NEW ORLEANS – Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical’s investigational allogeneic stem cell–derived islets (VX-880), with the first person now completely insulin independent at 9 months post transplant.

Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem cell–derived islet transplants as they are “foreign” to the recipient).

The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post transplant. Both patients were given just half the targeted VX-880 dose.

Data for those two patients – the first in Vertex’s phase 1/2 multicenter, single-arm, open-label clinical trial of VX-880 – were reported at the annual scientific sessions of the American Diabetes Association, by James F. Markmann, MD, PhD.

He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.

Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they’re limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.

“This is a new area. ... We hope this will be the same or potentially better. With stem cell–derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets,” he commented during a press briefing here.

A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Dr. Markmann said.

In answer to a question about how patient 1 is doing now, Dr. Markmann replied, “He’s doing great. He’s probably the most appreciative patient I’ve ever met. His life was being destroyed by diabetes. He couldn’t work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate.”

When Dr. Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied: “I want to participate. If I die from this and I help somebody else I’d be happy, but I can’t go on living the way I’m living.”

“These people really suffer and this, I think, brings hope to them,” Dr. Markmann said.
 

‘Beautiful data’ seen in two patients, with ‘transformational’ potential

Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told this news organization: “It’s beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells ... it was impossible to get sufficient beta cells from cadaveric transplants. It’s just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like patient 1, this will be transformational.”

Dr. Markmann presented data for the most recent study visit for each of the two patients, 270 days for patient 1 and 150 days for patient 2. Prior to the transplants, patient 1 had experienced five severe hypoglycemic events and patient 2 had experienced three.

Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, patient 1 showed a “robust” C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, “possibly due to improved insulin sensitivity,” Dr. Markmann said.

Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.

Hemoglobin A1c dropped in patient 1 from 8.6% at baseline to 6.9% at day 180, to a “remarkable” 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.  

Both patients also had significant reductions in insulin dose. For patient 1, the dose reduction was more than 90% – from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.

Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.

Asked why Patient 2’s results weren’t quite as impressive as patient 1’s, Dr. Markmann replied “I think what’s important is that both patients did great. And since this was a half-dose, we might have expected that the outcome was going to be more like patient 2 rather than patient 1. So, I think we’re just going to have to [study this in] more patients to understand where it falls.” 

Although patient 1 experienced a cluster of six severe hypoglycemic events early in the posttransplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.

Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a “mild and self-limited” rise in liver function test and also experienced two severe adverse events: A rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2’s adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.

Immunosuppression: Work is ongoing

The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well tolerated, Dr. Markmann said.

Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.

“This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn’t require immunosuppression. ... But if we had a way of transplanting the cells without the need for immunosuppression, then it could be really widely available. That’s an opportunity for the future since these cells can be made in unlimited quantities,” Dr. Markmann commented during the press briefing.

Asked for his thoughts about the immunosuppression aspect, Dr. Pragnell told this news organization: “Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They’re going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it’s amazing.”

He added: “The ‘artificial pancreas’ is a huge step forward, but it’s just a bridge to a cure, whereas if they’re able to show safety and efficacy, this is potentially a cure. ... I’m very excited about it.”

Dr. Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Dr. Pragnell is an ADA employee and has no further disclosures.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical’s investigational allogeneic stem cell–derived islets (VX-880), with the first person now completely insulin independent at 9 months post transplant.

Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem cell–derived islet transplants as they are “foreign” to the recipient).

The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post transplant. Both patients were given just half the targeted VX-880 dose.

Data for those two patients – the first in Vertex’s phase 1/2 multicenter, single-arm, open-label clinical trial of VX-880 – were reported at the annual scientific sessions of the American Diabetes Association, by James F. Markmann, MD, PhD.

He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.

Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they’re limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.

“This is a new area. ... We hope this will be the same or potentially better. With stem cell–derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets,” he commented during a press briefing here.

A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Dr. Markmann said.

In answer to a question about how patient 1 is doing now, Dr. Markmann replied, “He’s doing great. He’s probably the most appreciative patient I’ve ever met. His life was being destroyed by diabetes. He couldn’t work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate.”

When Dr. Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied: “I want to participate. If I die from this and I help somebody else I’d be happy, but I can’t go on living the way I’m living.”

“These people really suffer and this, I think, brings hope to them,” Dr. Markmann said.
 

‘Beautiful data’ seen in two patients, with ‘transformational’ potential

Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told this news organization: “It’s beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells ... it was impossible to get sufficient beta cells from cadaveric transplants. It’s just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like patient 1, this will be transformational.”

Dr. Markmann presented data for the most recent study visit for each of the two patients, 270 days for patient 1 and 150 days for patient 2. Prior to the transplants, patient 1 had experienced five severe hypoglycemic events and patient 2 had experienced three.

Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, patient 1 showed a “robust” C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, “possibly due to improved insulin sensitivity,” Dr. Markmann said.

Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.

Hemoglobin A1c dropped in patient 1 from 8.6% at baseline to 6.9% at day 180, to a “remarkable” 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.  

Both patients also had significant reductions in insulin dose. For patient 1, the dose reduction was more than 90% – from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.

Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.

Asked why Patient 2’s results weren’t quite as impressive as patient 1’s, Dr. Markmann replied “I think what’s important is that both patients did great. And since this was a half-dose, we might have expected that the outcome was going to be more like patient 2 rather than patient 1. So, I think we’re just going to have to [study this in] more patients to understand where it falls.” 

Although patient 1 experienced a cluster of six severe hypoglycemic events early in the posttransplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.

Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a “mild and self-limited” rise in liver function test and also experienced two severe adverse events: A rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2’s adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.

Immunosuppression: Work is ongoing

The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well tolerated, Dr. Markmann said.

Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.

“This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn’t require immunosuppression. ... But if we had a way of transplanting the cells without the need for immunosuppression, then it could be really widely available. That’s an opportunity for the future since these cells can be made in unlimited quantities,” Dr. Markmann commented during the press briefing.

Asked for his thoughts about the immunosuppression aspect, Dr. Pragnell told this news organization: “Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They’re going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it’s amazing.”

He added: “The ‘artificial pancreas’ is a huge step forward, but it’s just a bridge to a cure, whereas if they’re able to show safety and efficacy, this is potentially a cure. ... I’m very excited about it.”

Dr. Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Dr. Pragnell is an ADA employee and has no further disclosures.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical’s investigational allogeneic stem cell–derived islets (VX-880), with the first person now completely insulin independent at 9 months post transplant.

Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem cell–derived islet transplants as they are “foreign” to the recipient).

The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post transplant. Both patients were given just half the targeted VX-880 dose.

Data for those two patients – the first in Vertex’s phase 1/2 multicenter, single-arm, open-label clinical trial of VX-880 – were reported at the annual scientific sessions of the American Diabetes Association, by James F. Markmann, MD, PhD.

He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.

Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they’re limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.

“This is a new area. ... We hope this will be the same or potentially better. With stem cell–derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets,” he commented during a press briefing here.

A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Dr. Markmann said.

In answer to a question about how patient 1 is doing now, Dr. Markmann replied, “He’s doing great. He’s probably the most appreciative patient I’ve ever met. His life was being destroyed by diabetes. He couldn’t work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate.”

When Dr. Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied: “I want to participate. If I die from this and I help somebody else I’d be happy, but I can’t go on living the way I’m living.”

“These people really suffer and this, I think, brings hope to them,” Dr. Markmann said.
 

‘Beautiful data’ seen in two patients, with ‘transformational’ potential

Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told this news organization: “It’s beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells ... it was impossible to get sufficient beta cells from cadaveric transplants. It’s just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like patient 1, this will be transformational.”

Dr. Markmann presented data for the most recent study visit for each of the two patients, 270 days for patient 1 and 150 days for patient 2. Prior to the transplants, patient 1 had experienced five severe hypoglycemic events and patient 2 had experienced three.

Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, patient 1 showed a “robust” C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, “possibly due to improved insulin sensitivity,” Dr. Markmann said.

Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.

Hemoglobin A1c dropped in patient 1 from 8.6% at baseline to 6.9% at day 180, to a “remarkable” 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.  

Both patients also had significant reductions in insulin dose. For patient 1, the dose reduction was more than 90% – from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.

Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.

Asked why Patient 2’s results weren’t quite as impressive as patient 1’s, Dr. Markmann replied “I think what’s important is that both patients did great. And since this was a half-dose, we might have expected that the outcome was going to be more like patient 2 rather than patient 1. So, I think we’re just going to have to [study this in] more patients to understand where it falls.” 

Although patient 1 experienced a cluster of six severe hypoglycemic events early in the posttransplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.

Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a “mild and self-limited” rise in liver function test and also experienced two severe adverse events: A rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2’s adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.

Immunosuppression: Work is ongoing

The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well tolerated, Dr. Markmann said.

Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.

“This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn’t require immunosuppression. ... But if we had a way of transplanting the cells without the need for immunosuppression, then it could be really widely available. That’s an opportunity for the future since these cells can be made in unlimited quantities,” Dr. Markmann commented during the press briefing.

Asked for his thoughts about the immunosuppression aspect, Dr. Pragnell told this news organization: “Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They’re going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it’s amazing.”

He added: “The ‘artificial pancreas’ is a huge step forward, but it’s just a bridge to a cure, whereas if they’re able to show safety and efficacy, this is potentially a cure. ... I’m very excited about it.”

Dr. Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Dr. Pragnell is an ADA employee and has no further disclosures.

A version of this article first appeared on Medscape.com.

The novel antidepressant seltorexant (Janssen Pharmaceuticals) may be beneficial for patients with concomitant major depressive disorder (MDD) and sleep disturbance, new research suggests.

In a randomized, placebo-controlled, adaptive dose–finding study conducted in more than 200 patients with MDD, those with more severe insomnia at baseline had a greater improvement in depressive symptoms versus those with less severe insomnia.

“As seltorexant is an orexin receptor antagonist, it is related to other medications that are marketed as sleeping pills, so it was important to show that its antidepressant efficacy was actually caused by improved sleep,” coinvestigator Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told this news organization.

University of Pennsylvania

Clinically meaningful?

In an earlier exploratory study, seltorexant showed antidepressant and sleep-promoting effects in patients with MDD. In a phase 2b study, a 20-mg dose of the drug showed clinically meaningful improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment.

In the current analysis, the investigators evaluated the effect of seltorexant in improving depressive symptoms beyond sleep-related improvement in patients with MDD, using the MADRS-WOSI (MADRS without the sleep item).

They also used the six-item core MADRS subscale, which excludes sleep, anxiety, and appetite items.

The 283 participants were randomly assigned 3:3:1 to receive seltorexant 10 mg or 20 mg or placebo once daily. They were also stratified into two groups according to the severity of their insomnia: those with a baseline Insomnia Severity Index [ISI] score of 15 or higher (58%) and those with a baseline ISI score of less than 15 (42%).

Results showed that the group receiving the 20-mg/day dose of seltorexant (n = 61 patients) obtained a statistically and clinically meaningful response, compared with the placebo group (n = 137 patients) after removing the insomnia and other “not core items” of the MADRS. The effect was clearest among those with high insomnia ratings.

Improvement in the MADRS-WOSI score was also observed in the seltorexant 20-mg group at week 3 and week 6, compared with the placebo group.
 

The LSM average distance

The least squares mean (LSM) average difference between the treatment and placebo groups in the MADRS-WOSI score at week 3 was −3.8 (90% confidence interval, −5.98 to −1.57; P = .005).

At week 6, the LSM between the groups in the MADRS-WOSI score was −2.5 (90% CI, −5.24 to 0.15; P = .12).

The results were consistent with improvement in the MADRS total score. At week 3, the LSM in the MADRS total score was -4.5 (90% CI, -6.96 to -2.07; P = .003) and, at week 6, it was -3.1 (90% CI, -6.13 to -0.16; P = .083).

Seltorexant 20 mg was especially effective in patients who had more severe insomnia.

Commenting on the study, Nagy Youssef, MD, PhD, professor of psychiatry, The Ohio State University Wexner Medical Center, Columbus, said this was “a well-designed study examining a promising compound.”

Ohio State University

A version of this article first appeared on Medscape.com.

The novel antidepressant seltorexant (Janssen Pharmaceuticals) may be beneficial for patients with concomitant major depressive disorder (MDD) and sleep disturbance, new research suggests.

In a randomized, placebo-controlled, adaptive dose–finding study conducted in more than 200 patients with MDD, those with more severe insomnia at baseline had a greater improvement in depressive symptoms versus those with less severe insomnia.

“As seltorexant is an orexin receptor antagonist, it is related to other medications that are marketed as sleeping pills, so it was important to show that its antidepressant efficacy was actually caused by improved sleep,” coinvestigator Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told this news organization.

University of Pennsylvania

Clinically meaningful?

In an earlier exploratory study, seltorexant showed antidepressant and sleep-promoting effects in patients with MDD. In a phase 2b study, a 20-mg dose of the drug showed clinically meaningful improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment.

In the current analysis, the investigators evaluated the effect of seltorexant in improving depressive symptoms beyond sleep-related improvement in patients with MDD, using the MADRS-WOSI (MADRS without the sleep item).

They also used the six-item core MADRS subscale, which excludes sleep, anxiety, and appetite items.

The 283 participants were randomly assigned 3:3:1 to receive seltorexant 10 mg or 20 mg or placebo once daily. They were also stratified into two groups according to the severity of their insomnia: those with a baseline Insomnia Severity Index [ISI] score of 15 or higher (58%) and those with a baseline ISI score of less than 15 (42%).

Results showed that the group receiving the 20-mg/day dose of seltorexant (n = 61 patients) obtained a statistically and clinically meaningful response, compared with the placebo group (n = 137 patients) after removing the insomnia and other “not core items” of the MADRS. The effect was clearest among those with high insomnia ratings.

Improvement in the MADRS-WOSI score was also observed in the seltorexant 20-mg group at week 3 and week 6, compared with the placebo group.
 

The LSM average distance

The least squares mean (LSM) average difference between the treatment and placebo groups in the MADRS-WOSI score at week 3 was −3.8 (90% confidence interval, −5.98 to −1.57; P = .005).

At week 6, the LSM between the groups in the MADRS-WOSI score was −2.5 (90% CI, −5.24 to 0.15; P = .12).

The results were consistent with improvement in the MADRS total score. At week 3, the LSM in the MADRS total score was -4.5 (90% CI, -6.96 to -2.07; P = .003) and, at week 6, it was -3.1 (90% CI, -6.13 to -0.16; P = .083).

Seltorexant 20 mg was especially effective in patients who had more severe insomnia.

Commenting on the study, Nagy Youssef, MD, PhD, professor of psychiatry, The Ohio State University Wexner Medical Center, Columbus, said this was “a well-designed study examining a promising compound.”

Ohio State University

A version of this article first appeared on Medscape.com.

The novel antidepressant seltorexant (Janssen Pharmaceuticals) may be beneficial for patients with concomitant major depressive disorder (MDD) and sleep disturbance, new research suggests.

In a randomized, placebo-controlled, adaptive dose–finding study conducted in more than 200 patients with MDD, those with more severe insomnia at baseline had a greater improvement in depressive symptoms versus those with less severe insomnia.

“As seltorexant is an orexin receptor antagonist, it is related to other medications that are marketed as sleeping pills, so it was important to show that its antidepressant efficacy was actually caused by improved sleep,” coinvestigator Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told this news organization.

University of Pennsylvania

Clinically meaningful?

In an earlier exploratory study, seltorexant showed antidepressant and sleep-promoting effects in patients with MDD. In a phase 2b study, a 20-mg dose of the drug showed clinically meaningful improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment.

In the current analysis, the investigators evaluated the effect of seltorexant in improving depressive symptoms beyond sleep-related improvement in patients with MDD, using the MADRS-WOSI (MADRS without the sleep item).

They also used the six-item core MADRS subscale, which excludes sleep, anxiety, and appetite items.

The 283 participants were randomly assigned 3:3:1 to receive seltorexant 10 mg or 20 mg or placebo once daily. They were also stratified into two groups according to the severity of their insomnia: those with a baseline Insomnia Severity Index [ISI] score of 15 or higher (58%) and those with a baseline ISI score of less than 15 (42%).

Results showed that the group receiving the 20-mg/day dose of seltorexant (n = 61 patients) obtained a statistically and clinically meaningful response, compared with the placebo group (n = 137 patients) after removing the insomnia and other “not core items” of the MADRS. The effect was clearest among those with high insomnia ratings.

Improvement in the MADRS-WOSI score was also observed in the seltorexant 20-mg group at week 3 and week 6, compared with the placebo group.
 

The LSM average distance

The least squares mean (LSM) average difference between the treatment and placebo groups in the MADRS-WOSI score at week 3 was −3.8 (90% confidence interval, −5.98 to −1.57; P = .005).

At week 6, the LSM between the groups in the MADRS-WOSI score was −2.5 (90% CI, −5.24 to 0.15; P = .12).

The results were consistent with improvement in the MADRS total score. At week 3, the LSM in the MADRS total score was -4.5 (90% CI, -6.96 to -2.07; P = .003) and, at week 6, it was -3.1 (90% CI, -6.13 to -0.16; P = .083).

Seltorexant 20 mg was especially effective in patients who had more severe insomnia.

Commenting on the study, Nagy Youssef, MD, PhD, professor of psychiatry, The Ohio State University Wexner Medical Center, Columbus, said this was “a well-designed study examining a promising compound.”

Ohio State University

A version of this article first appeared on Medscape.com.

As the use of biologics for dermatologic conditions has increased, so have questions from patients about their safety during pregnancy and lactation, their effects on fertility, and potential effects on the developing fetus and the child’s development.

“I get asked a lot about fertility,” Vivian Shi, MD, associate professor of dermatology at the University of Arkansas, Little Rock, said at MedscapeLive’s Women’s and Pediatric Dermatology Seminar. Patients want to know, she said, if they go on a specific drug, whether it will affect their chances of conceiving and what else they need to know about safety.

She told the audience what she tells her patients: The answers are not complete but are evolving at a steady pace.

“Putting this talk together was kind of like a scavenger hunt,” said Dr. Shi, who gathered data from pregnancy exposure registries, published research, the Food and Drug Administration, and other sources on biologics. As more studies emerge each year, she said, recommendations will become stronger for considering treatment by certain biological drugs, taking into account effects on fertility, pregnancy, lactation, and the infant.

Among the biologics commonly used in dermatology are:

• Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, certolizumab).
• Interleukin (IL)–12 and -23 antagonist (ustekinumab).
• IL-17 antagonists (ixekizumab, secukinumab, brodalumab).
• IL-23 antagonists (risankizumab, tildrakizumab, guselkumab).
• IL-4, -13 antagonist (dupilumab) and IL-13 antagonist (tralokinumab).
• CD20-directed cytolytic antibody (rituximab).

To help with decision-making, Dr. Shi discussed the relatively new FDA labeling regulations as well as pregnancy exposure registries, research studies, and recommendations.
 

FDA pregnancy risk summaries

Under the previous system of classification of drugs in pregnancy, the FDA rated drugs as A, B, C, D, X. These categories ranged from showing no risks to the fetus to clear risk, but were oversimplistic and confusing, Dr. Shi said. Category C was especially confusing, as a drug with no animal or human data was put in the same category as a drug with adverse fetal effects on animals, she noted.

However, effective June 30, 2015, the FDA replaced pregnancy categories with risk summaries by medication. As of June, 2020, all prescription drugs were to remove pregnancy letter labeling. The risk summaries note human data when they are available and also note when no data are available. This information, Dr. Shi said, originates from many sources, including studies published in the medical literature, postmarketing studies conducted by companies, and pregnancy exposure registries, conducted by some companies and others. The FDA does not endorse any specific registries, but does post a list of such registries. Another helpful resource, she said, is Mother to Baby, a service of the nonprofit Organization of Teratology Information Specialists (OTIS).



Known, not known

Citing published literature, Dr. Shi said that TNF inhibitors have the most robust safety data from preconception to after birth. Less is known, she said, about the reproductive safety effects of other biologics used for dermatologic conditions, as they are newer than the anti-TNF medicines.

She reviewed a variety of research studies evaluating the safety of biologics during pregnancy and beyond. Highlights include results from a large registry, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), of 298 pregnancies in about 220 women from 2007 to 2019, looking at 13 different biologics. The overall and live-birth outcomes in the women on biologics for psoriasis were similar to those for the general population and the rate of congenital anomalies was 0.8%, researchers reported in 2021, lower than the generally cited annual figure of U.S. births.

Studies evaluating biologics for nondermatologic conditions suggest safety. A prospective cohort study of women who took adalimumab in pregnancy (for rheumatoid arthritis or Crohn’s disease) found no increased risk for birth defects. In another study looking at women who were breastfeeding, researchers found no increased risk of infections or delay in developmental milestones in the children of women taking biologics for inflammatory bowel disease, compared with those not on the medications.

A report using data from the World Health Organization concludes that dupilumab appears to be safe during pregnancy, based on an evaluation of 36 pregnancy-related reports among more than 37,000 unique adverse event reports related to dupilumab in a global database.

Recommendations about biologic use from different organizations don’t always mesh, Dr. Shi said, noting that European guidelines tend to be stricter, as some reviews show.

If a mother is exposed to any biologic therapy other than certolizumab during the third trimester, after 27 weeks, Dr. Shi said, “you want to consider avoiding a live vaccine for the first 6 months of the baby’s life.” It turns out, she said, the only recommended live vaccine during that period is the rotavirus vaccine, and she suggests doctors recommend postponing that one until the babies are older if women have been on biologics other than certolizumab.

Her other take-home messages: TNF inhibitors have the most robust safety data from before conception through lactation. Under current guidelines, certolizumab is viewed as the safest to use throughout pregnancy. Dr. Shi’s message to her colleagues fielding the same questions she gets from patients: “There is more data coming out every year. Ultimately, we will have better information to inform our patients.”

At the conference, Lawrence F. Eichenfield, MD, a course director and professor of dermatology and pediatrics at the University of California, San Diego and Rady Children’s Hospital San Diego, encouraged Dr. Shi to write up her presentation as a resource for other dermatologists – which she said is in progress.

Medscape Live and this news organization are owned by the same parent company. Dr. Shi disclosed consulting and investigative and research funding from several pharmaceutical firms, but not directly related to the content of her presentation.

As the use of biologics for dermatologic conditions has increased, so have questions from patients about their safety during pregnancy and lactation, their effects on fertility, and potential effects on the developing fetus and the child’s development.

“I get asked a lot about fertility,” Vivian Shi, MD, associate professor of dermatology at the University of Arkansas, Little Rock, said at MedscapeLive’s Women’s and Pediatric Dermatology Seminar. Patients want to know, she said, if they go on a specific drug, whether it will affect their chances of conceiving and what else they need to know about safety.

She told the audience what she tells her patients: The answers are not complete but are evolving at a steady pace.

“Putting this talk together was kind of like a scavenger hunt,” said Dr. Shi, who gathered data from pregnancy exposure registries, published research, the Food and Drug Administration, and other sources on biologics. As more studies emerge each year, she said, recommendations will become stronger for considering treatment by certain biological drugs, taking into account effects on fertility, pregnancy, lactation, and the infant.

Among the biologics commonly used in dermatology are:

• Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, certolizumab).
• Interleukin (IL)–12 and -23 antagonist (ustekinumab).
• IL-17 antagonists (ixekizumab, secukinumab, brodalumab).
• IL-23 antagonists (risankizumab, tildrakizumab, guselkumab).
• IL-4, -13 antagonist (dupilumab) and IL-13 antagonist (tralokinumab).
• CD20-directed cytolytic antibody (rituximab).

To help with decision-making, Dr. Shi discussed the relatively new FDA labeling regulations as well as pregnancy exposure registries, research studies, and recommendations.
 

FDA pregnancy risk summaries

Under the previous system of classification of drugs in pregnancy, the FDA rated drugs as A, B, C, D, X. These categories ranged from showing no risks to the fetus to clear risk, but were oversimplistic and confusing, Dr. Shi said. Category C was especially confusing, as a drug with no animal or human data was put in the same category as a drug with adverse fetal effects on animals, she noted.

However, effective June 30, 2015, the FDA replaced pregnancy categories with risk summaries by medication. As of June, 2020, all prescription drugs were to remove pregnancy letter labeling. The risk summaries note human data when they are available and also note when no data are available. This information, Dr. Shi said, originates from many sources, including studies published in the medical literature, postmarketing studies conducted by companies, and pregnancy exposure registries, conducted by some companies and others. The FDA does not endorse any specific registries, but does post a list of such registries. Another helpful resource, she said, is Mother to Baby, a service of the nonprofit Organization of Teratology Information Specialists (OTIS).



Known, not known

Citing published literature, Dr. Shi said that TNF inhibitors have the most robust safety data from preconception to after birth. Less is known, she said, about the reproductive safety effects of other biologics used for dermatologic conditions, as they are newer than the anti-TNF medicines.

She reviewed a variety of research studies evaluating the safety of biologics during pregnancy and beyond. Highlights include results from a large registry, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), of 298 pregnancies in about 220 women from 2007 to 2019, looking at 13 different biologics. The overall and live-birth outcomes in the women on biologics for psoriasis were similar to those for the general population and the rate of congenital anomalies was 0.8%, researchers reported in 2021, lower than the generally cited annual figure of U.S. births.

Studies evaluating biologics for nondermatologic conditions suggest safety. A prospective cohort study of women who took adalimumab in pregnancy (for rheumatoid arthritis or Crohn’s disease) found no increased risk for birth defects. In another study looking at women who were breastfeeding, researchers found no increased risk of infections or delay in developmental milestones in the children of women taking biologics for inflammatory bowel disease, compared with those not on the medications.

A report using data from the World Health Organization concludes that dupilumab appears to be safe during pregnancy, based on an evaluation of 36 pregnancy-related reports among more than 37,000 unique adverse event reports related to dupilumab in a global database.

Recommendations about biologic use from different organizations don’t always mesh, Dr. Shi said, noting that European guidelines tend to be stricter, as some reviews show.

If a mother is exposed to any biologic therapy other than certolizumab during the third trimester, after 27 weeks, Dr. Shi said, “you want to consider avoiding a live vaccine for the first 6 months of the baby’s life.” It turns out, she said, the only recommended live vaccine during that period is the rotavirus vaccine, and she suggests doctors recommend postponing that one until the babies are older if women have been on biologics other than certolizumab.

Her other take-home messages: TNF inhibitors have the most robust safety data from before conception through lactation. Under current guidelines, certolizumab is viewed as the safest to use throughout pregnancy. Dr. Shi’s message to her colleagues fielding the same questions she gets from patients: “There is more data coming out every year. Ultimately, we will have better information to inform our patients.”

At the conference, Lawrence F. Eichenfield, MD, a course director and professor of dermatology and pediatrics at the University of California, San Diego and Rady Children’s Hospital San Diego, encouraged Dr. Shi to write up her presentation as a resource for other dermatologists – which she said is in progress.

Medscape Live and this news organization are owned by the same parent company. Dr. Shi disclosed consulting and investigative and research funding from several pharmaceutical firms, but not directly related to the content of her presentation.

As the use of biologics for dermatologic conditions has increased, so have questions from patients about their safety during pregnancy and lactation, their effects on fertility, and potential effects on the developing fetus and the child’s development.

“I get asked a lot about fertility,” Vivian Shi, MD, associate professor of dermatology at the University of Arkansas, Little Rock, said at MedscapeLive’s Women’s and Pediatric Dermatology Seminar. Patients want to know, she said, if they go on a specific drug, whether it will affect their chances of conceiving and what else they need to know about safety.

She told the audience what she tells her patients: The answers are not complete but are evolving at a steady pace.

“Putting this talk together was kind of like a scavenger hunt,” said Dr. Shi, who gathered data from pregnancy exposure registries, published research, the Food and Drug Administration, and other sources on biologics. As more studies emerge each year, she said, recommendations will become stronger for considering treatment by certain biological drugs, taking into account effects on fertility, pregnancy, lactation, and the infant.

Among the biologics commonly used in dermatology are:

• Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, certolizumab).
• Interleukin (IL)–12 and -23 antagonist (ustekinumab).
• IL-17 antagonists (ixekizumab, secukinumab, brodalumab).
• IL-23 antagonists (risankizumab, tildrakizumab, guselkumab).
• IL-4, -13 antagonist (dupilumab) and IL-13 antagonist (tralokinumab).
• CD20-directed cytolytic antibody (rituximab).

To help with decision-making, Dr. Shi discussed the relatively new FDA labeling regulations as well as pregnancy exposure registries, research studies, and recommendations.
 

FDA pregnancy risk summaries

Under the previous system of classification of drugs in pregnancy, the FDA rated drugs as A, B, C, D, X. These categories ranged from showing no risks to the fetus to clear risk, but were oversimplistic and confusing, Dr. Shi said. Category C was especially confusing, as a drug with no animal or human data was put in the same category as a drug with adverse fetal effects on animals, she noted.

However, effective June 30, 2015, the FDA replaced pregnancy categories with risk summaries by medication. As of June, 2020, all prescription drugs were to remove pregnancy letter labeling. The risk summaries note human data when they are available and also note when no data are available. This information, Dr. Shi said, originates from many sources, including studies published in the medical literature, postmarketing studies conducted by companies, and pregnancy exposure registries, conducted by some companies and others. The FDA does not endorse any specific registries, but does post a list of such registries. Another helpful resource, she said, is Mother to Baby, a service of the nonprofit Organization of Teratology Information Specialists (OTIS).



Known, not known

Citing published literature, Dr. Shi said that TNF inhibitors have the most robust safety data from preconception to after birth. Less is known, she said, about the reproductive safety effects of other biologics used for dermatologic conditions, as they are newer than the anti-TNF medicines.

She reviewed a variety of research studies evaluating the safety of biologics during pregnancy and beyond. Highlights include results from a large registry, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), of 298 pregnancies in about 220 women from 2007 to 2019, looking at 13 different biologics. The overall and live-birth outcomes in the women on biologics for psoriasis were similar to those for the general population and the rate of congenital anomalies was 0.8%, researchers reported in 2021, lower than the generally cited annual figure of U.S. births.

Studies evaluating biologics for nondermatologic conditions suggest safety. A prospective cohort study of women who took adalimumab in pregnancy (for rheumatoid arthritis or Crohn’s disease) found no increased risk for birth defects. In another study looking at women who were breastfeeding, researchers found no increased risk of infections or delay in developmental milestones in the children of women taking biologics for inflammatory bowel disease, compared with those not on the medications.

A report using data from the World Health Organization concludes that dupilumab appears to be safe during pregnancy, based on an evaluation of 36 pregnancy-related reports among more than 37,000 unique adverse event reports related to dupilumab in a global database.

Recommendations about biologic use from different organizations don’t always mesh, Dr. Shi said, noting that European guidelines tend to be stricter, as some reviews show.

If a mother is exposed to any biologic therapy other than certolizumab during the third trimester, after 27 weeks, Dr. Shi said, “you want to consider avoiding a live vaccine for the first 6 months of the baby’s life.” It turns out, she said, the only recommended live vaccine during that period is the rotavirus vaccine, and she suggests doctors recommend postponing that one until the babies are older if women have been on biologics other than certolizumab.

Her other take-home messages: TNF inhibitors have the most robust safety data from before conception through lactation. Under current guidelines, certolizumab is viewed as the safest to use throughout pregnancy. Dr. Shi’s message to her colleagues fielding the same questions she gets from patients: “There is more data coming out every year. Ultimately, we will have better information to inform our patients.”

At the conference, Lawrence F. Eichenfield, MD, a course director and professor of dermatology and pediatrics at the University of California, San Diego and Rady Children’s Hospital San Diego, encouraged Dr. Shi to write up her presentation as a resource for other dermatologists – which she said is in progress.

Medscape Live and this news organization are owned by the same parent company. Dr. Shi disclosed consulting and investigative and research funding from several pharmaceutical firms, but not directly related to the content of her presentation.

French investigators are warning about using acetaminophen in patients with cancer who are taking immune checkpoint blockers.

The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.

Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.

The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.

The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.

“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.

They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
 

Reconsider acetaminophen pretreatment

After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.

“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.

There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.

Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.

“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.

However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.

She was also unsure of how much acetaminophen is too much.

Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.

Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”

She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
 

Study details

Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.

All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.

In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).

None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).

In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).

A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.

There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.

A version of this article first appeared on Medscape.com.

French investigators are warning about using acetaminophen in patients with cancer who are taking immune checkpoint blockers.

The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.

Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.

The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.

The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.

“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.

They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
 

Reconsider acetaminophen pretreatment

After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.

“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.

There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.

Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.

“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.

However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.

She was also unsure of how much acetaminophen is too much.

Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.

Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”

She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
 

Study details

Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.

All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.

In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).

None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).

In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).

A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.

There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.

A version of this article first appeared on Medscape.com.

French investigators are warning about using acetaminophen in patients with cancer who are taking immune checkpoint blockers.

The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.

Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.

The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.

The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.

“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.

They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
 

Reconsider acetaminophen pretreatment

After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.

“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.

There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.

Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.

“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.

However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.

She was also unsure of how much acetaminophen is too much.

Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.

Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”

She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
 

Study details

Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.

All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.

In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).

None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).

In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).

A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.

There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.

A version of this article first appeared on Medscape.com.

Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Such disturbances are especially common among Black people, new research shows.

The “high” prevalence of moderate to severe sleep disturbances is “alarming,” study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, said in an interview.

The findings were presented at the annual meeting of the Associated Professional Sleep Societies.

Dr. Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.

More than two-thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Dr. Pena reported.

In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, “which may impair quality of life,” Dr. Pena said.

Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.

Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.

“We don’t know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions,” Dr. Pena said.

How long after COVID the fatigue and sleep problems last “remains uncertain,” Dr. Pena acknowledged. However, in her clinical experience with therapy, patients’ sleep and fatigue may improve after 6 or 8 months.

Ruth Benca, MD, PhD, cochair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.

“Sleep disturbances and fatigue are part of the sequelae of COVID,” Dr. Benca, who was not involved in the study, said in an interview.

“We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there’s an actual impact of having the infection itself on worsening sleep,” said Dr. Benca, with Wake Forest University and Atrium Health Wake Forest Baptist, both in Winston-Salem, N.C.

The study had no specific funding. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals.

A version of this article first appeared on Medscape.com.

Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Such disturbances are especially common among Black people, new research shows.

The “high” prevalence of moderate to severe sleep disturbances is “alarming,” study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, said in an interview.

The findings were presented at the annual meeting of the Associated Professional Sleep Societies.

Dr. Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.

More than two-thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Dr. Pena reported.

In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, “which may impair quality of life,” Dr. Pena said.

Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.

Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.

“We don’t know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions,” Dr. Pena said.

How long after COVID the fatigue and sleep problems last “remains uncertain,” Dr. Pena acknowledged. However, in her clinical experience with therapy, patients’ sleep and fatigue may improve after 6 or 8 months.

Ruth Benca, MD, PhD, cochair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.

“Sleep disturbances and fatigue are part of the sequelae of COVID,” Dr. Benca, who was not involved in the study, said in an interview.

“We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there’s an actual impact of having the infection itself on worsening sleep,” said Dr. Benca, with Wake Forest University and Atrium Health Wake Forest Baptist, both in Winston-Salem, N.C.

The study had no specific funding. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals.

A version of this article first appeared on Medscape.com.

Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Such disturbances are especially common among Black people, new research shows.

The “high” prevalence of moderate to severe sleep disturbances is “alarming,” study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, said in an interview.

The findings were presented at the annual meeting of the Associated Professional Sleep Societies.

Dr. Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.

More than two-thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Dr. Pena reported.

In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, “which may impair quality of life,” Dr. Pena said.

Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.

Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.

“We don’t know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions,” Dr. Pena said.

How long after COVID the fatigue and sleep problems last “remains uncertain,” Dr. Pena acknowledged. However, in her clinical experience with therapy, patients’ sleep and fatigue may improve after 6 or 8 months.

Ruth Benca, MD, PhD, cochair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.

“Sleep disturbances and fatigue are part of the sequelae of COVID,” Dr. Benca, who was not involved in the study, said in an interview.

“We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there’s an actual impact of having the infection itself on worsening sleep,” said Dr. Benca, with Wake Forest University and Atrium Health Wake Forest Baptist, both in Winston-Salem, N.C.

The study had no specific funding. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals.

A version of this article first appeared on Medscape.com.

If you have bacteria in your urine but don’t have symptoms of a urinary tract infection (UTI), such as burning or frequent urination, you probably don’t need antibiotics. So why did you get that prescription?

The Infectious Diseases Society of America recommends against antibiotics in this scenario, with exceptions for patients who are pregnant or undergoing certain urologic procedures.

Antibiotics for asymptomatic bacteriuria (ASB) generally do not help; are costly; and can cause side effects, Clostridioides difficile infection, and antibiotic resistance.

Still, antibiotic treatment for asymptomatic bacteriuria remains common, despite guidelines.

And when researchers recently surveyed 551 primary care clinicians to see which ones would inappropriately prescribe antibiotics for a positive urine culture, the answer was most of them: 71%.

“Regardless of years in practice, training background, or professional degree, most clinicians indicated that they would prescribe antibiotics for asymptomatic bacteriuria,” the researchers reported in JAMA Network Open.

Some groups of clinicians seemed especially likely to prescribe antibiotics unnecessarily.

“Medical maximizers” – clinicians who prefer treatment even when its value is ambiguous – and family medicine clinicians were more likely to prescribe antibiotics in response to a hypothetical case.

What to do for Mr. Williams?

To examine clinician attitudes and characteristics associated with prescribing antibiotics for asymptomatic bacteriuria, Dr. Baghdadi and his colleagues analyzed survey responses from 490 physicians and 61 advanced practice clinicians.

Study participants completed tests that measure numeracy, risk-taking preferences, burnout, and tendency to maximize care. They were presented with four hypothetical clinical scenarios, including a case of asymptomatic bacteriuria: “Mr. Williams, a 65-year-old man, comes to the office for follow-up of his osteoarthritis. He has noted foul-smelling urine and no pain or difficulty with urination. A urine dipstick shows trace blood. He has no particular preference for testing and wants your advice.”

Clinicians who had been in practice for at least 10 years were more likely to prescribe antibiotics (82%) to “Mr. Williams” than were those with 3-9 years in practice (73%) or less than 3 years in practice (64%).

Breaking a habit

Some prescribers may know not to treat asymptomatic bacteriuria but mistakenly consider certain findings to be symptoms of UTI.

Bradley Langford, PharmD, an antimicrobial stewardship expert with Public Health Ontario, said in his experience, most clinicians who say they know not to treat ASB incorrectly believe that cloudy urine, altered cognition, and other nonspecific symptoms indicate a UTI.

“The fact that most clinicians would treat ASB suggests that there is still a lot of work to do to improve antimicrobial stewardship, particularly outside of the hospital setting,” Dr. Langford told this news organization.

Avoiding unnecessary antibiotics is important not just because of the lack of benefit, but also because of the potential harms, said Dr. Langford. He has created a list of rebuttals for commonly given reasons for testing and treating asymptomatic bacteriuria.

“Using antibiotics for ASB can counterintuitively increase the risk for symptomatic UTI due to the disruption of protective local microflora, allowing for the growth of more pathogenic/resistant organisms,” he said.

One approach to addressing the problem: Don’t test urine in the first place if patients are asymptomatic. Virtual learning sessions have been shown to reduce urine culturing and urinary antibiotic prescribing in long-term care homes, Dr. Langford noted.

Updated training for health care professionals from the outset may also be key, and the lower rate of prescribing intent among resident physicians is reassuring, he said.
 

A role for patients

Patients could also help decrease the inappropriate use of antibiotics.

“Be clear with your doctor about your expectations for the health care interaction, including whether you are expecting to receive antibiotics,” Dr. Baghdadi said. “Your doctor may assume you contacted them because you wanted a prescription. If you are not expecting antibiotics, you should feel free to say so. And if you are asymptomatic, you may not need antibiotics, even if the urine culture is positive.”

The study was funded by a grant from the National Institutes of Health, and Dr. Baghdadi received grant support from the University of Maryland, Baltimore Institute for Clinical and Translational Research. Coauthors disclosed government grants and ties to Memorial Sloan Kettering Cancer Center, Vedanta Biosciences, Opentrons, and Fimbrion. Dr. Langford reported no relevant financial conflicts of interest.

A version of this article first appeared on Medscape.com.

If you have bacteria in your urine but don’t have symptoms of a urinary tract infection (UTI), such as burning or frequent urination, you probably don’t need antibiotics. So why did you get that prescription?

The Infectious Diseases Society of America recommends against antibiotics in this scenario, with exceptions for patients who are pregnant or undergoing certain urologic procedures.

Antibiotics for asymptomatic bacteriuria (ASB) generally do not help; are costly; and can cause side effects, Clostridioides difficile infection, and antibiotic resistance.

Still, antibiotic treatment for asymptomatic bacteriuria remains common, despite guidelines.

And when researchers recently surveyed 551 primary care clinicians to see which ones would inappropriately prescribe antibiotics for a positive urine culture, the answer was most of them: 71%.

“Regardless of years in practice, training background, or professional degree, most clinicians indicated that they would prescribe antibiotics for asymptomatic bacteriuria,” the researchers reported in JAMA Network Open.

Some groups of clinicians seemed especially likely to prescribe antibiotics unnecessarily.

“Medical maximizers” – clinicians who prefer treatment even when its value is ambiguous – and family medicine clinicians were more likely to prescribe antibiotics in response to a hypothetical case.

What to do for Mr. Williams?

To examine clinician attitudes and characteristics associated with prescribing antibiotics for asymptomatic bacteriuria, Dr. Baghdadi and his colleagues analyzed survey responses from 490 physicians and 61 advanced practice clinicians.

Study participants completed tests that measure numeracy, risk-taking preferences, burnout, and tendency to maximize care. They were presented with four hypothetical clinical scenarios, including a case of asymptomatic bacteriuria: “Mr. Williams, a 65-year-old man, comes to the office for follow-up of his osteoarthritis. He has noted foul-smelling urine and no pain or difficulty with urination. A urine dipstick shows trace blood. He has no particular preference for testing and wants your advice.”

Clinicians who had been in practice for at least 10 years were more likely to prescribe antibiotics (82%) to “Mr. Williams” than were those with 3-9 years in practice (73%) or less than 3 years in practice (64%).

Breaking a habit

Some prescribers may know not to treat asymptomatic bacteriuria but mistakenly consider certain findings to be symptoms of UTI.

Bradley Langford, PharmD, an antimicrobial stewardship expert with Public Health Ontario, said in his experience, most clinicians who say they know not to treat ASB incorrectly believe that cloudy urine, altered cognition, and other nonspecific symptoms indicate a UTI.

“The fact that most clinicians would treat ASB suggests that there is still a lot of work to do to improve antimicrobial stewardship, particularly outside of the hospital setting,” Dr. Langford told this news organization.

Avoiding unnecessary antibiotics is important not just because of the lack of benefit, but also because of the potential harms, said Dr. Langford. He has created a list of rebuttals for commonly given reasons for testing and treating asymptomatic bacteriuria.

“Using antibiotics for ASB can counterintuitively increase the risk for symptomatic UTI due to the disruption of protective local microflora, allowing for the growth of more pathogenic/resistant organisms,” he said.

One approach to addressing the problem: Don’t test urine in the first place if patients are asymptomatic. Virtual learning sessions have been shown to reduce urine culturing and urinary antibiotic prescribing in long-term care homes, Dr. Langford noted.

Updated training for health care professionals from the outset may also be key, and the lower rate of prescribing intent among resident physicians is reassuring, he said.
 

A role for patients

Patients could also help decrease the inappropriate use of antibiotics.

“Be clear with your doctor about your expectations for the health care interaction, including whether you are expecting to receive antibiotics,” Dr. Baghdadi said. “Your doctor may assume you contacted them because you wanted a prescription. If you are not expecting antibiotics, you should feel free to say so. And if you are asymptomatic, you may not need antibiotics, even if the urine culture is positive.”

The study was funded by a grant from the National Institutes of Health, and Dr. Baghdadi received grant support from the University of Maryland, Baltimore Institute for Clinical and Translational Research. Coauthors disclosed government grants and ties to Memorial Sloan Kettering Cancer Center, Vedanta Biosciences, Opentrons, and Fimbrion. Dr. Langford reported no relevant financial conflicts of interest.

A version of this article first appeared on Medscape.com.

If you have bacteria in your urine but don’t have symptoms of a urinary tract infection (UTI), such as burning or frequent urination, you probably don’t need antibiotics. So why did you get that prescription?

The Infectious Diseases Society of America recommends against antibiotics in this scenario, with exceptions for patients who are pregnant or undergoing certain urologic procedures.

Antibiotics for asymptomatic bacteriuria (ASB) generally do not help; are costly; and can cause side effects, Clostridioides difficile infection, and antibiotic resistance.

Still, antibiotic treatment for asymptomatic bacteriuria remains common, despite guidelines.

And when researchers recently surveyed 551 primary care clinicians to see which ones would inappropriately prescribe antibiotics for a positive urine culture, the answer was most of them: 71%.

“Regardless of years in practice, training background, or professional degree, most clinicians indicated that they would prescribe antibiotics for asymptomatic bacteriuria,” the researchers reported in JAMA Network Open.

Some groups of clinicians seemed especially likely to prescribe antibiotics unnecessarily.

“Medical maximizers” – clinicians who prefer treatment even when its value is ambiguous – and family medicine clinicians were more likely to prescribe antibiotics in response to a hypothetical case.

What to do for Mr. Williams?

To examine clinician attitudes and characteristics associated with prescribing antibiotics for asymptomatic bacteriuria, Dr. Baghdadi and his colleagues analyzed survey responses from 490 physicians and 61 advanced practice clinicians.

Study participants completed tests that measure numeracy, risk-taking preferences, burnout, and tendency to maximize care. They were presented with four hypothetical clinical scenarios, including a case of asymptomatic bacteriuria: “Mr. Williams, a 65-year-old man, comes to the office for follow-up of his osteoarthritis. He has noted foul-smelling urine and no pain or difficulty with urination. A urine dipstick shows trace blood. He has no particular preference for testing and wants your advice.”

Clinicians who had been in practice for at least 10 years were more likely to prescribe antibiotics (82%) to “Mr. Williams” than were those with 3-9 years in practice (73%) or less than 3 years in practice (64%).

Breaking a habit

Some prescribers may know not to treat asymptomatic bacteriuria but mistakenly consider certain findings to be symptoms of UTI.

Bradley Langford, PharmD, an antimicrobial stewardship expert with Public Health Ontario, said in his experience, most clinicians who say they know not to treat ASB incorrectly believe that cloudy urine, altered cognition, and other nonspecific symptoms indicate a UTI.

“The fact that most clinicians would treat ASB suggests that there is still a lot of work to do to improve antimicrobial stewardship, particularly outside of the hospital setting,” Dr. Langford told this news organization.

Avoiding unnecessary antibiotics is important not just because of the lack of benefit, but also because of the potential harms, said Dr. Langford. He has created a list of rebuttals for commonly given reasons for testing and treating asymptomatic bacteriuria.

“Using antibiotics for ASB can counterintuitively increase the risk for symptomatic UTI due to the disruption of protective local microflora, allowing for the growth of more pathogenic/resistant organisms,” he said.

One approach to addressing the problem: Don’t test urine in the first place if patients are asymptomatic. Virtual learning sessions have been shown to reduce urine culturing and urinary antibiotic prescribing in long-term care homes, Dr. Langford noted.

Updated training for health care professionals from the outset may also be key, and the lower rate of prescribing intent among resident physicians is reassuring, he said.
 

A role for patients

Patients could also help decrease the inappropriate use of antibiotics.

“Be clear with your doctor about your expectations for the health care interaction, including whether you are expecting to receive antibiotics,” Dr. Baghdadi said. “Your doctor may assume you contacted them because you wanted a prescription. If you are not expecting antibiotics, you should feel free to say so. And if you are asymptomatic, you may not need antibiotics, even if the urine culture is positive.”

The study was funded by a grant from the National Institutes of Health, and Dr. Baghdadi received grant support from the University of Maryland, Baltimore Institute for Clinical and Translational Research. Coauthors disclosed government grants and ties to Memorial Sloan Kettering Cancer Center, Vedanta Biosciences, Opentrons, and Fimbrion. Dr. Langford reported no relevant financial conflicts of interest.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved dupilumab as an add-on maintenance treatment for children aged 6 months to 5 years with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

The approval, announced on June 7, 2022, makes dupilumab (Dupixent), an interleukin-4 receptor alpha antagonist, the first biologic available in the United States to treat uncontrolled moderate to severe atopic dermatitis in this age group. In this age group, it is administered subcutaneously every 4 weeks. Dupilumab remains the only biologic treatment approved for patients aged 6 years and older for this indication.

Approval was based on data from a 16-week pivotal phase 3 trial that evaluated the efficacy and safety of dupilumab added to standard of care topical corticosteroids (TCS) in children aged 6 months to 5 years with uncontrolled moderate to severe atopic dermatitis. The trial’s principal investigator, Amy S. Paller, MD, professor and chair of dermatology at Northwestern University, Chicago, and colleagues, found that, at 16 weeks, 28% of patients who were treated with dupilumab, added to low-potency TCS, met the primary endpoint of clear or almost clear skin, compared with 4% of those who received low-potency TCS alone (P < .0001).

In addition, patients who received the combined treatment experienced a 70% average improvement in disease severity from baseline, compared with a 20% improvement among those in the TCS-only group (P < .0001). They also experienced a 49% improvement in itch, compared with a 2% improvement among their counterparts in the TCS-only group (P < .0001).

Outside of the United States, the study’s coprimary endpoint was achievement of 75% or greater improvement in overall disease severity. More than half of the patients who received combined treatment (53%) met this endpoint, compared with 11% in the TCS-only group (P < .0001), according to the company.

Safety results were generally consistent with the safety profile of dupilumab in atopic dermatitis for patients aged 6 years and older. The most common adverse events that were more commonly observed with dupilumab included conjunctivitis (5% vs 0% in the placebo group) and herpes viral infections (6% vs. 5% in the placebo group). Among those on dupilumab, ages 6 months to 5 years, hand,foot, and mouth disease was reported in 5% and skin papilloma were reported in 2%, but these cases did not lead to discontinuation of treatment, according to the company release.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved dupilumab as an add-on maintenance treatment for children aged 6 months to 5 years with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

The approval, announced on June 7, 2022, makes dupilumab (Dupixent), an interleukin-4 receptor alpha antagonist, the first biologic available in the United States to treat uncontrolled moderate to severe atopic dermatitis in this age group. In this age group, it is administered subcutaneously every 4 weeks. Dupilumab remains the only biologic treatment approved for patients aged 6 years and older for this indication.

Approval was based on data from a 16-week pivotal phase 3 trial that evaluated the efficacy and safety of dupilumab added to standard of care topical corticosteroids (TCS) in children aged 6 months to 5 years with uncontrolled moderate to severe atopic dermatitis. The trial’s principal investigator, Amy S. Paller, MD, professor and chair of dermatology at Northwestern University, Chicago, and colleagues, found that, at 16 weeks, 28% of patients who were treated with dupilumab, added to low-potency TCS, met the primary endpoint of clear or almost clear skin, compared with 4% of those who received low-potency TCS alone (P < .0001).

In addition, patients who received the combined treatment experienced a 70% average improvement in disease severity from baseline, compared with a 20% improvement among those in the TCS-only group (P < .0001). They also experienced a 49% improvement in itch, compared with a 2% improvement among their counterparts in the TCS-only group (P < .0001).

Outside of the United States, the study’s coprimary endpoint was achievement of 75% or greater improvement in overall disease severity. More than half of the patients who received combined treatment (53%) met this endpoint, compared with 11% in the TCS-only group (P < .0001), according to the company.

Safety results were generally consistent with the safety profile of dupilumab in atopic dermatitis for patients aged 6 years and older. The most common adverse events that were more commonly observed with dupilumab included conjunctivitis (5% vs 0% in the placebo group) and herpes viral infections (6% vs. 5% in the placebo group). Among those on dupilumab, ages 6 months to 5 years, hand,foot, and mouth disease was reported in 5% and skin papilloma were reported in 2%, but these cases did not lead to discontinuation of treatment, according to the company release.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved dupilumab as an add-on maintenance treatment for children aged 6 months to 5 years with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

The approval, announced on June 7, 2022, makes dupilumab (Dupixent), an interleukin-4 receptor alpha antagonist, the first biologic available in the United States to treat uncontrolled moderate to severe atopic dermatitis in this age group. In this age group, it is administered subcutaneously every 4 weeks. Dupilumab remains the only biologic treatment approved for patients aged 6 years and older for this indication.

Approval was based on data from a 16-week pivotal phase 3 trial that evaluated the efficacy and safety of dupilumab added to standard of care topical corticosteroids (TCS) in children aged 6 months to 5 years with uncontrolled moderate to severe atopic dermatitis. The trial’s principal investigator, Amy S. Paller, MD, professor and chair of dermatology at Northwestern University, Chicago, and colleagues, found that, at 16 weeks, 28% of patients who were treated with dupilumab, added to low-potency TCS, met the primary endpoint of clear or almost clear skin, compared with 4% of those who received low-potency TCS alone (P < .0001).

In addition, patients who received the combined treatment experienced a 70% average improvement in disease severity from baseline, compared with a 20% improvement among those in the TCS-only group (P < .0001). They also experienced a 49% improvement in itch, compared with a 2% improvement among their counterparts in the TCS-only group (P < .0001).

Outside of the United States, the study’s coprimary endpoint was achievement of 75% or greater improvement in overall disease severity. More than half of the patients who received combined treatment (53%) met this endpoint, compared with 11% in the TCS-only group (P < .0001), according to the company.

Safety results were generally consistent with the safety profile of dupilumab in atopic dermatitis for patients aged 6 years and older. The most common adverse events that were more commonly observed with dupilumab included conjunctivitis (5% vs 0% in the placebo group) and herpes viral infections (6% vs. 5% in the placebo group). Among those on dupilumab, ages 6 months to 5 years, hand,foot, and mouth disease was reported in 5% and skin papilloma were reported in 2%, but these cases did not lead to discontinuation of treatment, according to the company release.

A version of this article first appeared on Medscape.com.

Actions taken against a physician’s license for substance use are more common than those for psychological impairment or actions related to physical health, according to a recent report. Despite a sharp uptick in 2011, substance use–specific license actions taken against physicians dropped in frequency between 2004 and 2020.

More than three fourths (76.3%) of license actions taken against physicians were related to substance use, according to a recent study published in JAMA. Psychological impairment was the reason associated with more than 1 in 10 (11.5%) actions taken against physicians’ licenses, while physical impairment was the reason behind approximately 12% of such actions, per the study.

Researchers analyzed 5032 actions taken against the licenses of U.S. physicians. The actions were reported to the National Practitioner Data Bank and were related to substance use, psychological impairment, and physical impairment. The National Practitioner Data Bank is a web-based repository of reports with information on medical malpractice payments and certain adverse actions related to healthcare practitioners, providers, and suppliers. It is provided by the Department of Health & Human Services.

“While there has been increased attention [on] the mental health of physicians, we wanted to understand the extent to which changes in attitudes and practices were reflected in actions taken by hospitals or licensing boards, which are reported in the National Practitioner Data Bank,” Lisa Rotenstein, MD, a primary care physician at Boston’s Brigham and Women’s Hospital and lead author of the study, told this news organization.

Dr. Rotenstein, who is an assistant professor at Harvard Medical School, Boston, studies issues of mental health among physicians and trainees. Dr. Rotenstein was the lead author of a 2016 study that found that more than a quarter (27.2%) of medical students have depressive symptoms. She was also lead author of a 2018 study published in JAMA on the prevalence of burnout among attending physicians.
 

Actions against physicians trending downward

2011 marked the peak in actions taken against physicians’ licenses for substance use, per the study, but actions related to substance use have otherwise maintained a steady decline over the past 17 years. Researchers found that physicians with license actions as a result of substance use or psychological impairment were more likely to receive indefinite penalties, while also having emergency action taken against their license to practice.

In addition, physicians who had actions taken against their licenses because of substance use or psychological impairment were more likely to accrue a greater number of actions over the course of their careers, according to the study.

About 47% of physicians reported experiencing burnout per Medscape’s Physician Burnout and Depression Report 2022: Stress, Anxiety, and Anger report. Burnout among emergency physicians spiked from 43% in 2020 to 60% in 2021, according to the report.

More than one quarter (26%) of physicians reported drinking alcohol to cope with burnout in 2020, according to Medscape’s 2021 Physician Burnout and Suicide Report. Per the 2021 report, 48% of physicians chose exercise to deal with burnout, while 35% indulged in eating junk food.

Peter Grinspoon, MD, a Boston-based primary care physician, wrote in The Los Angeles Times in 2016 that the rate of substance abuse among physicians starts at 10% and can go as high as 15%; by comparison, rates of substance use among the general population are 8%-10%. “What appears to account for the difference is physician distress, and in the case of drug abuse, plentiful access,” he added.

Dr. Grinspoon wrote a 2016 book called “Free Refills: A Doctor Confronts His Addiction,” which chronicles his experience in recovery and relapse as a physician who was dependent on opioid painkillers.

The findings from the recent study in JAMA “suggest we have made some progress in addressing issues related to substance use in ways that don’t result in license actions or even in meeting physicians’ need for support related to substance use,” said Dr. Rotenstein.

Still, she insists that there’s “substantial opportunity to improve mental health and support offerings for physicians and to reduce stigma related to seeking and receiving mental health support, ideally averting the need for license actions.”

According to Dr. Rotenstein, the cases listed in the National Practitioner Data Bank represent the most severe cases; these reports have risen to a high level of attention or concern and are the result of adverse action reports submitted by healthcare institutions and state licensing boards.

“There are many, many more physicians whose cases are not represented here but who struggle with depression, anxiety, substance use, and more,” said Dr. Rotenstein.

A version of this article first appeared on Medscape.com.

Actions taken against a physician’s license for substance use are more common than those for psychological impairment or actions related to physical health, according to a recent report. Despite a sharp uptick in 2011, substance use–specific license actions taken against physicians dropped in frequency between 2004 and 2020.

More than three fourths (76.3%) of license actions taken against physicians were related to substance use, according to a recent study published in JAMA. Psychological impairment was the reason associated with more than 1 in 10 (11.5%) actions taken against physicians’ licenses, while physical impairment was the reason behind approximately 12% of such actions, per the study.

Researchers analyzed 5032 actions taken against the licenses of U.S. physicians. The actions were reported to the National Practitioner Data Bank and were related to substance use, psychological impairment, and physical impairment. The National Practitioner Data Bank is a web-based repository of reports with information on medical malpractice payments and certain adverse actions related to healthcare practitioners, providers, and suppliers. It is provided by the Department of Health & Human Services.

“While there has been increased attention [on] the mental health of physicians, we wanted to understand the extent to which changes in attitudes and practices were reflected in actions taken by hospitals or licensing boards, which are reported in the National Practitioner Data Bank,” Lisa Rotenstein, MD, a primary care physician at Boston’s Brigham and Women’s Hospital and lead author of the study, told this news organization.

Dr. Rotenstein, who is an assistant professor at Harvard Medical School, Boston, studies issues of mental health among physicians and trainees. Dr. Rotenstein was the lead author of a 2016 study that found that more than a quarter (27.2%) of medical students have depressive symptoms. She was also lead author of a 2018 study published in JAMA on the prevalence of burnout among attending physicians.
 

Actions against physicians trending downward

2011 marked the peak in actions taken against physicians’ licenses for substance use, per the study, but actions related to substance use have otherwise maintained a steady decline over the past 17 years. Researchers found that physicians with license actions as a result of substance use or psychological impairment were more likely to receive indefinite penalties, while also having emergency action taken against their license to practice.

In addition, physicians who had actions taken against their licenses because of substance use or psychological impairment were more likely to accrue a greater number of actions over the course of their careers, according to the study.

About 47% of physicians reported experiencing burnout per Medscape’s Physician Burnout and Depression Report 2022: Stress, Anxiety, and Anger report. Burnout among emergency physicians spiked from 43% in 2020 to 60% in 2021, according to the report.

More than one quarter (26%) of physicians reported drinking alcohol to cope with burnout in 2020, according to Medscape’s 2021 Physician Burnout and Suicide Report. Per the 2021 report, 48% of physicians chose exercise to deal with burnout, while 35% indulged in eating junk food.

Peter Grinspoon, MD, a Boston-based primary care physician, wrote in The Los Angeles Times in 2016 that the rate of substance abuse among physicians starts at 10% and can go as high as 15%; by comparison, rates of substance use among the general population are 8%-10%. “What appears to account for the difference is physician distress, and in the case of drug abuse, plentiful access,” he added.

Dr. Grinspoon wrote a 2016 book called “Free Refills: A Doctor Confronts His Addiction,” which chronicles his experience in recovery and relapse as a physician who was dependent on opioid painkillers.

The findings from the recent study in JAMA “suggest we have made some progress in addressing issues related to substance use in ways that don’t result in license actions or even in meeting physicians’ need for support related to substance use,” said Dr. Rotenstein.

Still, she insists that there’s “substantial opportunity to improve mental health and support offerings for physicians and to reduce stigma related to seeking and receiving mental health support, ideally averting the need for license actions.”

According to Dr. Rotenstein, the cases listed in the National Practitioner Data Bank represent the most severe cases; these reports have risen to a high level of attention or concern and are the result of adverse action reports submitted by healthcare institutions and state licensing boards.

“There are many, many more physicians whose cases are not represented here but who struggle with depression, anxiety, substance use, and more,” said Dr. Rotenstein.

A version of this article first appeared on Medscape.com.

Actions taken against a physician’s license for substance use are more common than those for psychological impairment or actions related to physical health, according to a recent report. Despite a sharp uptick in 2011, substance use–specific license actions taken against physicians dropped in frequency between 2004 and 2020.

More than three fourths (76.3%) of license actions taken against physicians were related to substance use, according to a recent study published in JAMA. Psychological impairment was the reason associated with more than 1 in 10 (11.5%) actions taken against physicians’ licenses, while physical impairment was the reason behind approximately 12% of such actions, per the study.

Researchers analyzed 5032 actions taken against the licenses of U.S. physicians. The actions were reported to the National Practitioner Data Bank and were related to substance use, psychological impairment, and physical impairment. The National Practitioner Data Bank is a web-based repository of reports with information on medical malpractice payments and certain adverse actions related to healthcare practitioners, providers, and suppliers. It is provided by the Department of Health & Human Services.

“While there has been increased attention [on] the mental health of physicians, we wanted to understand the extent to which changes in attitudes and practices were reflected in actions taken by hospitals or licensing boards, which are reported in the National Practitioner Data Bank,” Lisa Rotenstein, MD, a primary care physician at Boston’s Brigham and Women’s Hospital and lead author of the study, told this news organization.

Dr. Rotenstein, who is an assistant professor at Harvard Medical School, Boston, studies issues of mental health among physicians and trainees. Dr. Rotenstein was the lead author of a 2016 study that found that more than a quarter (27.2%) of medical students have depressive symptoms. She was also lead author of a 2018 study published in JAMA on the prevalence of burnout among attending physicians.
 

Actions against physicians trending downward

2011 marked the peak in actions taken against physicians’ licenses for substance use, per the study, but actions related to substance use have otherwise maintained a steady decline over the past 17 years. Researchers found that physicians with license actions as a result of substance use or psychological impairment were more likely to receive indefinite penalties, while also having emergency action taken against their license to practice.

In addition, physicians who had actions taken against their licenses because of substance use or psychological impairment were more likely to accrue a greater number of actions over the course of their careers, according to the study.

About 47% of physicians reported experiencing burnout per Medscape’s Physician Burnout and Depression Report 2022: Stress, Anxiety, and Anger report. Burnout among emergency physicians spiked from 43% in 2020 to 60% in 2021, according to the report.

More than one quarter (26%) of physicians reported drinking alcohol to cope with burnout in 2020, according to Medscape’s 2021 Physician Burnout and Suicide Report. Per the 2021 report, 48% of physicians chose exercise to deal with burnout, while 35% indulged in eating junk food.

Peter Grinspoon, MD, a Boston-based primary care physician, wrote in The Los Angeles Times in 2016 that the rate of substance abuse among physicians starts at 10% and can go as high as 15%; by comparison, rates of substance use among the general population are 8%-10%. “What appears to account for the difference is physician distress, and in the case of drug abuse, plentiful access,” he added.

Dr. Grinspoon wrote a 2016 book called “Free Refills: A Doctor Confronts His Addiction,” which chronicles his experience in recovery and relapse as a physician who was dependent on opioid painkillers.

The findings from the recent study in JAMA “suggest we have made some progress in addressing issues related to substance use in ways that don’t result in license actions or even in meeting physicians’ need for support related to substance use,” said Dr. Rotenstein.

Still, she insists that there’s “substantial opportunity to improve mental health and support offerings for physicians and to reduce stigma related to seeking and receiving mental health support, ideally averting the need for license actions.”

According to Dr. Rotenstein, the cases listed in the National Practitioner Data Bank represent the most severe cases; these reports have risen to a high level of attention or concern and are the result of adverse action reports submitted by healthcare institutions and state licensing boards.

“There are many, many more physicians whose cases are not represented here but who struggle with depression, anxiety, substance use, and more,” said Dr. Rotenstein.

A version of this article first appeared on Medscape.com.

A federal advisory panel strongly supported a bid for Novavax to win U.S. emergency authorization for its COVID-19 vaccine, which is based on a more traditional, protein-based approach than the cutting-edge technology used in mRNA-based shots.

The Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration voted almost unanimously June 7 in favor of Novavax’s two-dose COVID-19 vaccine for those 18 or older – despite some concerns over rare events of myocarditis and pericarditis.

The tally was 21 “yes” votes, without any “no” votes, but one abstention from a panelist who then offered a largely positive take on this vaccine.

Panelist Bruce Gellin, MD, explained at the end of the meeting that he would have cast a conditional vote in favor of the Novavax vaccine, called NVX-CoV2373, had that been an option. Dr. Gellin, chief of global public health strategy for the Rockefeller Foundation and a vaccine expert, said he didn’t want his abstention to be considered as signaling opposition to the Novavax shot.

Instead, he said, he expects FDA officials will gather more data and evidence about the Novavax vaccine, especially in relation to certain manufacturing issues, before making its decision on the company’s application.

Earlier in the day, a top FDA vaccine reviewer, Doran Fink, MD, PhD, noted that there were important manufacturing differences between the Novavax vaccine supply used in different projects, complicating efforts to assess the company’s application for emergency use authorization (EUA).

But Dr. Fink noted that the FDA staff already had made a convincing case in its briefing document, with enough evidence for an initial conditional clearance to be found in available data.

The FDA is not bound to follow the suggestions of its advisory committees but it often does.
 

Using the ‘bully pulpit’

At the beginning of the meeting, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said he was seizing the “bully pulpit” in addressing the need to persuade more people in the United States to take shots against COVID-19.

About 67% of people in the United States aged 18 and older are fully vaccinated, but only about 50% of those in this group have had a first booster, according to the Centers for Disease Control and Prevention.

The two-dose mRNA vaccines from Pfizer and Moderna have been the subject of intense misinformation campaigns on social media, despite efforts by the FDA and other public health officials to convey the message about their strong benefit-risk profile. The FDA in May limited the authorized use of Johnson & Johnson’s single-dose COVID-19 shot, which is based on a different technology, because of concerns about rare and potentially life-threatening blood clots.

Novavax has been described as a more traditional vaccine – a protein subunit shot similar to one people have long received for protection against influenza, pertussis (whooping cough), diphtheria, and tetanus.

“Having a protein-based alternative may be more comfortable for some in terms of their acceptance of vaccines,” Dr. Marks said. “We do have a problem with vaccine uptake that is very serious in the United States. And anything we can do to get people more comfortable to be able to accept these potentially life-saving medical products is something that we feel we are compelled to do.”

Dr. Marks offered these remarks in answer to an FDA panelist’s question about the need to consider an EUA for yet another vaccine.

EUAs are special clearances the FDA can grant in connection with public health emergencies such as the pandemic. The FDA used EUAs for the initial December 2020 clearances of the Pfizer-BioNTech and Moderna vaccines. It has since granted normal approvals for both of these mRNA-based vaccines, based on larger bodies of evidence gathered and submitted by their developers.

During the meeting, the FDA panelists in general appeared comfortable with the idea of granting another EUA for a vaccine. There was agreement that the shot appeared to work in key tests, although these were done before the rise of the Omicron variant.

In a key test, known as study 301, the Novavax vaccine was judged to be 90.4% effective. In the study, 17 of the 17,272 people who got the Novavax vaccine developed COVID-19, compared with 79 of the 8,385 in the placebo group.

Panelists expressed disappointment with the lack of information about how the shot would work now.

“We’re looking at the efficacy against strains that don’t exist any longer,” said panelist Eric J. Rubin, MD, PhD, a Harvard professor and editor of the New England Journal of Medicine.

Still, Dr. Rubin added that he agreed with the argument the FDA’s Dr. Marks had made earlier for an EUA for the Novavax vaccine.

“If there really is a population of patients who are willing to take this and not willing to take the existing vaccines, I think it’s pretty compelling,” Dr. Rubin said.

Other FDA panelists were skeptical of this argument. Jay Portnoy, MD, who was listed on the FDA roster as the panel’s consumer representative, said he has close friends who are vaccine skeptics.

“Their hesitancy is more ideological than technological,” said Dr. Portnoy of Children’s Mercy Hospital, Kansas City, Mo. “So I really doubt that this vaccine is going to crack that nut, but perhaps some individuals would get this when they wouldn’t get the other ones.”
 

Myocarditis, pericarditis

The Novavax vaccine is already authorized in other countries, including Canada. Novavax in February announced that it had begun shipping its first doses of the vaccine to European Union member states. The vaccine can be moved through existing vaccine supply and cold chain channels instead of requiring complex new delivery procedures.

That could prove an advantage in time, said FDA panelist Michael Nelson, MD, PhD, of the University of Virginia, Charlottesville.

“Who knows even with supply chain challenges down the road, it will be nice to have options going forward,” Dr. Nelson said. 

As with other COVID-19 vaccines, clinicians and researchers are still working to understand the potential risk for inflammation of heart muscle and nearby tissue with vaccination. Most patients with myocarditis or pericarditis who sought medical care for these conditions responded well to medicine and rest and felt better quickly, the CDC says on its website. They usually return to their normal daily activities after their symptoms improve.

At the June 7 meeting, Dr. Nelson said there may be cases of myocarditis that go undetected.

“Our signals are those who get admitted to the emergency room and the hospital,” he said. “I’m quite convinced that there are others who are experiencing cardiac events of lesser severity that are worthy of being studied, both from mechanistic and outcomes standpoints. So we have a lot of work to do.”

In looking at results for an initial pool of 40,000 people who received the Novavax vaccine, there were five reported cases of myocarditis or pericarditis developing within 20 days of people getting the shot, the FDA staff said in its presentation on safety.

In a briefing document released ahead of the advisory committee meeting, the FDA staff flagged this number of cases in a relatively small database as a concern, noting it “could be higher than reported during postauthorization use of mRNA COVID-19 vaccines (for which no cases were identified in preauthorization evaluation).”

Novavax officials took a somewhat unusual step of responding in public. The Gaithersburg, Md.–based company on June 3 issued a statement saying researchers had come to “expect to see natural background events of myocarditis in any sufficiently large database, and that young males are at higher risk.”

The data from the company’s placebo-controlled studies show that, overall, in its clinical development program, the rate of myocarditis was balanced between the vaccine and placebo arms (0.007% and 0.005%), Novavax said.

At the June 7 meeting, FDA panelists including Dr. Nelson, and Paul A. Offit, MD, of Children’s Hospital of Philadelphia, urged continued study to try to determine whether and how the vaccines could trigger myocarditis. Investments made now in pursuing these questions related to COVID-19 shots may pay off later, Dr. Offit said.

“We can use that knowledge to make safer vaccines for a disease that is going to be with us for decades, if not longer,” he said.

A version of this article first appeared on Medscape.com.

A federal advisory panel strongly supported a bid for Novavax to win U.S. emergency authorization for its COVID-19 vaccine, which is based on a more traditional, protein-based approach than the cutting-edge technology used in mRNA-based shots.

The Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration voted almost unanimously June 7 in favor of Novavax’s two-dose COVID-19 vaccine for those 18 or older – despite some concerns over rare events of myocarditis and pericarditis.

The tally was 21 “yes” votes, without any “no” votes, but one abstention from a panelist who then offered a largely positive take on this vaccine.

Panelist Bruce Gellin, MD, explained at the end of the meeting that he would have cast a conditional vote in favor of the Novavax vaccine, called NVX-CoV2373, had that been an option. Dr. Gellin, chief of global public health strategy for the Rockefeller Foundation and a vaccine expert, said he didn’t want his abstention to be considered as signaling opposition to the Novavax shot.

Instead, he said, he expects FDA officials will gather more data and evidence about the Novavax vaccine, especially in relation to certain manufacturing issues, before making its decision on the company’s application.

Earlier in the day, a top FDA vaccine reviewer, Doran Fink, MD, PhD, noted that there were important manufacturing differences between the Novavax vaccine supply used in different projects, complicating efforts to assess the company’s application for emergency use authorization (EUA).

But Dr. Fink noted that the FDA staff already had made a convincing case in its briefing document, with enough evidence for an initial conditional clearance to be found in available data.

The FDA is not bound to follow the suggestions of its advisory committees but it often does.
 

Using the ‘bully pulpit’

At the beginning of the meeting, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said he was seizing the “bully pulpit” in addressing the need to persuade more people in the United States to take shots against COVID-19.

About 67% of people in the United States aged 18 and older are fully vaccinated, but only about 50% of those in this group have had a first booster, according to the Centers for Disease Control and Prevention.

The two-dose mRNA vaccines from Pfizer and Moderna have been the subject of intense misinformation campaigns on social media, despite efforts by the FDA and other public health officials to convey the message about their strong benefit-risk profile. The FDA in May limited the authorized use of Johnson & Johnson’s single-dose COVID-19 shot, which is based on a different technology, because of concerns about rare and potentially life-threatening blood clots.

Novavax has been described as a more traditional vaccine – a protein subunit shot similar to one people have long received for protection against influenza, pertussis (whooping cough), diphtheria, and tetanus.

“Having a protein-based alternative may be more comfortable for some in terms of their acceptance of vaccines,” Dr. Marks said. “We do have a problem with vaccine uptake that is very serious in the United States. And anything we can do to get people more comfortable to be able to accept these potentially life-saving medical products is something that we feel we are compelled to do.”

Dr. Marks offered these remarks in answer to an FDA panelist’s question about the need to consider an EUA for yet another vaccine.

EUAs are special clearances the FDA can grant in connection with public health emergencies such as the pandemic. The FDA used EUAs for the initial December 2020 clearances of the Pfizer-BioNTech and Moderna vaccines. It has since granted normal approvals for both of these mRNA-based vaccines, based on larger bodies of evidence gathered and submitted by their developers.

During the meeting, the FDA panelists in general appeared comfortable with the idea of granting another EUA for a vaccine. There was agreement that the shot appeared to work in key tests, although these were done before the rise of the Omicron variant.

In a key test, known as study 301, the Novavax vaccine was judged to be 90.4% effective. In the study, 17 of the 17,272 people who got the Novavax vaccine developed COVID-19, compared with 79 of the 8,385 in the placebo group.

Panelists expressed disappointment with the lack of information about how the shot would work now.

“We’re looking at the efficacy against strains that don’t exist any longer,” said panelist Eric J. Rubin, MD, PhD, a Harvard professor and editor of the New England Journal of Medicine.

Still, Dr. Rubin added that he agreed with the argument the FDA’s Dr. Marks had made earlier for an EUA for the Novavax vaccine.

“If there really is a population of patients who are willing to take this and not willing to take the existing vaccines, I think it’s pretty compelling,” Dr. Rubin said.

Other FDA panelists were skeptical of this argument. Jay Portnoy, MD, who was listed on the FDA roster as the panel’s consumer representative, said he has close friends who are vaccine skeptics.

“Their hesitancy is more ideological than technological,” said Dr. Portnoy of Children’s Mercy Hospital, Kansas City, Mo. “So I really doubt that this vaccine is going to crack that nut, but perhaps some individuals would get this when they wouldn’t get the other ones.”
 

Myocarditis, pericarditis

The Novavax vaccine is already authorized in other countries, including Canada. Novavax in February announced that it had begun shipping its first doses of the vaccine to European Union member states. The vaccine can be moved through existing vaccine supply and cold chain channels instead of requiring complex new delivery procedures.

That could prove an advantage in time, said FDA panelist Michael Nelson, MD, PhD, of the University of Virginia, Charlottesville.

“Who knows even with supply chain challenges down the road, it will be nice to have options going forward,” Dr. Nelson said. 

As with other COVID-19 vaccines, clinicians and researchers are still working to understand the potential risk for inflammation of heart muscle and nearby tissue with vaccination. Most patients with myocarditis or pericarditis who sought medical care for these conditions responded well to medicine and rest and felt better quickly, the CDC says on its website. They usually return to their normal daily activities after their symptoms improve.

At the June 7 meeting, Dr. Nelson said there may be cases of myocarditis that go undetected.

“Our signals are those who get admitted to the emergency room and the hospital,” he said. “I’m quite convinced that there are others who are experiencing cardiac events of lesser severity that are worthy of being studied, both from mechanistic and outcomes standpoints. So we have a lot of work to do.”

In looking at results for an initial pool of 40,000 people who received the Novavax vaccine, there were five reported cases of myocarditis or pericarditis developing within 20 days of people getting the shot, the FDA staff said in its presentation on safety.

In a briefing document released ahead of the advisory committee meeting, the FDA staff flagged this number of cases in a relatively small database as a concern, noting it “could be higher than reported during postauthorization use of mRNA COVID-19 vaccines (for which no cases were identified in preauthorization evaluation).”

Novavax officials took a somewhat unusual step of responding in public. The Gaithersburg, Md.–based company on June 3 issued a statement saying researchers had come to “expect to see natural background events of myocarditis in any sufficiently large database, and that young males are at higher risk.”

The data from the company’s placebo-controlled studies show that, overall, in its clinical development program, the rate of myocarditis was balanced between the vaccine and placebo arms (0.007% and 0.005%), Novavax said.

At the June 7 meeting, FDA panelists including Dr. Nelson, and Paul A. Offit, MD, of Children’s Hospital of Philadelphia, urged continued study to try to determine whether and how the vaccines could trigger myocarditis. Investments made now in pursuing these questions related to COVID-19 shots may pay off later, Dr. Offit said.

“We can use that knowledge to make safer vaccines for a disease that is going to be with us for decades, if not longer,” he said.

A version of this article first appeared on Medscape.com.

A federal advisory panel strongly supported a bid for Novavax to win U.S. emergency authorization for its COVID-19 vaccine, which is based on a more traditional, protein-based approach than the cutting-edge technology used in mRNA-based shots.

The Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration voted almost unanimously June 7 in favor of Novavax’s two-dose COVID-19 vaccine for those 18 or older – despite some concerns over rare events of myocarditis and pericarditis.

The tally was 21 “yes” votes, without any “no” votes, but one abstention from a panelist who then offered a largely positive take on this vaccine.

Panelist Bruce Gellin, MD, explained at the end of the meeting that he would have cast a conditional vote in favor of the Novavax vaccine, called NVX-CoV2373, had that been an option. Dr. Gellin, chief of global public health strategy for the Rockefeller Foundation and a vaccine expert, said he didn’t want his abstention to be considered as signaling opposition to the Novavax shot.

Instead, he said, he expects FDA officials will gather more data and evidence about the Novavax vaccine, especially in relation to certain manufacturing issues, before making its decision on the company’s application.

Earlier in the day, a top FDA vaccine reviewer, Doran Fink, MD, PhD, noted that there were important manufacturing differences between the Novavax vaccine supply used in different projects, complicating efforts to assess the company’s application for emergency use authorization (EUA).

But Dr. Fink noted that the FDA staff already had made a convincing case in its briefing document, with enough evidence for an initial conditional clearance to be found in available data.

The FDA is not bound to follow the suggestions of its advisory committees but it often does.
 

Using the ‘bully pulpit’

At the beginning of the meeting, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said he was seizing the “bully pulpit” in addressing the need to persuade more people in the United States to take shots against COVID-19.

About 67% of people in the United States aged 18 and older are fully vaccinated, but only about 50% of those in this group have had a first booster, according to the Centers for Disease Control and Prevention.

The two-dose mRNA vaccines from Pfizer and Moderna have been the subject of intense misinformation campaigns on social media, despite efforts by the FDA and other public health officials to convey the message about their strong benefit-risk profile. The FDA in May limited the authorized use of Johnson & Johnson’s single-dose COVID-19 shot, which is based on a different technology, because of concerns about rare and potentially life-threatening blood clots.

Novavax has been described as a more traditional vaccine – a protein subunit shot similar to one people have long received for protection against influenza, pertussis (whooping cough), diphtheria, and tetanus.

“Having a protein-based alternative may be more comfortable for some in terms of their acceptance of vaccines,” Dr. Marks said. “We do have a problem with vaccine uptake that is very serious in the United States. And anything we can do to get people more comfortable to be able to accept these potentially life-saving medical products is something that we feel we are compelled to do.”

Dr. Marks offered these remarks in answer to an FDA panelist’s question about the need to consider an EUA for yet another vaccine.

EUAs are special clearances the FDA can grant in connection with public health emergencies such as the pandemic. The FDA used EUAs for the initial December 2020 clearances of the Pfizer-BioNTech and Moderna vaccines. It has since granted normal approvals for both of these mRNA-based vaccines, based on larger bodies of evidence gathered and submitted by their developers.

During the meeting, the FDA panelists in general appeared comfortable with the idea of granting another EUA for a vaccine. There was agreement that the shot appeared to work in key tests, although these were done before the rise of the Omicron variant.

In a key test, known as study 301, the Novavax vaccine was judged to be 90.4% effective. In the study, 17 of the 17,272 people who got the Novavax vaccine developed COVID-19, compared with 79 of the 8,385 in the placebo group.

Panelists expressed disappointment with the lack of information about how the shot would work now.

“We’re looking at the efficacy against strains that don’t exist any longer,” said panelist Eric J. Rubin, MD, PhD, a Harvard professor and editor of the New England Journal of Medicine.

Still, Dr. Rubin added that he agreed with the argument the FDA’s Dr. Marks had made earlier for an EUA for the Novavax vaccine.

“If there really is a population of patients who are willing to take this and not willing to take the existing vaccines, I think it’s pretty compelling,” Dr. Rubin said.

Other FDA panelists were skeptical of this argument. Jay Portnoy, MD, who was listed on the FDA roster as the panel’s consumer representative, said he has close friends who are vaccine skeptics.

“Their hesitancy is more ideological than technological,” said Dr. Portnoy of Children’s Mercy Hospital, Kansas City, Mo. “So I really doubt that this vaccine is going to crack that nut, but perhaps some individuals would get this when they wouldn’t get the other ones.”
 

Myocarditis, pericarditis

The Novavax vaccine is already authorized in other countries, including Canada. Novavax in February announced that it had begun shipping its first doses of the vaccine to European Union member states. The vaccine can be moved through existing vaccine supply and cold chain channels instead of requiring complex new delivery procedures.

That could prove an advantage in time, said FDA panelist Michael Nelson, MD, PhD, of the University of Virginia, Charlottesville.

“Who knows even with supply chain challenges down the road, it will be nice to have options going forward,” Dr. Nelson said. 

As with other COVID-19 vaccines, clinicians and researchers are still working to understand the potential risk for inflammation of heart muscle and nearby tissue with vaccination. Most patients with myocarditis or pericarditis who sought medical care for these conditions responded well to medicine and rest and felt better quickly, the CDC says on its website. They usually return to their normal daily activities after their symptoms improve.

At the June 7 meeting, Dr. Nelson said there may be cases of myocarditis that go undetected.

“Our signals are those who get admitted to the emergency room and the hospital,” he said. “I’m quite convinced that there are others who are experiencing cardiac events of lesser severity that are worthy of being studied, both from mechanistic and outcomes standpoints. So we have a lot of work to do.”

In looking at results for an initial pool of 40,000 people who received the Novavax vaccine, there were five reported cases of myocarditis or pericarditis developing within 20 days of people getting the shot, the FDA staff said in its presentation on safety.

In a briefing document released ahead of the advisory committee meeting, the FDA staff flagged this number of cases in a relatively small database as a concern, noting it “could be higher than reported during postauthorization use of mRNA COVID-19 vaccines (for which no cases were identified in preauthorization evaluation).”

Novavax officials took a somewhat unusual step of responding in public. The Gaithersburg, Md.–based company on June 3 issued a statement saying researchers had come to “expect to see natural background events of myocarditis in any sufficiently large database, and that young males are at higher risk.”

The data from the company’s placebo-controlled studies show that, overall, in its clinical development program, the rate of myocarditis was balanced between the vaccine and placebo arms (0.007% and 0.005%), Novavax said.

At the June 7 meeting, FDA panelists including Dr. Nelson, and Paul A. Offit, MD, of Children’s Hospital of Philadelphia, urged continued study to try to determine whether and how the vaccines could trigger myocarditis. Investments made now in pursuing these questions related to COVID-19 shots may pay off later, Dr. Offit said.

“We can use that knowledge to make safer vaccines for a disease that is going to be with us for decades, if not longer,” he said.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved adding adult patients with rheumatoid arthritis to the list of indications for the rituximab biosimilar Riabni (rituximab-arrx) on the basis of results of a randomized, double-blind, comparative clinical study with the CD20-directed cytolytic antibody reference product, Rituxan, the biosimilar’s manufacturer, Amgen, announced June 6.

The RA indication is specifically for adults with moderate to severely active disease who have had an inadequate response to one or more tumor necrosis factor inhibitors. Riabni was approved in December 2020 for the treatment of adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The clinical study testing Riabni against Rituxan involved 311 patients with moderate to severe RA who received Riabni, Rituxan manufactured in the United States, and Rituxan manufactured in the European Union. The patients who received the U.S.-manufactured Rituxan were transitioned to receive Riabni for their second dose of rituximab, whereas patients in other groups stayed with the same treatment. The trial’s primary efficacy endpoint of the change in Disease Activity Score in 28 joints using C-reactive protein from baseline to week 24 was within the predefined equivalence margin for clinical efficacy between Riabni and Rituxan. The two products also had similar safety, pharmacokinetics, and immunogenicity profiles, according to Amgen.

Currently, Riabni and Ruxience (rituximab-pvvr) are the only two approved rituximab biosimilars in the United States. Ruxience is approved for the same indications. Rituxan alone has protected orphan drug status for the indication of adult patients with moderate to severe pemphigus vulgaris.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved adding adult patients with rheumatoid arthritis to the list of indications for the rituximab biosimilar Riabni (rituximab-arrx) on the basis of results of a randomized, double-blind, comparative clinical study with the CD20-directed cytolytic antibody reference product, Rituxan, the biosimilar’s manufacturer, Amgen, announced June 6.

The RA indication is specifically for adults with moderate to severely active disease who have had an inadequate response to one or more tumor necrosis factor inhibitors. Riabni was approved in December 2020 for the treatment of adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The clinical study testing Riabni against Rituxan involved 311 patients with moderate to severe RA who received Riabni, Rituxan manufactured in the United States, and Rituxan manufactured in the European Union. The patients who received the U.S.-manufactured Rituxan were transitioned to receive Riabni for their second dose of rituximab, whereas patients in other groups stayed with the same treatment. The trial’s primary efficacy endpoint of the change in Disease Activity Score in 28 joints using C-reactive protein from baseline to week 24 was within the predefined equivalence margin for clinical efficacy between Riabni and Rituxan. The two products also had similar safety, pharmacokinetics, and immunogenicity profiles, according to Amgen.

Currently, Riabni and Ruxience (rituximab-pvvr) are the only two approved rituximab biosimilars in the United States. Ruxience is approved for the same indications. Rituxan alone has protected orphan drug status for the indication of adult patients with moderate to severe pemphigus vulgaris.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved adding adult patients with rheumatoid arthritis to the list of indications for the rituximab biosimilar Riabni (rituximab-arrx) on the basis of results of a randomized, double-blind, comparative clinical study with the CD20-directed cytolytic antibody reference product, Rituxan, the biosimilar’s manufacturer, Amgen, announced June 6.

The RA indication is specifically for adults with moderate to severely active disease who have had an inadequate response to one or more tumor necrosis factor inhibitors. Riabni was approved in December 2020 for the treatment of adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The clinical study testing Riabni against Rituxan involved 311 patients with moderate to severe RA who received Riabni, Rituxan manufactured in the United States, and Rituxan manufactured in the European Union. The patients who received the U.S.-manufactured Rituxan were transitioned to receive Riabni for their second dose of rituximab, whereas patients in other groups stayed with the same treatment. The trial’s primary efficacy endpoint of the change in Disease Activity Score in 28 joints using C-reactive protein from baseline to week 24 was within the predefined equivalence margin for clinical efficacy between Riabni and Rituxan. The two products also had similar safety, pharmacokinetics, and immunogenicity profiles, according to Amgen.

Currently, Riabni and Ruxience (rituximab-pvvr) are the only two approved rituximab biosimilars in the United States. Ruxience is approved for the same indications. Rituxan alone has protected orphan drug status for the indication of adult patients with moderate to severe pemphigus vulgaris.

A version of this article first appeared on Medscape.com.