Conference Coverage

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

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

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

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

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

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

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

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

Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.

A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.

The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.

In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.

To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.

They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.

During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.  

This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.

However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”

Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”

‘Trial is not definitive’

Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.

Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.

While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.

“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.

Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.

“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.

On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”

“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
 

Earlier data inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
 

Meta-analysis results

Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m², and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.

However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”

“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
 

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

CHARLOTTE, N.C. – Overnight sleep electroencephalography (EEG) contains an abundance of brain wave data that could be mined to identify an individual’s risk for a host of health outcomes, including dementia, cognitive impairment, and cardiovascular events, a researcher reported at the annual meeting of the Associated Professional Sleep Societies. “Sleep EEGs contain decodable information about the risk of unfavorable outcomes,” said Haoqi Sun, PhD, an instructor of neurology at Massachusetts General Hospital, Boston, and lead study author. “The results suggest that it’s feasible to use sleep to identify people with high risk of unfavorable outcomes and it strengthens the concept of sleep as a window into brain and general health.”

The researchers performed a quantitative analysis of sleep data collected on 8,673 adults who had diagnostic sleep studies that included polysomnography (PSG). The analysis used ICD codes to consider these 11 health outcomes: dementia, mild cognitive impairment (MCI) or dementia, ischemic stroke, intracranial hemorrhage, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality.

Then, Dr. Sun explained, they extracted 86 spectral and time-domain features of REM and non-REM sleep from sleep EEG recordings, and analyzed that data by adjusting for eight covariates including age, sex, body mass index, and use of benzodiazepines, antidepressants, sedatives, antiseizure drugs, and stimulants.

Participants were partitioned into three sleep-quality groups: poor, average, and good. The outcome-wise mean prediction difference in 10-year cumulative incidence was 2.3% for the poor sleep group, 0.5% for the average sleep group, and 1.3% for the good sleep group.

The outcomes with the three greatest poor to average risk ratios were dementia (6.2; 95% confidence interval, 4.5-9.3), mortality (5.7; 95% CI, 5-7.5) and MCI or dementia (4; 95% CI, 3.2-4.9).
 

Ready for the clinic?

In an interview, Dr. Sun said the results demonstrated the potential of using EEG brain wave data to predict health outcomes on an individual basis, although he acknowledged that most of the 86 sleep features the researchers used are not readily available in the clinic.

He noted the spectral features used in the study can be captured through software compatible with PSG. “From there you can identify the various bands, the different frequency ranges, and then you can easily see within this range whether a person has a higher power or lower power,” he said. However, the spindle and slow-oscillation features that researchers used in the study are beyond the reach of most clinics.
 

Next steps

This research is in its early stage, Dr. Sun said, but at some point the data collected from sleep studies could be paired with machine learning to make the model workable for evaluating individual patients. “Our goal is to first make this individualized,” he said. “We want to minimize the noise in the recording and minimize the night-to-night variability in the findings. There is some clinical-informed approach and there is also some algorithm-informed approach where you can minimize the variation over time.”

The model also has the potential to predict outcomes, particularly with chronic diseases such as diabetes and dementia, well before a diagnosis is made, he said.
 

‘Fascinating’ and ‘provocative’

Donald Bliwise, PhD, professor of neurology at Emory Sleep Center in Atlanta, said the study was “fascinating; it’s provocative; it’s exciting and interesting,” but added, “Sleep is vital for health. That’s abundantly clear in a study like that, but trying to push it a little bit further with all of these 86 measurements of the EEG, I think it becomes complicated.”

The study methodology, particularly the use of cumulative incidence of various diseases, was laudable, he said, and the use of simpler EEG-measured sleep features, such as alpha band power, “make intuitive sense.”

But it’s less clear on how the more sophisticated features the study model used – for example, kurtosis of theta frequency or coupling between spindle and slow oscillation – rank on sleep quality, he said, adding that the researchers have most likely done that but couldn’t add that into the format of the presentation.

“Kurtosis of the theta frequency band we don’t get on everyone in the sleep lab,” Dr. Bliwise said. “We might be able to, but I don’t know how to quite plug that into a turnkey model.”

The clinical components of the study were conducted by M. Brandon Westover, MD, PhD, at Massachusetts General Hospital, and Robert J. Thomas, MD, at Beth Israel Deaconess Medical Center, both in Boston. The study received support from the American Academy of Sleep Medicine Foundation. Dr. Sun has no relevant disclosures. Dr. Bliwise has no disclosures.

CHARLOTTE, N.C. – Overnight sleep electroencephalography (EEG) contains an abundance of brain wave data that could be mined to identify an individual’s risk for a host of health outcomes, including dementia, cognitive impairment, and cardiovascular events, a researcher reported at the annual meeting of the Associated Professional Sleep Societies. “Sleep EEGs contain decodable information about the risk of unfavorable outcomes,” said Haoqi Sun, PhD, an instructor of neurology at Massachusetts General Hospital, Boston, and lead study author. “The results suggest that it’s feasible to use sleep to identify people with high risk of unfavorable outcomes and it strengthens the concept of sleep as a window into brain and general health.”

The researchers performed a quantitative analysis of sleep data collected on 8,673 adults who had diagnostic sleep studies that included polysomnography (PSG). The analysis used ICD codes to consider these 11 health outcomes: dementia, mild cognitive impairment (MCI) or dementia, ischemic stroke, intracranial hemorrhage, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality.

Then, Dr. Sun explained, they extracted 86 spectral and time-domain features of REM and non-REM sleep from sleep EEG recordings, and analyzed that data by adjusting for eight covariates including age, sex, body mass index, and use of benzodiazepines, antidepressants, sedatives, antiseizure drugs, and stimulants.

Participants were partitioned into three sleep-quality groups: poor, average, and good. The outcome-wise mean prediction difference in 10-year cumulative incidence was 2.3% for the poor sleep group, 0.5% for the average sleep group, and 1.3% for the good sleep group.

The outcomes with the three greatest poor to average risk ratios were dementia (6.2; 95% confidence interval, 4.5-9.3), mortality (5.7; 95% CI, 5-7.5) and MCI or dementia (4; 95% CI, 3.2-4.9).
 

Ready for the clinic?

In an interview, Dr. Sun said the results demonstrated the potential of using EEG brain wave data to predict health outcomes on an individual basis, although he acknowledged that most of the 86 sleep features the researchers used are not readily available in the clinic.

He noted the spectral features used in the study can be captured through software compatible with PSG. “From there you can identify the various bands, the different frequency ranges, and then you can easily see within this range whether a person has a higher power or lower power,” he said. However, the spindle and slow-oscillation features that researchers used in the study are beyond the reach of most clinics.
 

Next steps

This research is in its early stage, Dr. Sun said, but at some point the data collected from sleep studies could be paired with machine learning to make the model workable for evaluating individual patients. “Our goal is to first make this individualized,” he said. “We want to minimize the noise in the recording and minimize the night-to-night variability in the findings. There is some clinical-informed approach and there is also some algorithm-informed approach where you can minimize the variation over time.”

The model also has the potential to predict outcomes, particularly with chronic diseases such as diabetes and dementia, well before a diagnosis is made, he said.
 

‘Fascinating’ and ‘provocative’

Donald Bliwise, PhD, professor of neurology at Emory Sleep Center in Atlanta, said the study was “fascinating; it’s provocative; it’s exciting and interesting,” but added, “Sleep is vital for health. That’s abundantly clear in a study like that, but trying to push it a little bit further with all of these 86 measurements of the EEG, I think it becomes complicated.”

The study methodology, particularly the use of cumulative incidence of various diseases, was laudable, he said, and the use of simpler EEG-measured sleep features, such as alpha band power, “make intuitive sense.”

But it’s less clear on how the more sophisticated features the study model used – for example, kurtosis of theta frequency or coupling between spindle and slow oscillation – rank on sleep quality, he said, adding that the researchers have most likely done that but couldn’t add that into the format of the presentation.

“Kurtosis of the theta frequency band we don’t get on everyone in the sleep lab,” Dr. Bliwise said. “We might be able to, but I don’t know how to quite plug that into a turnkey model.”

The clinical components of the study were conducted by M. Brandon Westover, MD, PhD, at Massachusetts General Hospital, and Robert J. Thomas, MD, at Beth Israel Deaconess Medical Center, both in Boston. The study received support from the American Academy of Sleep Medicine Foundation. Dr. Sun has no relevant disclosures. Dr. Bliwise has no disclosures.

CHARLOTTE, N.C. – Overnight sleep electroencephalography (EEG) contains an abundance of brain wave data that could be mined to identify an individual’s risk for a host of health outcomes, including dementia, cognitive impairment, and cardiovascular events, a researcher reported at the annual meeting of the Associated Professional Sleep Societies. “Sleep EEGs contain decodable information about the risk of unfavorable outcomes,” said Haoqi Sun, PhD, an instructor of neurology at Massachusetts General Hospital, Boston, and lead study author. “The results suggest that it’s feasible to use sleep to identify people with high risk of unfavorable outcomes and it strengthens the concept of sleep as a window into brain and general health.”

The researchers performed a quantitative analysis of sleep data collected on 8,673 adults who had diagnostic sleep studies that included polysomnography (PSG). The analysis used ICD codes to consider these 11 health outcomes: dementia, mild cognitive impairment (MCI) or dementia, ischemic stroke, intracranial hemorrhage, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality.

Then, Dr. Sun explained, they extracted 86 spectral and time-domain features of REM and non-REM sleep from sleep EEG recordings, and analyzed that data by adjusting for eight covariates including age, sex, body mass index, and use of benzodiazepines, antidepressants, sedatives, antiseizure drugs, and stimulants.

Participants were partitioned into three sleep-quality groups: poor, average, and good. The outcome-wise mean prediction difference in 10-year cumulative incidence was 2.3% for the poor sleep group, 0.5% for the average sleep group, and 1.3% for the good sleep group.

The outcomes with the three greatest poor to average risk ratios were dementia (6.2; 95% confidence interval, 4.5-9.3), mortality (5.7; 95% CI, 5-7.5) and MCI or dementia (4; 95% CI, 3.2-4.9).
 

Ready for the clinic?

In an interview, Dr. Sun said the results demonstrated the potential of using EEG brain wave data to predict health outcomes on an individual basis, although he acknowledged that most of the 86 sleep features the researchers used are not readily available in the clinic.

He noted the spectral features used in the study can be captured through software compatible with PSG. “From there you can identify the various bands, the different frequency ranges, and then you can easily see within this range whether a person has a higher power or lower power,” he said. However, the spindle and slow-oscillation features that researchers used in the study are beyond the reach of most clinics.
 

Next steps

This research is in its early stage, Dr. Sun said, but at some point the data collected from sleep studies could be paired with machine learning to make the model workable for evaluating individual patients. “Our goal is to first make this individualized,” he said. “We want to minimize the noise in the recording and minimize the night-to-night variability in the findings. There is some clinical-informed approach and there is also some algorithm-informed approach where you can minimize the variation over time.”

The model also has the potential to predict outcomes, particularly with chronic diseases such as diabetes and dementia, well before a diagnosis is made, he said.
 

‘Fascinating’ and ‘provocative’

Donald Bliwise, PhD, professor of neurology at Emory Sleep Center in Atlanta, said the study was “fascinating; it’s provocative; it’s exciting and interesting,” but added, “Sleep is vital for health. That’s abundantly clear in a study like that, but trying to push it a little bit further with all of these 86 measurements of the EEG, I think it becomes complicated.”

The study methodology, particularly the use of cumulative incidence of various diseases, was laudable, he said, and the use of simpler EEG-measured sleep features, such as alpha band power, “make intuitive sense.”

But it’s less clear on how the more sophisticated features the study model used – for example, kurtosis of theta frequency or coupling between spindle and slow oscillation – rank on sleep quality, he said, adding that the researchers have most likely done that but couldn’t add that into the format of the presentation.

“Kurtosis of the theta frequency band we don’t get on everyone in the sleep lab,” Dr. Bliwise said. “We might be able to, but I don’t know how to quite plug that into a turnkey model.”

The clinical components of the study were conducted by M. Brandon Westover, MD, PhD, at Massachusetts General Hospital, and Robert J. Thomas, MD, at Beth Israel Deaconess Medical Center, both in Boston. The study received support from the American Academy of Sleep Medicine Foundation. Dr. Sun has no relevant disclosures. Dr. Bliwise has no disclosures.

NATIONAL HARBOR, MD – Just 2 days before she spoke in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers, University of Colorado neurologist Anna Shah, MD, asked a 26-year-old patient with MS about whether she planned to have children. Absolutely not, the young woman replied. “I read online that I can give birth to a baby with MS, which is crazy.”

The patient didn’t understand the risk of having a child with MS – it’s thought to be 2%-5% if one parent has the condition – but she wouldn’t have learned the facts if Dr. Shah hadn’t asked the right questions. “It’s really important for us as a community to know how to be proactive with discussions [about pregnancy],” she said.

As she noted, an estimated 75% of patients with MS are women, most are diagnosed during prime child-bearing years, and many pregnancies in general – an estimated half – are not planned. And while a higher percentage of women with MS are having children than in the past, she said, misinformation remains common. In fact, physicians can be part of the problem.

Dr. Shaw highlighted a 2019 Italian survey that found that 16% of 395 people with MS reported that they were discouraged from having children, mainly by medical professionals, after their diagnosis. Seven percent said they never wanted to become parents because of their MS. A 2021 survey of 332 patients with MS in the United States, United Kingdom, France, Germany, Italy, and Spain, found that 56% reported that MS played a role in their decisions about family planning, and 14% of those decided not to have children.

In regard to women of child-bearing age, Dr. Shah recommends that family planning and contraception should be discussed at the initial visit and every subsequent visit. Open-ended, individualized questions are key. “We don’t know what patients don’t share with us,” she said.

Make sure to consider the timing of any plans to have children, she said. If the patient wants to have children within a year, talk about matters such as whether disease activity is well-controlled (6-12 months of good control is ideal) and whether current disease-modifying therapies are safe. Make sure to get a baseline prepartum MRI scan, she said.

If the patients don’t want to have children, make sure they are using a reliable strategy to avoid conception. Be aware that modafinil – “not one that immediately comes to mind” – may decrease the efficacy of oral contraceptives, she said, as can anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, and primidone). Oral contraceptives, meanwhile, may decrease levels of lamotrigine.

What if a patient has trouble conceiving? There are some hints in research that MS may boost the risk of infertility in women, Dr. Shah said. That’s why she recommends that colleagues consider referring a patient to an infertility specialist after attempting conception for 6 months as opposed to the general recommendation for 12 months.

Dr. Shah disclosed advisory board service (Genentech) and development of nonbranded educational programming through Novartis and the National Committee for Quality Assurance.

NATIONAL HARBOR, MD – Just 2 days before she spoke in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers, University of Colorado neurologist Anna Shah, MD, asked a 26-year-old patient with MS about whether she planned to have children. Absolutely not, the young woman replied. “I read online that I can give birth to a baby with MS, which is crazy.”

The patient didn’t understand the risk of having a child with MS – it’s thought to be 2%-5% if one parent has the condition – but she wouldn’t have learned the facts if Dr. Shah hadn’t asked the right questions. “It’s really important for us as a community to know how to be proactive with discussions [about pregnancy],” she said.

As she noted, an estimated 75% of patients with MS are women, most are diagnosed during prime child-bearing years, and many pregnancies in general – an estimated half – are not planned. And while a higher percentage of women with MS are having children than in the past, she said, misinformation remains common. In fact, physicians can be part of the problem.

Dr. Shaw highlighted a 2019 Italian survey that found that 16% of 395 people with MS reported that they were discouraged from having children, mainly by medical professionals, after their diagnosis. Seven percent said they never wanted to become parents because of their MS. A 2021 survey of 332 patients with MS in the United States, United Kingdom, France, Germany, Italy, and Spain, found that 56% reported that MS played a role in their decisions about family planning, and 14% of those decided not to have children.

In regard to women of child-bearing age, Dr. Shah recommends that family planning and contraception should be discussed at the initial visit and every subsequent visit. Open-ended, individualized questions are key. “We don’t know what patients don’t share with us,” she said.

Make sure to consider the timing of any plans to have children, she said. If the patient wants to have children within a year, talk about matters such as whether disease activity is well-controlled (6-12 months of good control is ideal) and whether current disease-modifying therapies are safe. Make sure to get a baseline prepartum MRI scan, she said.

If the patients don’t want to have children, make sure they are using a reliable strategy to avoid conception. Be aware that modafinil – “not one that immediately comes to mind” – may decrease the efficacy of oral contraceptives, she said, as can anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, and primidone). Oral contraceptives, meanwhile, may decrease levels of lamotrigine.

What if a patient has trouble conceiving? There are some hints in research that MS may boost the risk of infertility in women, Dr. Shah said. That’s why she recommends that colleagues consider referring a patient to an infertility specialist after attempting conception for 6 months as opposed to the general recommendation for 12 months.

Dr. Shah disclosed advisory board service (Genentech) and development of nonbranded educational programming through Novartis and the National Committee for Quality Assurance.

NATIONAL HARBOR, MD – Just 2 days before she spoke in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers, University of Colorado neurologist Anna Shah, MD, asked a 26-year-old patient with MS about whether she planned to have children. Absolutely not, the young woman replied. “I read online that I can give birth to a baby with MS, which is crazy.”

The patient didn’t understand the risk of having a child with MS – it’s thought to be 2%-5% if one parent has the condition – but she wouldn’t have learned the facts if Dr. Shah hadn’t asked the right questions. “It’s really important for us as a community to know how to be proactive with discussions [about pregnancy],” she said.

As she noted, an estimated 75% of patients with MS are women, most are diagnosed during prime child-bearing years, and many pregnancies in general – an estimated half – are not planned. And while a higher percentage of women with MS are having children than in the past, she said, misinformation remains common. In fact, physicians can be part of the problem.

Dr. Shaw highlighted a 2019 Italian survey that found that 16% of 395 people with MS reported that they were discouraged from having children, mainly by medical professionals, after their diagnosis. Seven percent said they never wanted to become parents because of their MS. A 2021 survey of 332 patients with MS in the United States, United Kingdom, France, Germany, Italy, and Spain, found that 56% reported that MS played a role in their decisions about family planning, and 14% of those decided not to have children.

In regard to women of child-bearing age, Dr. Shah recommends that family planning and contraception should be discussed at the initial visit and every subsequent visit. Open-ended, individualized questions are key. “We don’t know what patients don’t share with us,” she said.

Make sure to consider the timing of any plans to have children, she said. If the patient wants to have children within a year, talk about matters such as whether disease activity is well-controlled (6-12 months of good control is ideal) and whether current disease-modifying therapies are safe. Make sure to get a baseline prepartum MRI scan, she said.

If the patients don’t want to have children, make sure they are using a reliable strategy to avoid conception. Be aware that modafinil – “not one that immediately comes to mind” – may decrease the efficacy of oral contraceptives, she said, as can anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, and primidone). Oral contraceptives, meanwhile, may decrease levels of lamotrigine.

What if a patient has trouble conceiving? There are some hints in research that MS may boost the risk of infertility in women, Dr. Shah said. That’s why she recommends that colleagues consider referring a patient to an infertility specialist after attempting conception for 6 months as opposed to the general recommendation for 12 months.

Dr. Shah disclosed advisory board service (Genentech) and development of nonbranded educational programming through Novartis and the National Committee for Quality Assurance.

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

MILAN, Italy – The antisense oligonucleotide vupanorsen substantially reduces very-low-density-lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non–high-density-lipoprotein cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by this news organization, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women’s Hospital, Boston, has presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Dr. Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, “may have an important role in patients with residual dyslipidemia despite current therapy.”

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Dr. Marston told this news organization that some of the reductions they saw with the lower doses of vupanorsen were “just as good as any other therapy, and the safety profile was … much better than at the highest dose.”

They wanted to pursue the subgroup analysis, despite Pfizer’s announcement, partly to “learn something in terms of the potential efficacy of the ANGPTL3 pathway in general.”

Dr. Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it “works very well,” so if other drugs are able to achieve the same efficacy as vupanorsen “but without the effects,” then it may “get elbowed out.”

Børge G. Nordestgaard, MD, PhD, of Herlev and Gentofte Hospital, Copenhagen, who was not involved in the study, called the findings “very encouraging.”

He told this news organization that being able to reduce LDL cholesterol as well as VLDL and remnant cholesterol is “exactly what I would be dreaming about” with a drug like vupanorsen.

Dr. Nordestgaard nevertheless underlined that “one would have to look carefully” at the safety of the drug.

“If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while,” he said.

“But of course, if this was persistent and triglycerides in the liver kept accumulating, then it’s a problem,” Dr. Nordestgaard added, “and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat.”

He also agreed with Dr. Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

“The target,” Dr. Nordestgaard said, seems “fantastic, from my point of view anyway.”

Dr. Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are “surrogates for triglyceride-rich” lipoproteins, and that they are “increasingly recognized” as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level of 100 mg/dL or higher.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m², 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs. placebo of 22%-28%, alongside a 6%-15% reduction in apolipoprotein B levels and an 8%-16% reduction in LDL cholesterol.

In contrast, Dr. Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52%-66% vs. placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42%-59% vs. placebo, and triglycerides were reduced by 44%-57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70%-95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Dr. Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were “most pronounced” only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Dr. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Dr. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

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

MILAN, Italy – The antisense oligonucleotide vupanorsen substantially reduces very-low-density-lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non–high-density-lipoprotein cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by this news organization, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women’s Hospital, Boston, has presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Dr. Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, “may have an important role in patients with residual dyslipidemia despite current therapy.”

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Dr. Marston told this news organization that some of the reductions they saw with the lower doses of vupanorsen were “just as good as any other therapy, and the safety profile was … much better than at the highest dose.”

They wanted to pursue the subgroup analysis, despite Pfizer’s announcement, partly to “learn something in terms of the potential efficacy of the ANGPTL3 pathway in general.”

Dr. Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it “works very well,” so if other drugs are able to achieve the same efficacy as vupanorsen “but without the effects,” then it may “get elbowed out.”

Børge G. Nordestgaard, MD, PhD, of Herlev and Gentofte Hospital, Copenhagen, who was not involved in the study, called the findings “very encouraging.”

He told this news organization that being able to reduce LDL cholesterol as well as VLDL and remnant cholesterol is “exactly what I would be dreaming about” with a drug like vupanorsen.

Dr. Nordestgaard nevertheless underlined that “one would have to look carefully” at the safety of the drug.

“If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while,” he said.

“But of course, if this was persistent and triglycerides in the liver kept accumulating, then it’s a problem,” Dr. Nordestgaard added, “and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat.”

He also agreed with Dr. Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

“The target,” Dr. Nordestgaard said, seems “fantastic, from my point of view anyway.”

Dr. Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are “surrogates for triglyceride-rich” lipoproteins, and that they are “increasingly recognized” as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level of 100 mg/dL or higher.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m², 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs. placebo of 22%-28%, alongside a 6%-15% reduction in apolipoprotein B levels and an 8%-16% reduction in LDL cholesterol.

In contrast, Dr. Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52%-66% vs. placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42%-59% vs. placebo, and triglycerides were reduced by 44%-57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70%-95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Dr. Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were “most pronounced” only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Dr. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Dr. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

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

MILAN, Italy – The antisense oligonucleotide vupanorsen substantially reduces very-low-density-lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non–high-density-lipoprotein cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by this news organization, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women’s Hospital, Boston, has presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Dr. Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, “may have an important role in patients with residual dyslipidemia despite current therapy.”

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Dr. Marston told this news organization that some of the reductions they saw with the lower doses of vupanorsen were “just as good as any other therapy, and the safety profile was … much better than at the highest dose.”

They wanted to pursue the subgroup analysis, despite Pfizer’s announcement, partly to “learn something in terms of the potential efficacy of the ANGPTL3 pathway in general.”

Dr. Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it “works very well,” so if other drugs are able to achieve the same efficacy as vupanorsen “but without the effects,” then it may “get elbowed out.”

Børge G. Nordestgaard, MD, PhD, of Herlev and Gentofte Hospital, Copenhagen, who was not involved in the study, called the findings “very encouraging.”

He told this news organization that being able to reduce LDL cholesterol as well as VLDL and remnant cholesterol is “exactly what I would be dreaming about” with a drug like vupanorsen.

Dr. Nordestgaard nevertheless underlined that “one would have to look carefully” at the safety of the drug.

“If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while,” he said.

“But of course, if this was persistent and triglycerides in the liver kept accumulating, then it’s a problem,” Dr. Nordestgaard added, “and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat.”

He also agreed with Dr. Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

“The target,” Dr. Nordestgaard said, seems “fantastic, from my point of view anyway.”

Dr. Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are “surrogates for triglyceride-rich” lipoproteins, and that they are “increasingly recognized” as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level of 100 mg/dL or higher.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m², 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs. placebo of 22%-28%, alongside a 6%-15% reduction in apolipoprotein B levels and an 8%-16% reduction in LDL cholesterol.

In contrast, Dr. Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52%-66% vs. placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42%-59% vs. placebo, and triglycerides were reduced by 44%-57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70%-95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Dr. Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were “most pronounced” only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Dr. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Dr. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

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

For dermatologists and others treating patients with atopic dermatitis (AD), it is “an incredible time,” Lawrence F. Eichenfield, MD, said at MedscapeLive’s Women’s & Pediatric Dermatology Seminar.

More and more treatment options are available and even more are in the pipeline, said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of dermatology at the University of California, San Diego and Rady Children’s Hospital. As he put it: “We got pills, injections, things to smear on the skin.”

Those options are welcome and needed, as AD affects up to 20% of children and up to 10% of adults. The course is variable, as is severity, and quality of life is impacted.

Besides new treatment options, there is a new understanding about comorbidities, environmental effects, and triggers, Dr. Eichenfield said. Among the potential comorbidities health care providers should be aware of are allergies, such as food allergies; asthma; rhinitis; mental health issues (depression, anxiety, ADHD, learning disabilities, or in adults, substance abuse); bone health; skin infections; immune disorders such as alopecia areata or urticaria; and cardiovascular issues that could affect adults.

Environmental effects can play a role in aggravating AD, as providers learned after visits for AD increased after Northern California wildfires and also in other areas with high air pollution, Dr. Eichenfield said. “I actually discuss this with my families,” when making them aware of factors that may affect AD, he noted.

Dr. Eichenfield provided an overview of available treatment options, and what treatments may be coming next. Among the highlights:

Topical ruxolitinib: A JAK1,2 inhibitor in a cream formulation, it is now approved for patients with mild to moderate AD aged 12 years and older in the United States. Of the two strengths studied, the higher strength, 1.5%, was approved, Dr. Eichenfield said. How well did it work? In two phase 3 studies in patients aged 12 and older, of those on 1.5%, 53% were clear or almost clear at 8 weeks, versus 11% in the control group given the vehicle; 52% had at least a 4-point reduction in itch from baseline, versus 15.4% on vehicle. Quality of life improved in up to 73.2% of those given the medication versus 19.7% of those on the vehicle. There was a marked and quick improvement in itch, as early as 12 hours, and safety measures also look good, he said.

Topical tapinarof: Approved in May 2022, for adults with plaque psoriasis, phase 3 trials began in September, 2021, for adults and children with AD, according to the manufacturer. Activation of the aryl hydrocarbon receptor mediates its anti-inflammatory properties.

Topical roflumilast: A potent PDE-4 inhibitor, phase 3 AD studies are underway. It appears to be well tolerated, Dr. Eichenfield said.

Dupilumab: An IL-4/13 blocker, this biologic produced an itch reduction of 50% and EASI of 80%, improved quality of life, and reduced anxiety and depression. The drug “led the revolution in systemic therapy for atopic dermatitis,” he said. First approved for treating AD in patients aged 18 years and up in 2017, approval for patients 12 years and up followed in March 2019, then for age 6 years and up May 2020.

At the meeting on June 3, Dr. Eichenfield said that approval in children 5 years and under was imminent, and on June 7, the FDA approved dupilumab for use in children aged 6 months to 5 years. In a phase 3, 16-week trial, 28% of children treated with dupilumab added on to low-potency topical corticosteroids met the endpoint of clear or nearly clear skin, compared with 4% of those on the corticosteroids alone (P < .0001).

Tralokinumab: There is no approved indication yet for adolescents, but the injected biologic, an interleukin-13 antagonist, is approved for adults with moderate to severe AD who are not well-controlled with topicals, or who cannot use topicals.

Oral JAK inhibitors: These include abrocitinib and upadacitinib, both approved by the FDA in January 2022 for treating moderate to severe AD, and baricitinib (the latter not in the United States). “For AD, you probably won’t see it in the U.S.,” Dr. Eichenfield said, referring to baricitinib. However, it might get approved for alopecia areata, he noted.

Upadacitinib is approved for adolescents 12 and older with AD. Abrocitinib is approved for adults 18 and older with AD.

Regarding safety and tolerance concerns with oral JAK inhibitors, Dr. Eichenfield cites headache, acne, nausea, and upper respiratory tract infections as relatively common, while herpes zoster, venous thromboembolism, and lab anomalies (neutropenia, elevated CPK) are uncommon.

As the options for AD treatments increase, and expectations by families and clinicians change, Dr. Eichenfield said he often focuses on “bucket duty” – whether a specific patient should be in the topical bucket or the systemic one. It’s a decision that will continue to be crucial, he said.

When presented with treatment options, patients – and parents – often worry about side effects, said Vivian Shi, MD, associate professor of dermatology at the University of Arkansas Medical Center, Little Rock, who also spoke at the meeting. She gently tells them: “The worst side effect you can have is probably not treating the disease itself.”

Medscape Live and this news organization are owned by the same parent company. Dr. Eichenfield is a consultant or investigator for numerous companies that manufacture treatments for AD, but based his discussion on evidence-based recommendations and public presentations or publications.

For dermatologists and others treating patients with atopic dermatitis (AD), it is “an incredible time,” Lawrence F. Eichenfield, MD, said at MedscapeLive’s Women’s & Pediatric Dermatology Seminar.

More and more treatment options are available and even more are in the pipeline, said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of dermatology at the University of California, San Diego and Rady Children’s Hospital. As he put it: “We got pills, injections, things to smear on the skin.”

Those options are welcome and needed, as AD affects up to 20% of children and up to 10% of adults. The course is variable, as is severity, and quality of life is impacted.

Besides new treatment options, there is a new understanding about comorbidities, environmental effects, and triggers, Dr. Eichenfield said. Among the potential comorbidities health care providers should be aware of are allergies, such as food allergies; asthma; rhinitis; mental health issues (depression, anxiety, ADHD, learning disabilities, or in adults, substance abuse); bone health; skin infections; immune disorders such as alopecia areata or urticaria; and cardiovascular issues that could affect adults.

Environmental effects can play a role in aggravating AD, as providers learned after visits for AD increased after Northern California wildfires and also in other areas with high air pollution, Dr. Eichenfield said. “I actually discuss this with my families,” when making them aware of factors that may affect AD, he noted.

Dr. Eichenfield provided an overview of available treatment options, and what treatments may be coming next. Among the highlights:

Topical ruxolitinib: A JAK1,2 inhibitor in a cream formulation, it is now approved for patients with mild to moderate AD aged 12 years and older in the United States. Of the two strengths studied, the higher strength, 1.5%, was approved, Dr. Eichenfield said. How well did it work? In two phase 3 studies in patients aged 12 and older, of those on 1.5%, 53% were clear or almost clear at 8 weeks, versus 11% in the control group given the vehicle; 52% had at least a 4-point reduction in itch from baseline, versus 15.4% on vehicle. Quality of life improved in up to 73.2% of those given the medication versus 19.7% of those on the vehicle. There was a marked and quick improvement in itch, as early as 12 hours, and safety measures also look good, he said.

Topical tapinarof: Approved in May 2022, for adults with plaque psoriasis, phase 3 trials began in September, 2021, for adults and children with AD, according to the manufacturer. Activation of the aryl hydrocarbon receptor mediates its anti-inflammatory properties.

Topical roflumilast: A potent PDE-4 inhibitor, phase 3 AD studies are underway. It appears to be well tolerated, Dr. Eichenfield said.

Dupilumab: An IL-4/13 blocker, this biologic produced an itch reduction of 50% and EASI of 80%, improved quality of life, and reduced anxiety and depression. The drug “led the revolution in systemic therapy for atopic dermatitis,” he said. First approved for treating AD in patients aged 18 years and up in 2017, approval for patients 12 years and up followed in March 2019, then for age 6 years and up May 2020.

At the meeting on June 3, Dr. Eichenfield said that approval in children 5 years and under was imminent, and on June 7, the FDA approved dupilumab for use in children aged 6 months to 5 years. In a phase 3, 16-week trial, 28% of children treated with dupilumab added on to low-potency topical corticosteroids met the endpoint of clear or nearly clear skin, compared with 4% of those on the corticosteroids alone (P < .0001).

Tralokinumab: There is no approved indication yet for adolescents, but the injected biologic, an interleukin-13 antagonist, is approved for adults with moderate to severe AD who are not well-controlled with topicals, or who cannot use topicals.

Oral JAK inhibitors: These include abrocitinib and upadacitinib, both approved by the FDA in January 2022 for treating moderate to severe AD, and baricitinib (the latter not in the United States). “For AD, you probably won’t see it in the U.S.,” Dr. Eichenfield said, referring to baricitinib. However, it might get approved for alopecia areata, he noted.

Upadacitinib is approved for adolescents 12 and older with AD. Abrocitinib is approved for adults 18 and older with AD.

Regarding safety and tolerance concerns with oral JAK inhibitors, Dr. Eichenfield cites headache, acne, nausea, and upper respiratory tract infections as relatively common, while herpes zoster, venous thromboembolism, and lab anomalies (neutropenia, elevated CPK) are uncommon.

As the options for AD treatments increase, and expectations by families and clinicians change, Dr. Eichenfield said he often focuses on “bucket duty” – whether a specific patient should be in the topical bucket or the systemic one. It’s a decision that will continue to be crucial, he said.

When presented with treatment options, patients – and parents – often worry about side effects, said Vivian Shi, MD, associate professor of dermatology at the University of Arkansas Medical Center, Little Rock, who also spoke at the meeting. She gently tells them: “The worst side effect you can have is probably not treating the disease itself.”

Medscape Live and this news organization are owned by the same parent company. Dr. Eichenfield is a consultant or investigator for numerous companies that manufacture treatments for AD, but based his discussion on evidence-based recommendations and public presentations or publications.

For dermatologists and others treating patients with atopic dermatitis (AD), it is “an incredible time,” Lawrence F. Eichenfield, MD, said at MedscapeLive’s Women’s & Pediatric Dermatology Seminar.

More and more treatment options are available and even more are in the pipeline, said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of dermatology at the University of California, San Diego and Rady Children’s Hospital. As he put it: “We got pills, injections, things to smear on the skin.”

Those options are welcome and needed, as AD affects up to 20% of children and up to 10% of adults. The course is variable, as is severity, and quality of life is impacted.

Besides new treatment options, there is a new understanding about comorbidities, environmental effects, and triggers, Dr. Eichenfield said. Among the potential comorbidities health care providers should be aware of are allergies, such as food allergies; asthma; rhinitis; mental health issues (depression, anxiety, ADHD, learning disabilities, or in adults, substance abuse); bone health; skin infections; immune disorders such as alopecia areata or urticaria; and cardiovascular issues that could affect adults.

Environmental effects can play a role in aggravating AD, as providers learned after visits for AD increased after Northern California wildfires and also in other areas with high air pollution, Dr. Eichenfield said. “I actually discuss this with my families,” when making them aware of factors that may affect AD, he noted.

Dr. Eichenfield provided an overview of available treatment options, and what treatments may be coming next. Among the highlights:

Topical ruxolitinib: A JAK1,2 inhibitor in a cream formulation, it is now approved for patients with mild to moderate AD aged 12 years and older in the United States. Of the two strengths studied, the higher strength, 1.5%, was approved, Dr. Eichenfield said. How well did it work? In two phase 3 studies in patients aged 12 and older, of those on 1.5%, 53% were clear or almost clear at 8 weeks, versus 11% in the control group given the vehicle; 52% had at least a 4-point reduction in itch from baseline, versus 15.4% on vehicle. Quality of life improved in up to 73.2% of those given the medication versus 19.7% of those on the vehicle. There was a marked and quick improvement in itch, as early as 12 hours, and safety measures also look good, he said.

Topical tapinarof: Approved in May 2022, for adults with plaque psoriasis, phase 3 trials began in September, 2021, for adults and children with AD, according to the manufacturer. Activation of the aryl hydrocarbon receptor mediates its anti-inflammatory properties.

Topical roflumilast: A potent PDE-4 inhibitor, phase 3 AD studies are underway. It appears to be well tolerated, Dr. Eichenfield said.

Dupilumab: An IL-4/13 blocker, this biologic produced an itch reduction of 50% and EASI of 80%, improved quality of life, and reduced anxiety and depression. The drug “led the revolution in systemic therapy for atopic dermatitis,” he said. First approved for treating AD in patients aged 18 years and up in 2017, approval for patients 12 years and up followed in March 2019, then for age 6 years and up May 2020.

At the meeting on June 3, Dr. Eichenfield said that approval in children 5 years and under was imminent, and on June 7, the FDA approved dupilumab for use in children aged 6 months to 5 years. In a phase 3, 16-week trial, 28% of children treated with dupilumab added on to low-potency topical corticosteroids met the endpoint of clear or nearly clear skin, compared with 4% of those on the corticosteroids alone (P < .0001).

Tralokinumab: There is no approved indication yet for adolescents, but the injected biologic, an interleukin-13 antagonist, is approved for adults with moderate to severe AD who are not well-controlled with topicals, or who cannot use topicals.

Oral JAK inhibitors: These include abrocitinib and upadacitinib, both approved by the FDA in January 2022 for treating moderate to severe AD, and baricitinib (the latter not in the United States). “For AD, you probably won’t see it in the U.S.,” Dr. Eichenfield said, referring to baricitinib. However, it might get approved for alopecia areata, he noted.

Upadacitinib is approved for adolescents 12 and older with AD. Abrocitinib is approved for adults 18 and older with AD.

Regarding safety and tolerance concerns with oral JAK inhibitors, Dr. Eichenfield cites headache, acne, nausea, and upper respiratory tract infections as relatively common, while herpes zoster, venous thromboembolism, and lab anomalies (neutropenia, elevated CPK) are uncommon.

As the options for AD treatments increase, and expectations by families and clinicians change, Dr. Eichenfield said he often focuses on “bucket duty” – whether a specific patient should be in the topical bucket or the systemic one. It’s a decision that will continue to be crucial, he said.

When presented with treatment options, patients – and parents – often worry about side effects, said Vivian Shi, MD, associate professor of dermatology at the University of Arkansas Medical Center, Little Rock, who also spoke at the meeting. She gently tells them: “The worst side effect you can have is probably not treating the disease itself.”

Medscape Live and this news organization are owned by the same parent company. Dr. Eichenfield is a consultant or investigator for numerous companies that manufacture treatments for AD, but based his discussion on evidence-based recommendations and public presentations or publications.

Deucravacitinib and orelabrutinib – two novel oral drugs under investigation for the treatment of systemic lupus erythematosus (SLE) – have performed well in early clinical trials reported as late-breaking abstracts at the annual European Congress of Rheumatology.

In the phase 2 PAISLEY study, up to 58% of patients treated with deucravacitinib versus 34% of placebo-treated patients met the primary study endpoint of an SLE Responder Index-4 (SRI-4) after 38 weeks of treatment. Deucravacitinib also “achieved or meaningfully improved” all of the secondary endpoints set out in the 363-patient trial and was reported to have a safety and tolerability profile that was generally similar to placebo.

“Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials,” said Eric F. Morand, MD, PhD, a clinical rheumatologist and head of the School of Clinical Sciences at Monash University in Melbourne.

In a separate, ongoing phase 1b/2a study designed to evaluate orelabrutinib as a potential treatment for SLE, no safety concerns were seen with the investigational drug, along with “trending efficacy,” that supports “further studies in larger and longer-term trials,” according to the study’s investigators.

“What sets these two new drugs apart from currently available targeted therapies are their mode of action,” said Md Yuzaiful Md Yusof, MBChB, PhD, who was not involved in either study.

“The results from the PAISLEY study are promising, and it’s good to see the patients recruited were of diverse ethnicity [50%–60% were White],” added Dr. Md Yusof, a senior research fellow within the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine and a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust.

He noted that the placebo rate was also low: “This could be contributed to by keeping the background prednisolone dose low, which is often a challenge in designing SLE trials.”
 

Deucravacitinib – the distant cousin of the JAK family?

“Deucravacitinib is a compound you might not have heard of before,” Dr. Morand said.

“It’s an inhibitor of a kinase called TYK2, which, broadly speaking, is a member of JAK [Janus kinase] family,” he explained in an interview. TYK2 regulates signal transduction downstream of receptors for interleukin (IL)-23 and IL-12 pathways and the type I interferon family.

“It’s a very finite set of cytokine signals” that are being blocked with deucravacitinib, he said, adding that this means it’s more directly targeting SLE pathogenic mechanisms than perhaps other JAK inhibitor compounds.

“It also means that it shouldn’t have some of the downsides of the other JAK inhibitors,” Dr. Morand said, “such as hematopoietic side effects, including cytopenias.”
 

The phase 2 PAISLEY study

This study involved 363 patients with moderate to severe, active SLE were recruited and randomized to receive placebo (n = 90) or one of three doses of deucravacitinib: 3 mg twice daily (n = 91), 6 mg twice daily (n = 93), or 12 mg once daily (n = 89). Most patients were also taking multiple background therapies, but this was similar across the four treatment arms.

The SRI-4 primary endpoint after 38 weeks of treatment was met by 34.4% of patients who received placebo, but 58.2% of those treated with deucravacitinib 3 mg twice daily (P = .0006 versus placebo), 49.5% (P = .021) of those treated with 6 mg twice daily, and 44.9% (P = .078) treated with 12 mg once daily.

“All secondary outcome measures were achieved or meaningfully improved at week 48, including SRI-4, BICLA [British Isles Lupus Assessment Group-based Composite Lupus Assessment], low-level disease activity state [LLDAS], reduction in skin disease and reduction in arthritis,” Dr. Morand said.

In addition, early biomarker results showed reductions in double-stranded DNA titers and increases in serum C4 complement with deucravacitinib across the duration of the study.

In discussion, Dr. Morand was asked about the seemingly negative or inverse dose response seen in the trial, with the best results seen with the 3-mg twice daily dose, then lower effects seen with two higher doses.

“Our analysis is that it’s not an inverse dose response, but rather a flat dose response above the 3-mg [twice daily] dose,” he said, noting that there was a higher dropout rate because of adverse effects in the 12-mg once daily group and those participants were recorded as nonresponders.

“We think what we’ve seen here is that 3 mg twice daily is a sufficient dose and there was no additional therapeutic gain above that.”

Rates of adverse events (AEs), serious AEs, and AEs of interest were overall fairly similar between deucravacitinib and placebo groups. The most common side effects seen with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. Skin reactions, such as acne, rash, and pruritis, among others, were more common in deucravacitinib- than in placebo-treated patients.

Importantly, Dr. Morand noted that there were no major cardiac events or thrombotic events and no deaths seen in the study. There was no signal for an increase in serious or opportunistic infections, including herpes zoster. There was no effect on common laboratory parameters.

“These are very encouraging results for patients with SLE,” Albert Roy, executive director of Lupus Therapeutics, said in a press release issued by the Lupus Research Alliance.

“We are honored to have played a role in this exciting work by helping to conduct this clinical trial through our Lupus Clinical Investigators Network of renowned North American academic centers.”

In an interview, he added: “We’re cautiously optimistic. Hopefully, if it continues to progress through phase 3, it’ll be the first oral agent that would be approved for lupus, notwithstanding prednisone and Plaquenil [hydroxychloroquine], back in the 50s.”

Orelabrutinib phase 2 study in SLE

Another approach to oral route of administration under investigation in SLE is the use of orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that was approved in China in December 2020 for the treatment of certain lymphomas and leukemias.

The rationale for testing it in SLE comes from two preclinical studies that had suggested a possible benefit in reducing disease activity, explained Zhanguo Li, MD, PhD, professor at Peking University People’s Hospital in Beijing. He presented the results of an ongoing randomized, double-blind, placebo-controlled, phase Ib/IIa dose-finding study comparing three different doses of orelabrutinib (50, 80, and 100 mg, once daily) to placebo.

As in the deucravacitinib trial, the SRI-4 was used to assess the potential efficacy of orelabrutinib, although in a much smaller patient population (n = 92) and at a shorter time point (12 weeks). Results showed an 11%-20% difference between the percentage of patients who met SRI-4 response criteria with orelabrutinib and those on placebo, at a respective 46.5%, 53.3%, 56.3% and 35.7%.

SLE Disease Activity Index (SLEDAI) scores showed a similar benefit of orelabrutinib over placebo, with 54%-63% and 30% of patients, respectively, achieving a score of 8 or more.

Adverse event rates were similar to those of placebo with most events being of mild or moderate nature. Three patients treated with orelabrutinib experienced serious adverse events, of which one was grade 3, but there were no reported deaths.

Pharmacokinetic and pharmacodynamic data showed a dose effect, and nearly complete occupancy of BTK was achieved at all dose levels for 24 hours, consistent with once-daily dosing.

“BTK plays an important role in B-cell regulation, thus B-cell and myeloid-cell blockade through BTK inhibition is an interesting potential new target for SLE,” Dr. Md Yusof said.

“Data from this early dose-ranging trial is encouraging. No major safety signal apart from mild reduction in lymphocyte and white cell counts,” he added.

“There are still plenty of challenges ahead for this drug’s development, particularly as none of the BTK inhibitors have yet to succeed in phase 3 trials in rheumatic and musculoskeletal diseases,” Dr. Md Yusof said.

Early days for both agents

While both seem currently promising, it’s very early days for deucravacitinib and orelabrutinib as possible new agents for SLE.

Aside from SLE, deucravacitinib is being tested across multiple immune-mediated diseases. This includes psoriasis, where two phase 3 trials – POETYK PSO-1 and POETYK PSO-2 – have already been completed, and psoriatic arthritis, where a phase 2 trial has been reported; all with positive results.

Phase 3 testing of deucravacitinib will go ahead and recruitment may start toward the end of this year, but it’ll take years to complete the studies, Dr. Morand said. Even if the trials prove positive, neither agent is going to be available for clinical use for several years.

A case in point is anifrolumab (Saphnelo), which Dr. Morand was involved in assessing. Despite gaining approval in the United States and across much of the world, the drug still going through reimbursement processes.

“The trial data, and lots of post hoc analysis, show clearly that it’s a major step forward in treating lupus,” he said in an interview, but “access is limited in most places, so hands-on experience with that new treatment is still limited for most clinicians.”

As for all the other new targeted approaches under investigation, “although there’s a lot of trial activity, there’s still a couple of years away before any of the current trials deliver new treatment. That’s if they provide positive findings. Indeed, there have been numerous agents that have shown promise at phase 2 but then fall at the final phase 3 hurdle, including baricitinib, which Dr. Morand reported on in a separate poster presentation.

Phase 3 data proved disappointing: “Results are not sufficiently positive for that to go forward,” he said, adding that “transitioning from a successful phase 2 to a successful phase 3 is challenging, and many products have failed.”

Dr. Morand added: “It’s a very exciting time to be in lupus research, and there’s a lot of optimism about the future. But when I go back to my clinic tomorrow, I treat my patients exactly the same as I did last week and last year.”

It’s yet to be seen if deucravacitinib will fulfill its early promise, but it’s off to an impressive start. A positive for patients is that it’s an oral drug, with the potential to improve access to treatment across the world where getting infusions may be an issue.

“These are some of the most exciting data that I’ve seen at the phase 2 level in terms of effect size across all the readouts that are used,” Dr. Morand said. “There’s no guesswork here; it worked across all the measures. That’s very reassuring.”

The PAISLEY study was sponsored by Bristol-Myers Squibb. Dr. Morand has acted as a consultant to the company and received research support for the conduct of the trial. He disclosed acting as a consultant or receiving research funding from AbbVie, Amgen, AstraZeneca, Biogen, Eli Lilly, EMD Serono, Janssen, Genentech, Servier, Novartis, and UCB. Mr. Roy is the executive director of Lupus Therapeutics, which manages the Lupus Clinical Investigators Network based in North America. Lupus Therapeutics is the clinical trials arm of the Lupus Research Alliance, a nongovernmental, nonprofit funder of lupus research worldwide. The orelabrutinib study was sponsored by InnoCare Pharma. Dr. Li is the principal investigator for the trial but had no conflicts of interest to declare. Dr. Md Yusof disclosed receiving consultancy fees from Aurinia Pharmaceuticals.

Deucravacitinib and orelabrutinib – two novel oral drugs under investigation for the treatment of systemic lupus erythematosus (SLE) – have performed well in early clinical trials reported as late-breaking abstracts at the annual European Congress of Rheumatology.

In the phase 2 PAISLEY study, up to 58% of patients treated with deucravacitinib versus 34% of placebo-treated patients met the primary study endpoint of an SLE Responder Index-4 (SRI-4) after 38 weeks of treatment. Deucravacitinib also “achieved or meaningfully improved” all of the secondary endpoints set out in the 363-patient trial and was reported to have a safety and tolerability profile that was generally similar to placebo.

“Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials,” said Eric F. Morand, MD, PhD, a clinical rheumatologist and head of the School of Clinical Sciences at Monash University in Melbourne.

In a separate, ongoing phase 1b/2a study designed to evaluate orelabrutinib as a potential treatment for SLE, no safety concerns were seen with the investigational drug, along with “trending efficacy,” that supports “further studies in larger and longer-term trials,” according to the study’s investigators.

“What sets these two new drugs apart from currently available targeted therapies are their mode of action,” said Md Yuzaiful Md Yusof, MBChB, PhD, who was not involved in either study.

“The results from the PAISLEY study are promising, and it’s good to see the patients recruited were of diverse ethnicity [50%–60% were White],” added Dr. Md Yusof, a senior research fellow within the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine and a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust.

He noted that the placebo rate was also low: “This could be contributed to by keeping the background prednisolone dose low, which is often a challenge in designing SLE trials.”
 

Deucravacitinib – the distant cousin of the JAK family?

“Deucravacitinib is a compound you might not have heard of before,” Dr. Morand said.

“It’s an inhibitor of a kinase called TYK2, which, broadly speaking, is a member of JAK [Janus kinase] family,” he explained in an interview. TYK2 regulates signal transduction downstream of receptors for interleukin (IL)-23 and IL-12 pathways and the type I interferon family.

“It’s a very finite set of cytokine signals” that are being blocked with deucravacitinib, he said, adding that this means it’s more directly targeting SLE pathogenic mechanisms than perhaps other JAK inhibitor compounds.

“It also means that it shouldn’t have some of the downsides of the other JAK inhibitors,” Dr. Morand said, “such as hematopoietic side effects, including cytopenias.”
 

The phase 2 PAISLEY study

This study involved 363 patients with moderate to severe, active SLE were recruited and randomized to receive placebo (n = 90) or one of three doses of deucravacitinib: 3 mg twice daily (n = 91), 6 mg twice daily (n = 93), or 12 mg once daily (n = 89). Most patients were also taking multiple background therapies, but this was similar across the four treatment arms.

The SRI-4 primary endpoint after 38 weeks of treatment was met by 34.4% of patients who received placebo, but 58.2% of those treated with deucravacitinib 3 mg twice daily (P = .0006 versus placebo), 49.5% (P = .021) of those treated with 6 mg twice daily, and 44.9% (P = .078) treated with 12 mg once daily.

“All secondary outcome measures were achieved or meaningfully improved at week 48, including SRI-4, BICLA [British Isles Lupus Assessment Group-based Composite Lupus Assessment], low-level disease activity state [LLDAS], reduction in skin disease and reduction in arthritis,” Dr. Morand said.

In addition, early biomarker results showed reductions in double-stranded DNA titers and increases in serum C4 complement with deucravacitinib across the duration of the study.

In discussion, Dr. Morand was asked about the seemingly negative or inverse dose response seen in the trial, with the best results seen with the 3-mg twice daily dose, then lower effects seen with two higher doses.

“Our analysis is that it’s not an inverse dose response, but rather a flat dose response above the 3-mg [twice daily] dose,” he said, noting that there was a higher dropout rate because of adverse effects in the 12-mg once daily group and those participants were recorded as nonresponders.

“We think what we’ve seen here is that 3 mg twice daily is a sufficient dose and there was no additional therapeutic gain above that.”

Rates of adverse events (AEs), serious AEs, and AEs of interest were overall fairly similar between deucravacitinib and placebo groups. The most common side effects seen with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. Skin reactions, such as acne, rash, and pruritis, among others, were more common in deucravacitinib- than in placebo-treated patients.

Importantly, Dr. Morand noted that there were no major cardiac events or thrombotic events and no deaths seen in the study. There was no signal for an increase in serious or opportunistic infections, including herpes zoster. There was no effect on common laboratory parameters.

“These are very encouraging results for patients with SLE,” Albert Roy, executive director of Lupus Therapeutics, said in a press release issued by the Lupus Research Alliance.

“We are honored to have played a role in this exciting work by helping to conduct this clinical trial through our Lupus Clinical Investigators Network of renowned North American academic centers.”

In an interview, he added: “We’re cautiously optimistic. Hopefully, if it continues to progress through phase 3, it’ll be the first oral agent that would be approved for lupus, notwithstanding prednisone and Plaquenil [hydroxychloroquine], back in the 50s.”

Orelabrutinib phase 2 study in SLE

Another approach to oral route of administration under investigation in SLE is the use of orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that was approved in China in December 2020 for the treatment of certain lymphomas and leukemias.

The rationale for testing it in SLE comes from two preclinical studies that had suggested a possible benefit in reducing disease activity, explained Zhanguo Li, MD, PhD, professor at Peking University People’s Hospital in Beijing. He presented the results of an ongoing randomized, double-blind, placebo-controlled, phase Ib/IIa dose-finding study comparing three different doses of orelabrutinib (50, 80, and 100 mg, once daily) to placebo.

As in the deucravacitinib trial, the SRI-4 was used to assess the potential efficacy of orelabrutinib, although in a much smaller patient population (n = 92) and at a shorter time point (12 weeks). Results showed an 11%-20% difference between the percentage of patients who met SRI-4 response criteria with orelabrutinib and those on placebo, at a respective 46.5%, 53.3%, 56.3% and 35.7%.

SLE Disease Activity Index (SLEDAI) scores showed a similar benefit of orelabrutinib over placebo, with 54%-63% and 30% of patients, respectively, achieving a score of 8 or more.

Adverse event rates were similar to those of placebo with most events being of mild or moderate nature. Three patients treated with orelabrutinib experienced serious adverse events, of which one was grade 3, but there were no reported deaths.

Pharmacokinetic and pharmacodynamic data showed a dose effect, and nearly complete occupancy of BTK was achieved at all dose levels for 24 hours, consistent with once-daily dosing.

“BTK plays an important role in B-cell regulation, thus B-cell and myeloid-cell blockade through BTK inhibition is an interesting potential new target for SLE,” Dr. Md Yusof said.

“Data from this early dose-ranging trial is encouraging. No major safety signal apart from mild reduction in lymphocyte and white cell counts,” he added.

“There are still plenty of challenges ahead for this drug’s development, particularly as none of the BTK inhibitors have yet to succeed in phase 3 trials in rheumatic and musculoskeletal diseases,” Dr. Md Yusof said.

Early days for both agents

While both seem currently promising, it’s very early days for deucravacitinib and orelabrutinib as possible new agents for SLE.

Aside from SLE, deucravacitinib is being tested across multiple immune-mediated diseases. This includes psoriasis, where two phase 3 trials – POETYK PSO-1 and POETYK PSO-2 – have already been completed, and psoriatic arthritis, where a phase 2 trial has been reported; all with positive results.

Phase 3 testing of deucravacitinib will go ahead and recruitment may start toward the end of this year, but it’ll take years to complete the studies, Dr. Morand said. Even if the trials prove positive, neither agent is going to be available for clinical use for several years.

A case in point is anifrolumab (Saphnelo), which Dr. Morand was involved in assessing. Despite gaining approval in the United States and across much of the world, the drug still going through reimbursement processes.

“The trial data, and lots of post hoc analysis, show clearly that it’s a major step forward in treating lupus,” he said in an interview, but “access is limited in most places, so hands-on experience with that new treatment is still limited for most clinicians.”

As for all the other new targeted approaches under investigation, “although there’s a lot of trial activity, there’s still a couple of years away before any of the current trials deliver new treatment. That’s if they provide positive findings. Indeed, there have been numerous agents that have shown promise at phase 2 but then fall at the final phase 3 hurdle, including baricitinib, which Dr. Morand reported on in a separate poster presentation.

Phase 3 data proved disappointing: “Results are not sufficiently positive for that to go forward,” he said, adding that “transitioning from a successful phase 2 to a successful phase 3 is challenging, and many products have failed.”

Dr. Morand added: “It’s a very exciting time to be in lupus research, and there’s a lot of optimism about the future. But when I go back to my clinic tomorrow, I treat my patients exactly the same as I did last week and last year.”

It’s yet to be seen if deucravacitinib will fulfill its early promise, but it’s off to an impressive start. A positive for patients is that it’s an oral drug, with the potential to improve access to treatment across the world where getting infusions may be an issue.

“These are some of the most exciting data that I’ve seen at the phase 2 level in terms of effect size across all the readouts that are used,” Dr. Morand said. “There’s no guesswork here; it worked across all the measures. That’s very reassuring.”

The PAISLEY study was sponsored by Bristol-Myers Squibb. Dr. Morand has acted as a consultant to the company and received research support for the conduct of the trial. He disclosed acting as a consultant or receiving research funding from AbbVie, Amgen, AstraZeneca, Biogen, Eli Lilly, EMD Serono, Janssen, Genentech, Servier, Novartis, and UCB. Mr. Roy is the executive director of Lupus Therapeutics, which manages the Lupus Clinical Investigators Network based in North America. Lupus Therapeutics is the clinical trials arm of the Lupus Research Alliance, a nongovernmental, nonprofit funder of lupus research worldwide. The orelabrutinib study was sponsored by InnoCare Pharma. Dr. Li is the principal investigator for the trial but had no conflicts of interest to declare. Dr. Md Yusof disclosed receiving consultancy fees from Aurinia Pharmaceuticals.

Deucravacitinib and orelabrutinib – two novel oral drugs under investigation for the treatment of systemic lupus erythematosus (SLE) – have performed well in early clinical trials reported as late-breaking abstracts at the annual European Congress of Rheumatology.

In the phase 2 PAISLEY study, up to 58% of patients treated with deucravacitinib versus 34% of placebo-treated patients met the primary study endpoint of an SLE Responder Index-4 (SRI-4) after 38 weeks of treatment. Deucravacitinib also “achieved or meaningfully improved” all of the secondary endpoints set out in the 363-patient trial and was reported to have a safety and tolerability profile that was generally similar to placebo.

“Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials,” said Eric F. Morand, MD, PhD, a clinical rheumatologist and head of the School of Clinical Sciences at Monash University in Melbourne.

In a separate, ongoing phase 1b/2a study designed to evaluate orelabrutinib as a potential treatment for SLE, no safety concerns were seen with the investigational drug, along with “trending efficacy,” that supports “further studies in larger and longer-term trials,” according to the study’s investigators.

“What sets these two new drugs apart from currently available targeted therapies are their mode of action,” said Md Yuzaiful Md Yusof, MBChB, PhD, who was not involved in either study.

“The results from the PAISLEY study are promising, and it’s good to see the patients recruited were of diverse ethnicity [50%–60% were White],” added Dr. Md Yusof, a senior research fellow within the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine and a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust.

He noted that the placebo rate was also low: “This could be contributed to by keeping the background prednisolone dose low, which is often a challenge in designing SLE trials.”
 

Deucravacitinib – the distant cousin of the JAK family?

“Deucravacitinib is a compound you might not have heard of before,” Dr. Morand said.

“It’s an inhibitor of a kinase called TYK2, which, broadly speaking, is a member of JAK [Janus kinase] family,” he explained in an interview. TYK2 regulates signal transduction downstream of receptors for interleukin (IL)-23 and IL-12 pathways and the type I interferon family.

“It’s a very finite set of cytokine signals” that are being blocked with deucravacitinib, he said, adding that this means it’s more directly targeting SLE pathogenic mechanisms than perhaps other JAK inhibitor compounds.

“It also means that it shouldn’t have some of the downsides of the other JAK inhibitors,” Dr. Morand said, “such as hematopoietic side effects, including cytopenias.”
 

The phase 2 PAISLEY study

This study involved 363 patients with moderate to severe, active SLE were recruited and randomized to receive placebo (n = 90) or one of three doses of deucravacitinib: 3 mg twice daily (n = 91), 6 mg twice daily (n = 93), or 12 mg once daily (n = 89). Most patients were also taking multiple background therapies, but this was similar across the four treatment arms.

The SRI-4 primary endpoint after 38 weeks of treatment was met by 34.4% of patients who received placebo, but 58.2% of those treated with deucravacitinib 3 mg twice daily (P = .0006 versus placebo), 49.5% (P = .021) of those treated with 6 mg twice daily, and 44.9% (P = .078) treated with 12 mg once daily.

“All secondary outcome measures were achieved or meaningfully improved at week 48, including SRI-4, BICLA [British Isles Lupus Assessment Group-based Composite Lupus Assessment], low-level disease activity state [LLDAS], reduction in skin disease and reduction in arthritis,” Dr. Morand said.

In addition, early biomarker results showed reductions in double-stranded DNA titers and increases in serum C4 complement with deucravacitinib across the duration of the study.

In discussion, Dr. Morand was asked about the seemingly negative or inverse dose response seen in the trial, with the best results seen with the 3-mg twice daily dose, then lower effects seen with two higher doses.

“Our analysis is that it’s not an inverse dose response, but rather a flat dose response above the 3-mg [twice daily] dose,” he said, noting that there was a higher dropout rate because of adverse effects in the 12-mg once daily group and those participants were recorded as nonresponders.

“We think what we’ve seen here is that 3 mg twice daily is a sufficient dose and there was no additional therapeutic gain above that.”

Rates of adverse events (AEs), serious AEs, and AEs of interest were overall fairly similar between deucravacitinib and placebo groups. The most common side effects seen with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. Skin reactions, such as acne, rash, and pruritis, among others, were more common in deucravacitinib- than in placebo-treated patients.

Importantly, Dr. Morand noted that there were no major cardiac events or thrombotic events and no deaths seen in the study. There was no signal for an increase in serious or opportunistic infections, including herpes zoster. There was no effect on common laboratory parameters.

“These are very encouraging results for patients with SLE,” Albert Roy, executive director of Lupus Therapeutics, said in a press release issued by the Lupus Research Alliance.

“We are honored to have played a role in this exciting work by helping to conduct this clinical trial through our Lupus Clinical Investigators Network of renowned North American academic centers.”

In an interview, he added: “We’re cautiously optimistic. Hopefully, if it continues to progress through phase 3, it’ll be the first oral agent that would be approved for lupus, notwithstanding prednisone and Plaquenil [hydroxychloroquine], back in the 50s.”

Orelabrutinib phase 2 study in SLE

Another approach to oral route of administration under investigation in SLE is the use of orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that was approved in China in December 2020 for the treatment of certain lymphomas and leukemias.

The rationale for testing it in SLE comes from two preclinical studies that had suggested a possible benefit in reducing disease activity, explained Zhanguo Li, MD, PhD, professor at Peking University People’s Hospital in Beijing. He presented the results of an ongoing randomized, double-blind, placebo-controlled, phase Ib/IIa dose-finding study comparing three different doses of orelabrutinib (50, 80, and 100 mg, once daily) to placebo.

As in the deucravacitinib trial, the SRI-4 was used to assess the potential efficacy of orelabrutinib, although in a much smaller patient population (n = 92) and at a shorter time point (12 weeks). Results showed an 11%-20% difference between the percentage of patients who met SRI-4 response criteria with orelabrutinib and those on placebo, at a respective 46.5%, 53.3%, 56.3% and 35.7%.

SLE Disease Activity Index (SLEDAI) scores showed a similar benefit of orelabrutinib over placebo, with 54%-63% and 30% of patients, respectively, achieving a score of 8 or more.

Adverse event rates were similar to those of placebo with most events being of mild or moderate nature. Three patients treated with orelabrutinib experienced serious adverse events, of which one was grade 3, but there were no reported deaths.

Pharmacokinetic and pharmacodynamic data showed a dose effect, and nearly complete occupancy of BTK was achieved at all dose levels for 24 hours, consistent with once-daily dosing.

“BTK plays an important role in B-cell regulation, thus B-cell and myeloid-cell blockade through BTK inhibition is an interesting potential new target for SLE,” Dr. Md Yusof said.

“Data from this early dose-ranging trial is encouraging. No major safety signal apart from mild reduction in lymphocyte and white cell counts,” he added.

“There are still plenty of challenges ahead for this drug’s development, particularly as none of the BTK inhibitors have yet to succeed in phase 3 trials in rheumatic and musculoskeletal diseases,” Dr. Md Yusof said.

Early days for both agents

While both seem currently promising, it’s very early days for deucravacitinib and orelabrutinib as possible new agents for SLE.

Aside from SLE, deucravacitinib is being tested across multiple immune-mediated diseases. This includes psoriasis, where two phase 3 trials – POETYK PSO-1 and POETYK PSO-2 – have already been completed, and psoriatic arthritis, where a phase 2 trial has been reported; all with positive results.

Phase 3 testing of deucravacitinib will go ahead and recruitment may start toward the end of this year, but it’ll take years to complete the studies, Dr. Morand said. Even if the trials prove positive, neither agent is going to be available for clinical use for several years.

A case in point is anifrolumab (Saphnelo), which Dr. Morand was involved in assessing. Despite gaining approval in the United States and across much of the world, the drug still going through reimbursement processes.

“The trial data, and lots of post hoc analysis, show clearly that it’s a major step forward in treating lupus,” he said in an interview, but “access is limited in most places, so hands-on experience with that new treatment is still limited for most clinicians.”

As for all the other new targeted approaches under investigation, “although there’s a lot of trial activity, there’s still a couple of years away before any of the current trials deliver new treatment. That’s if they provide positive findings. Indeed, there have been numerous agents that have shown promise at phase 2 but then fall at the final phase 3 hurdle, including baricitinib, which Dr. Morand reported on in a separate poster presentation.

Phase 3 data proved disappointing: “Results are not sufficiently positive for that to go forward,” he said, adding that “transitioning from a successful phase 2 to a successful phase 3 is challenging, and many products have failed.”

Dr. Morand added: “It’s a very exciting time to be in lupus research, and there’s a lot of optimism about the future. But when I go back to my clinic tomorrow, I treat my patients exactly the same as I did last week and last year.”

It’s yet to be seen if deucravacitinib will fulfill its early promise, but it’s off to an impressive start. A positive for patients is that it’s an oral drug, with the potential to improve access to treatment across the world where getting infusions may be an issue.

“These are some of the most exciting data that I’ve seen at the phase 2 level in terms of effect size across all the readouts that are used,” Dr. Morand said. “There’s no guesswork here; it worked across all the measures. That’s very reassuring.”

The PAISLEY study was sponsored by Bristol-Myers Squibb. Dr. Morand has acted as a consultant to the company and received research support for the conduct of the trial. He disclosed acting as a consultant or receiving research funding from AbbVie, Amgen, AstraZeneca, Biogen, Eli Lilly, EMD Serono, Janssen, Genentech, Servier, Novartis, and UCB. Mr. Roy is the executive director of Lupus Therapeutics, which manages the Lupus Clinical Investigators Network based in North America. Lupus Therapeutics is the clinical trials arm of the Lupus Research Alliance, a nongovernmental, nonprofit funder of lupus research worldwide. The orelabrutinib study was sponsored by InnoCare Pharma. Dr. Li is the principal investigator for the trial but had no conflicts of interest to declare. Dr. Md Yusof disclosed receiving consultancy fees from Aurinia Pharmaceuticals.

NEW ORLEANS – In an unexpected finding, researchers discovered that Asian American adolescents had the highest rate of suicidal ideation, per a 2019 national survey of high-school students. According to a weighted analysis, 24% of Asian Americans reported thinking about or planning suicide vs. 22% of Whites and Blacks and 20% of Hispanics (P < .01).

“We were shocked,” said study lead author Esha Hansoti, MD, who conducted the research at UT Southwestern Medical Center, Dallas, and is now a psychiatry resident at Zucker Hillside Hospital Northwell/Hofstra in Glen Oaks, NY. The findings were released at the annual meeting of the American Psychiatric Association.

Dr. Hansoti and colleagues launched the analysis in light of sparse research into Asian American mental health, she said. Even within this population, she said, mental illness “tends to be overlooked” and discussion of the topic may be considered taboo.

For the new study, researchers analyzed the 2019 Youth Risk Behavior Survey, conducted biennially by the Centers for Disease Control and Prevention, which had more than 13,000 participants in grades 9-12.

A weighted bivariate analysis of 618 Asian American adolescents – adjusted for age, sex, and depressive symptoms – found no statistically significant impact on suicidal ideation by gender, age, substance use, sexual/physical dating violence, or fluency in English.

However, several groups had a statistically significant higher risk, including victims of forced sexual intercourse and those who were threatened or bullied at school.

Those who didn’t get mostly A grades were also at high risk: Adolescents with mostly Ds and Fs were more likely to have acknowledged suicidal ideation than those with mostly As (adjusted odds ratio [AOR] = 3.2).

Gays and lesbians (AOR = 7.9 vs. heterosexuals), and bisexuals (AOR = 5.2 vs. heterosexuals) also showed sharply higher rates of suicidal ideation.

It’s not clear why Asian American adolescents may be at higher risk of suicidal ideation. The survey was completed prior to the COVID-19 pandemic, which spawned bigotry against people of Asian descent and an ongoing outbreak of high-profile violence against Asian Americans across the country.

Dr. Hansoti noted that Asian Americans face the pressures to live up to the standards of being a “model minority.” In addition, “very few Asian American adolescents are taken to a therapist, and few mental health providers are Asian Americans.”

She urged fellow psychiatrists “to remember that our perceptions of Asian Americans might hinder some of the diagnoses we could be making. Be thoughtful about how their ethnicity and race affects their presentation and their own perception of their illness.”

She added that Asian Americans may experience mental illness and anxiety “more somatically and physically than emotionally.”

In an interview, Anne Saw, PhD, associate professor of clinical-community psychology at DePaul University, Chicago, said the findings are “helpful for corroborating other studies identifying risk factors of suicidal ideation among Asian American adolescents. Since this research utilizes the Youth Risk Behavior Survey, these findings can be compared with risk factors of suicidal ideation among adolescents from other racial/ethnic backgrounds to pinpoint general as well as specific risk factors, thus informing how we can tailor interventions for specific groups.”

According to Dr. Saw, while it’s clear that suicide is a leading cause of death among Asian American adolescents, it’s still unknown which specific subgroups other than girls and LGBTIA+ individuals are especially vulnerable and which culturally tailored interventions are most effective for decreasing suicide risk.

“Psychiatrists should understand that risk and protective factors for suicidal behavior in Asian American adolescents are multifaceted and require careful attention and intervention across different environments,” she said.

No funding and no disclosures were reported.

NEW ORLEANS – In an unexpected finding, researchers discovered that Asian American adolescents had the highest rate of suicidal ideation, per a 2019 national survey of high-school students. According to a weighted analysis, 24% of Asian Americans reported thinking about or planning suicide vs. 22% of Whites and Blacks and 20% of Hispanics (P < .01).

“We were shocked,” said study lead author Esha Hansoti, MD, who conducted the research at UT Southwestern Medical Center, Dallas, and is now a psychiatry resident at Zucker Hillside Hospital Northwell/Hofstra in Glen Oaks, NY. The findings were released at the annual meeting of the American Psychiatric Association.

Dr. Hansoti and colleagues launched the analysis in light of sparse research into Asian American mental health, she said. Even within this population, she said, mental illness “tends to be overlooked” and discussion of the topic may be considered taboo.

For the new study, researchers analyzed the 2019 Youth Risk Behavior Survey, conducted biennially by the Centers for Disease Control and Prevention, which had more than 13,000 participants in grades 9-12.

A weighted bivariate analysis of 618 Asian American adolescents – adjusted for age, sex, and depressive symptoms – found no statistically significant impact on suicidal ideation by gender, age, substance use, sexual/physical dating violence, or fluency in English.

However, several groups had a statistically significant higher risk, including victims of forced sexual intercourse and those who were threatened or bullied at school.

Those who didn’t get mostly A grades were also at high risk: Adolescents with mostly Ds and Fs were more likely to have acknowledged suicidal ideation than those with mostly As (adjusted odds ratio [AOR] = 3.2).

Gays and lesbians (AOR = 7.9 vs. heterosexuals), and bisexuals (AOR = 5.2 vs. heterosexuals) also showed sharply higher rates of suicidal ideation.

It’s not clear why Asian American adolescents may be at higher risk of suicidal ideation. The survey was completed prior to the COVID-19 pandemic, which spawned bigotry against people of Asian descent and an ongoing outbreak of high-profile violence against Asian Americans across the country.

Dr. Hansoti noted that Asian Americans face the pressures to live up to the standards of being a “model minority.” In addition, “very few Asian American adolescents are taken to a therapist, and few mental health providers are Asian Americans.”

She urged fellow psychiatrists “to remember that our perceptions of Asian Americans might hinder some of the diagnoses we could be making. Be thoughtful about how their ethnicity and race affects their presentation and their own perception of their illness.”

She added that Asian Americans may experience mental illness and anxiety “more somatically and physically than emotionally.”

In an interview, Anne Saw, PhD, associate professor of clinical-community psychology at DePaul University, Chicago, said the findings are “helpful for corroborating other studies identifying risk factors of suicidal ideation among Asian American adolescents. Since this research utilizes the Youth Risk Behavior Survey, these findings can be compared with risk factors of suicidal ideation among adolescents from other racial/ethnic backgrounds to pinpoint general as well as specific risk factors, thus informing how we can tailor interventions for specific groups.”

According to Dr. Saw, while it’s clear that suicide is a leading cause of death among Asian American adolescents, it’s still unknown which specific subgroups other than girls and LGBTIA+ individuals are especially vulnerable and which culturally tailored interventions are most effective for decreasing suicide risk.

“Psychiatrists should understand that risk and protective factors for suicidal behavior in Asian American adolescents are multifaceted and require careful attention and intervention across different environments,” she said.

No funding and no disclosures were reported.

NEW ORLEANS – In an unexpected finding, researchers discovered that Asian American adolescents had the highest rate of suicidal ideation, per a 2019 national survey of high-school students. According to a weighted analysis, 24% of Asian Americans reported thinking about or planning suicide vs. 22% of Whites and Blacks and 20% of Hispanics (P < .01).

“We were shocked,” said study lead author Esha Hansoti, MD, who conducted the research at UT Southwestern Medical Center, Dallas, and is now a psychiatry resident at Zucker Hillside Hospital Northwell/Hofstra in Glen Oaks, NY. The findings were released at the annual meeting of the American Psychiatric Association.

Dr. Hansoti and colleagues launched the analysis in light of sparse research into Asian American mental health, she said. Even within this population, she said, mental illness “tends to be overlooked” and discussion of the topic may be considered taboo.

For the new study, researchers analyzed the 2019 Youth Risk Behavior Survey, conducted biennially by the Centers for Disease Control and Prevention, which had more than 13,000 participants in grades 9-12.

A weighted bivariate analysis of 618 Asian American adolescents – adjusted for age, sex, and depressive symptoms – found no statistically significant impact on suicidal ideation by gender, age, substance use, sexual/physical dating violence, or fluency in English.

However, several groups had a statistically significant higher risk, including victims of forced sexual intercourse and those who were threatened or bullied at school.

Those who didn’t get mostly A grades were also at high risk: Adolescents with mostly Ds and Fs were more likely to have acknowledged suicidal ideation than those with mostly As (adjusted odds ratio [AOR] = 3.2).

Gays and lesbians (AOR = 7.9 vs. heterosexuals), and bisexuals (AOR = 5.2 vs. heterosexuals) also showed sharply higher rates of suicidal ideation.

It’s not clear why Asian American adolescents may be at higher risk of suicidal ideation. The survey was completed prior to the COVID-19 pandemic, which spawned bigotry against people of Asian descent and an ongoing outbreak of high-profile violence against Asian Americans across the country.

Dr. Hansoti noted that Asian Americans face the pressures to live up to the standards of being a “model minority.” In addition, “very few Asian American adolescents are taken to a therapist, and few mental health providers are Asian Americans.”

She urged fellow psychiatrists “to remember that our perceptions of Asian Americans might hinder some of the diagnoses we could be making. Be thoughtful about how their ethnicity and race affects their presentation and their own perception of their illness.”

She added that Asian Americans may experience mental illness and anxiety “more somatically and physically than emotionally.”

In an interview, Anne Saw, PhD, associate professor of clinical-community psychology at DePaul University, Chicago, said the findings are “helpful for corroborating other studies identifying risk factors of suicidal ideation among Asian American adolescents. Since this research utilizes the Youth Risk Behavior Survey, these findings can be compared with risk factors of suicidal ideation among adolescents from other racial/ethnic backgrounds to pinpoint general as well as specific risk factors, thus informing how we can tailor interventions for specific groups.”

According to Dr. Saw, while it’s clear that suicide is a leading cause of death among Asian American adolescents, it’s still unknown which specific subgroups other than girls and LGBTIA+ individuals are especially vulnerable and which culturally tailored interventions are most effective for decreasing suicide risk.

“Psychiatrists should understand that risk and protective factors for suicidal behavior in Asian American adolescents are multifaceted and require careful attention and intervention across different environments,” she said.

No funding and no disclosures were reported.