine, physiology, and cell biology; and a College of Medicine Distinguished Professor in the division of cardiovascular medicine at The Ohio State University in Columbus, reported that between Mar. 27, 2018, and Nov. 30, 2021, subjects in the training phase made recordings on 83% of days. They were followed for up to 44 months. The test group made recordings on 81% of days between Feb. 1, 2020, and Apr. 30, 2023, and were followed for up to 31 months. Heart failure events were defined as hospitalization or outpatient intravenous diuretic treatment for worsening heart failure.
In the training phase, the app accurately predicted 44 of 58 heart failure events (76%) and 81% of first events (n = 35) on average 24 days before hospitalization or need for intravenous fluids. In the validation phase, the app was 71% accurate in detecting 10 of 14 heart failure events and 77% of first events (n = 10) on average 26 days in advance of events. In both periods, the app generated about 3 unnecessary alerts per patient year.
Dr. Abraham concluded, “This technology has the potential to improve patient outcomes, keeping patients well and out of the hospital, through the implementation of proactive, outpatient care in response to voice changes.”
The HearO® technology is being evaluated in an ongoing pivotal trial in the United State4s, Dr. Abraham said. The study is limited, he added, by the small number of patients and heart failure events, particularly in the test group.
“We continue to struggle with the burden of heart failure morbidity,” observed AHA press briefing moderator (and past AHA president) Clyde Yancy, MD, Magerstadt Professor at Northwestern University, Chicago. “So any tool that we can utilize and further refine that helps us address the need for hospitalization becomes very important. The idea that speech evaluation might give us sufficient early warning to forestall any admissions – and consider the cost savings attributable to that – is a very credible goal that we should continue to follow.” He pointed out that the technology enables assessments in the home environment for older patients who are less mobile.
In response to a press briefing question about the potential for physicians to be trained to hear early subtle voice changes on their own, Dr. Abraham stated, “I guess that is unknown, but the important difference is the system’s ability to take data in every day from patients and then process it automatically with AI.”
Joining in, Dr. Yancy said, “You know, this is interesting because even if you saw a patient once a month, which is an incredible frequency for any practice, there’s still 353 days that you haven’t seen the patient.” He noted that the AHA had just announced a multi-million dollar program to more deeply understand telemanagement. “So I think this is here to stay,” Dr. Yancy said.
Dr. Ouyang posed a further question. “Like with most AI recognition tools, we can now identify individuals at risk. How do we get from that step of identifying those at risk to improving their outcomes? This has been a critical question about heart failure, remote management, and remote monitoring, and I think it is a critical question for many of our AI tools.”
Dr. Abraham disclosed that he has received personal fees from Cordio Medical. Dr. Ouyang said that he had no disclosures relevant to this presentation.
Worsening heart failure is accompanied by a build-up of fluid in the lungs. An AI smartphone app that picks up changes in a heart failure patient’s voice quality caused by this fluid accumulation and then alerts the physician about them – nearly 3 weeks before that ongoing decompensation would necessitate hospitalization and/or lead the physician to urgently introduce intravenous diuretics – is getting experts to sit up and take notice.
“In this incredibly prevalent waxing and waning condition, finding ways to identify worsening heart failure to prevent hospitalization and progressive disease is incredibly important,” observed American Heart Association (AHA)-appointed discussant David Ouyang, MD, assistant professor, Smidt Heart Institute, Division of Artificial Intelligence in Medicine, Cedars Sinai, Los Angeles. “Heart failure remains among the most common causes of hospitalization for older adults in the United States.
“The other standout feature is that we all use our cell phones on a daily basis,” Dr. Ouyang said at a late-breaking trial press briefing at the AHA 2023 annual meeting where results of the HearO Community Study were presented. “The ability to capture data from routine speech (patients speak five sentences into their phones every morning) is remarkable ... The HearO® technology was able to detect a substantial proportion of worsening heart failure events, with an average per individual of only three false positives over the course of a year. And, adherence to the study protocol was 81%. That’s higher than in many other kinds of routine patient monitoring studies,” he added.
Accumulating fluid changes speech
(e.g., pharynx, velum, tongue, and vocal folds). In the Israeli study, investigators enrolled 416 adults (75% were male, average age was 68 years) whose New York Heart Association (NYHA) 2-3 heart failure with either reduced or preserved ejection fraction was stable but placed them at-risk for heart failure events. The study goal was to analyze their speech data using the HearO® system to refine and test its ability to detect impending heart failure deterioration. Patients recorded five sentences in their native language (Hebrew, Russian, Arabic, or English) into the smartphone app daily. In a training phase of the study, distinct speech measures from 263 participants were used to develop the AI algorithm. Then, the algorithm was used in the remaining 153 participants to validate the tool’s effectiveness. In its ultimate form, once a deviation from the patient’s predefined baseline is detected, the app will generate a notice and send it to the health care practitioners.
Lead study author William T. Abraham, MD, FAHA, professor of medicine, physiology, and cell biology; and a College of Medicine Distinguished Professor in the division of cardiovascular medicine at The Ohio State University in Columbus, reported that between Mar. 27, 2018, and Nov. 30, 2021, subjects in the training phase made recordings on 83% of days. They were followed for up to 44 months. The test group made recordings on 81% of days between Feb. 1, 2020, and Apr. 30, 2023, and were followed for up to 31 months. Heart failure events were defined as hospitalization or outpatient intravenous diuretic treatment for worsening heart failure.
In the training phase, the app accurately predicted 44 of 58 heart failure events (76%) and 81% of first events (n = 35) on average 24 days before hospitalization or need for intravenous fluids. In the validation phase, the app was 71% accurate in detecting 10 of 14 heart failure events and 77% of first events (n = 10) on average 26 days in advance of events. In both periods, the app generated about 3 unnecessary alerts per patient year.
Dr. Abraham concluded, “This technology has the potential to improve patient outcomes, keeping patients well and out of the hospital, through the implementation of proactive, outpatient care in response to voice changes.”
The HearO® technology is being evaluated in an ongoing pivotal trial in the United State4s, Dr. Abraham said. The study is limited, he added, by the small number of patients and heart failure events, particularly in the test group.
“We continue to struggle with the burden of heart failure morbidity,” observed AHA press briefing moderator (and past AHA president) Clyde Yancy, MD, Magerstadt Professor at Northwestern University, Chicago. “So any tool that we can utilize and further refine that helps us address the need for hospitalization becomes very important. The idea that speech evaluation might give us sufficient early warning to forestall any admissions – and consider the cost savings attributable to that – is a very credible goal that we should continue to follow.” He pointed out that the technology enables assessments in the home environment for older patients who are less mobile.
In response to a press briefing question about the potential for physicians to be trained to hear early subtle voice changes on their own, Dr. Abraham stated, “I guess that is unknown, but the important difference is the system’s ability to take data in every day from patients and then process it automatically with AI.”
Joining in, Dr. Yancy said, “You know, this is interesting because even if you saw a patient once a month, which is an incredible frequency for any practice, there’s still 353 days that you haven’t seen the patient.” He noted that the AHA had just announced a multi-million dollar program to more deeply understand telemanagement. “So I think this is here to stay,” Dr. Yancy said.
Dr. Ouyang posed a further question. “Like with most AI recognition tools, we can now identify individuals at risk. How do we get from that step of identifying those at risk to improving their outcomes? This has been a critical question about heart failure, remote management, and remote monitoring, and I think it is a critical question for many of our AI tools.”
Dr. Abraham disclosed that he has received personal fees from Cordio Medical. Dr. Ouyang said that he had no disclosures relevant to this presentation.
Worsening heart failure is accompanied by a build-up of fluid in the lungs. An AI smartphone app that picks up changes in a heart failure patient’s voice quality caused by this fluid accumulation and then alerts the physician about them – nearly 3 weeks before that ongoing decompensation would necessitate hospitalization and/or lead the physician to urgently introduce intravenous diuretics – is getting experts to sit up and take notice.
“In this incredibly prevalent waxing and waning condition, finding ways to identify worsening heart failure to prevent hospitalization and progressive disease is incredibly important,” observed American Heart Association (AHA)-appointed discussant David Ouyang, MD, assistant professor, Smidt Heart Institute, Division of Artificial Intelligence in Medicine, Cedars Sinai, Los Angeles. “Heart failure remains among the most common causes of hospitalization for older adults in the United States.
“The other standout feature is that we all use our cell phones on a daily basis,” Dr. Ouyang said at a late-breaking trial press briefing at the AHA 2023 annual meeting where results of the HearO Community Study were presented. “The ability to capture data from routine speech (patients speak five sentences into their phones every morning) is remarkable ... The HearO® technology was able to detect a substantial proportion of worsening heart failure events, with an average per individual of only three false positives over the course of a year. And, adherence to the study protocol was 81%. That’s higher than in many other kinds of routine patient monitoring studies,” he added.
Accumulating fluid changes speech
(e.g., pharynx, velum, tongue, and vocal folds). In the Israeli study, investigators enrolled 416 adults (75% were male, average age was 68 years) whose New York Heart Association (NYHA) 2-3 heart failure with either reduced or preserved ejection fraction was stable but placed them at-risk for heart failure events. The study goal was to analyze their speech data using the HearO® system to refine and test its ability to detect impending heart failure deterioration. Patients recorded five sentences in their native language (Hebrew, Russian, Arabic, or English) into the smartphone app daily. In a training phase of the study, distinct speech measures from 263 participants were used to develop the AI algorithm. Then, the algorithm was used in the remaining 153 participants to validate the tool’s effectiveness. In its ultimate form, once a deviation from the patient’s predefined baseline is detected, the app will generate a notice and send it to the health care practitioners.
Lead study author William T. Abraham, MD, FAHA, professor of medicine, physiology, and cell biology; and a College of Medicine Distinguished Professor in the division of cardiovascular medicine at The Ohio State University in Columbus, reported that between Mar. 27, 2018, and Nov. 30, 2021, subjects in the training phase made recordings on 83% of days. They were followed for up to 44 months. The test group made recordings on 81% of days between Feb. 1, 2020, and Apr. 30, 2023, and were followed for up to 31 months. Heart failure events were defined as hospitalization or outpatient intravenous diuretic treatment for worsening heart failure.
In the training phase, the app accurately predicted 44 of 58 heart failure events (76%) and 81% of first events (n = 35) on average 24 days before hospitalization or need for intravenous fluids. In the validation phase, the app was 71% accurate in detecting 10 of 14 heart failure events and 77% of first events (n = 10) on average 26 days in advance of events. In both periods, the app generated about 3 unnecessary alerts per patient year.
Dr. Abraham concluded, “This technology has the potential to improve patient outcomes, keeping patients well and out of the hospital, through the implementation of proactive, outpatient care in response to voice changes.”
The HearO® technology is being evaluated in an ongoing pivotal trial in the United State4s, Dr. Abraham said. The study is limited, he added, by the small number of patients and heart failure events, particularly in the test group.
“We continue to struggle with the burden of heart failure morbidity,” observed AHA press briefing moderator (and past AHA president) Clyde Yancy, MD, Magerstadt Professor at Northwestern University, Chicago. “So any tool that we can utilize and further refine that helps us address the need for hospitalization becomes very important. The idea that speech evaluation might give us sufficient early warning to forestall any admissions – and consider the cost savings attributable to that – is a very credible goal that we should continue to follow.” He pointed out that the technology enables assessments in the home environment for older patients who are less mobile.
In response to a press briefing question about the potential for physicians to be trained to hear early subtle voice changes on their own, Dr. Abraham stated, “I guess that is unknown, but the important difference is the system’s ability to take data in every day from patients and then process it automatically with AI.”
Joining in, Dr. Yancy said, “You know, this is interesting because even if you saw a patient once a month, which is an incredible frequency for any practice, there’s still 353 days that you haven’t seen the patient.” He noted that the AHA had just announced a multi-million dollar program to more deeply understand telemanagement. “So I think this is here to stay,” Dr. Yancy said.
Dr. Ouyang posed a further question. “Like with most AI recognition tools, we can now identify individuals at risk. How do we get from that step of identifying those at risk to improving their outcomes? This has been a critical question about heart failure, remote management, and remote monitoring, and I think it is a critical question for many of our AI tools.”
Dr. Abraham disclosed that he has received personal fees from Cordio Medical. Dr. Ouyang said that he had no disclosures relevant to this presentation.
FROM AHA 2023
Promising first results with DNA editing to lower LDL
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
AT AHA 2023
Novel blood test can detect RA
SAN DIEGO – Researchers say they’ve developed a novel blood-based assay that can differentiate patients with seropositive or seronegative rheumatoid arthritis from healthy people and those with other inflammatory diseases or osteoarthritis.
While cautioning that the results need to be confirmed, University of Oxford (England) rheumatologist Peter Taylor, PhD, MA, told an audience at the annual meeting of the American College of Rheumatology that the test has an overall mean sensitivity of 90.8% (standard deviation, 0.94%; 95% confidence interval, 83.2%-95.4%) and mean specificity of 96.1% (SD, 0.64%; 95% CI, 92.7%-97.9%). The mean area under the curve (AUC) is 0.991 (SD, 0.001; 95% CI, 97.2%-99.6%).
“That is to say that it can correctly identify 96% of people without rheumatoid arthritis, and it can correctly identify over 90% of those who do have rheumatoid arthritis,” Dr. Taylor said. In the big picture, he said, “we’ve developed a blood-based assay that detects both organ-specific and systemic biological processes in patients with rheumatoid arthritis.”
Rheumatologist Kevin W. Byram, MD, of Vanderbilt University, Nashville, Tenn., who did not take part in the study but is familiar with its findings, noted in an interview that “there is a constant search for biomarkers to help aide in more accurate and faster diagnosis of all rheumatic conditions, including RA.”
He added that “a common clinical scenario for the rheumatologist is a patient presenting with painful and/or swollen joints and other features that might suggest a few different diagnoses. A diagnostic assay like this might help distinguish patients with RA from other inflammatory conditions or non-inflammatory conditions that might mimic RA.”
In his presentation, Dr. Taylor noted that “we haven’t yet integrated precision medicine into routine clinical practice in rheumatology.” While blood-based assays are prevalent in other types of clinical diagnostics, rheumatology relies on synovial biopsies that are “rarely used in routine clinical practice,” he said.
The new test is a “non-invasive DNA capture assay that can identify specific gene expression from synovium-specific signatures in blood plasma of patients with rheumatoid arthritis,” Dr. Taylor said. Specifically, it focuses on the “unique patterns and sizes of cell-free DNA,” he said. “Analysis of [long] fragments has the potential to give us a great deal of information about disease progression, potentially about customizing treatments and even evaluating the effectiveness of therapies.”
For the new study, researchers examined 229 samples from 191 patients, of whom 63.3% were White and 67.9% were female, with a median age of 56. A total of 89 patients with RA provided 89 samples and 102 without RA provided 140 samples, including 29 healthy controls (66 samples) and others with conditions such as psoriatic arthritis, ulcerative colitis, and osteoarthritis.
The machine learning model “identified 3,425 epigenetic features with statistically significant discrimination between the patients with and without rheumatoid arthritis,” Dr. Taylor said. These features were mapped to 929 genes which had some overlap with known blood pathway genes.
“Over and above that, there’s a whole set of these epigenetic features which represent novel pathways and potentially rich hunting ground for therapeutic targets and other translational investigation,” he said.
For seronegative cases, mean AUC was 0.971 (SD, 0.001; 95% CI, 93.8%-99.2%), sensitivity was 83.7% (SD, 2.03; 95% CI, 63.3%-91.8%) and specificity was 95.4% (SD, 0.69; 95% CI, 90.8%-97.5%).
Specificity for RA versus healthy controls was 100 (SD, 0; 95% CI, 94.4-100.0).
Dr. Byram described the study as small but intriguing. He cautioned that “there is always some likelihood that the actual components of the test are just recognizing some combination of things we are already testing in the clinic,” he said. Details about the patients in the study can offer insight into “whether the assay is actually just recognizing something about patients with RA that is truly different, or rather is it recognizing how a common factor among patients with RA is transcribed by the cell.”
Moving forward, “it is important to get a grasp of how these biomarkers might perform in various settings,” he said.
Dr. Taylor did not discuss the potential cost of the assay in his presentation. “Tests like these have to strike a real balance in being useful and cost-effective and, since they are still made by commercial companies with commercial interests, also make a margin for their owner,” Dr. Byram said. “Turnaround time is also an important factor to think about.”
Aqtual funded the study. Dr. Taylor reports consulting for AbbVie, Aqtual, Biogen, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Sanofi, and UCB and receiving grant support from Galapagos. The other study authors all have relationships with Aqtual, and some report various other disclosures. Dr. Byram has no disclosures.
SAN DIEGO – Researchers say they’ve developed a novel blood-based assay that can differentiate patients with seropositive or seronegative rheumatoid arthritis from healthy people and those with other inflammatory diseases or osteoarthritis.
While cautioning that the results need to be confirmed, University of Oxford (England) rheumatologist Peter Taylor, PhD, MA, told an audience at the annual meeting of the American College of Rheumatology that the test has an overall mean sensitivity of 90.8% (standard deviation, 0.94%; 95% confidence interval, 83.2%-95.4%) and mean specificity of 96.1% (SD, 0.64%; 95% CI, 92.7%-97.9%). The mean area under the curve (AUC) is 0.991 (SD, 0.001; 95% CI, 97.2%-99.6%).
“That is to say that it can correctly identify 96% of people without rheumatoid arthritis, and it can correctly identify over 90% of those who do have rheumatoid arthritis,” Dr. Taylor said. In the big picture, he said, “we’ve developed a blood-based assay that detects both organ-specific and systemic biological processes in patients with rheumatoid arthritis.”
Rheumatologist Kevin W. Byram, MD, of Vanderbilt University, Nashville, Tenn., who did not take part in the study but is familiar with its findings, noted in an interview that “there is a constant search for biomarkers to help aide in more accurate and faster diagnosis of all rheumatic conditions, including RA.”
He added that “a common clinical scenario for the rheumatologist is a patient presenting with painful and/or swollen joints and other features that might suggest a few different diagnoses. A diagnostic assay like this might help distinguish patients with RA from other inflammatory conditions or non-inflammatory conditions that might mimic RA.”
In his presentation, Dr. Taylor noted that “we haven’t yet integrated precision medicine into routine clinical practice in rheumatology.” While blood-based assays are prevalent in other types of clinical diagnostics, rheumatology relies on synovial biopsies that are “rarely used in routine clinical practice,” he said.
The new test is a “non-invasive DNA capture assay that can identify specific gene expression from synovium-specific signatures in blood plasma of patients with rheumatoid arthritis,” Dr. Taylor said. Specifically, it focuses on the “unique patterns and sizes of cell-free DNA,” he said. “Analysis of [long] fragments has the potential to give us a great deal of information about disease progression, potentially about customizing treatments and even evaluating the effectiveness of therapies.”
For the new study, researchers examined 229 samples from 191 patients, of whom 63.3% were White and 67.9% were female, with a median age of 56. A total of 89 patients with RA provided 89 samples and 102 without RA provided 140 samples, including 29 healthy controls (66 samples) and others with conditions such as psoriatic arthritis, ulcerative colitis, and osteoarthritis.
The machine learning model “identified 3,425 epigenetic features with statistically significant discrimination between the patients with and without rheumatoid arthritis,” Dr. Taylor said. These features were mapped to 929 genes which had some overlap with known blood pathway genes.
“Over and above that, there’s a whole set of these epigenetic features which represent novel pathways and potentially rich hunting ground for therapeutic targets and other translational investigation,” he said.
For seronegative cases, mean AUC was 0.971 (SD, 0.001; 95% CI, 93.8%-99.2%), sensitivity was 83.7% (SD, 2.03; 95% CI, 63.3%-91.8%) and specificity was 95.4% (SD, 0.69; 95% CI, 90.8%-97.5%).
Specificity for RA versus healthy controls was 100 (SD, 0; 95% CI, 94.4-100.0).
Dr. Byram described the study as small but intriguing. He cautioned that “there is always some likelihood that the actual components of the test are just recognizing some combination of things we are already testing in the clinic,” he said. Details about the patients in the study can offer insight into “whether the assay is actually just recognizing something about patients with RA that is truly different, or rather is it recognizing how a common factor among patients with RA is transcribed by the cell.”
Moving forward, “it is important to get a grasp of how these biomarkers might perform in various settings,” he said.
Dr. Taylor did not discuss the potential cost of the assay in his presentation. “Tests like these have to strike a real balance in being useful and cost-effective and, since they are still made by commercial companies with commercial interests, also make a margin for their owner,” Dr. Byram said. “Turnaround time is also an important factor to think about.”
Aqtual funded the study. Dr. Taylor reports consulting for AbbVie, Aqtual, Biogen, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Sanofi, and UCB and receiving grant support from Galapagos. The other study authors all have relationships with Aqtual, and some report various other disclosures. Dr. Byram has no disclosures.
SAN DIEGO – Researchers say they’ve developed a novel blood-based assay that can differentiate patients with seropositive or seronegative rheumatoid arthritis from healthy people and those with other inflammatory diseases or osteoarthritis.
While cautioning that the results need to be confirmed, University of Oxford (England) rheumatologist Peter Taylor, PhD, MA, told an audience at the annual meeting of the American College of Rheumatology that the test has an overall mean sensitivity of 90.8% (standard deviation, 0.94%; 95% confidence interval, 83.2%-95.4%) and mean specificity of 96.1% (SD, 0.64%; 95% CI, 92.7%-97.9%). The mean area under the curve (AUC) is 0.991 (SD, 0.001; 95% CI, 97.2%-99.6%).
“That is to say that it can correctly identify 96% of people without rheumatoid arthritis, and it can correctly identify over 90% of those who do have rheumatoid arthritis,” Dr. Taylor said. In the big picture, he said, “we’ve developed a blood-based assay that detects both organ-specific and systemic biological processes in patients with rheumatoid arthritis.”
Rheumatologist Kevin W. Byram, MD, of Vanderbilt University, Nashville, Tenn., who did not take part in the study but is familiar with its findings, noted in an interview that “there is a constant search for biomarkers to help aide in more accurate and faster diagnosis of all rheumatic conditions, including RA.”
He added that “a common clinical scenario for the rheumatologist is a patient presenting with painful and/or swollen joints and other features that might suggest a few different diagnoses. A diagnostic assay like this might help distinguish patients with RA from other inflammatory conditions or non-inflammatory conditions that might mimic RA.”
In his presentation, Dr. Taylor noted that “we haven’t yet integrated precision medicine into routine clinical practice in rheumatology.” While blood-based assays are prevalent in other types of clinical diagnostics, rheumatology relies on synovial biopsies that are “rarely used in routine clinical practice,” he said.
The new test is a “non-invasive DNA capture assay that can identify specific gene expression from synovium-specific signatures in blood plasma of patients with rheumatoid arthritis,” Dr. Taylor said. Specifically, it focuses on the “unique patterns and sizes of cell-free DNA,” he said. “Analysis of [long] fragments has the potential to give us a great deal of information about disease progression, potentially about customizing treatments and even evaluating the effectiveness of therapies.”
For the new study, researchers examined 229 samples from 191 patients, of whom 63.3% were White and 67.9% were female, with a median age of 56. A total of 89 patients with RA provided 89 samples and 102 without RA provided 140 samples, including 29 healthy controls (66 samples) and others with conditions such as psoriatic arthritis, ulcerative colitis, and osteoarthritis.
The machine learning model “identified 3,425 epigenetic features with statistically significant discrimination between the patients with and without rheumatoid arthritis,” Dr. Taylor said. These features were mapped to 929 genes which had some overlap with known blood pathway genes.
“Over and above that, there’s a whole set of these epigenetic features which represent novel pathways and potentially rich hunting ground for therapeutic targets and other translational investigation,” he said.
For seronegative cases, mean AUC was 0.971 (SD, 0.001; 95% CI, 93.8%-99.2%), sensitivity was 83.7% (SD, 2.03; 95% CI, 63.3%-91.8%) and specificity was 95.4% (SD, 0.69; 95% CI, 90.8%-97.5%).
Specificity for RA versus healthy controls was 100 (SD, 0; 95% CI, 94.4-100.0).
Dr. Byram described the study as small but intriguing. He cautioned that “there is always some likelihood that the actual components of the test are just recognizing some combination of things we are already testing in the clinic,” he said. Details about the patients in the study can offer insight into “whether the assay is actually just recognizing something about patients with RA that is truly different, or rather is it recognizing how a common factor among patients with RA is transcribed by the cell.”
Moving forward, “it is important to get a grasp of how these biomarkers might perform in various settings,” he said.
Dr. Taylor did not discuss the potential cost of the assay in his presentation. “Tests like these have to strike a real balance in being useful and cost-effective and, since they are still made by commercial companies with commercial interests, also make a margin for their owner,” Dr. Byram said. “Turnaround time is also an important factor to think about.”
Aqtual funded the study. Dr. Taylor reports consulting for AbbVie, Aqtual, Biogen, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Sanofi, and UCB and receiving grant support from Galapagos. The other study authors all have relationships with Aqtual, and some report various other disclosures. Dr. Byram has no disclosures.
AT ACR 2023
Split-dose methotrexate speeds RA response over single dose
SAN DIEGO – A split dose of methotrexate (MTX) given orally once per week showed significantly higher efficacy in patients with rheumatoid arthritis at 16 weeks, compared with a single MTX dose weekly, according to new research. By 24 weeks, efficacy measures were similar for both groups.
However, fewer patients in the split-dose group needed additional disease-modifying antirheumatic drugs (DMARDs) to control disease activity.
MTX is a highly utilized, inexpensive drug for RA, but only about 30% of patients can achieve low disease activity or remission on MTX monotherapy, said Varun Dhir, MD, MBBS, of the Postgraduate Institute of Medical Education and Research, Chandigarh, India. He co-authored and presented the research at the annual meeting of the American College of Rheumatology.
Part of the problem is that “oral methotrexate absorption from the gut reduces as the doses go up,” Dr. Dhir noted, because the transport mechanism gets saturated. MTX delivered subcutaneously is one way to improve efficacy, but patients can be needle-averse, and in some countries, like India, pre-filled syringes are not available, he said.
There is pharmacokinetic data dating back 20 years that suggest split-dose MTX could be more efficacious. “However, there are no randomized controlled trials to date, and the guidelines therefore are silent on this approach,” Dr. Dhir said.
To address this question, Dr. Dhir and colleagues recruited patients with RA from six centers across India. Patients were aged 18-60 years, seropositive (rheumatoid factor or anti-citrullinated protein antibodies), and had a disease duration of 5 years or fewer. Patients had active disease, defined as at least four tender joints and at least two swollen joints, and were not taking any DMARDs except for hydroxychloroquine and/or low-dose prednisolone.
A total of 253 patients were randomly assigned to a single 25-mg dose or a split-dose of MTX once weekly (10 mg in the morning and 15 mg in the evening on the same day). The primary outcome was a European Alliance of Associations for Rheumatology (EULAR) good response at 24 weeks. At the 16-week mark, if patients had not achieved low disease activity based on a 28-joint Disease Activity Score (DAS28) greater than 3.2, a blinded assessor could add either leflunomide or sulfasalazine to the continued MTX therapy.
At baseline, there was no difference between the groups’ DAS28, but after 16 weeks, DAS28 was significantly lower in the split-dose group, compared with the single-dose group (4.4 vs. 5.1; P < .001), and a higher percentage of patients in the split-dose group had a EULAR good response.
About three-quarters (76.6%) of patients in the split-dose group experienced an improvement of at least 20% in ACR response criteria (ACR20), compared with 52% in the single-dose group. The split-dose group also had higher proportion of patients achieving ACR50 and ACR70.
About one-third of the split-dose group (35%) added an additional DMARD at 16 weeks, compared with 54.5% of the single-dose group (P = .005).
After 24 weeks, DAS28 scores remained lower in the split-dose group (4.1 vs. 4.5; P = .03), but there were no other differences in treatment responses. Health Assessment Questionnaire scores were the same between both groups at 16 and 24 weeks.
The primary outcome was not met, although Dr. Dhir noted a flaw in the study design that could have affected the results. By allowing patients to add additional DMARDs at 16 weeks, “there were two factors which were affecting the primary outcome” at 24 weeks, he told this news organization. “I feel there was a robust result at least at 16 weeks.”
While there were no major adverse events, the split-dose group had higher rates of transaminitis (elevated liver enzymes) during the study, and low white blood cell count was higher in the single-dose group at 24 weeks. There was no difference in MTX intolerance between the two groups.
“It looks like [the split-dose group] gets out of the block faster. It’s a faster effect,” although the other group did catch up, Janet Pope, MD, MPH, of Western University, London, Ont., said in an interview. She was not involved with the research. Two positive results were the earlier ACR responses in the split-dose group as well as fewer patients in that same group needing to add another DMARD to therapy.
“In my opinion, if it’s equal cost, why not try it and see?” she said.
In a separate presentation referring to the abstract, Joan Bathon, MD, director of rheumatology at Columbia University, New York City, noted that these results align with ACR 2021 recommendations. Dr. Bathon was not involved with this study but was on the writing committee establishing those 2021 guidelines.
“The recommendation – with low certainty of evidence – was that for patients who are intolerant to MTX, that split-dose of oral MTX is worth trying before you switch to a different DMARD,” she said. “I think these data support that concept.”
Dr. Dhir and Dr. Bathon had no relevant financial relationships. Dr. Pope disclosed financial relationships with AbbVie/Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fresenius Kabi, GlaxoSmithKline, Janssen, Mallinckrodt, Novartis, Organon, Pfizer, Sandoz, and Viatris.
A version of this article first appeared on Medscape.com.
SAN DIEGO – A split dose of methotrexate (MTX) given orally once per week showed significantly higher efficacy in patients with rheumatoid arthritis at 16 weeks, compared with a single MTX dose weekly, according to new research. By 24 weeks, efficacy measures were similar for both groups.
However, fewer patients in the split-dose group needed additional disease-modifying antirheumatic drugs (DMARDs) to control disease activity.
MTX is a highly utilized, inexpensive drug for RA, but only about 30% of patients can achieve low disease activity or remission on MTX monotherapy, said Varun Dhir, MD, MBBS, of the Postgraduate Institute of Medical Education and Research, Chandigarh, India. He co-authored and presented the research at the annual meeting of the American College of Rheumatology.
Part of the problem is that “oral methotrexate absorption from the gut reduces as the doses go up,” Dr. Dhir noted, because the transport mechanism gets saturated. MTX delivered subcutaneously is one way to improve efficacy, but patients can be needle-averse, and in some countries, like India, pre-filled syringes are not available, he said.
There is pharmacokinetic data dating back 20 years that suggest split-dose MTX could be more efficacious. “However, there are no randomized controlled trials to date, and the guidelines therefore are silent on this approach,” Dr. Dhir said.
To address this question, Dr. Dhir and colleagues recruited patients with RA from six centers across India. Patients were aged 18-60 years, seropositive (rheumatoid factor or anti-citrullinated protein antibodies), and had a disease duration of 5 years or fewer. Patients had active disease, defined as at least four tender joints and at least two swollen joints, and were not taking any DMARDs except for hydroxychloroquine and/or low-dose prednisolone.
A total of 253 patients were randomly assigned to a single 25-mg dose or a split-dose of MTX once weekly (10 mg in the morning and 15 mg in the evening on the same day). The primary outcome was a European Alliance of Associations for Rheumatology (EULAR) good response at 24 weeks. At the 16-week mark, if patients had not achieved low disease activity based on a 28-joint Disease Activity Score (DAS28) greater than 3.2, a blinded assessor could add either leflunomide or sulfasalazine to the continued MTX therapy.
At baseline, there was no difference between the groups’ DAS28, but after 16 weeks, DAS28 was significantly lower in the split-dose group, compared with the single-dose group (4.4 vs. 5.1; P < .001), and a higher percentage of patients in the split-dose group had a EULAR good response.
About three-quarters (76.6%) of patients in the split-dose group experienced an improvement of at least 20% in ACR response criteria (ACR20), compared with 52% in the single-dose group. The split-dose group also had higher proportion of patients achieving ACR50 and ACR70.
About one-third of the split-dose group (35%) added an additional DMARD at 16 weeks, compared with 54.5% of the single-dose group (P = .005).
After 24 weeks, DAS28 scores remained lower in the split-dose group (4.1 vs. 4.5; P = .03), but there were no other differences in treatment responses. Health Assessment Questionnaire scores were the same between both groups at 16 and 24 weeks.
The primary outcome was not met, although Dr. Dhir noted a flaw in the study design that could have affected the results. By allowing patients to add additional DMARDs at 16 weeks, “there were two factors which were affecting the primary outcome” at 24 weeks, he told this news organization. “I feel there was a robust result at least at 16 weeks.”
While there were no major adverse events, the split-dose group had higher rates of transaminitis (elevated liver enzymes) during the study, and low white blood cell count was higher in the single-dose group at 24 weeks. There was no difference in MTX intolerance between the two groups.
“It looks like [the split-dose group] gets out of the block faster. It’s a faster effect,” although the other group did catch up, Janet Pope, MD, MPH, of Western University, London, Ont., said in an interview. She was not involved with the research. Two positive results were the earlier ACR responses in the split-dose group as well as fewer patients in that same group needing to add another DMARD to therapy.
“In my opinion, if it’s equal cost, why not try it and see?” she said.
In a separate presentation referring to the abstract, Joan Bathon, MD, director of rheumatology at Columbia University, New York City, noted that these results align with ACR 2021 recommendations. Dr. Bathon was not involved with this study but was on the writing committee establishing those 2021 guidelines.
“The recommendation – with low certainty of evidence – was that for patients who are intolerant to MTX, that split-dose of oral MTX is worth trying before you switch to a different DMARD,” she said. “I think these data support that concept.”
Dr. Dhir and Dr. Bathon had no relevant financial relationships. Dr. Pope disclosed financial relationships with AbbVie/Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fresenius Kabi, GlaxoSmithKline, Janssen, Mallinckrodt, Novartis, Organon, Pfizer, Sandoz, and Viatris.
A version of this article first appeared on Medscape.com.
SAN DIEGO – A split dose of methotrexate (MTX) given orally once per week showed significantly higher efficacy in patients with rheumatoid arthritis at 16 weeks, compared with a single MTX dose weekly, according to new research. By 24 weeks, efficacy measures were similar for both groups.
However, fewer patients in the split-dose group needed additional disease-modifying antirheumatic drugs (DMARDs) to control disease activity.
MTX is a highly utilized, inexpensive drug for RA, but only about 30% of patients can achieve low disease activity or remission on MTX monotherapy, said Varun Dhir, MD, MBBS, of the Postgraduate Institute of Medical Education and Research, Chandigarh, India. He co-authored and presented the research at the annual meeting of the American College of Rheumatology.
Part of the problem is that “oral methotrexate absorption from the gut reduces as the doses go up,” Dr. Dhir noted, because the transport mechanism gets saturated. MTX delivered subcutaneously is one way to improve efficacy, but patients can be needle-averse, and in some countries, like India, pre-filled syringes are not available, he said.
There is pharmacokinetic data dating back 20 years that suggest split-dose MTX could be more efficacious. “However, there are no randomized controlled trials to date, and the guidelines therefore are silent on this approach,” Dr. Dhir said.
To address this question, Dr. Dhir and colleagues recruited patients with RA from six centers across India. Patients were aged 18-60 years, seropositive (rheumatoid factor or anti-citrullinated protein antibodies), and had a disease duration of 5 years or fewer. Patients had active disease, defined as at least four tender joints and at least two swollen joints, and were not taking any DMARDs except for hydroxychloroquine and/or low-dose prednisolone.
A total of 253 patients were randomly assigned to a single 25-mg dose or a split-dose of MTX once weekly (10 mg in the morning and 15 mg in the evening on the same day). The primary outcome was a European Alliance of Associations for Rheumatology (EULAR) good response at 24 weeks. At the 16-week mark, if patients had not achieved low disease activity based on a 28-joint Disease Activity Score (DAS28) greater than 3.2, a blinded assessor could add either leflunomide or sulfasalazine to the continued MTX therapy.
At baseline, there was no difference between the groups’ DAS28, but after 16 weeks, DAS28 was significantly lower in the split-dose group, compared with the single-dose group (4.4 vs. 5.1; P < .001), and a higher percentage of patients in the split-dose group had a EULAR good response.
About three-quarters (76.6%) of patients in the split-dose group experienced an improvement of at least 20% in ACR response criteria (ACR20), compared with 52% in the single-dose group. The split-dose group also had higher proportion of patients achieving ACR50 and ACR70.
About one-third of the split-dose group (35%) added an additional DMARD at 16 weeks, compared with 54.5% of the single-dose group (P = .005).
After 24 weeks, DAS28 scores remained lower in the split-dose group (4.1 vs. 4.5; P = .03), but there were no other differences in treatment responses. Health Assessment Questionnaire scores were the same between both groups at 16 and 24 weeks.
The primary outcome was not met, although Dr. Dhir noted a flaw in the study design that could have affected the results. By allowing patients to add additional DMARDs at 16 weeks, “there were two factors which were affecting the primary outcome” at 24 weeks, he told this news organization. “I feel there was a robust result at least at 16 weeks.”
While there were no major adverse events, the split-dose group had higher rates of transaminitis (elevated liver enzymes) during the study, and low white blood cell count was higher in the single-dose group at 24 weeks. There was no difference in MTX intolerance between the two groups.
“It looks like [the split-dose group] gets out of the block faster. It’s a faster effect,” although the other group did catch up, Janet Pope, MD, MPH, of Western University, London, Ont., said in an interview. She was not involved with the research. Two positive results were the earlier ACR responses in the split-dose group as well as fewer patients in that same group needing to add another DMARD to therapy.
“In my opinion, if it’s equal cost, why not try it and see?” she said.
In a separate presentation referring to the abstract, Joan Bathon, MD, director of rheumatology at Columbia University, New York City, noted that these results align with ACR 2021 recommendations. Dr. Bathon was not involved with this study but was on the writing committee establishing those 2021 guidelines.
“The recommendation – with low certainty of evidence – was that for patients who are intolerant to MTX, that split-dose of oral MTX is worth trying before you switch to a different DMARD,” she said. “I think these data support that concept.”
Dr. Dhir and Dr. Bathon had no relevant financial relationships. Dr. Pope disclosed financial relationships with AbbVie/Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fresenius Kabi, GlaxoSmithKline, Janssen, Mallinckrodt, Novartis, Organon, Pfizer, Sandoz, and Viatris.
A version of this article first appeared on Medscape.com.
AT ACR 2023
IV secukinumab, alternative to self-injections, reaches primary endpoints in PsA, axSpA
SAN DIEGO – Monthly use of intravenously administered secukinumab (Cosentyx) proved its efficacy over placebo in treating psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) in two industry-sponsored, randomized, double-blinded, phase 3 trials of the drug’s second and newly approved route of administration.
The studies of the human monoclonal antibody secukinumab, an interleukin-17 inhibitor, were presented at the annual meeting of the American College of Rheumatology. A subcutaneously injectable formulation of the drug is available, and the Food and Drug Administration approved the IV form for the conditions in October, although at a recommended lower monthly dose than the new trials examined.
In the PsA trial, 191 patients took IV secukinumab, and 190 took placebo. For the primary endpoint, the percentages who reached at least a 50% improvement in American College of Rheumatology response criteria (ACR 50) at 16 weeks were 31.4% and 6.3%, respectively (P < .0001).
In the axSpA trial, 264 patients took IV secukinumab, and 262 took placebo. The primary endpoint, at least a 40% improvement in Assessment of the Spondyloarthritis International Society response criteria (ASAS 40), was met at 16 weeks by 40.9% and 22.9%, respectively (P < .0001).
“Both studies appear to present clear efficacy of IV route administration of secukinumab with no clear increase in safety signals,” consultant rheumatologist Nicola Goodson, MBChB, PhD, of Aintree University Hospital in Liverpool, England, said in an interview.
“Offering IV administration as an option to patients is helpful,” added Dr. Goodson, who was not involved with the study but is familiar with its findings.
As Dr. Goodson explained, secukinumab “was the first IL [interleukin]-17 inhibitor used to treat spondyloarthropathies, and we have been using subcutaneous secukinumab to treat psoriasis, psoriatic arthritis, and axial spondyloarthritis/ankylosing spondylitis since 2016 in the U.K. Our experience with this medication has been good with similar efficacy to anti-TNF [tumor necrosis factor] therapy in axial spondyloarthritis. The medication is generally well-tolerated, and the subcutaneous pen injection device is easy for patients to use.”
However, IV treatment may speed up onset of action, she said, and it may be useful in situations when compliance is a challenge.
PsA trial details
In the PsA trial, known as INVIGORATE-2, researchers recruited patients who met the CASPAR criteria for active PsA with symptoms for ≥ 6 months, and had ≥ 3 tender joints out of 78 joints and ≥ 3 swollen joints out of 76.
Participants with a mean age of 48, including 55% females, were randomized 1:1 to receive placebo or secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks). Those in the placebo group were switched to the same monthly doses of secukinumab at 16 weeks.
“Patients who switched from the placebo had a similar increase of efficacy as the original treated group,” rheumatologist Alan J. Kivitz, MD, of the Altoona Center for Clinical Research, in Duncansville, Penn., said in his presentation at the meeting. Specifically, at 52 weeks, the groups had similar ACR 50 response rates: 58% with secukinumab and 64% with placebo-to-secukinumab.
The fact that patients in the original placebo group who received 3 mg IV doses without 6-mg loading doses achieved ACR response rates similar to those who took secukinumab during the whole trial “could suggest that the IV loading dose may not be required. This would need to be explored in a randomized head-to-head study, but it’s an interesting observation that may reduce costs and exposure to higher doses of medication at the start of treatment,” Dr. Goodson said.
Among the patients who received secukinumab at any point in the study, 63% had a treatment-emergent adverse event, including 5.9% with serious events. One death was reported in the placebo group before week 16. No other deaths were reported.
AxSpA trial details
In the axSpA trial, called INVIGORATE-1, researchers recruited people aged ≥18 years with a diagnosis of active radiographic axSpA according to modified New York criteria or nonradiographic axSpA according to ASAS criteria, and all had inflammatory back pain for ≥6 months with an onset before age 45. They were randomized at a 1:1 ratio to receive IV secukinumab (6 mg/kg loading dose, followed by 3 mg/kg every 4 weeks) or placebo for 16 weeks. At that point, the placebo group switched to the same monthly doses of IV secukinumab.
Participants had a mean age of about 39, and about one-third were female.
Following the statistical superiority in ASAS 40 response rates seen with IV secukinumab at week 16, patients who from there switched from placebo to IV secukinumab achieved comparable ASAS 40 response rates to those of patients originally randomized to secukinumab by week 24, reaching 66.8% for those on secukinumab the whole time and 74.9% for those who switched.
Secondary outcome measures were similar in both groups at week 52.
Among all patients who took secukinumab – the percentage with any adverse event was 63.2%, and 6% had a nonfatal adverse event deemed serious. There was one death during secukinumab treatment not suspected to be related to treatment.
In a presentation about the axSpA study findings, Atul Deodhar, MD, of Oregon Health & Science University, noted that “having an IV biologic available in the U.S. has some advantages. There are certain insurance providers such as Medicare where it is more economical for the patient to have an IV drug available.”
Dr. Deodhar also noted that in October the FDA approved a recommended lower dose for the IV treatment than in the study: 1.75 mg/kg instead of 3 mg/kg following the loading dose. That’s because the 3 mg/kg dose caused blood levels to be higher than those in the subcutaneous form, he said.
The FDA made the same dose recommendation for PsA.
Study limitations
Dr. Goodson, the U.K. consultant rheumatologist, noted a limitation of the trials: “It would have been interesting to compare IV to subcutaneous route secukinumab.” Still, the findings suggest that “the safety and efficacy of IV administration appears comparable,” she said.
“IV administration will have associated costs of attending hospital or infusion clinics,” she added, “and the cost of additional staff and administration need to be considered.”
Novartis, the maker of secukinumab, funded both studies. The PsA study authors report multiple relationships with industry, and some, such as Dr. Kivitz, have connections to Novartis. The axSpA study authors also report multiple relationships with industry, and some, such as Dr. Deodhar, have connections to Novartis. Some authors of both studies are Novartis employees. Dr. Goodson disclosed financial relationships with UCB and AbbVie.
SAN DIEGO – Monthly use of intravenously administered secukinumab (Cosentyx) proved its efficacy over placebo in treating psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) in two industry-sponsored, randomized, double-blinded, phase 3 trials of the drug’s second and newly approved route of administration.
The studies of the human monoclonal antibody secukinumab, an interleukin-17 inhibitor, were presented at the annual meeting of the American College of Rheumatology. A subcutaneously injectable formulation of the drug is available, and the Food and Drug Administration approved the IV form for the conditions in October, although at a recommended lower monthly dose than the new trials examined.
In the PsA trial, 191 patients took IV secukinumab, and 190 took placebo. For the primary endpoint, the percentages who reached at least a 50% improvement in American College of Rheumatology response criteria (ACR 50) at 16 weeks were 31.4% and 6.3%, respectively (P < .0001).
In the axSpA trial, 264 patients took IV secukinumab, and 262 took placebo. The primary endpoint, at least a 40% improvement in Assessment of the Spondyloarthritis International Society response criteria (ASAS 40), was met at 16 weeks by 40.9% and 22.9%, respectively (P < .0001).
“Both studies appear to present clear efficacy of IV route administration of secukinumab with no clear increase in safety signals,” consultant rheumatologist Nicola Goodson, MBChB, PhD, of Aintree University Hospital in Liverpool, England, said in an interview.
“Offering IV administration as an option to patients is helpful,” added Dr. Goodson, who was not involved with the study but is familiar with its findings.
As Dr. Goodson explained, secukinumab “was the first IL [interleukin]-17 inhibitor used to treat spondyloarthropathies, and we have been using subcutaneous secukinumab to treat psoriasis, psoriatic arthritis, and axial spondyloarthritis/ankylosing spondylitis since 2016 in the U.K. Our experience with this medication has been good with similar efficacy to anti-TNF [tumor necrosis factor] therapy in axial spondyloarthritis. The medication is generally well-tolerated, and the subcutaneous pen injection device is easy for patients to use.”
However, IV treatment may speed up onset of action, she said, and it may be useful in situations when compliance is a challenge.
PsA trial details
In the PsA trial, known as INVIGORATE-2, researchers recruited patients who met the CASPAR criteria for active PsA with symptoms for ≥ 6 months, and had ≥ 3 tender joints out of 78 joints and ≥ 3 swollen joints out of 76.
Participants with a mean age of 48, including 55% females, were randomized 1:1 to receive placebo or secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks). Those in the placebo group were switched to the same monthly doses of secukinumab at 16 weeks.
“Patients who switched from the placebo had a similar increase of efficacy as the original treated group,” rheumatologist Alan J. Kivitz, MD, of the Altoona Center for Clinical Research, in Duncansville, Penn., said in his presentation at the meeting. Specifically, at 52 weeks, the groups had similar ACR 50 response rates: 58% with secukinumab and 64% with placebo-to-secukinumab.
The fact that patients in the original placebo group who received 3 mg IV doses without 6-mg loading doses achieved ACR response rates similar to those who took secukinumab during the whole trial “could suggest that the IV loading dose may not be required. This would need to be explored in a randomized head-to-head study, but it’s an interesting observation that may reduce costs and exposure to higher doses of medication at the start of treatment,” Dr. Goodson said.
Among the patients who received secukinumab at any point in the study, 63% had a treatment-emergent adverse event, including 5.9% with serious events. One death was reported in the placebo group before week 16. No other deaths were reported.
AxSpA trial details
In the axSpA trial, called INVIGORATE-1, researchers recruited people aged ≥18 years with a diagnosis of active radiographic axSpA according to modified New York criteria or nonradiographic axSpA according to ASAS criteria, and all had inflammatory back pain for ≥6 months with an onset before age 45. They were randomized at a 1:1 ratio to receive IV secukinumab (6 mg/kg loading dose, followed by 3 mg/kg every 4 weeks) or placebo for 16 weeks. At that point, the placebo group switched to the same monthly doses of IV secukinumab.
Participants had a mean age of about 39, and about one-third were female.
Following the statistical superiority in ASAS 40 response rates seen with IV secukinumab at week 16, patients who from there switched from placebo to IV secukinumab achieved comparable ASAS 40 response rates to those of patients originally randomized to secukinumab by week 24, reaching 66.8% for those on secukinumab the whole time and 74.9% for those who switched.
Secondary outcome measures were similar in both groups at week 52.
Among all patients who took secukinumab – the percentage with any adverse event was 63.2%, and 6% had a nonfatal adverse event deemed serious. There was one death during secukinumab treatment not suspected to be related to treatment.
In a presentation about the axSpA study findings, Atul Deodhar, MD, of Oregon Health & Science University, noted that “having an IV biologic available in the U.S. has some advantages. There are certain insurance providers such as Medicare where it is more economical for the patient to have an IV drug available.”
Dr. Deodhar also noted that in October the FDA approved a recommended lower dose for the IV treatment than in the study: 1.75 mg/kg instead of 3 mg/kg following the loading dose. That’s because the 3 mg/kg dose caused blood levels to be higher than those in the subcutaneous form, he said.
The FDA made the same dose recommendation for PsA.
Study limitations
Dr. Goodson, the U.K. consultant rheumatologist, noted a limitation of the trials: “It would have been interesting to compare IV to subcutaneous route secukinumab.” Still, the findings suggest that “the safety and efficacy of IV administration appears comparable,” she said.
“IV administration will have associated costs of attending hospital or infusion clinics,” she added, “and the cost of additional staff and administration need to be considered.”
Novartis, the maker of secukinumab, funded both studies. The PsA study authors report multiple relationships with industry, and some, such as Dr. Kivitz, have connections to Novartis. The axSpA study authors also report multiple relationships with industry, and some, such as Dr. Deodhar, have connections to Novartis. Some authors of both studies are Novartis employees. Dr. Goodson disclosed financial relationships with UCB and AbbVie.
SAN DIEGO – Monthly use of intravenously administered secukinumab (Cosentyx) proved its efficacy over placebo in treating psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) in two industry-sponsored, randomized, double-blinded, phase 3 trials of the drug’s second and newly approved route of administration.
The studies of the human monoclonal antibody secukinumab, an interleukin-17 inhibitor, were presented at the annual meeting of the American College of Rheumatology. A subcutaneously injectable formulation of the drug is available, and the Food and Drug Administration approved the IV form for the conditions in October, although at a recommended lower monthly dose than the new trials examined.
In the PsA trial, 191 patients took IV secukinumab, and 190 took placebo. For the primary endpoint, the percentages who reached at least a 50% improvement in American College of Rheumatology response criteria (ACR 50) at 16 weeks were 31.4% and 6.3%, respectively (P < .0001).
In the axSpA trial, 264 patients took IV secukinumab, and 262 took placebo. The primary endpoint, at least a 40% improvement in Assessment of the Spondyloarthritis International Society response criteria (ASAS 40), was met at 16 weeks by 40.9% and 22.9%, respectively (P < .0001).
“Both studies appear to present clear efficacy of IV route administration of secukinumab with no clear increase in safety signals,” consultant rheumatologist Nicola Goodson, MBChB, PhD, of Aintree University Hospital in Liverpool, England, said in an interview.
“Offering IV administration as an option to patients is helpful,” added Dr. Goodson, who was not involved with the study but is familiar with its findings.
As Dr. Goodson explained, secukinumab “was the first IL [interleukin]-17 inhibitor used to treat spondyloarthropathies, and we have been using subcutaneous secukinumab to treat psoriasis, psoriatic arthritis, and axial spondyloarthritis/ankylosing spondylitis since 2016 in the U.K. Our experience with this medication has been good with similar efficacy to anti-TNF [tumor necrosis factor] therapy in axial spondyloarthritis. The medication is generally well-tolerated, and the subcutaneous pen injection device is easy for patients to use.”
However, IV treatment may speed up onset of action, she said, and it may be useful in situations when compliance is a challenge.
PsA trial details
In the PsA trial, known as INVIGORATE-2, researchers recruited patients who met the CASPAR criteria for active PsA with symptoms for ≥ 6 months, and had ≥ 3 tender joints out of 78 joints and ≥ 3 swollen joints out of 76.
Participants with a mean age of 48, including 55% females, were randomized 1:1 to receive placebo or secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks). Those in the placebo group were switched to the same monthly doses of secukinumab at 16 weeks.
“Patients who switched from the placebo had a similar increase of efficacy as the original treated group,” rheumatologist Alan J. Kivitz, MD, of the Altoona Center for Clinical Research, in Duncansville, Penn., said in his presentation at the meeting. Specifically, at 52 weeks, the groups had similar ACR 50 response rates: 58% with secukinumab and 64% with placebo-to-secukinumab.
The fact that patients in the original placebo group who received 3 mg IV doses without 6-mg loading doses achieved ACR response rates similar to those who took secukinumab during the whole trial “could suggest that the IV loading dose may not be required. This would need to be explored in a randomized head-to-head study, but it’s an interesting observation that may reduce costs and exposure to higher doses of medication at the start of treatment,” Dr. Goodson said.
Among the patients who received secukinumab at any point in the study, 63% had a treatment-emergent adverse event, including 5.9% with serious events. One death was reported in the placebo group before week 16. No other deaths were reported.
AxSpA trial details
In the axSpA trial, called INVIGORATE-1, researchers recruited people aged ≥18 years with a diagnosis of active radiographic axSpA according to modified New York criteria or nonradiographic axSpA according to ASAS criteria, and all had inflammatory back pain for ≥6 months with an onset before age 45. They were randomized at a 1:1 ratio to receive IV secukinumab (6 mg/kg loading dose, followed by 3 mg/kg every 4 weeks) or placebo for 16 weeks. At that point, the placebo group switched to the same monthly doses of IV secukinumab.
Participants had a mean age of about 39, and about one-third were female.
Following the statistical superiority in ASAS 40 response rates seen with IV secukinumab at week 16, patients who from there switched from placebo to IV secukinumab achieved comparable ASAS 40 response rates to those of patients originally randomized to secukinumab by week 24, reaching 66.8% for those on secukinumab the whole time and 74.9% for those who switched.
Secondary outcome measures were similar in both groups at week 52.
Among all patients who took secukinumab – the percentage with any adverse event was 63.2%, and 6% had a nonfatal adverse event deemed serious. There was one death during secukinumab treatment not suspected to be related to treatment.
In a presentation about the axSpA study findings, Atul Deodhar, MD, of Oregon Health & Science University, noted that “having an IV biologic available in the U.S. has some advantages. There are certain insurance providers such as Medicare where it is more economical for the patient to have an IV drug available.”
Dr. Deodhar also noted that in October the FDA approved a recommended lower dose for the IV treatment than in the study: 1.75 mg/kg instead of 3 mg/kg following the loading dose. That’s because the 3 mg/kg dose caused blood levels to be higher than those in the subcutaneous form, he said.
The FDA made the same dose recommendation for PsA.
Study limitations
Dr. Goodson, the U.K. consultant rheumatologist, noted a limitation of the trials: “It would have been interesting to compare IV to subcutaneous route secukinumab.” Still, the findings suggest that “the safety and efficacy of IV administration appears comparable,” she said.
“IV administration will have associated costs of attending hospital or infusion clinics,” she added, “and the cost of additional staff and administration need to be considered.”
Novartis, the maker of secukinumab, funded both studies. The PsA study authors report multiple relationships with industry, and some, such as Dr. Kivitz, have connections to Novartis. The axSpA study authors also report multiple relationships with industry, and some, such as Dr. Deodhar, have connections to Novartis. Some authors of both studies are Novartis employees. Dr. Goodson disclosed financial relationships with UCB and AbbVie.
AT ACR 2023
Sepsis mortality greater in Black than White children despite similar interventions
WASHINGTON – , according to research presented at the annual meeting of the American Academy of Pediatrics.
The only other difference between Black and White pediatric patients was the length of hospital stay and the length of time in the ICU among those who died. In both cases, Black children who died spent more time in the hospital and in the ICU, reported Michael H. Stroud, MD, a pediatric critical care physician at the University of Arkansas for Medical Sciences in Little Rock, and his colleagues.
“Further investigations are needed to identify biases, conscious and unconscious, potential socioeconomic factors, and genetic predispositions leading to racial disparities in outcomes of children with pediatric sepsis, severe sepsis, and septic shock,” Dr Stroud and his colleagues said.
Nathan T. Chomilo, MD, adjunct assistant professor of pediatrics at the University of Minnesota, Minneapolis, who was not involved in the study but reviewed it, said the research “builds upon existing evidence that our health care system has work to do to meet its goal of treating patients equitably and provide everyone the opportunity for health.” He found the racial disparity in death particularly striking in 2023. “In the U.S., with all our wealth, knowledge, and resources, very few children should die from this, let alone there be such a stark gap,” Dr. Chomilo wrote.
Racial disparities persist
Dr. Stroud noted that many institutions currently use “automated, real-time, algorithm-based detection of sepsis, severe sepsis, and septic shock incorporated into the electronic medical record,” which leads to earlier recognition and resuscitation and overall better outcomes. Yet racial disparities in sepsis mortality rates persist, and he and his colleagues wanted to explore whether they remained even with these EMR-incorporated systems.
The researchers analyzed data from all patients at Arkansas Children’s Hospital who had sepsis, severe sepsis, or septic shock between January 2018 and April 2022. The hospital uses a best practice advisory (BPA) in the EMR whose activation leads to a bedside huddle and clinical interventions. For this study, the researchers defined a sepsis episode as either a BPA activation or an EMR diagnosis of sepsis, severe sepsis, or septic shock.
Among the 3,514 patients who had a sepsis episode during the study, 60.5% were White (n = 2,126) and 20.9% were Black (n = 736). Overall mortality was 1.65%, but that included 3.13% of Black children versus 1.27% of White children (odds ratio [OR] 2.51, P = .001). No significant differences in mortality were seen in gender or age.
Clinical interventions in the two groups were also similar: Total IV antibiotic days were 23.8 days for Black children and 21.6 days for White children (P = .38); total vasoactive infusion days were 2.2 for Black children and 2.6 for White (P = .18); and extracorporeal membrane oxygenation was necessary for 26.1% of Black children and 18.5% of White children (P = .52).
Length of hospitalization stay, however, was an average 4 days longer for Black children (16.7 days) versus White children (12.7 days) who died (P = .03). ICU stay for Black children who died was also an average 1.9 days longer (7.57 vs. 5.7 days; P = .01). There were no significant differences in the EMR between Black and White patients, however, in the percent who were over the threshold for antibiotic administration and the percent who received an IV fluid bolus.
Contributing factors
Dr. Chomilo said that most BPA systems require staff – including rooming and triage staff, nurses. and physicians – to enter vital signs, order labs, enter the results into the system, and enter other data used by the algorithm. “So even though the time from when those BPA warnings flagged to when clinical interventions were documented didn’t show a significant difference, there are numerous other points along a child’s illness that may be contributing to these numbers,” Dr. Chomilo said.
For example, he pointed out that differences in health insurance coverage could have influenced whether their parent or caregiver was able to bring them in early enough to be diagnosed since studies have revealed disparate access to regular care due to structural racism in the health care system. Studies have also shown disparate rates of patients being triaged or having to wait longer in emergency departments, he added.
“When the child was brought in, how were they triaged? How long did they wait before they had vitals taken? How long until they were seen by a clinician?” Dr. Chomilo said. “Was their care on the inpatient ward the same or different? What was the source of sepsis? Was it all infectious or other issues [since] cancer and autoimmune illnesses can also trigger a sepsis evaluation, for example? Overall, I suspect answers to several of these questions would reveal a disparity due to structural racism that contributed to the ultimate disparity in deaths.”
Other social determinants of health that could have played a role in the outcome disparities here might include the family’s access to transportation options, parental employment or child care options, and nutrition access since baseline nutritional status can be a factor in the outcomes of severe illnesses like sepsis.
”I don’t think this study provided enough information about the potential causative factors to come to any strong conclusions,” Dr. Chomilo said. But it’s important for clinicians to be aware of how biases in the health care system put Black, Indigenous and other communities at higher risk for worse clinical outcomes.
“I would reiterate that clinicians in the hospital can help improve outcomes by being aware of structural racism and structural inequity and how that may contribute to their patient’s risk of severe illness as the decide how to approach their treatment and engaging the patient’s family,” Dr. Chomilo said. “We cannot rely solely on universal tools that don’t take this into account when we are looking to improve clinical outcomes for everyone. Otherwise we will see these gaps persist.”
No external funding sources were noted. Dr. Stroud and Dr. Chomilo had no disclosures.
WASHINGTON – , according to research presented at the annual meeting of the American Academy of Pediatrics.
The only other difference between Black and White pediatric patients was the length of hospital stay and the length of time in the ICU among those who died. In both cases, Black children who died spent more time in the hospital and in the ICU, reported Michael H. Stroud, MD, a pediatric critical care physician at the University of Arkansas for Medical Sciences in Little Rock, and his colleagues.
“Further investigations are needed to identify biases, conscious and unconscious, potential socioeconomic factors, and genetic predispositions leading to racial disparities in outcomes of children with pediatric sepsis, severe sepsis, and septic shock,” Dr Stroud and his colleagues said.
Nathan T. Chomilo, MD, adjunct assistant professor of pediatrics at the University of Minnesota, Minneapolis, who was not involved in the study but reviewed it, said the research “builds upon existing evidence that our health care system has work to do to meet its goal of treating patients equitably and provide everyone the opportunity for health.” He found the racial disparity in death particularly striking in 2023. “In the U.S., with all our wealth, knowledge, and resources, very few children should die from this, let alone there be such a stark gap,” Dr. Chomilo wrote.
Racial disparities persist
Dr. Stroud noted that many institutions currently use “automated, real-time, algorithm-based detection of sepsis, severe sepsis, and septic shock incorporated into the electronic medical record,” which leads to earlier recognition and resuscitation and overall better outcomes. Yet racial disparities in sepsis mortality rates persist, and he and his colleagues wanted to explore whether they remained even with these EMR-incorporated systems.
The researchers analyzed data from all patients at Arkansas Children’s Hospital who had sepsis, severe sepsis, or septic shock between January 2018 and April 2022. The hospital uses a best practice advisory (BPA) in the EMR whose activation leads to a bedside huddle and clinical interventions. For this study, the researchers defined a sepsis episode as either a BPA activation or an EMR diagnosis of sepsis, severe sepsis, or septic shock.
Among the 3,514 patients who had a sepsis episode during the study, 60.5% were White (n = 2,126) and 20.9% were Black (n = 736). Overall mortality was 1.65%, but that included 3.13% of Black children versus 1.27% of White children (odds ratio [OR] 2.51, P = .001). No significant differences in mortality were seen in gender or age.
Clinical interventions in the two groups were also similar: Total IV antibiotic days were 23.8 days for Black children and 21.6 days for White children (P = .38); total vasoactive infusion days were 2.2 for Black children and 2.6 for White (P = .18); and extracorporeal membrane oxygenation was necessary for 26.1% of Black children and 18.5% of White children (P = .52).
Length of hospitalization stay, however, was an average 4 days longer for Black children (16.7 days) versus White children (12.7 days) who died (P = .03). ICU stay for Black children who died was also an average 1.9 days longer (7.57 vs. 5.7 days; P = .01). There were no significant differences in the EMR between Black and White patients, however, in the percent who were over the threshold for antibiotic administration and the percent who received an IV fluid bolus.
Contributing factors
Dr. Chomilo said that most BPA systems require staff – including rooming and triage staff, nurses. and physicians – to enter vital signs, order labs, enter the results into the system, and enter other data used by the algorithm. “So even though the time from when those BPA warnings flagged to when clinical interventions were documented didn’t show a significant difference, there are numerous other points along a child’s illness that may be contributing to these numbers,” Dr. Chomilo said.
For example, he pointed out that differences in health insurance coverage could have influenced whether their parent or caregiver was able to bring them in early enough to be diagnosed since studies have revealed disparate access to regular care due to structural racism in the health care system. Studies have also shown disparate rates of patients being triaged or having to wait longer in emergency departments, he added.
“When the child was brought in, how were they triaged? How long did they wait before they had vitals taken? How long until they were seen by a clinician?” Dr. Chomilo said. “Was their care on the inpatient ward the same or different? What was the source of sepsis? Was it all infectious or other issues [since] cancer and autoimmune illnesses can also trigger a sepsis evaluation, for example? Overall, I suspect answers to several of these questions would reveal a disparity due to structural racism that contributed to the ultimate disparity in deaths.”
Other social determinants of health that could have played a role in the outcome disparities here might include the family’s access to transportation options, parental employment or child care options, and nutrition access since baseline nutritional status can be a factor in the outcomes of severe illnesses like sepsis.
”I don’t think this study provided enough information about the potential causative factors to come to any strong conclusions,” Dr. Chomilo said. But it’s important for clinicians to be aware of how biases in the health care system put Black, Indigenous and other communities at higher risk for worse clinical outcomes.
“I would reiterate that clinicians in the hospital can help improve outcomes by being aware of structural racism and structural inequity and how that may contribute to their patient’s risk of severe illness as the decide how to approach their treatment and engaging the patient’s family,” Dr. Chomilo said. “We cannot rely solely on universal tools that don’t take this into account when we are looking to improve clinical outcomes for everyone. Otherwise we will see these gaps persist.”
No external funding sources were noted. Dr. Stroud and Dr. Chomilo had no disclosures.
WASHINGTON – , according to research presented at the annual meeting of the American Academy of Pediatrics.
The only other difference between Black and White pediatric patients was the length of hospital stay and the length of time in the ICU among those who died. In both cases, Black children who died spent more time in the hospital and in the ICU, reported Michael H. Stroud, MD, a pediatric critical care physician at the University of Arkansas for Medical Sciences in Little Rock, and his colleagues.
“Further investigations are needed to identify biases, conscious and unconscious, potential socioeconomic factors, and genetic predispositions leading to racial disparities in outcomes of children with pediatric sepsis, severe sepsis, and septic shock,” Dr Stroud and his colleagues said.
Nathan T. Chomilo, MD, adjunct assistant professor of pediatrics at the University of Minnesota, Minneapolis, who was not involved in the study but reviewed it, said the research “builds upon existing evidence that our health care system has work to do to meet its goal of treating patients equitably and provide everyone the opportunity for health.” He found the racial disparity in death particularly striking in 2023. “In the U.S., with all our wealth, knowledge, and resources, very few children should die from this, let alone there be such a stark gap,” Dr. Chomilo wrote.
Racial disparities persist
Dr. Stroud noted that many institutions currently use “automated, real-time, algorithm-based detection of sepsis, severe sepsis, and septic shock incorporated into the electronic medical record,” which leads to earlier recognition and resuscitation and overall better outcomes. Yet racial disparities in sepsis mortality rates persist, and he and his colleagues wanted to explore whether they remained even with these EMR-incorporated systems.
The researchers analyzed data from all patients at Arkansas Children’s Hospital who had sepsis, severe sepsis, or septic shock between January 2018 and April 2022. The hospital uses a best practice advisory (BPA) in the EMR whose activation leads to a bedside huddle and clinical interventions. For this study, the researchers defined a sepsis episode as either a BPA activation or an EMR diagnosis of sepsis, severe sepsis, or septic shock.
Among the 3,514 patients who had a sepsis episode during the study, 60.5% were White (n = 2,126) and 20.9% were Black (n = 736). Overall mortality was 1.65%, but that included 3.13% of Black children versus 1.27% of White children (odds ratio [OR] 2.51, P = .001). No significant differences in mortality were seen in gender or age.
Clinical interventions in the two groups were also similar: Total IV antibiotic days were 23.8 days for Black children and 21.6 days for White children (P = .38); total vasoactive infusion days were 2.2 for Black children and 2.6 for White (P = .18); and extracorporeal membrane oxygenation was necessary for 26.1% of Black children and 18.5% of White children (P = .52).
Length of hospitalization stay, however, was an average 4 days longer for Black children (16.7 days) versus White children (12.7 days) who died (P = .03). ICU stay for Black children who died was also an average 1.9 days longer (7.57 vs. 5.7 days; P = .01). There were no significant differences in the EMR between Black and White patients, however, in the percent who were over the threshold for antibiotic administration and the percent who received an IV fluid bolus.
Contributing factors
Dr. Chomilo said that most BPA systems require staff – including rooming and triage staff, nurses. and physicians – to enter vital signs, order labs, enter the results into the system, and enter other data used by the algorithm. “So even though the time from when those BPA warnings flagged to when clinical interventions were documented didn’t show a significant difference, there are numerous other points along a child’s illness that may be contributing to these numbers,” Dr. Chomilo said.
For example, he pointed out that differences in health insurance coverage could have influenced whether their parent or caregiver was able to bring them in early enough to be diagnosed since studies have revealed disparate access to regular care due to structural racism in the health care system. Studies have also shown disparate rates of patients being triaged or having to wait longer in emergency departments, he added.
“When the child was brought in, how were they triaged? How long did they wait before they had vitals taken? How long until they were seen by a clinician?” Dr. Chomilo said. “Was their care on the inpatient ward the same or different? What was the source of sepsis? Was it all infectious or other issues [since] cancer and autoimmune illnesses can also trigger a sepsis evaluation, for example? Overall, I suspect answers to several of these questions would reveal a disparity due to structural racism that contributed to the ultimate disparity in deaths.”
Other social determinants of health that could have played a role in the outcome disparities here might include the family’s access to transportation options, parental employment or child care options, and nutrition access since baseline nutritional status can be a factor in the outcomes of severe illnesses like sepsis.
”I don’t think this study provided enough information about the potential causative factors to come to any strong conclusions,” Dr. Chomilo said. But it’s important for clinicians to be aware of how biases in the health care system put Black, Indigenous and other communities at higher risk for worse clinical outcomes.
“I would reiterate that clinicians in the hospital can help improve outcomes by being aware of structural racism and structural inequity and how that may contribute to their patient’s risk of severe illness as the decide how to approach their treatment and engaging the patient’s family,” Dr. Chomilo said. “We cannot rely solely on universal tools that don’t take this into account when we are looking to improve clinical outcomes for everyone. Otherwise we will see these gaps persist.”
No external funding sources were noted. Dr. Stroud and Dr. Chomilo had no disclosures.
AT AAP 2023